WO2006082743A1 - Therapeutic agent - Google Patents

Therapeutic agent Download PDF

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Publication number
WO2006082743A1
WO2006082743A1 PCT/JP2006/301200 JP2006301200W WO2006082743A1 WO 2006082743 A1 WO2006082743 A1 WO 2006082743A1 JP 2006301200 W JP2006301200 W JP 2006301200W WO 2006082743 A1 WO2006082743 A1 WO 2006082743A1
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WO
WIPO (PCT)
Prior art keywords
present
active ingredient
action
treatment
derivatives
Prior art date
Application number
PCT/JP2006/301200
Other languages
French (fr)
Japanese (ja)
Inventor
Tatsuji Enoki
Yoko Kudo
Katsumi Sugiyama
Hiromu Ohnogi
Hiroaki Sagawa
Ikunoshin Kato
Original Assignee
Takara Bio Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takara Bio Inc. filed Critical Takara Bio Inc.
Priority to JP2007501541A priority Critical patent/JPWO2006082743A1/en
Publication of WO2006082743A1 publication Critical patent/WO2006082743A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention is useful for the treatment or prevention of diseases requiring an antifoaming action of cells and an inhibitory action of Z or acyl CoA cholesterol transferase, such as arteriosclerosis and hyperlipidemia, in the treatment or prevention.
  • diseases requiring an antifoaming action of cells and an inhibitory action of Z or acyl CoA cholesterol transferase such as arteriosclerosis and hyperlipidemia, in the treatment or prevention.
  • Z or acyl CoA cholesterol transferase such as arteriosclerosis and hyperlipidemia
  • arteriosclerosis, hyperlipidemia, hypertension, and diabetes have been accompanied by changes in dietary habits that are rich in high-calorie and high-cholesterol diets, and an increase in the age group due to an increase in life expectancy.
  • the increase in so-called lifestyle-related diseases is rapidly increasing and has become a major social problem.
  • the fatty streak eventually becomes a fibrous hard spot and protrudes into the vascular wall, and as the lesion progresses further, calcification and thrombus attachment accompany the narrowing of the blood vessel cavity, and the hard spot breaks down causing thrombotic occlusion.
  • hard plaques contain a large amount of lipid components such as cholesterol esters, which are easy to break. Therefore, by suppressing the foaming of macrophages, such as vascular smooth muscle cells, and inhibiting the activity of acyl-CoA cholesterol cholesterol-mediated transferase, the stabilization and regression of atherosclerotic lesions can be achieved.
  • button bow fu has a cancer suppressive effect (eg, Non-patent Document 1), a disaccharide-degrading enzyme inhibitory action (eg, Patent Document 1), an antioxidant action (eg, Patent Document 2, Non-patent Document 2). It is also known that it has the ability to activate cells (for example, Patent Document 2) and suppress melanin production (for example, Patent Document 2).
  • Non-Patent Document 3 As a characteristic chemical component contained in button bow fu, a plurality of types of coumarin derivatives are known, and their tumor promoter suppression action and the like have been studied (for example, Non-Patent Document 3).
  • Patent Document 1 JP 2003-26694 A
  • Patent Document 2 JP 2004-26697 A
  • Non-Patent Document 1 T. Morioka and 8 others, Cancer Letters, 2004, Vol. 205, pl33-141
  • Non-Patent Document 2 M. Hisamoto and 2 others, Agric. Food Chem., 2004, Vol. 5 2, p445 -450
  • Non-Patent Document 3 B. Fan and 5 others, Journal of Japanese Botany, 2000, Vol. 7 5, No. 4, p257-261
  • An object of the present invention is to develop a safe and easily ingestible substance that has a cell antifoaming action suitable as a food material and a pharmaceutical material, and uses the composition or the substance. To provide food or feed.
  • the first invention of the present invention is characterized in that it contains a processed product derived from button bow as an active ingredient, and the anti-foaming action of cells in treatment or prevention and Z Or, it requires an inhibitory effect on the acyl CoA cholesterol acyltransferase
  • the present invention relates to a therapeutic or preventive agent for diseases.
  • a second invention of the present invention relates to an antifoaming agent for cells, characterized by containing a processed product derived from button bow as an active ingredient.
  • a third invention of the present invention relates to an acyl CoA cholesterol acyltransferase inhibitor, characterized by containing a processed product derived from button bowfish as an active ingredient.
  • a fourth invention of the present invention comprises a processed product derived from button bow fu as an active ingredient, for cell antifoam and for inhibiting Z or acyl CoA cholesterol acyltransferase. Relating to food or feed.
  • the fifth invention of the present invention is selected from the group consisting of 3, -acetoxyl 4, mono-senecyoxyoxy 3, 4, 4-zino, idroseserine, derivatives thereof and pharmaceutically acceptable salts thereof.
  • the sixth invention of the present invention is selected from the group consisting of 3, -acetooxy 4 'senesioxyloxy 3', 4'-dino, idroseserine, derivatives thereof and pharmaceutically acceptable salts thereof.
  • the present invention relates to a cell antifoaming agent characterized by containing one or more active ingredients.
  • the seventh invention of the present invention is selected from the group consisting of 3, -acetoxy 4 ′ senesioxyloxy 3 ′, 4′-dino, idrothelin, derivatives thereof and pharmaceutically acceptable salts thereof.
  • the present invention relates to an isyl CoA cholesterol transferase inhibitor characterized by containing one or more active ingredients.
  • the eighth invention of the present invention is selected from the group consisting of 3, -acetoxy-4, mono-senecyoxyoxy 3, 4, 4-zino, idroseserine, derivatives thereof and pharmaceutically acceptable salts thereof.
  • the present invention relates to a food or feed for anti-foaming of cells and / or for inhibition of acyl-CoA cholesterol acyltransferase.
  • the ninth invention of the present invention is that a subject is administered with an effective amount of a processed product derived from button bow.
  • the present invention relates to a method for treating or preventing a disease requiring an antifoaming action of a cell and an inhibitory action of Z or acyl CoA cholesterol acyltransferase for treatment or prevention.
  • the tenth invention of the present invention is for the manufacture of a therapeutic or prophylactic agent for a disease requiring an antifoaming action of cells and an inhibitory action of Z or acyl CoA cholesterol acyltransferase in the treatment or prevention. It relates to the use of processed products derived from button bow.
  • the eleventh invention of the present invention provides a subject with an effective amount of 3'-acetoxy 4 'seneciyloxy-3,4, -dinoidoid roseserin, a derivative thereof, and a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method for treating or preventing a disease requiring an antifoaming action of a cell and an inhibitory action of Z or acyl CoA cholesterol acyltransferase, including administering one or more selected from a group that also has strength. .
  • the twelfth invention of the present invention is for the manufacture of a therapeutic or prophylactic agent for a disease requiring an anti-foaming action of a cell and an inhibitory action of Z or acyl CoA cholesterol acyltransferase in the treatment or prevention. 3, -acetoxy-4, -senesioyloxy-3,4, -dinohydrodroserine, its derivatives and pharmaceutically acceptable salts thereof.
  • a medicament, food or feed for treating or preventing a disease requiring an antifoaming action of cells and an inhibitory action of Z or acyl Co A cholesterol acyltransferase in the treatment or prevention.
  • the medicament is useful for arteriosclerosis, hyperlipidemia, and diseases caused thereby.
  • the food of the present invention is a functional food useful for maintaining the homeostasis of the living body by the antifoaming action of cells and the inhibitory action of Z or acyl CoA cholesterol acyltransferase.
  • Cell foaming is caused by accumulation of cholesterol ester in the cell.
  • the anti-foaming action of the cells can be easily measured by using an assay system with the amount of cholesterol ester in the cells as an index as described in Example 1 described later. That is, by culturing macrophages in the presence of a test substance and acetyl LDL and evaluating the amount of cholesterol ester in the cells, the antifoaming action of the cells can be easily measured.
  • the cells to be antifoamed are not particularly limited, and examples thereof include vascular cells such as macrophages and smooth muscle cells, and blood cells.
  • Acyl CoA cholesterol acyltransferase also known as acyl CoA: cholesterol O-acyltransferase, hereinafter also abbreviated as ACAT
  • ACAT cholesterol O-acyltransferase
  • transfers long-chain fatty acids from cholesterol acyl to cholesterol It is an enzyme that catalyzes ester synthesis.
  • the ACAT inhibitory action can be easily measured using an assay system as described in Example 2 described later. That is, by mixing a test substance and an enzyme source containing ACAT, and evaluating the transfer of the Oleoyl group from radiolabeled Oleoyl-CoA to cholesterol, the ACAT inhibitory action can be easily measured.
  • the button bow fu used in the present invention is not particularly limited, and fruits, seeds, seed coats, flowers, leaves, stems, roots, rhizomes and Z, or whole plants can be used as they are.
  • the processed product derived from buttonbow fu (hereinafter sometimes referred to as the processed product of the present invention) used as an active ingredient of the present invention is a raw material plant that has been subjected to some processing and is a cell
  • the processed product of the present invention used as an active ingredient of the present invention is a raw material plant that has been subjected to some processing and is a cell
  • There is no particular limitation as long as it has antifoaming action and Z or ACAT inhibitory action but for example, extract, pulverized product, juice, crushed product, chemically treated product, enzyme treated product, particularly preferably Examples are extracts, pulverized products and juices.
  • the treated product of the present invention is particularly preferably a cell anti-foaming agent and an ACAT inhibitory agent described later 3, -acetoxyl 4, monosenecioinoxy 3, 4, 4, 4, A treated product containing a high content of cerine can be used.
  • high content means that 3, 4-acetoxy 4 in the raw material plant, 3, 4-acetoxyyloxy 3, 4, 4-dihydroceserine contained in the treated product 3, 4-acetoxy 4 , 1 Senesioiloxy 3, 4, 4-means that the concentration of Gino and Idoloserine is high, and it is preferably 1.5 times or more of the concentration in buttonbow, more than 2 times more preferable.
  • an extract refers to an extraction operation performed on an original plant using an extraction solvent. It refers to the substance itself obtained through the process. Extraction can be carried out by a known extraction method as follows. For example, after pulverizing or chopping the raw material, it can be carried out batchwise or continuously 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, Methylethyl ketone, etc.) and hydrophilic or lipophilic solvents (black mouth form, methyl acetate, ethyl acetate, etc.) can be mentioned, and they can be used alone or as a mixture as desired.
  • Examples of using the mixed solution as an extraction solvent are not particularly limited, but various aqueous solutions can be used, for example, 10 to 95%, preferably 15 to 90%, more preferably 20 to 85% alcohol. An aqueous solution can be used.
  • the amount of the extraction solvent may be determined as appropriate, but it is generally preferably 0. What is necessary is just to use 1-100 times amount extraction solvent.
  • the extraction temperature may be appropriately determined according to the purpose, but in the case of water extraction, it is usually preferably 4 to 130 ° C, more preferably 25 to: LOO ° C. When ethanol is contained in the solvent, a temperature range of 4 to 60 ° C. is preferable from the viewpoint of safety.
  • the extraction time may be determined in consideration of the extraction efficiency, but usually the raw material, extraction solvent, and extraction temperature are set to be preferably in the range of several seconds to several days, more preferably 5 minutes to 24 hours. It is preferable to do this.
  • the extraction operation may be performed, for example, with stirring or standing, and may be repeated several times as necessary.
  • an extract derived from button bow fu used in the present invention hereinafter sometimes referred to as the extract of the present invention
  • the extract is treated by filtration, centrifugation, concentration, ultrafiltration, molecular sieving, etc., so that the cell antifoaming agent or ACAT inhibitory agent, such as 3, -acetoxy-4, described below, can be obtained.
  • An extract enriched with one-senecyoxy3,4, -dihydroserine can be prepared.
  • the cell antifoaming action and ACAT inhibitory action of the extract or concentrated extract can be easily measured by the methods described in Examples 1 and 2 described later.
  • the button bow used in the present invention is a known method. If an extract using the same has an antifoaming effect on cells and a Z or ACAT inhibitory effect, it can be used as the extract of the present invention. It is also possible to use two or more of the above extracts. It is also possible to use two or more extracts obtained by extraction methods with different raw plant power.
  • the extraction of the present invention also applies to a fraction obtained by fractionating the extract of the present invention by a known method and a fraction obtained by repeating the fractionation operation a plurality of times. It is included in the thing.
  • the fractionation means include extraction, fractional precipitation, column chromatography, thin layer chromatography and the like.
  • the processed product derived from the button bow used in the present invention includes, for example, a powdered product derived from the button bow used in the present invention (hereinafter referred to as the present invention). May be referred to as a pulverized product of the invention).
  • a powdered product derived from the button bow used in the present invention hereinafter referred to as the present invention.
  • Examples of the method for producing a pulverized product of the present invention include a method of obtaining a pulverized product derived from a button-shaped button bow by drying a plant and using a pulverizer. Further, a pulverized product may be obtained by freeze pulverization.
  • the squeezed juice derived from button bow fu used in the present invention can also be used as the treated product of the present invention.
  • the method for producing the juice is not particularly limited as long as it is a known method for squeezing a plant.
  • the juice can be squeezed using a screw type, gear type, cutter type or other squeezer or juicer.
  • the juice can be obtained by chopping or grinding and squeezing with the above-mentioned juicer or cloth.
  • the crushed material is a material obtained by pulverizing a raw plant, and generally has a larger tissue piece than the pulverized material, and can be produced, for example, by using a crusher.
  • the chemical treatment product is not particularly limited, but refers to a product obtained by subjecting the plant to acid treatment, alkali treatment, oxidation treatment, reduction treatment, etc., for example, hydrochloric acid, sulfuric acid, nitric acid, citrate, It can be produced by immersing the raw material plant in an aqueous solution containing an inorganic or organic acid such as acetic acid, or an inorganic or organic base such as sodium hydroxide, potassium hydroxide or ammonia.
  • Chemically treated products include all those derived from plants that have undergone chemical treatment as described above. Fermentation An untreated product refers to, for example, an enzyme-treated product such as pectinase, cellulase, xylanase, amylase, mannanase, and dalcosidase, and an enzyme-reacted product (eg, fermented product) from microorganisms. Can be produced by acting in a suitable buffer. Enzyme-treated products include all those derived from plants that have been subjected to the enzyme treatment as described above. Further, the processed product derived from the button bow of the present invention includes, for example, a juice obtained by cutting a stem of a raw material plant and obtaining the cut surface.
  • the shape of the treated product of the present invention is particularly limited as long as it can exhibit an antifoaming action of cells and a Z or ACAT inhibitory action when used as an active ingredient in each aspect of the present invention.
  • it may be in the form of powder, solid or liquid.
  • the treated product can be granulated by a known method and used as a granular solid.
  • the granulation method is not particularly limited, but rolling granulation, stirring granulation, fluidized bed granulation, air flow granulation, extrusion granulation, compression molding granulation, pulverization granulation, spray granulation, spray granulation or spraying Examples include granulation.
  • the treated product in a powder form can be dissolved in a liquid, for example, water or alcohol, to obtain a liquid and used as a treated product derived from the button bow of the present invention.
  • 3'-acetoxy which will be described later, is preferably used as the treated product of the present invention.
  • -4 'Senesyl oiloxy 3', 4'-dinoidoid roseserine is a processed product containing a high amount of the compound, and from the viewpoint of further serving as edible, for example, ethanol extract, water-containing ethanol extraction Products, hot water extracts, glycerol extracts or water-containing glycerol extracts, glycol extracts such as ethylene glycol and propylene glycol, water-containing dallicol extracts, and pulverized products are preferred.
  • a derivative for example, an ester or the like is easily hydrolyzed in the body to produce the above-mentioned 3, -acetooxy-4, mono-senecioinoleoxy 3,4, -dihydroserine
  • Derivatives (prodrugs) that can exhibit the desired effect can be prepared. Preparation of a strong prodrug may be performed according to a known method.
  • derivatives obtained by metabolizing the compound of the present invention to a mammal are also included in the derivatives of the present invention.
  • the powerful derivative may be a salt of 3, -acetoxy-4, -senesioyloxy-3,4, -dihydroserine.
  • the 3,1-acetoxy-1,4-senesinoinoreoxy-1,4, -dino and idrothelin according to the present invention are their derivatives and their derivatives as long as the desired effects of the present invention can be obtained. It also includes salts.
  • various isomers such as optical isomers of 3'-acetoxy-4'-senecioyloxy 3,4, monozinoidroseserine, ketoeenol tautomers and geometric isomers, and isomers were isolated. Can be used in the present invention as long as they have anti-foaming action or ACAT inhibitory action on cells.
  • Examples of the salt used in the present invention include alkali metal salts, alkaline earth metal salts, salts with organic bases, and the like.
  • the pharmaceutically acceptable salt used in the present invention means a salt of a compound that is substantially nontoxic to living organisms and has an antifoaming action on cells.
  • Such salts include, for example, sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N, N'-dibenzylethylenediamine), choline, ethanolamine, diethanolamine.
  • salts such as amine, ethylenediamine, megramin (N-methyldalcumamine), venetamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).
  • the treated product of the present invention and 3'-acetoxy 4'-senesyloxy-3 ', 4'-dihydroserine, a derivative thereof and / or a pharmaceutically acceptable salt thereof Is referred to as an active ingredient of the present invention, and a therapeutic or preventive agent for a disease requiring an antifoaming action and a Z or ACAT inhibitory action of a cell containing the active ingredient of the present invention is referred to as a therapeutic or preventive agent of the present invention.
  • a therapeutic or preventive agent of the present invention is referred to as a therapeutic or preventive agent of the present invention.
  • the cell antifoaming agent and ACAT inhibitor described later are included.
  • the active ingredient of the present invention is derived from button bow fu which has been edible since ancient times, and is compared with a synthetic compound having an ACAT inhibitory activity known so far (for example, FR179254 described later). However, since it is highly safe, there is no particular toxicity as described later, and there is no risk of side effects. Therefore, the disease can be treated or prevented safely and appropriately. Therefore, the therapeutic agent, prophylactic agent, food or feed of the present invention comprising the active ingredient is effective for the treatment or prevention of diseases requiring anti-foaming action and ACAT inhibitory action of cells, and particularly easily. Useful as a health food ingredient that can be ingested
  • the disease requiring an anti-foaming action of cells for treatment or prevention is a disease that exhibits a therapeutic or preventive effect by suppressing cell foaming.
  • arteriosclerosis a disease caused by this, for example, Ischemic heart disease, acute myocardial infarction, unstable angina, sudden ischemic death, cerebrovascular disorder, chronic obstructive arteriosclerosis, myocardial infarction, angina, cerebral infarction, subarachnoid hemorrhage, obesity, etc. (See, for example, O'Rourke et al., J. Biol. Chem., 2002, 277 (45), 42557-4 2562).
  • the disease that requires an ACAT inhibitory action for treatment or prevention is not particularly limited.
  • the disease that requires an anti-foaming action of cells for the treatment or prevention is not limited.
  • examples include hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, multiple risk factor syndrome, or diseases caused by these factors (eg, O'Rourke et al., Biol. Chem., 2002, 277 (45), 42557—42562, Ohishi et al., Biol. Pharm. Bull., 2003, 26 (8), 1125—1128, and Ohishi et al., Chem. Pharm. Bull., 2001, 49 (7) , 830-839).
  • Examples of the therapeutic or prophylactic agent of the present invention include those prepared by combining the above-mentioned active ingredient according to the present invention with a known pharmaceutical carrier.
  • the active ingredient can be used for other ingredients that can be used for the same purpose as the active ingredient, for example, known hyperlipidemia and arteriosclerosis treatment or prevention action.
  • HMG-CoA reductase inhibitors such as stava compounds such as pravastatin, simpastatin, flupastatin, cerivastatin, atorvastatin, antifoaming agents such as fucoidan, ACAT inhibitors such as melinamide, cholesterol Ester transfer protein (CET P) inhibitor, cholesterol absorption inhibitor, squalene synthase inhibitor, LDL oxidation inhibitor, microsomal triglyceride transfer protein (MTP) inhibitor, apolipoprotein A1 production promoter, ATP—binding Cassette subfamily Al (ABCA1) inducer, squalene epoxidase inhibitor, choles Bile acid binding ⁇ Ramin such, Fuibureto system such Kurofu Ibureto, nicotinic acid, such as Naiashin, may be blended with such triglyceride lowering agent such as Ikosapento acid Echiru.
  • stava compounds such as pravastatin, simpa
  • the therapeutic agent or prophylactic agent of the present invention is usually produced by blending the active ingredient with a pharmaceutically acceptable liquid or solid carrier, and optionally, a solvent, a dispersant, an emulsifier, Add buffers, stabilizers, excipients, binders, disintegrants, lubricants, etc., solids such as tablets, condyles, powders, powders, capsules, etc., ordinary solutions, suspensions, emulsions And so on can do. Further, it can be made into a dry product that can be made liquid by adding a suitable carrier before use, or other external preparations.
  • the pharmaceutical carrier can be selected according to the administration form and formulation form of the therapeutic or prophylactic agent.
  • an oral preparation comprising a solid composition
  • it can be a tablet, pill, capsule, powder, fine granule, granule, etc., for example, starch, lactose, sucrose, mant, carboxymethylcellulose
  • Pharmaceutical carriers such as corn starch and inorganic salts are used.
  • a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a corrigent, a colorant, a fragrance and the like can be further added.
  • a sugar coating such as sucrose, gelatin or hydroxypropylcellulose, or a film of a gastric or enteric substance, if desired.
  • a pharmaceutically acceptable emulsion, solution, suspension, syrup, etc. for example, purified water, ethanol or the like as a carrier.
  • auxiliary agents such as wetting agents and suspending agents, sweetening agents, flavoring agents, preservatives and the like may be added.
  • distilled water for injection physiological saline, aqueous dextrose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, and the active ingredient of the present invention as a diluent according to a conventional method It can be prepared by dissolving or suspending in corn oil, propylene glycol, polyethylene glycol or the like, and adding a bactericidal agent, stabilizer, tonicity agent, soothing agent, etc., if necessary.
  • a solid composition can be produced and used by dissolving in sterile water or a sterilized solvent for injection before use.
  • the external preparation includes solid, semi-solid or liquid preparations for transdermal administration or transmucosal (intraoral or intranasal) administration. Also included are suppositories and the like. For example, emulsions such as emulsions and mouth preparations, external tinctures, liquid preparations such as liquids for transmucosal administration, ointments such as oil-based ointments and hydrophilic ointments, transdermal such as film agents, tapes, and nops. It can be a patch for administration or transmucosal administration.
  • the therapeutic agent or prophylactic agent in the above-described various preparation forms can be appropriately produced by a conventional method using a known pharmaceutical carrier or the like.
  • the content of the active ingredient in such a therapeutic agent or prophylactic agent is preferably determined in consideration of its administration form and administration method. It is not particularly limited as long as the active ingredient can be administered within the dosage range described below.
  • the content of the active ingredient in the medicament of the present invention is usually about 1 to: LOO weight%.
  • the therapeutic agent or prophylactic agent of the present invention is administered by an appropriate administration method according to the preparation form.
  • the administration method is not particularly limited, and can be administered by, for example, internal use, external use or injection.
  • the therapeutic agent or prophylactic agent of the present invention when administered by injection, it can be administered, for example, intravenously, intramuscularly, subcutaneously, intradermally, and when administered externally, for example, as an external preparation such as a suppository. And may be administered by the appropriate administration method.
  • the dosage of the therapeutic agent or prophylactic agent of the present invention is appropriately set according to the formulation form, administration method, purpose of use and the age, weight, and symptoms of the patient to whom the therapeutic agent or prophylactic agent is administered, and is constant. Absent.
  • the dosage of the active ingredient contained in the preparation for example, when the processed product of the present invention is used as an active ingredient, preferably 0.1 ⁇ g to 10 gZkg body weight per day for an adult, more preferably 1 ⁇ m.
  • g to 5 gZkg body weight more preferably 10 ⁇ g to lgZkg body weight, and 3, -acetoxy-4, -senesioyloxy-3 ′, 4′-dihydroserine, its derivatives and / or pharmaceuticals as active ingredients
  • those salts acceptable in adults preferably adults per day are 0.1 ⁇ g to 5 gZkg body weight, more preferably 1 ⁇ g to 2 gZkg body weight, more preferably g to: LgZkg body weight .
  • an amount smaller than the above-mentioned dose may be sufficient or may be necessary beyond the range.
  • Administration may be carried out once or divided into several times within a desired dose range within a day. The administration period is also arbitrary. Further, the therapeutic agent or prophylactic agent of the present invention can be administered orally as it is, or can be added daily to any food.
  • the present invention also provides a cell antifoaming agent comprising the active ingredient.
  • the antifoaming agent may be the active ingredient itself or a composition containing the active ingredient.
  • the antifoaming agent includes, for example, other components that can be used in the same application as the active ingredient, for example, components having a known therapeutic or preventive action for arteriosclerosis, such as plananostatin, sympastatin, HMG-CoA reductase inhibition of statin compounds such as flupastatin, serivastatin and atorvastatin Agents, antifoaming agents for cells such as fucoidan, ACAT inhibitors such as melinamide, cholesterol ester transfer protein (CETP) inhibitors, cholesterol absorption inhibitors, squalene synthetase inhibitors, LDL oxidation inhibitors, microsomal triglycerides Transfer protein (MTP) inhibitor, apolipoprotein A1 production promoter, ATP-binding cassette subfamily Al (ABCA1) inducer, squal
  • the antifoaming agent can also be produced in the form of a reagent that is usually used according to the method for producing the therapeutic agent or prophylactic agent.
  • the content of the active ingredient in the antifoaming agent should be such an amount that the expression of the desired effect of the present invention can be obtained in consideration of the administration method and purpose of use of the antifoaming agent. There is no particular limitation.
  • the content of the active ingredient in the antifoaming agent of the present invention is usually 1 to about LOO% by weight.
  • the amount of the antifoaming agent used is not particularly limited as long as the desired effect of the present invention can be obtained.
  • it is preferably used in such an amount that the active ingredient can be administered within the dose range of the active ingredient in the therapeutic or preventive agent.
  • the administration method is not particularly limited, and may be appropriately set in the same manner as the therapeutic agent or prophylactic agent.
  • the antifoaming agent is useful in the treatment or prevention of a disease requiring an antifoaming action of a cell for the above-mentioned treatment or prevention, for example, arteriosclerosis or a disease caused by this.
  • the anti-foaming agent is also useful for screening drugs for diseases that require anti-foaming action of cells for treatment or prevention. Furthermore, the antifoaming agent is useful for studying the mechanism of arteriosclerosis and foaming of various cells, and for functional studies on physical changes of the cells. The antifoaming agent can also be added to foods or beverages.
  • the present invention also provides an ACAT inhibitor containing the active ingredient.
  • the ACAT inhibitor may be the active ingredient itself or a composition containing the active ingredient.
  • the ACAT inhibitor may be, for example, another component that can be used for the same purpose as the active ingredient, such as a known hyperlipidemia or arteriosclerosis treatment or prevention component, such as pravastatin.
  • HMG-CoA reductase inhibitors such as statins such as cerivastatin and atorvastatin, cellular antifoaming agents such as fucoidan, ACAT inhibitors such as melinamide, cholesterol ester transfer protein (CETP) inhibitors, cholesterol absorption Inhibitor, squalene synthase inhibitor, LDL oxidation inhibitor, microsomal triglyceride transfer protein (MTP) inhibitor, apolipoprotein A1 production promoter, ATP-binding cassette subfamily Al (ABCA1) inducer, squalene epoxidase It can also be combined with inhibitors, bile acid-binding rosins such as cholestyramine, fibrates such as clofibrate, nicotinic acids such as niacin, and neutral fat lowering agents such as ethyl icosapentate.
  • statins such as cerivastatin and atorvastatin
  • the ACAT inhibitor can also be produced in the form of a commonly used reagent in accordance with the method for producing the therapeutic agent or prophylactic agent.
  • the content of the active ingredient in the ACAT inhibitor is not particularly limited as long as the desired effect of the present invention can be obtained in consideration of the administration method and purpose of use of the ACAT inhibitor. There is no particular limitation.
  • the content of the active ingredient in the ACAT inhibitor of the present invention is usually 1 to about L00% by weight.
  • the amount of the ACAT inhibitor used is not particularly limited as long as the desired effect of the present invention can be obtained. In particular, when it is used after being administered to a living body, it is preferably used in such an amount that the active ingredient can be administered within the dose range of the active ingredient in the therapeutic agent or prophylactic agent.
  • the administration method is not particularly limited, and may be appropriately set in the same manner as the therapeutic agent or prophylactic agent.
  • the ACAT inhibitor is useful in the treatment or prevention of diseases requiring ACAT inhibitory action for the above-mentioned treatment or prevention, such as arteriosclerosis and hyperlipidemia, and diseases caused by these factors.
  • the ACAT inhibitor is also useful for screening drugs for diseases that require ACAT inhibitory action for treatment or prevention.
  • the ACAT inhibitor is also useful for studying the mechanism of cholesterol ester production and the mechanism for the development of the aforementioned diseases such as hyperlipidemia and arteriosclerosis.
  • the ACAT inhibitor can also be added to foods or beverages.
  • the active ingredient of the present invention is not particularly toxic as will be described later. In addition, there is no worry of side effects. Therefore, the cell antifoaming action and the Z or A CAT inhibitory action can be expressed in vivo safely and appropriately. Therefore, including the active ingredient
  • the medicament, food or feed according to the present invention comprises an antifoaming action of cells and
  • the present invention provides a food or feed for cell antifoaming and Z or ACAT inhibition comprising the active ingredient (in the present specification, referred to as the food or feed of the present invention).
  • the food or feed of the present invention has a cell anti-foaming action and a Z or ACAT inhibitory action, thereby causing a disease that requires a cell anti-foaming action and a Z or ACAT inhibitory action for treatment or prevention, ie, arteriosclerosis as described above.
  • the food or drink of the present invention is extremely useful as a functional food (specific health food, etc.) with the purpose of preventing, ameliorating or treating the above-mentioned diseases, and the blood cholesterol level is a concern. For those who are concerned about neutral fat, those who are concerned about body fat
  • the active ingredient of the present invention and other substances having an action for improving, treating or preventing hyperlipidemia and arteriosclerosis, such as known hyperlipidemia and arteries.
  • Ingredients having therapeutic or prophylactic effects on sclerosis for example, HMG-CoA reductase inhibitors such as pravastatin, sympastatin, flupastatin, cerivastatin, atorvastatin and the like, and antifoaming agents for cells such as fucoidan, melinamide ACAT inhibitor, cholesterol ester transfer protein (CETP) inhibitor, cholesterol absorption inhibitor, squalene synthase inhibitor, LDL oxidation inhibitor, microsomal triglyceride transfer protein (MTP) inhibitor, apolipoprotein A1 production promoter, ATP—binding cassette subfamily Al (ABCA1) inducer, square More effective by combining with Renepoxidase inhibitors, bile acid-binding rosins such as cholestyramine, fi
  • High food or feed can also be produced. It can also be blended with known health food materials such as ashitapa and processed products thereof, peptides, dalcomannan, chitosan, plant sterol esters, EPA, DHA and the like.
  • the term "containing" in the food or feed of the present invention means inclusion, addition and / or dilution.
  • “containing” means that the active ingredient used in the present invention is contained in food or feed
  • additional means that the active ingredient used in the present invention is added to the raw material of food or feed.
  • “dilution” refers to a mode in which a raw material for food or feed is added to the active ingredient used in the present invention.
  • the method for producing the food or feed of the present invention is not particularly limited.
  • compounding, cooking, cooking, etc. can be produced by their production method according to general foods or feeds, and the resulting foods or feeds can have anti-foaming action of cells and Z or It would be good if the active ingredient according to the present invention having ACAT inhibitory action was contained!
  • the food of the present invention is not particularly limited.
  • a processed cereal product processed flour product, processed starch product, premixed caloche product, rice cake, etc.
  • a processed cereal product containing the active ingredient according to the present invention.
  • Macaro- Bread, Anzu, Buckwheat, Rice cake, Rice noodles, Harusame, Packaging rice cake, etc.
  • Oil and fat processed products Oil and fat processed products (Plastic oil, Tempura oil, Salad oil, Mayonnaise, Dressing, etc.), Processed soybean products (Tofu , Bean paste, natto, etc.), processed meat products (ham, bacon, pressed ham, sausage, etc.), marine products (frozen groundnut, power boiled rice cake, chikuwa, hanpen, fried fish, tsumire, streaks, fish ham, sausage Bonito, dried bonito, processed fish eggs, canned fish, boiled tsukudani, etc.), dairy products (raw milk, cream, yogurt, butter, cheese, con
  • the active ingredient is contained alone or in plural, added and Z or diluted, and the content thereof exhibits an anti-foaming action of cells and a Z or ACAT inhibitory action.
  • the shape is not particularly limited, and includes powders, tablets, granules, capsules and the like that can be taken orally.
  • the food of the present invention includes a processed product of button bow as it is or mixed appropriately with an appropriate emulsifier or excipient. These foods can be eaten as drinks as they are or mixed with water.
  • the active ingredient of the present invention is mixed with the juice of a plant other than the plant used in the present invention (vegetables, fruits, etc.) or simultaneously with the plant used in the present invention. It can be squeezed into a health drink.
  • the juices of various plants used in the present invention are diluted with water, or assipida, parsley, celery, licorice, carrot, komatsuna, turnip, tomato, tangerine, lemon, grapefruit, kiwi, spinach, radish.
  • the content of the active ingredient in the food of the present invention is not particularly limited, and can be selected as appropriate in terms of its functionality and activity expression.
  • the content is preferably 0.1% by weight or more, more preferably 0.5 to 95% by weight, and further preferably 1 to 90% by weight.
  • the active ingredient contained therein is preferably 0.1 ⁇ g to 10 gZkg body weight per day for an adult.
  • the active ingredient is 3, -acetooxy-4, mono-senesioxyloxy 3,4, -dihydroceserin, its derivatives and Z or pharmaceutically
  • adults should preferably take 0.1 ⁇ g to 5 gZkg body weight, more preferably 1 ⁇ g to 2 gZkg body weight, more preferably 10 g to lgZkg body weight per day.
  • the present invention provides a biological feed having an anti-foaming action of cells and an action of inhibiting Z or ACAT, comprising the above-mentioned active ingredient, that is, containing, adding and Z or diluting. Furthermore, as another aspect, there is also provided a method for breeding an organism characterized by administering the active ingredient to the organism. Moreover, as another aspect of the present invention, there is provided a biological breeding agent comprising the above-mentioned active ingredient.
  • the organism is not limited, and examples thereof include farm animals and pet animals.
  • farm animals and pet animals As farmed animals, livestock such as horses, rushes, pigs, hidges, goats, ratadas, llamas, laboratory animals such as mice, rats, guinea pigs, magpies, etc. Examples include crustaceans or shellfish.
  • pet animals include Inu and cats.
  • feed include feed for maintenance and Z or improvement.
  • biological breeding agents include soaking agents, feed additives, and beverage additives.
  • the present invention is based on the antifoaming action and Z or ACAT inhibitory action of the cells of the active ingredient used in the present invention in the above-described organisms to which they are applied. It is expected that the same effects as those of the therapeutic agent or preventive agent will be exhibited. That is, the feed of the present invention is caused by a disease that requires an antifoaming action of cells and a Z or ACAT inhibitory action for treatment or prevention in the organism, such as arteriosclerosis and hyperlipidemia, which are caused by these factors. It can exert a therapeutic or preventive effect on the disease.
  • the active ingredient used in the present invention is usually, for example, when the processed product of the present invention is used as an active ingredient, the active ingredient contained therein is preferably 0.1 ⁇ g to 10 g Zkg per day of the target organism.
  • Body weight more preferably 1 ⁇ g to 5 gZkg body weight, still more preferably 10 g to 2 gZkg body weight, and 3′-acetoxy-4 ′ senecioyloxy-3 ′, 4′-dihydroserine as an active ingredient
  • the target organism is preferably 0.1 ⁇ g to 5 g Zkg body weight, more preferably per day.
  • the administration is performed, for example, by adding and mixing the active ingredient in the raw material of the artificially mixed feed to be provided to the target organism, or by mixing it with the powdered raw material of the artificially mixed feed and further adding and mixing it with the other raw materials. be able to.
  • the content of the active ingredient in the feed is not particularly limited, and may be set as appropriate according to the purpose. For example, when the processed product of the present invention is used as an active ingredient, it is preferably 0 in the feed. 1% by weight or more, preferably 0.5 to 95% by weight, more preferably 1 to 90% by weight.
  • the method for producing the feed of the present invention is not particularly limited, and if the formulation is similar to that of a general feed, the presently produced feed has a cell antifoaming action and a sputum or ACAT inhibitory action. It suffices if the active ingredient according to the invention is included.
  • a biological rearing agent can be prepared in the same manner.
  • a feed comprising the active ingredient used in the present invention having an antifoaming effect on cells and a wrinkle or ACAT inhibitory effect, or a cell anti-foaming effect is used.
  • a liquid containing the active ingredient used in the present invention having a foaming action for example, a solution obtained by dissolving the immersion agent in water
  • livestock, laboratory animals, poultry, pets It is possible to maintain or improve the physical condition of animals and the like.
  • these aspects are one aspect
  • the present invention also includes a method for treating or preventing a disease requiring an anti-foaming action of cells and an anther or ACAT inhibitory action for treatment or prevention, comprising administering the active ingredient to a subject.
  • a method for treating or preventing a disease requiring an anti-foaming action of cells and an anther or ACAT inhibitory action for treatment or prevention comprising administering the active ingredient to a subject.
  • I will provide a.
  • the subject is preferably a human being who requires a cell antifoaming action and a Z or ACAT inhibitory action, such as a cultured animal or a pet animal as described above. Good.
  • the effective amount means that when the active ingredient is administered to the subject, the antifoaming action of the cells compared to the subject not administered the active ingredient. And the amount of the component exhibiting Z or ACAT inhibitory action.
  • the specific effective amount is appropriately set according to the administration form, administration method, purpose of use and age, weight, symptom, etc. of the subject.
  • the active ingredient contained therein is preferably 0.1 ⁇ g to 10 gZkg body weight, more preferably 1 ⁇ g to 5 gZkg body weight, more preferably human (eg, adult) per day. 10g ⁇ 2gZkg body weight and using 3, -acetoxy-4, -seneci oiloxy-3 ', 4'-dinoidoidoserine, its derivatives and / or pharmaceutically acceptable salts as active ingredients
  • human for example, an adult
  • human is preferably administered at a dose of 0.1 ⁇ g to 5 g Zkg body weight, more preferably 1 ⁇ g to 2 g Zkg body weight, still more preferably g to LgZkg body weight per day.
  • an effective amount of the active ingredient is added to the method for treating or preventing a disease requiring an antifoaming action and Z or ACAT inhibitory action of cells. It may be administered to the subject as it is, or may be administered as a pharmaceutical, food, or feed as described above. Further, there is no limitation on the administration method. For example, it may be administered by oral administration, injection or the like, as in the case of the above-mentioned medicine.
  • the target disease of the medicament, food or feed of the present invention can be treated or prevented, for example, arteriosclerosis or hyperlipidemia, An effect of treating or preventing a disease caused by these as causative factors can be exhibited.
  • the active ingredient used in the present invention does not show toxicity even if the living body is administered in an effective amount for expression of the action.
  • the active ingredient used in the present invention does not show toxicity even if the living body is administered in an effective amount for expression of the action.
  • the active ingredient used in the present invention does not show toxicity even if the living body is administered in an effective amount for expression of the action.
  • a single dose of buttonbofu ethanol extract, 3, -acetoxy-4, -senesioyloxy-3,4, -dihydroceserin at lgZkg body weight is given to mice, unacceptable.
  • no mortality was observed even if the lgZkg body weight was administered orally once.
  • Macrophages take denatured LDL (such as acetyl LDL (Ac-LDL)) into cells and synthesize cholesterol esters into foam. The anti-foaming activity of macrophages by each test sample was measured.
  • LDL such as acetyl LDL (Ac-LDL)
  • RAW264 Containing RAW264. 7 cells (ATCC TIB 71) at 4 x 10 5 cells / ml in Dulbecco's modified Eagle's medium (Sigma, D5796), containing 10% urine fetal serum (Camprex) After turbidity, 1 mL was added to each well of a 24-well microtiter plate and cultured at 37 ° C in the presence of 5% carbon dioxide. Next, replace with UltraCHO medium (Camprex B2 724), and each well has a concentration of dimethyl sulfoxide solution 2 / z L of each test sample prepared in the above preparation example as shown in Table 1 below. Was added as follows.
  • the amount of total cholesterol in the cell and the amount of free cholesterol were measured, and the amount of cholesterol ester was calculated.
  • the total cholesterol content in 10 ⁇ L of the solution is measured using the Cholesterol® test (manufactured by Wako Pure Chemical Industries, Ltd., 439-17501) and the amount of free cholesterol is determined. It was measured using a free cholesterol test (Wako Pure Chemical Industries, 435-35801). All measurements were performed in duplicate. Total cholesterol ester biosynthesis Cholesterol capacity was determined by subtracting the amount of free cholesterol. The antifoaming activity was calculated by the following formula.
  • Anti-foaming activity (%) 100- ((Cholesterol ester biosynthesis amount when test sample is added) 1 (Cholesterol ester biosynthesis amount in the case where Ac— LDL is not added)) ⁇ ((Cholesterol ester biosynthesis amount when dimethyl sulfoxide is added) 1 (Cholesterol ester biosynthesis amount in the category without Ac— LDL addition)) X 100
  • Table 1 shows the inhibitory activity against cholesterol ester accumulated in the Macphage phage at each final concentration of each test sample, and each sample listed in the table shows significant antifoam activity. It was.
  • Spmgue—4 Dawley rats were raised for 1 week and sacrificed.
  • the liver was immediately removed, washed gently with cold saline, and then sucrose buffer (0.3 M sucrose, 50 mM Tris HC1, 1 mM EDTA, 50 mM NaCl, pH 7. Immersion (25mLZl) in 4).
  • sucrose buffer 0.3 M sucrose, 50 mM Tris HC1, 1 mM EDTA, 50 mM NaCl, pH 7. Immersion (25mLZl) in 4
  • the obtained liver was homogenized, and the operation of removing the precipitate by centrifuging at 10,000 ⁇ g for 30 minutes was repeated twice.
  • the obtained supernatant was centrifuged at 105,000 xg for 70 minutes to collect the precipitate, and suspended in an appropriate amount of lOOmM phosphate buffer (pH 7.4). Protein concentration to 10mg / ml
  • the suspension was suspended again in a phosphate buffer, and after adding ED
  • ACAT enzyme activity of ACAT was measured with some improvement according to the method of Lee et al. (Planta Med., 2004, 70, 678-679).
  • a group in which only a dimethyl sulfoxide solution was added without adding a compound and a group in which a compound FR179254 (final concentration M, manufactured by Merck & Co., 344235) known to have ACAT inhibitory activity was added as a positive control.
  • a compound FR179254 final concentration M, manufactured by Merck & Co., 344235
  • ACAT inhibitory activity was added as a positive control.
  • the radioactivity was measured with a liquid scintillation counter LS6500 (manufactured by Beckman) using Ultima Gold (Perkin Elma Life Science Co., 6013329) as a scintillation cocktail.
  • Each reaction was performed in duplicate.
  • the ACAT inhibitory activity (%) of each test sample was calculated by using the following formula as the inhibition rate when 10 ⁇ of FR179254 as a positive control was added to 100%.
  • Inhibitory activity (%) (([Radioactivity of control category (cpm)] [Radioactivity of test sample addition category (cpm)]) / ([Radioactivity of control category (cpm)] — [10 M FR179254 Caro Category radioactivity (cpm)])) X 100
  • Table 2 shows AC at each final concentration of each test sample.
  • a processed product derived from button bow fu, 3'-acetoxy 4 'senecioyloxy-3', 4'-dihydroserine, a derivative thereof and / or a pharmaceutically acceptable salt thereof is contained.
  • a medicament, food, or feed for treating or preventing a disease that requires anti-foaming action of cells and Z or ACAT inhibitory action for treatment or prevention.
  • the medicament is useful as a therapeutic or prophylactic agent for arteriosclerosis, hyperlipidemia, and diseases caused by these factors.
  • the food containing the active ingredient of the present invention is a functional food useful for maintaining the homeostasis of the living body by the antifoaming action of the cells and the Z or ACAT inhibitory action.

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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

明 細 書  Specification
治療剤  Therapeutic agent
技術分野  Technical field
[0001] 本発明は、治療又は予防において細胞の抗泡沫ィ匕作用及び Z又はァシル CoAコ レステロールァシルトランスフェラーゼ阻害作用を要する疾患、例えば動脈硬化症、 高脂血症等の治療または予防に有用な医薬、食品又は飼料に関する。  [0001] The present invention is useful for the treatment or prevention of diseases requiring an antifoaming action of cells and an inhibitory action of Z or acyl CoA cholesterol transferase, such as arteriosclerosis and hyperlipidemia, in the treatment or prevention. Related to various pharmaceuticals, foods or feeds.
背景技術  Background art
[0002] 近年、高カロリー'高コレステロール食を多く含む食生活の変化や、平均寿命の伸 びによる高年齢層の増加に伴って、動脈硬化症、高脂血症、高血圧症、糖尿病とい つたいわゆる生活習慣病の増加が急増しており、大きな社会問題となってきている。  [0002] In recent years, arteriosclerosis, hyperlipidemia, hypertension, and diabetes have been accompanied by changes in dietary habits that are rich in high-calorie and high-cholesterol diets, and an increase in the age group due to an increase in life expectancy. The increase in so-called lifestyle-related diseases is rapidly increasing and has become a major social problem.
[0003] 動脈硬化症の初期病変には脂肪線条と呼ばれる斑点状もしくは線状の脂肪沈着 が見られる。この変化は主に泡沫ィ匕されたマクロファージが血管内皮に集積すること によるものである。マクロファージの泡沫化は、マクロファージが変性 LDLを取り込ん で遊離コレステロールを生成し、ァシル CoAコレステロールァシルトランスフェラーゼ によってエステルイ匕され、これが蓄積すること〖こより起こる。このような初期の泡沫ィ匕 細胞病変は血管平滑筋細胞の泡沫化を含む複雑な病変に進行する。脂肪線条は やがて繊維性硬斑となって血管壁に突出し、さらに病変が進むと石灰化、血栓の付 着を伴って、血管腔を狭めたり、硬斑が破錠して血栓性閉塞をきたす。また、破錠し やす 、硬斑はコレステロールエステル等の脂質成分を多く含むことも知られて 、る。 従って、マクロファージゃ血管平滑筋細胞等の泡沫化の抑制やァシル CoAコレステ ロールァシルトランスフェラーゼの活性を阻害することにより、動脈硬化病変の安定 化と退縮をもたらし、動脈硬化や高脂血症に基づく急性冠症候群の発症や再発の低 減につながることが期待される。また、ァシル CoAコレステロールァシルトランスフェラ ーゼ活性を阻害することにより、肝臓において VLDLの構成をなすコレステロールェ ステルの合成低下がおこり VLDL合成が減少したり、小腸においてコレステロールの エステル結合を阻害しコレステロールの吸収が低下することが知られていることから、 血中コレステロール、血中中性脂肪を減少させることが期待できる。 [0004] ボタンボウフゥは、学名 Peucedanum japonicumというセリ科力ワラボウフゥ属に 属する多年草で、海岸の岩場や草地に生え、茎は高さが 30〜： LOOcmで、花期の 6 〜9月になると小さい白色の花を多数つける。その生理活性については、原産地で ある沖縛では感冒、疲労回復、滋養強壮に効果があると言われ、昔力 重宝されてき た。最近の研究では、ボタンボウフゥにはがん抑制効果 (例えば、非特許文献 1)、二 糖類分解酵素阻害作用（例えば、特許文献 1)、抗酸化作用（例えば、特許文献 2、 非特許文献 2)、細胞賦活作用（例えば、特許文献 2)、メラニン産生抑制作用（例え ば、特許文献 2)力あることも知られている。 [0003] In early lesions of arteriosclerosis, spotted or linear fat deposits called fat streaks are seen. This change is mainly due to the accumulation of foamed macrophages on the vascular endothelium. Macrophage foaming occurs when macrophages take up denatured LDL to produce free cholesterol, which is esterified by the acyl CoA cholesterol acyltransferase, which accumulates. Such early foamy sputum cell lesions progress to complex lesions that include vascular smooth muscle cell foaming. The fatty streak eventually becomes a fibrous hard spot and protrudes into the vascular wall, and as the lesion progresses further, calcification and thrombus attachment accompany the narrowing of the blood vessel cavity, and the hard spot breaks down causing thrombotic occlusion. Come on. In addition, it is known that hard plaques contain a large amount of lipid components such as cholesterol esters, which are easy to break. Therefore, by suppressing the foaming of macrophages, such as vascular smooth muscle cells, and inhibiting the activity of acyl-CoA cholesterol cholesterol-mediated transferase, the stabilization and regression of atherosclerotic lesions can be achieved. Based on arteriosclerosis and hyperlipidemia It is expected to lead to the onset and recurrence of acute coronary syndromes. Furthermore, inhibition of the acyl CoA cholesterol acyltransferase activity results in a decrease in the synthesis of cholesteryl ester that constitutes VLDL in the liver, resulting in a decrease in VLDL synthesis, and an inhibition of the ester bond of cholesterol in the small intestine. Since it is known that the absorption of blood is reduced, it can be expected to reduce blood cholesterol and blood neutral fat. [0004] The button bow is a perennial belonging to the genus Waraboufu, a scientific name Peucedanum japonicum, grows on the coastal rocks and grassland, the stem is 30 ~ height: LOOcm, small white in June to September of the flowering season Put a lot of flowers. With regard to its physiological activity, it is said that its origin, offshore, is said to have an effect on colds, recovery from fatigue, and nourishing tonic, and it has been useful for a long time. In recent studies, button bow fu has a cancer suppressive effect (eg, Non-patent Document 1), a disaccharide-degrading enzyme inhibitory action (eg, Patent Document 1), an antioxidant action (eg, Patent Document 2, Non-patent Document 2). It is also known that it has the ability to activate cells (for example, Patent Document 2) and suppress melanin production (for example, Patent Document 2).
[0005] ボタンボウフゥに含まれる特徴的な化学成分としては、複数種のクマリン誘導体が 知られており、その発がんプロモーター抑制作用等についての検討がなされている（ 例えば、非特許文献 3)。  [0005] As a characteristic chemical component contained in button bow fu, a plurality of types of coumarin derivatives are known, and their tumor promoter suppression action and the like have been studied (for example, Non-Patent Document 3).
特許文献 1：特開 2003 - 26694  Patent Document 1: JP 2003-26694 A
特許文献 2：特開 2004— 26697  Patent Document 2: JP 2004-26697 A
非特許文献 1 :T. Morioka 他 8名， Cancer Letters, 2004年， Vol. 205, pl33 - 141  Non-Patent Document 1: T. Morioka and 8 others, Cancer Letters, 2004, Vol. 205, pl33-141
非特許文献 2 : M. Hisamoto 他 2名， Agric. Food Chem. , 2004年， Vol. 5 2, p445 -450  Non-Patent Document 2: M. Hisamoto and 2 others, Agric. Food Chem., 2004, Vol. 5 2, p445 -450
非特許文献 3 : B. Fan 他 5名， Journal of Japanese Botany, 2000年， Vol. 7 5, No. 4, p257 - 261  Non-Patent Document 3: B. Fan and 5 others, Journal of Japanese Botany, 2000, Vol. 7 5, No. 4, p257-261
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0006] 本発明の目的は、安全で、簡便に摂取可能な、食品素材、医薬品素材として適し た細胞の抗泡沫化作用を有する物質を開発し、当該組成物もしくは物質を用いた、 医薬、食品または飼料を提供することにある。 [0006] An object of the present invention is to develop a safe and easily ingestible substance that has a cell antifoaming action suitable as a food material and a pharmaceutical material, and uses the composition or the substance. To provide food or feed.
課題を解決するための手段  Means for solving the problem
[0007] 本発明を概説すれば、本発明の第 1の発明は、ボタンボウフゥ由来の処理物を有 効成分として含有することを特徴とする、治療又は予防において細胞の抗泡沫化作 用及び Z又はァシル CoAコレステロールァシルトランスフェラーゼ阻害作用を要する 疾患の治療剤又は予防剤に関する。 [0007] Briefly describing the present invention, the first invention of the present invention is characterized in that it contains a processed product derived from button bow as an active ingredient, and the anti-foaming action of cells in treatment or prevention and Z Or, it requires an inhibitory effect on the acyl CoA cholesterol acyltransferase The present invention relates to a therapeutic or preventive agent for diseases.
[0008] 本発明の第 2の発明は、ボタンボウフゥ由来の処理物を有効成分として含有するこ とを特徴とする、細胞の抗泡沫化剤に関する。  [0008] A second invention of the present invention relates to an antifoaming agent for cells, characterized by containing a processed product derived from button bow as an active ingredient.
[0009] 本発明の第 3の発明は、ボタンボウフゥ由来の処理物を有効成分として含有するこ とを特徴とする、ァシル CoAコレステロールァシルトランスフェラーゼ阻害剤に関する [0009] A third invention of the present invention relates to an acyl CoA cholesterol acyltransferase inhibitor, characterized by containing a processed product derived from button bowfish as an active ingredient.
[0010] 本発明の第 4の発明は、ボタンボウフゥ由来の処理物を有効成分として含有するこ とを特徴とする、細胞の抗泡沫ィ匕用及び Z又はァシル CoAコレステロールァシルトラ ンスフェラーゼ阻害用の食品又は飼料に関する。 [0010] A fourth invention of the present invention comprises a processed product derived from button bow fu as an active ingredient, for cell antifoam and for inhibiting Z or acyl CoA cholesterol acyltransferase. Relating to food or feed.
[0011] 本発明の第 5の発明は、 3，ーァセトキシー4，一セネシオイルォキシ 3，， 4，ージ ノ、イドロセセリン、その誘導体及び薬学的に許容されるそれらの塩からなる群より選 ばれる一種以上を有効成分として含有することを特徴とする、治療又は予防にぉ 、 て細胞の抗泡沫化作用及び Z又はァシル CoAコレステロールァシルトランスフェラ ーゼ阻害作用を要する疾患の治療剤又は予防剤に関する。  [0011] The fifth invention of the present invention is selected from the group consisting of 3, -acetoxyl 4, mono-senecyoxyoxy 3, 4, 4-zino, idroseserine, derivatives thereof and pharmaceutically acceptable salts thereof. A therapeutic agent or prevention of a disease requiring an antifoaming action of cells and an inhibitory action of Z or acyl CoA cholesterol acyltransferase, for treatment or prevention, It relates to the agent.
[0012] 本発明の第 6の発明は、 3，ーァセトキシ 4' セネシオイルォキシ 3' , 4'—ジ ノ、イドロセセリン、その誘導体及び薬学的に許容されるそれらの塩からなる群より選 ばれる一種以上を有効成分として含有することを特徴とする、細胞の抗泡沫化剤に 関する。  [0012] The sixth invention of the present invention is selected from the group consisting of 3, -acetooxy 4 'senesioxyloxy 3', 4'-dino, idroseserine, derivatives thereof and pharmaceutically acceptable salts thereof. The present invention relates to a cell antifoaming agent characterized by containing one or more active ingredients.
[0013] 本発明の第 7の発明は、 3，ーァセトキシ 4' セネシオイルォキシ 3' , 4'—ジ ノ、イドロセセリン、その誘導体及び薬学的に許容されるそれらの塩からなる群より選 ばれる一種以上を有効成分として含有することを特徴とする、ァシル CoAコレステロ ールァシルトランスフェラーゼ阻害剤に関する。  [0013] The seventh invention of the present invention is selected from the group consisting of 3, -acetoxy 4 ′ senesioxyloxy 3 ′, 4′-dino, idrothelin, derivatives thereof and pharmaceutically acceptable salts thereof. The present invention relates to an isyl CoA cholesterol transferase inhibitor characterized by containing one or more active ingredients.
[0014] 本発明の第 8の発明は、 3，ーァセトキシー4，一セネシオイルォキシ 3，， 4，ージ ノ、イドロセセリン、その誘導体及び薬学的に許容されるそれらの塩からなる群より選 ばれる一種以上を有効成分として含有することを特徴とする、細胞の抗泡沫化用及 び/又はァシル CoAコレステロールァシルトランスフェラーゼ阻害用の食品又は飼 料に関する。  [0014] The eighth invention of the present invention is selected from the group consisting of 3, -acetoxy-4, mono-senecyoxyoxy 3, 4, 4-zino, idroseserine, derivatives thereof and pharmaceutically acceptable salts thereof. The present invention relates to a food or feed for anti-foaming of cells and / or for inhibition of acyl-CoA cholesterol acyltransferase.
[0015] 本発明の第 9の発明は、被験体に、有効量のボタンボウフゥ由来の処理物を投与 することを含む、治療又は予防にぉ 、て細胞の抗泡沫ィ匕作用及び Z又はァシル Co Aコレステロールァシルトランスフェラーゼ阻害作用を要する疾患の治療方法又は予 防方法に関する。 [0015] The ninth invention of the present invention is that a subject is administered with an effective amount of a processed product derived from button bow. The present invention relates to a method for treating or preventing a disease requiring an antifoaming action of a cell and an inhibitory action of Z or acyl CoA cholesterol acyltransferase for treatment or prevention.
[0016] 本発明の第 10の発明は、治療又は予防において細胞の抗泡沫ィ匕作用及び Z又 はァシル CoAコレステロールァシルトランスフェラーゼ阻害作用を要する疾患の治療 剤又は予防剤の製造のための、ボタンボウフゥ由来の処理物の使用に関する。  [0016] The tenth invention of the present invention is for the manufacture of a therapeutic or prophylactic agent for a disease requiring an antifoaming action of cells and an inhibitory action of Z or acyl CoA cholesterol acyltransferase in the treatment or prevention. It relates to the use of processed products derived from button bow.
[0017] 本発明の第 11の発明は、被験体に、有効量の 3'—ァセトキシー 4' セネシオイル ォキシ—3，， 4，—ジノヽイドロセセリン、その誘導体及び薬学的に許容されるそれらの 塩力もなる群より選ばれる一種以上を投与することを含む、治療又は予防にぉ 、て 細胞の抗泡沫化作用及び Z又はァシル CoAコレステロールァシルトランスフェラー ゼ阻害作用を要する疾患の治療方法又は予防方法に関する。  [0017] The eleventh invention of the present invention provides a subject with an effective amount of 3'-acetoxy 4 'seneciyloxy-3,4, -dinoidoid roseserin, a derivative thereof, and a pharmaceutically acceptable salt thereof. The present invention relates to a method for treating or preventing a disease requiring an antifoaming action of a cell and an inhibitory action of Z or acyl CoA cholesterol acyltransferase, including administering one or more selected from a group that also has strength. .
[0018] 本発明の第 12の発明は、治療又は予防において細胞の抗泡沫ィ匕作用及び Z又 はァシル CoAコレステロールァシルトランスフェラーゼ阻害作用を要する疾患の治療 剤又は予防剤の製造のための、 3，—ァセトキシ— 4，—セネシオイルォキシ—3，， 4， —ジノヽィドロセセリン、その誘導体及び薬学的に許容されるそれらの塩からなる群より 選ばれる一種以上の使用に関する。  [0018] The twelfth invention of the present invention is for the manufacture of a therapeutic or prophylactic agent for a disease requiring an anti-foaming action of a cell and an inhibitory action of Z or acyl CoA cholesterol acyltransferase in the treatment or prevention. 3, -acetoxy-4, -senesioyloxy-3,4, -dinohydrodroserine, its derivatives and pharmaceutically acceptable salts thereof.
発明の効果  The invention's effect
[0019] 本発明により、治療又は予防において細胞の抗泡沫ィ匕作用及び Z又はァシル Co Aコレステロールァシルトランスフェラーゼ阻害作用を要する疾患の治療用又は予防 用の医薬、食品又は飼料が提供される。該医薬は動脈硬化症や高脂血症、それに 起因する疾患に対して有用である。また、該食品は、 日常の飲食品として摂取するこ とにより、治療又は予防に細胞の抗泡沫ィ匕作用及び Z又はァシル CoAコレステロ一 ルァシルトランスフェラーゼ阻害作用を要する疾患の症状改善等が可能となる。従つ て、本発明の食品は細胞の抗泡沫ィ匕作用及び Z又はァシル CoAコレステロールァ シルトランスフェラーゼ阻害作用により生体の恒常性の維持に有用な機能性食品で ある。  [0019] According to the present invention, there is provided a medicament, food or feed for treating or preventing a disease requiring an antifoaming action of cells and an inhibitory action of Z or acyl Co A cholesterol acyltransferase in the treatment or prevention. The medicament is useful for arteriosclerosis, hyperlipidemia, and diseases caused thereby. In addition, when the food is taken as a daily food or drink, it is possible to improve the symptoms of diseases that require anti-foaming action of cells and inhibition of Z or acyl CoA cholesterol transferase for treatment or prevention. Become. Therefore, the food of the present invention is a functional food useful for maintaining the homeostasis of the living body by the antifoaming action of cells and the inhibitory action of Z or acyl CoA cholesterol acyltransferase.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0020] 細胞の泡沫化は細胞内にコレステロールエステルが蓄積することによって起こる。 細胞の抗泡沫化作用は、後述の実施例 1に記載のような細胞中のコレステロールェ ステル量を指標としたアツセィ系を用いて簡便に測定することができる。すなわち、被 験物質とァセチル LDLの存在下にマクロファージを培養し、細胞中のコレステロール エステル量を評価することで、細胞の抗泡沫化作用を簡便に測定することができる。 なお、本発明において抗泡沫ィ匕の対象となる細胞としては、特に限定はないが、例 えばマクロファージゃ平滑筋細胞等の血管系細胞や血液細胞が例示される。 [0020] Cell foaming is caused by accumulation of cholesterol ester in the cell. The anti-foaming action of the cells can be easily measured by using an assay system with the amount of cholesterol ester in the cells as an index as described in Example 1 described later. That is, by culturing macrophages in the presence of a test substance and acetyl LDL and evaluating the amount of cholesterol ester in the cells, the antifoaming action of the cells can be easily measured. In the present invention, the cells to be antifoamed are not particularly limited, and examples thereof include vascular cells such as macrophages and smooth muscle cells, and blood cells.
[0021] ァシル CoAコレステロールァシルトランスフェラーゼ（別名、ァシル CoA：コレステロ ール O ァシルトランスフェラーゼとも称する。以下、 ACATと略称することがある）は 、コレステロールにァシル CoAから長鎖脂肪酸を転移し、コレステロールエステル合 成を触媒する酵素である。 ACAT阻害作用は、後述の実施例 2に記載のようなアツ セィ系を用いて簡便に測定することができる。すなわち、被験物質と ACATを含む酵 素源を混合し、放射ラベルされた Oleoyl— CoAからコレステロールへの Oleoyl基の 転移を評価することで、 ACAT阻害作用を簡便に測定することができる。  [0021] Acyl CoA cholesterol acyltransferase (also known as acyl CoA: cholesterol O-acyltransferase, hereinafter also abbreviated as ACAT) transfers long-chain fatty acids from cholesterol acyl to cholesterol, It is an enzyme that catalyzes ester synthesis. The ACAT inhibitory action can be easily measured using an assay system as described in Example 2 described later. That is, by mixing a test substance and an enzyme source containing ACAT, and evaluating the transfer of the Oleoyl group from radiolabeled Oleoyl-CoA to cholesterol, the ACAT inhibitory action can be easily measured.
[0022] 本発明に使用されるボタンボウフゥとしては、特に限定はないが、果実、種子、種皮 、花、葉、茎、根、根茎及び Z又は植物全体そのままを使用することができる。  [0022] The button bow fu used in the present invention is not particularly limited, and fruits, seeds, seed coats, flowers, leaves, stems, roots, rhizomes and Z, or whole plants can be used as they are.
[0023] 本発明の有効成分として使用される、ボタンボウフゥ由来の処理物（以下、本発明 の処理物と称することがある）としては、原料植物に対し何らかの加工を施したもので あって細胞の抗泡沫化作用及び Z又は ACAT阻害作用を有していれば特に限定 はないが、例えば抽出物、粉砕物、搾汁液、破砕物、化学処理物、酵素処理物をい い、特に好適には抽出物、粉砕物および搾汁液が例示される。なお、本発明の処理 物としては、特に好適には、細胞の抗泡沫化作用物質であり、 ACAT阻害作用物質 である後述の 3，ーァセトキシー4，一セネシオイノレォキシ 3，， 4，ージハイド口セセリ ンが高含有された処理物を使用することができる。なお、ここで高含有とは、原料植 物中の 3，ーァセトキシー 4，一セネシオイルォキシ 3，， 4，ージハイドロセセリンの含 有濃度よりも、当該処理物中の 3，ーァセトキシー 4，一セネシオイルォキシー3，， 4， —ジノ、イドロセセリンの含有濃度が高いことを意味し、ボタンボウフゥ中の濃度の 1. 5 倍以上であることが好ましぐ 2倍以上であることがより好ましい。  [0023] The processed product derived from buttonbow fu (hereinafter sometimes referred to as the processed product of the present invention) used as an active ingredient of the present invention is a raw material plant that has been subjected to some processing and is a cell There is no particular limitation as long as it has antifoaming action and Z or ACAT inhibitory action, but for example, extract, pulverized product, juice, crushed product, chemically treated product, enzyme treated product, particularly preferably Examples are extracts, pulverized products and juices. The treated product of the present invention is particularly preferably a cell anti-foaming agent and an ACAT inhibitory agent described later 3, -acetoxyl 4, monosenecioinoxy 3, 4, 4, A treated product containing a high content of cerine can be used. Here, high content means that 3, 4-acetoxy 4 in the raw material plant, 3, 4-acetoxyyloxy 3, 4, 4-dihydroceserine contained in the treated product 3, 4-acetoxy 4 , 1 Senesioiloxy 3, 4, 4-means that the concentration of Gino and Idoloserine is high, and it is preferably 1.5 times or more of the concentration in buttonbow, more than 2 times more preferable.
[0024] 本発明において、抽出物とは原料植物に対し抽出溶媒を用いて抽出操作を行うェ 程を経て得られる物質そのもののことをいう。抽出は、公知の抽出方法により以下の ように行うことができる。例えば原料を粉砕もしくは細断した後、溶媒を用いてバッチ 式もしくは連続式で行うことができる。抽出物を得る際の抽出溶媒としては、特に限定 はないが、水、グリセロール、グリコール類（エチレングリコール、プロピレングリコール 等）、アルコール類（エタノール、メタノール、イソプロピルアルコール等）、ケトン類（ァ セトン、メチルェチルケトン等）、親水性もしくは親油性の溶媒 (クロ口ホルム、酢酸メ チル、酢酸ェチル等)を挙げることができ、所望により単独で、もしくは適宜混合液と して用いることができる。混合液を抽出溶媒として用いる例としては、特に限定はない が、例えば各種水溶液を用いることができ、例えば 10〜95%、好適には 15〜90% 、さらに好適には 20〜85%のアルコール水溶液を使用することができる。また、ダリ セロール、グリコール類（エチレングリコール、プロピレングリコールなど）を溶媒として 使用する場合も、好適にはこれらの水溶液として使用することが好ましい。抽出溶媒 の量は適宜決定すればよいが、通常、原料植物に対し、使用時の原料植物の形態 そのまま (例えば原料植物が生の植物であれば生の植物）の重量の、好ましくは 0. 1 〜100倍量の抽出溶媒を使用すれば良い。抽出温度も適宜、 目的に応じて決定す れば良いが、水抽出の場合は通常、好ましくは 4〜130°C、より好ましくは 25〜： LOO °Cである。また、溶媒中にエタノールが含まれる場合は安全性の観点から 4〜60°C の範囲が好適である。抽出時間も、抽出効率を考慮し決定すればよいが、通常、好 ましくは数秒〜数日間、より好ましくは 5分〜 24時間の範囲となるように、原料、抽出 溶媒、抽出温度を設定するのが好適である。抽出操作は、たとえば、攪拌しながら又 は静置して行えばよぐまた、必要に応じて数回繰り返してもよい。以上の操作により 、本発明に使用されるボタンボウフゥ由来の抽出物（以下、本発明の抽出物と称する ことがある）を得ることができる。抽出物は必要に応じ、ろ過、遠心分離、濃縮、限外ろ 過、分子ふるい等の処理を行うことで、細胞の抗泡沫化作用物質や ACAT阻害作用 物質、例えば後述の 3，ーァセトキシー4， 一セネシオイルォキシ 3，， 4，ージハイド ロセセリンが濃縮された抽出物を調製することができる。抽出物や濃縮抽出物の細胞 の抗泡沫化作用や ACAT阻害作用は、後述の実施例 1および 2記載の方法により 簡便に測定することができる。また、本発明に使用されるボタンボウフゥを公知の方法 で茶葉状にし、これを用いた抽出物も細胞の抗泡沫ィ匕作用及び Z又は ACAT阻害 作用を有していれば、本発明の抽出物として使用することができる。また、以上の抽 出物を 2種以上含有させて使用することもできる。また、原料植物力も異なった抽出 法で得られた抽出物を 2種以上含有させて使用することもできる。 [0024] In the present invention, an extract refers to an extraction operation performed on an original plant using an extraction solvent. It refers to the substance itself obtained through the process. Extraction can be carried out by a known extraction method as follows. For example, after pulverizing or chopping the raw material, it can be carried out batchwise or continuously 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, Methylethyl ketone, etc.) and hydrophilic or lipophilic solvents (black mouth form, methyl acetate, ethyl acetate, etc.) can be mentioned, and they can be used alone or as a mixture as desired. Examples of using the mixed solution as an extraction solvent are not particularly limited, but various aqueous solutions can be used, for example, 10 to 95%, preferably 15 to 90%, more preferably 20 to 85% alcohol. An aqueous solution can be used. Moreover, when using daricerol and glycols (ethylene glycol, propylene glycol, etc.) as a solvent, it is preferable to use these aqueous solutions suitably. The amount of the extraction solvent may be determined as appropriate, but it is generally preferably 0. What is necessary is just to use 1-100 times amount extraction solvent. The extraction temperature may be appropriately determined according to the purpose, but in the case of water extraction, it is usually preferably 4 to 130 ° C, more preferably 25 to: LOO ° C. When ethanol is contained in the solvent, a temperature range of 4 to 60 ° C. is preferable from the viewpoint of safety. The extraction time may be determined in consideration of the extraction efficiency, but usually the raw material, extraction solvent, and extraction temperature are set to be preferably in the range of several seconds to several days, more preferably 5 minutes to 24 hours. It is preferable to do this. The extraction operation may be performed, for example, with stirring or standing, and may be repeated several times as necessary. By the above operation, an extract derived from button bow fu used in the present invention (hereinafter sometimes referred to as the extract of the present invention) can be obtained. If necessary, the extract is treated by filtration, centrifugation, concentration, ultrafiltration, molecular sieving, etc., so that the cell antifoaming agent or ACAT inhibitory agent, such as 3, -acetoxy-4, described below, can be obtained. An extract enriched with one-senecyoxy3,4, -dihydroserine can be prepared. The cell antifoaming action and ACAT inhibitory action of the extract or concentrated extract can be easily measured by the methods described in Examples 1 and 2 described later. In addition, the button bow used in the present invention is a known method. If an extract using the same has an antifoaming effect on cells and a Z or ACAT inhibitory effect, it can be used as the extract of the present invention. It is also possible to use two or more of the above extracts. It is also possible to use two or more extracts obtained by extraction methods with different raw plant power.
[0025] また、本発明においては、本発明の抽出物を公知の方法で分画することによって得 られる画分や、分画操作を複数回繰り返すことにより得られる画分についても本発明 の抽出物に包含される。上記の分画手段としては、抽出、分別沈殿、カラムクロマトグ ラフィー、薄層クロマトグラフィー等が挙げられる。得られた画分の精製を、細胞の抗 泡沫ィ匕作用や ACAT阻害作用を指標としてさらに進めることにより、細胞の抗泡沫 化作用物質や ACAT阻害物質を単離することもできる。  [0025] In the present invention, the extraction of the present invention also applies to a fraction obtained by fractionating the extract of the present invention by a known method and a fraction obtained by repeating the fractionation operation a plurality of times. It is included in the thing. Examples of the fractionation means include extraction, fractional precipitation, column chromatography, thin layer chromatography and the like. By further purifying the obtained fraction using the cell antifoam function and ACAT inhibitory activity as an index, the cell antifoam agent and ACAT inhibitor can also be isolated.
[0026] また、本発明に使用されるボタンボウフゥ由来の処理物であって、前述した本発明 の抽出物以外のものとしては、例えば、本発明に使用されるボタンボウフゥ由来の粉 砕物（以下、本発明の粉砕物と称することがある）が例示される。本発明の粉砕物の 製造方法としては、例えば植物を乾燥させ、粉砕機を使用して粉砕することで粉状の ボタンボウフゥ由来の粉砕物を得る方法が挙げられる。また、凍結粉砕により粉砕物 を得てもよい。  [0026] In addition, the processed product derived from the button bow used in the present invention, other than the aforementioned extract of the present invention, includes, for example, a powdered product derived from the button bow used in the present invention (hereinafter referred to as the present invention). May be referred to as a pulverized product of the invention). Examples of the method for producing a pulverized product of the present invention include a method of obtaining a pulverized product derived from a button-shaped button bow by drying a plant and using a pulverizer. Further, a pulverized product may be obtained by freeze pulverization.
[0027] また、本発明に使用されるボタンボウフゥ由来の搾汁液も、本発明の処理物として 使用できる。当該搾汁の製造方法としては、公知の植物の搾汁方法であれば特に限 定はないが、例えばスクリュー式、ギア式、カッター式等の搾り機やジューサーを用い て搾汁することができる。また、前処理として細断あるいはすりつぶして、上述のジュ ーサ一又は布等で絞って搾汁液を得ることもできる。  [0027] In addition, the squeezed juice derived from button bow fu used in the present invention can also be used as the treated product of the present invention. The method for producing the juice is not particularly limited as long as it is a known method for squeezing a plant. For example, the juice can be squeezed using a screw type, gear type, cutter type or other squeezer or juicer. . Further, as a pretreatment, the juice can be obtained by chopping or grinding and squeezing with the above-mentioned juicer or cloth.
[0028] 破砕物とは、原料植物を砕き壊したものであり、一般には粉砕物よりも組織片が大 きぐ例えば、破砕機を使用することにより製造することができる。また、化学処理物と は、特に限定はないが、原料植物を酸処理、アルカリ処理、酸化処理、還元処理等 に供して得られた物をいい、例えば、塩酸、硫酸、硝酸、クェン酸、酢酸等の無機酸 や有機酸、又は水酸化ナトリウム、水酸化カリウム、アンモニア等の無機塩基や有機 塩基を含む水溶液に原料植物を浸漬することにより製造することができる。化学処理 物には、前記のような化学処理を受けた植物体に由来するすべてのものを含む。酵 素処理物とは、例えば、ぺクチナーゼ、セルラーゼ、キシラナーゼ、アミラーゼ、マン ナナーゼ、ダルコシダーゼ等による酵素処理物、微生物による酵素反応物（例えば、 発酵物）をいい、例えば、原料植物に対して上記酵素を適当な緩衝液中で作用させ ることにより製造することができる。酵素処理物には、前記のような酵素処理を受けた 植物体に由来するすべてのものを含む。さらに、本発明のボタンボウフゥ由来処理物 としては、例えば、原料植物の茎を切断し、その切断面カゝら得られる汁液も包含され る。 [0028] The crushed material is a material obtained by pulverizing a raw plant, and generally has a larger tissue piece than the pulverized material, and can be produced, for example, by using a crusher. The chemical treatment product is not particularly limited, but refers to a product obtained by subjecting the plant to acid treatment, alkali treatment, oxidation treatment, reduction treatment, etc., for example, hydrochloric acid, sulfuric acid, nitric acid, citrate, It can be produced by immersing the raw material plant in an aqueous solution containing an inorganic or organic acid such as acetic acid, or an inorganic or organic base such as sodium hydroxide, potassium hydroxide or ammonia. Chemically treated products include all those derived from plants that have undergone chemical treatment as described above. Fermentation An untreated product refers to, for example, an enzyme-treated product such as pectinase, cellulase, xylanase, amylase, mannanase, and dalcosidase, and an enzyme-reacted product (eg, fermented product) from microorganisms. Can be produced by acting in a suitable buffer. Enzyme-treated products include all those derived from plants that have been subjected to the enzyme treatment as described above. Further, the processed product derived from the button bow of the present invention includes, for example, a juice obtained by cutting a stem of a raw material plant and obtaining the cut surface.
[0029] 本発明において、本発明の処理物の形状としては、本発明の各態様で有効成分と して使用した際に細胞の抗泡沫ィヒ作用及び Z又は ACAT阻害作用を発揮できれば 特に限定はないが、粉状、固形状、液状のいずれの形状であってもよい。また、処理 物を公知の方法で造粒して粒状の固形物として使用することができる。造粒方法とし ては、特に限定はないが、転動造粒、攪拌造粒、流動層造粒、気流造粒、押出し造 粒、圧縮成型造粒、解砕造粒、噴射造粒又は噴霧造粒等が例示される。粉状の当 該処理物を液体、例えば水やアルコール等に溶解して液状とし、本発明のボタンボ ゥフゥ由来の処理物として使用することもできる。  [0029] In the present invention, the shape of the treated product of the present invention is particularly limited as long as it can exhibit an antifoaming action of cells and a Z or ACAT inhibitory action when used as an active ingredient in each aspect of the present invention. However, it may be in the form of powder, solid or liquid. The treated product can be granulated by a known method and used as a granular solid. The granulation method is not particularly limited, but rolling granulation, stirring granulation, fluidized bed granulation, air flow granulation, extrusion granulation, compression molding granulation, pulverization granulation, spray granulation, spray granulation or spraying Examples include granulation. The treated product in a powder form can be dissolved in a liquid, for example, water or alcohol, to obtain a liquid and used as a treated product derived from the button bow of the present invention.
[0030] 本発明において、本発明の処理物として好適に使用される後述の 3'—ァセトキシ  [0030] In the present invention, 3'-acetoxy, which will be described later, is preferably used as the treated product of the present invention.
-4' セネシオイルォキシ 3' , 4'—ジノヽイドロセセリンが高含有された処理物とし ては、当該化合物を含有し、さらに食用として供するという観点から、例えばエタノー ル抽出物、含水エタノール抽出物、熱水抽出物、グリセロール抽出物もしくは含水グ リセロール抽出物、エチレングリコール、プロピレングリコールなどのグリコール抽出 物もしくは含水ダリコール抽出物、粉砕物が好ましい。  -4 'Senesyl oiloxy 3', 4'-dinoidoid roseserine is a processed product containing a high amount of the compound, and from the viewpoint of further serving as edible, for example, ethanol extract, water-containing ethanol extraction Products, hot water extracts, glycerol extracts or water-containing glycerol extracts, glycol extracts such as ethylene glycol and propylene glycol, water-containing dallicol extracts, and pulverized products are preferred.
[0031] また、本発明者らはボタンボウフゥ由来の細胞の抗泡沫ィ匕作用物質および ACAT 阻害作用物質を探索したところ、下記式 (I)に示す 3'—ァセトキシー 4' セネシオイ ルォキシー 3' , 4'—ジハイドロセセリンが細胞の抗泡沫化作用物質であり、 ACAT 阻害作用物質であることを見出した。すなわち、本発明の有効成分としては、上記の ボタンボウフゥ由来の処理物のほかに、ボタンボウフゥ由来のクマリンの一種である 3 ，ーァセトキシー 4，一セネシオイルォキシ 3，， 4，ージハイドロセセリン、その誘導体 及び Z又は薬学的に許容されるそれらの塩を使用することもできる。 [0032] [化 1] [0031] In addition, the present inventors searched for an antifoaming agent and an ACAT inhibitory agent of button bud-derived cells, and as a result, 3'-acetoxyl 4 'senecioyloxy 3', 4 represented by the following formula (I): '—We found that dihydroserine is an antifoaming agent for cells and an ACAT inhibitory agent. That is, as an active ingredient of the present invention, in addition to the processed product derived from the above-mentioned button bow, 3, a kind of coumarin derived from button bow, 3, 4-acetoxy, 1, senesioxyloxy 3, 4, 4-dihydroserine, Derivatives thereof and Z or pharmaceutically acceptable salts thereof can also be used. [0032] [Chemical 1]
Figure imgf000010_0001
Figure imgf000010_0001
[0033] 上記 3，ーァセトキシー4，一セネシオイルォキシ 3，， 4，ージハイドロセセリンの製 造方法としては、特に限定はないが、例えばボタンボウフゥのエタノール抽出物から 各種クロマトグラフィーを行って得ることができ、また合成する場合は公知の方法を組 み合わせること〖こより得ることちできる。 [0033] There are no particular limitations on the method for producing the above-mentioned 3, -acetooxy-4, mono-senecyoxyoxy 3,4, -dihydrosethelin, but various chromatographies are carried out, for example, from an ethanol extract of button bow fu. In the case of synthesis, it can be obtained from a combination of known methods.
[0034] 本願明細書にぉ 、て誘導体としては、例えばエステルなど、体内で容易に加水分 解されて上記の 3，ーァセトキシー 4，一セネシオイノレォキシ 3，， 4，ージハイドロセ セリンを生成し、所望の効果を発揮し得る誘導体 (プロドラッグ)を調製可能である。 力かるプロドラッグの調製は公知の方法に従えばよい。また、例えば本発明の化合物 をほ乳動物に投与して代謝されてできた誘導体も本発明の誘導体に包含される。な お、力かる誘導体は、 3，—ァセトキシ— 4，—セネシオイルォキシ—3，， 4，—ジハイド ロセセリンの塩であってもよ 、。  In the present specification, as a derivative, for example, an ester or the like is easily hydrolyzed in the body to produce the above-mentioned 3, -acetooxy-4, mono-senecioinoleoxy 3,4, -dihydroserine, Derivatives (prodrugs) that can exhibit the desired effect can be prepared. Preparation of a strong prodrug may be performed according to a known method. In addition, for example, derivatives obtained by metabolizing the compound of the present invention to a mammal are also included in the derivatives of the present invention. The powerful derivative may be a salt of 3, -acetoxy-4, -senesioyloxy-3,4, -dihydroserine.
[0035] また、本発明に使用される 3'—ァセトキシ一 4'—セネシオイルォキシ 3' , 4' - ジノ、イドロセセリンまたはその誘導体の塩としては薬学的に許容される塩が好ましい [0035] Further, as the salt of 3'-acetoxy-4'-senesioxyloxy 3 ', 4'-dino, idroseserine or a derivative thereof used in the present invention, a pharmaceutically acceptable salt is preferable.
。また、前述するようにプロドラッグとして機能し得る当該化合物の誘導体であっても よい。従って、本発明に係る 3，一ァセトキシ一 4，一セネシォイノレオキシ一 3，， 4， - ジノ、イドロセセリンとは、本発明の所望の効果が得られ得る限り、その誘導体ならび にそれらの塩も包含するものである。また、 3'—ァセトキシ— 4'—セネシオイルォキ シー 3，， 4，一ジノヽイドロセセリンの光学異性体、ケトーエノール互変異性体、幾何異 性体などの各種異性体、各異性体の単離されたものであっても、細胞の抗泡沫化作 用もしくは ACAT阻害作用を有する限り、全て本発明において使用することができる [0036] 本発明で使用される塩としては、例えば、アルカリ金属塩、アルカリ土類金属塩、有 機塩基との塩などが例示される。なお、本発明において使用される薬学的に許容さ れる塩とは生物に対して実質的に無毒であって、かつ細胞の抗泡沫化作用を有する 化合物の塩を意味する。当該塩としては、たとえば、ナトリウム、カリウム、カルシウム、 マグネシウム、アンモ-ゥムまたはプロトン化されたベンザチン（N, N' —ジ一べンジ ルエチレンジァミン）、コリン、エタノールァミン、ジエタノールァミン、エチレンジァミン 、メグラミン（N—メチルダルカミン）、ベネタミン（N ベンジルフエネチルァミン）、ピぺ ラジンもしくはトロメタミン (2-ァミノ 2 ハイドロキシメチル 1, 3 プロパンジォー ル)等の塩が挙げられる。 . Further, as described above, it may be a derivative of the compound that can function as a prodrug. Therefore, the 3,1-acetoxy-1,4-senesinoinoreoxy-1,4, -dino and idrothelin according to the present invention are their derivatives and their derivatives as long as the desired effects of the present invention can be obtained. It also includes salts. In addition, various isomers such as optical isomers of 3'-acetoxy-4'-senecioyloxy 3,4, monozinoidroseserine, ketoeenol tautomers and geometric isomers, and isomers were isolated. Can be used in the present invention as long as they have anti-foaming action or ACAT inhibitory action on cells. [0036] Examples of the salt used in the present invention include alkali metal salts, alkaline earth metal salts, salts with organic bases, and the like. The pharmaceutically acceptable salt used in the present invention means a salt of a compound that is substantially nontoxic to living organisms and has an antifoaming action on cells. Such salts include, for example, sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N, N'-dibenzylethylenediamine), choline, ethanolamine, diethanolamine. And salts such as amine, ethylenediamine, megramin (N-methyldalcumamine), venetamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol).
[0037] なお、本発明において、本発明の処理物、および 3'—ァセトキシー 4'ーセネシォ ィルォキシ— 3' , 4'—ジハイドロセセリン、その誘導体及び/又は薬学的に許容さ れるそれらの塩を本発明の有効成分と称し、本発明の有効成分を含有する細胞の抗 泡沫化作用及び Z又は ACAT阻害作用を要する疾患の治療剤又は予防剤を本発 明の治療剤又は予防剤と称することがある。また、本発明の医薬という場合、治療剤 および予防剤に加え、後述の細胞の抗泡沫化剤および ACAT阻害剤が含まれる場 合がある。  [0037] In the present invention, the treated product of the present invention and 3'-acetoxy 4'-senesyloxy-3 ', 4'-dihydroserine, a derivative thereof and / or a pharmaceutically acceptable salt thereof. Is referred to as an active ingredient of the present invention, and a therapeutic or preventive agent for a disease requiring an antifoaming action and a Z or ACAT inhibitory action of a cell containing the active ingredient of the present invention is referred to as a therapeutic or preventive agent of the present invention. Sometimes. In addition, in the case of the medicament of the present invention, in addition to the therapeutic agent and the preventive agent, there are cases where the cell antifoaming agent and ACAT inhibitor described later are included.
[0038] 本発明の有効成分は、古来より食用とされてきたボタンボウフゥに由来するものであ り、これまでに知られている ACAT阻害作用を有する合成化合物（例えば、後述の F R179254)と比較しても安全性が高ぐ後述するように特に毒性は認められず、副作 用の発生の心配もない。それゆえ、安全かつ適切に疾患の治療又は予防を行うこと ができる。従って、当該有効成分を含んでなる本発明の治療剤、予防剤、食品また は飼料は、細胞の抗泡沫化作用および AC AT阻害作用を要する疾患の治療または 予防に有効であり、特に手軽に摂取することのできる健康食品素材として有用である  [0038] The active ingredient of the present invention is derived from button bow fu which has been edible since ancient times, and is compared with a synthetic compound having an ACAT inhibitory activity known so far (for example, FR179254 described later). However, since it is highly safe, there is no particular toxicity as described later, and there is no risk of side effects. Therefore, the disease can be treated or prevented safely and appropriately. Therefore, the therapeutic agent, prophylactic agent, food or feed of the present invention comprising the active ingredient is effective for the treatment or prevention of diseases requiring anti-foaming action and ACAT inhibitory action of cells, and particularly easily. Useful as a health food ingredient that can be ingested
[0039] また、本発明にお 、て、治療又は予防に細胞の抗泡沫ィ匕作用を要する疾患として は、細胞の泡沫ィヒを抑制することにより治療又は予防効果がみられる疾患であれば 特に限定はないが、例えば、動脈硬化症、これが原因因子となって起こる疾患、例え ば虚血性心疾患、急性心筋梗塞、不安定狭心症、虚血性突然死、脳血管障害、慢 性閉塞性動脈硬化症、心筋梗塞、狭心症、脳梗塞、くも膜下出血、肥満症等が例示 される（例えば、 O'Rourkeら、 J. Biol. Chem. , 2002, 277 (45) , 42557—4 2562参照）。 [0039] In the present invention, the disease requiring an anti-foaming action of cells for treatment or prevention is a disease that exhibits a therapeutic or preventive effect by suppressing cell foaming. Although there is no particular limitation, for example, arteriosclerosis, a disease caused by this, for example, Ischemic heart disease, acute myocardial infarction, unstable angina, sudden ischemic death, cerebrovascular disorder, chronic obstructive arteriosclerosis, myocardial infarction, angina, cerebral infarction, subarachnoid hemorrhage, obesity, etc. (See, for example, O'Rourke et al., J. Biol. Chem., 2002, 277 (45), 42557-4 2562).
[0040] また、本発明にお 、て、治療又は予防に ACAT阻害作用を要する疾患としては、 特に限定はな 、が、上記の治療又は予防に細胞の抗泡沫ィ匕作用を要する疾患にカロ えて、高脂血症、高コレステロール血症、高トリグリセライド血症、マルチプルリスクフ アクター症候群、またはこれらが原因因子となって起こる疾患が例示される（例えば、 O'Rourkeら、 Biol. Chem. , 2002, 277 (45) , 42557— 42562、 Ohishiら 、 Biol. Pharm. Bull. , 2003, 26 (8) , 1125— 1128、および Ohishiら、 Che m. Pharm. Bull. , 2001, 49 (7) , 830— 839参照）。  [0040] In the present invention, the disease that requires an ACAT inhibitory action for treatment or prevention is not particularly limited. However, the disease that requires an anti-foaming action of cells for the treatment or prevention is not limited. Examples include hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, multiple risk factor syndrome, or diseases caused by these factors (eg, O'Rourke et al., Biol. Chem., 2002, 277 (45), 42557—42562, Ohishi et al., Biol. Pharm. Bull., 2003, 26 (8), 1125—1128, and Ohishi et al., Chem. Pharm. Bull., 2001, 49 (7) , 830-839).
[0041] 本発明の治療剤または予防剤としては、本発明に係る前記有効成分を公知の医薬 用担体と組み合わせて製剤化したものが挙げられる。また、本発明の治療剤又は予 防剤としては、前記有効成分を当該有効成分と同じ用途に使用可能な他の成分、例 えば公知の高脂血症や動脈硬化症の治療または予防作用を有する成分、例えばプ ラバスタチン、シンパスタチン、フルパスタチン、セリバスタチン、アトルバスタチン等 のスタチン系の化合物等の HMG— CoAレダクターゼ阻害剤、フコィダン等の抗泡 沫化剤、メリナミド等の AC AT阻害剤、コレステロールエステル転送タンパク質 (CET P)抑制剤、コレステロール吸収阻害剤、スクアレン合成酵素阻害剤、 LDL酸化抑制 剤、ミクロソーマルトリグリセリドトランスファータンパク（MTP)阻害剤、アポリポタンパ ク質 A1産生促進剤、 ATP—バインディングカセットサブファミリー Al (ABCA1)誘 導剤、スクアレンエポキシダーゼ阻害剤、コレスチラミン等の胆汁酸結合榭脂、クロフ イブレート等のフイブレート系、ナイァシン等のニコチン酸系、ィコサペント酸ェチル等 の中性脂肪低下剤などと配合することもできる。  [0041] Examples of the therapeutic or prophylactic agent of the present invention include those prepared by combining the above-mentioned active ingredient according to the present invention with a known pharmaceutical carrier. In addition, as the therapeutic agent or preventive agent of the present invention, the active ingredient can be used for other ingredients that can be used for the same purpose as the active ingredient, for example, known hyperlipidemia and arteriosclerosis treatment or prevention action. Ingredients such as HMG-CoA reductase inhibitors such as stava compounds such as pravastatin, simpastatin, flupastatin, cerivastatin, atorvastatin, antifoaming agents such as fucoidan, ACAT inhibitors such as melinamide, cholesterol Ester transfer protein (CET P) inhibitor, cholesterol absorption inhibitor, squalene synthase inhibitor, LDL oxidation inhibitor, microsomal triglyceride transfer protein (MTP) inhibitor, apolipoprotein A1 production promoter, ATP—binding Cassette subfamily Al (ABCA1) inducer, squalene epoxidase inhibitor, choles Bile acid binding 榭脂 Ramin such, Fuibureto system such Kurofu Ibureto, nicotinic acid, such as Naiashin, may be blended with such triglyceride lowering agent such as Ikosapento acid Echiru.
[0042] 本発明の治療剤または予防剤の製造は、通常、前記有効成分を薬学的に許容で きる液状または固体状の担体と配合することにより行われ、所望により溶剤、分散剤、 乳化剤、緩衝剤、安定剤、賦形剤、結合剤、崩壊剤、滑沢剤等を加えて、錠剤、顆 粒剤、散剤、粉末剤、カプセル剤等の固形剤、通常液剤、懸濁剤、乳剤等の液剤と することができる。また、使用前に適当な担体の添カ卩によって液状となし得る乾燥品 や、その他、外用剤とすることもできる。 [0042] The therapeutic agent or prophylactic agent of the present invention is usually produced by blending the active ingredient with a pharmaceutically acceptable liquid or solid carrier, and optionally, a solvent, a dispersant, an emulsifier, Add buffers, stabilizers, excipients, binders, disintegrants, lubricants, etc., solids such as tablets, condyles, powders, powders, capsules, etc., ordinary solutions, suspensions, emulsions And so on can do. Further, it can be made into a dry product that can be made liquid by adding a suitable carrier before use, or other external preparations.
[0043] 医薬用担体は、治療剤または予防剤の投与形態および製剤形態に応じて選択す ることができる。固体組成物からなる経口剤とする場合は、錠剤、丸剤、カプセル剤、 散剤、細粒剤、顆粒剤等とすることができ、たとえば、デンプン、乳糖、白糖、マン-ッ ト、カルボキシメチルセルロース、コーンスターチ、無機塩などの医薬用担体が利用さ れる。また経口剤の調製に当っては、更に結合剤、崩壊剤、界面活性剤、潤沢剤、 流動性促進剤、矯味剤、着色剤、香料などを配合することもできる。たとえば、錠剤ま たは丸剤とする場合は、所望によりショ糖、ゼラチン、ハイドロキシプロピルセルロース などの糖衣または胃溶性もしくは腸溶性物質のフィルムで被覆してもよ ヽ。液体組成 物からなる経口剤とする場合は、薬学的に許容される乳濁剤、溶液剤、懸濁剤、シロ ップ剤などとすることができ、たとえば、精製水、エタノールなどが担体として利用され る。また、さらに所望により湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、防腐剤 などを添カ卩してもよい。  [0043] The pharmaceutical carrier can be selected according to the administration form and formulation form of the therapeutic or prophylactic agent. In the case of an oral preparation comprising a solid composition, it can be a tablet, pill, capsule, powder, fine granule, granule, etc., for example, starch, lactose, sucrose, mant, carboxymethylcellulose Pharmaceutical carriers such as corn starch and inorganic salts are used. In preparation of the oral preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a corrigent, a colorant, a fragrance and the like can be further added. For example, in the case of tablets or pills, it may be coated with a sugar coating such as sucrose, gelatin or hydroxypropylcellulose, or a film of a gastric or enteric substance, if desired. In the case of an oral preparation comprising a liquid composition, it can be a pharmaceutically acceptable emulsion, solution, suspension, syrup, etc., for example, purified water, ethanol or the like as a carrier. Used. Further, if desired, auxiliary agents such as wetting agents and suspending agents, sweetening agents, flavoring agents, preservatives and the like may be added.
[0044] 一方、非経口剤とする場合は、常法に従い本発明の前記有効成分を希釈剤として の注射用蒸留水、生理食塩水、ブドウ糖水溶液、注射用植物油、ゴマ油、落花生油 、大豆油、トウモロコシ油、プロピレングリコール、ポリエチレングリコールなどに溶解 ないし懸濁させ、必要に応じ、殺菌剤、安定剤、等張化剤、無痛化剤などを加えるこ とにより調製することができる。また、固体組成物を製造し、使用前に無菌水または無 菌の注射用溶媒に溶解して使用することもできる。  [0044] On the other hand, in the case of a parenteral preparation, distilled water for injection, physiological saline, aqueous dextrose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, and the active ingredient of the present invention as a diluent according to a conventional method It can be prepared by dissolving or suspending in corn oil, propylene glycol, polyethylene glycol or the like, and adding a bactericidal agent, stabilizer, tonicity agent, soothing agent, etc., if necessary. In addition, a solid composition can be produced and used by dissolving in sterile water or a sterilized solvent for injection before use.
[0045] 外用剤としては、経皮投与用または経粘膜（口腔内、鼻腔内)投与用の、固体、半 固体状または液状の製剤が含まれる。また、座剤なども含まれる。たとえば、乳剤、口 ーシヨン剤などの乳濁剤、外用チンキ剤、経粘膜投与用液剤などの液状製剤、油性 軟膏、親水性軟膏などの軟膏剤、フィルム剤、テープ剤、ノップ剤などの経皮投与用 または経粘膜投与用の貼付剤などとすることができる。  [0045] The external preparation includes solid, semi-solid or liquid preparations for transdermal administration or transmucosal (intraoral or intranasal) administration. Also included are suppositories and the like. For example, emulsions such as emulsions and mouth preparations, external tinctures, liquid preparations such as liquids for transmucosal administration, ointments such as oil-based ointments and hydrophilic ointments, transdermal such as film agents, tapes, and nops. It can be a patch for administration or transmucosal administration.
[0046] 上記のような各種製剤形態での治療剤又は予防剤は、それぞれ公知の医薬用担 体などを利用して、適宜、常法により製造することができる。また、かかる治療剤また は予防剤における有効成分の含有量は、その投与形態、投与方法などを考慮し、好 ましくは後述の投与量範囲で当該有効成分を投与できるような量であれば特に限定 されるものではない。本発明の医薬中の有効成分の含有量としては通常 1〜： LOO重 量％程度である。 [0046] The therapeutic agent or prophylactic agent in the above-described various preparation forms can be appropriately produced by a conventional method using a known pharmaceutical carrier or the like. In addition, the content of the active ingredient in such a therapeutic agent or prophylactic agent is preferably determined in consideration of its administration form and administration method. It is not particularly limited as long as the active ingredient can be administered within the dosage range described below. The content of the active ingredient in the medicament of the present invention is usually about 1 to: LOO weight%.
[0047] 本発明の治療剤又は予防剤は、製剤形態に応じた適当な投与方法で投与される。  [0047] The therapeutic agent or prophylactic agent of the present invention is administered by an appropriate administration method according to the preparation form.
投与方法も特に限定はなぐ例えば内用、外用および注射により投与することができ る。本発明の治療剤又は予防剤を注射により投与する場合は、たとえば静脈内、筋 肉内、皮下、皮内などに投与し得、外用により投与する場合は、たとえば、座剤等の 外用剤として、その適する投与方法により投与すればよい。  The administration method is not particularly limited, and can be administered by, for example, internal use, external use or injection. When the therapeutic agent or prophylactic agent of the present invention is administered by injection, it can be administered, for example, intravenously, intramuscularly, subcutaneously, intradermally, and when administered externally, for example, as an external preparation such as a suppository. And may be administered by the appropriate administration method.
[0048] 本発明の治療剤または予防剤の投与量は、その製剤形態、投与方法、使用目的 および当該治療剤または予防剤の投与対象である患者の年齢、体重、症状によって 適宜設定され一定ではない。一般には、製剤中に含有される前記有効成分の投与 量で、例えば有効成分として本発明の処理物を使用する場合、成人 1日当り好ましく は 0. 1 μ g〜10gZkg体重、より好ましくは 1 μ g〜5gZkg体重、さらに好ましくは 10 μ g〜lgZkg体重であり、また有効成分として 3，—ァセトキシ— 4，—セネシオイルォ キシ— 3' , 4'—ジハイドロセセリン、その誘導体及び/又は薬学的に許容されるそ れらの塩を使用する場合、成人 1日当り好ましくは 0. 1 μ g〜5gZkg体重、より好まし くは 1 μ g〜2gZkg体重、さらに好ましくは g〜： LgZkg体重である。もちろん投 与量は、種々の条件によって変動するので、上記投与量より少ない量で十分な場合 もあるし、あるいは範囲を超えて必要な場合もある。投与は、所望の投与量範囲内に おいて、 1日内において単回で、または数回に分けて行ってもよい。投与期間も任意 である。また、本発明の治療剤または予防剤はそのまま経口投与するほか、任意の 食品に添加して日常的に摂取させることもできる。  [0048] The dosage of the therapeutic agent or prophylactic agent of the present invention is appropriately set according to the formulation form, administration method, purpose of use and the age, weight, and symptoms of the patient to whom the therapeutic agent or prophylactic agent is administered, and is constant. Absent. In general, the dosage of the active ingredient contained in the preparation, for example, when the processed product of the present invention is used as an active ingredient, preferably 0.1 μg to 10 gZkg body weight per day for an adult, more preferably 1 μm. g to 5 gZkg body weight, more preferably 10 μg to lgZkg body weight, and 3, -acetoxy-4, -senesioyloxy-3 ′, 4′-dihydroserine, its derivatives and / or pharmaceuticals as active ingredients When using those salts acceptable in adults, preferably adults per day are 0.1 μg to 5 gZkg body weight, more preferably 1 μg to 2 gZkg body weight, more preferably g to: LgZkg body weight . Of course, since the dosage varies depending on various conditions, an amount smaller than the above-mentioned dose may be sufficient or may be necessary beyond the range. Administration may be carried out once or divided into several times within a desired dose range within a day. The administration period is also arbitrary. Further, the therapeutic agent or prophylactic agent of the present invention can be administered orally as it is, or can be added daily to any food.
[0049] また、本発明は前記有効成分を含む細胞の抗泡沫化剤を提供する。当該抗泡沫 ィ匕剤としては、前記有効成分そのものであってもよぐまた、前記有効成分を含む組 成物であってもよい。当該抗泡沫化剤は、たとえば、前記有効成分を当該有効成分 と同じ用途に使用可能な他の成分、例えば公知の動脈硬化症の治療または予防作 用を有する成分、例えばプラノ スタチン、シンパスタチン、フルパスタチン、セリバスタ チン、アトルバスタチン等のスタチン系の化合物等の HMG— CoAレダクターゼ阻害 剤、フコィダン等の細胞の抗泡沫化剤、メリナミド等の ACAT阻害剤、コレステロール エステル転送タンパク質 (CETP)抑制剤、コレステロール吸収阻害剤、スクアレン合 成酵素阻害剤、 LDL酸化抑制剤、ミクロソーマルトリグリセリドトランスファータンパク（ MTP)阻害剤、アポリポタンパク質 A1産生促進剤、 ATP—バインディングカセットサ ブファミリー Al (ABCA1)誘導剤、スクアレンエポキシダーゼ阻害剤、コレスチラミン 等の胆汁酸結合榭脂、クロフイブレート等のフイブレート系、ナイァシン等のニコチン 酸系、ィコサベント酸ェチル等の中性脂肪低下剤などと配合することもできる。当該 抗泡沫化剤は、上記治療剤または予防剤の製造方法に準じて通常使用される試薬 の形態に製造することもできる。当該抗泡沫化剤における前記有効成分の含有量は 、当該抗泡沫化剤の投与方法、使用目的などを考慮し、本発明の所望の効果の発 現が得られ得るような量であればよぐ特に限定されるものではない。本発明の抗泡 沫化剤中の有効成分の含有量としては通常 1〜： LOO重量％程度である。また、当該 抗泡沫化剤の使用量も、本発明の所望の効果の発現が得られ得る量であれば特に 限定されるものではない。特に、生体に投与して使用する場合には、好ましくは前記 治療剤または予防剤における有効成分の投与量の範囲内で有効成分を投与できる ような量で使用すればよい。投与方法についても特に限定されるものではなぐ前記 治療剤または予防剤と同様に適宜設定すればよい。当該抗泡沫化剤は、前述の治 療又は予防に細胞の抗泡沫化作用を要する疾患、例えば動脈硬化症、これが原因 因子となって起こる疾患の治療または予防において有用である。また、当該抗泡沫 化剤は治療又は予防に細胞の抗泡沫化作用を要する疾患に対する薬物のスクリー ニングにも有用である。さらに当該抗泡沫化剤は、動脈硬化や各種細胞の泡沫化の メカニズム研究や、その細胞の物理的変化に関する機能研究にも有用である。また、 当該抗泡沫化剤は食品又は飲料に添加することもできる。 [0049] The present invention also provides a cell antifoaming agent comprising the active ingredient. The antifoaming agent may be the active ingredient itself or a composition containing the active ingredient. The antifoaming agent includes, for example, other components that can be used in the same application as the active ingredient, for example, components having a known therapeutic or preventive action for arteriosclerosis, such as plananostatin, sympastatin, HMG-CoA reductase inhibition of statin compounds such as flupastatin, serivastatin and atorvastatin Agents, antifoaming agents for cells such as fucoidan, ACAT inhibitors such as melinamide, cholesterol ester transfer protein (CETP) inhibitors, cholesterol absorption inhibitors, squalene synthetase inhibitors, LDL oxidation inhibitors, microsomal triglycerides Transfer protein (MTP) inhibitor, apolipoprotein A1 production promoter, ATP-binding cassette subfamily Al (ABCA1) inducer, squalene epoxidase inhibitor, cholestyramine and other bile acid-binding oils, clofibrate, etc. It can also be blended with neutral fat reducing agents such as fibrates, nicotinic acids such as niacin, and ethyl icosaventate. The antifoaming agent can also be produced in the form of a reagent that is usually used according to the method for producing the therapeutic agent or prophylactic agent. The content of the active ingredient in the antifoaming agent should be such an amount that the expression of the desired effect of the present invention can be obtained in consideration of the administration method and purpose of use of the antifoaming agent. There is no particular limitation. The content of the active ingredient in the antifoaming agent of the present invention is usually 1 to about LOO% by weight. Further, the amount of the antifoaming agent used is not particularly limited as long as the desired effect of the present invention can be obtained. In particular, when it is used after being administered to a living body, it is preferably used in such an amount that the active ingredient can be administered within the dose range of the active ingredient in the therapeutic or preventive agent. The administration method is not particularly limited, and may be appropriately set in the same manner as the therapeutic agent or prophylactic agent. The antifoaming agent is useful in the treatment or prevention of a disease requiring an antifoaming action of a cell for the above-mentioned treatment or prevention, for example, arteriosclerosis or a disease caused by this. The anti-foaming agent is also useful for screening drugs for diseases that require anti-foaming action of cells for treatment or prevention. Furthermore, the antifoaming agent is useful for studying the mechanism of arteriosclerosis and foaming of various cells, and for functional studies on physical changes of the cells. The antifoaming agent can also be added to foods or beverages.
また、本発明は前記有効成分を含む ACAT阻害剤を提供する。当該 ACAT阻害 剤としては、前記有効成分そのものであってもよぐまた、前記有効成分を含む組成 物であってもよい。当該 ACAT阻害剤は、たとえば、前記有効成分を当該有効成分 と同じ用途に使用可能な他の成分、例えば公知の高脂血症や動脈硬化症の治療ま たは予防作用を有する成分、例えばプラバスタチン、シンパスタチン、フルパスタチン 、セリバスタチン、アトルバスタチン等のスタチン系の化合物等の HMG— CoAレダク ターゼ阻害剤、フコィダン等の細胞の抗泡沫化剤、メリナミド等の ACAT阻害剤、コ レステロールエステル転送タンパク質 (CETP)抑制剤、コレステロール吸収阻害剤、 スクアレン合成酵素阻害剤、 LDL酸化抑制剤、ミクロソーマルトリグリセリドトランスフ ァータンパク（MTP)阻害剤、アポリポタンパク質 A1産生促進剤、 ATP—バインディ ングカセットサブファミリー Al (ABCA1)誘導剤、スクアレンエポキシダーゼ阻害剤、 コレスチラミン等の胆汁酸結合榭脂、クロフイブレート等のフイブレート系、ナイァシン 等のニコチン酸系、ィコサペント酸ェチル等の中性脂肪低下剤などと配合することも できる。当該 ACAT阻害剤は、上記治療剤または予防剤の製造方法に準じて通常 使用される試薬の形態に製造することもできる。当該 ACAT阻害剤における前記有 効成分の含有量は、当該 ACAT阻害剤の投与方法、使用目的などを考慮し、本発 明の所望の効果の発現が得られ得るような量であればよぐ特に限定されるものでは ない。本発明の ACAT阻害剤中の有効成分の含有量としては通常 1〜： L00重量％ 程度である。また、当該 ACAT阻害剤の使用量も、本発明の所望の効果の発現が得 られ得る量であれば特に限定されるものではない。特に、生体に投与して使用する 場合には、好ましくは前記治療剤または予防剤における有効成分の投与量の範囲 内で有効成分を投与できるような量で使用すればよい。投与方法についても特に限 定されるものではなぐ前記治療剤または予防剤と同様に適宜設定すればよい。当 該 ACAT阻害剤は、前述の治療又は予防に ACAT阻害作用を要する疾患、例えば 動脈硬化症や高脂血症、これらが原因因子となって起こる疾患の治療または予防に おいて有用である。また、当該 ACAT阻害剤は治療又は予防に ACAT阻害作用を 要する疾患に対する薬物のスクリーニングにも有用である。さらに当該 ACAT阻害剤 は、コレステロールエステル生成のメカニズム研究や、それによる高脂血症、動脈硬 化症等前述の疾患への進展に関わるメカニズム研究にも有用である。また、当該 AC AT阻害剤は食品又は飲料に添加することもできる。 The present invention also provides an ACAT inhibitor containing the active ingredient. The ACAT inhibitor may be the active ingredient itself or a composition containing the active ingredient. The ACAT inhibitor may be, for example, another component that can be used for the same purpose as the active ingredient, such as a known hyperlipidemia or arteriosclerosis treatment or prevention component, such as pravastatin. , Sympastatin, flupastatin , HMG-CoA reductase inhibitors such as statins such as cerivastatin and atorvastatin, cellular antifoaming agents such as fucoidan, ACAT inhibitors such as melinamide, cholesterol ester transfer protein (CETP) inhibitors, cholesterol absorption Inhibitor, squalene synthase inhibitor, LDL oxidation inhibitor, microsomal triglyceride transfer protein (MTP) inhibitor, apolipoprotein A1 production promoter, ATP-binding cassette subfamily Al (ABCA1) inducer, squalene epoxidase It can also be combined with inhibitors, bile acid-binding rosins such as cholestyramine, fibrates such as clofibrate, nicotinic acids such as niacin, and neutral fat lowering agents such as ethyl icosapentate. The ACAT inhibitor can also be produced in the form of a commonly used reagent in accordance with the method for producing the therapeutic agent or prophylactic agent. The content of the active ingredient in the ACAT inhibitor is not particularly limited as long as the desired effect of the present invention can be obtained in consideration of the administration method and purpose of use of the ACAT inhibitor. There is no particular limitation. The content of the active ingredient in the ACAT inhibitor of the present invention is usually 1 to about L00% by weight. Further, the amount of the ACAT inhibitor used is not particularly limited as long as the desired effect of the present invention can be obtained. In particular, when it is used after being administered to a living body, it is preferably used in such an amount that the active ingredient can be administered within the dose range of the active ingredient in the therapeutic agent or prophylactic agent. The administration method is not particularly limited, and may be appropriately set in the same manner as the therapeutic agent or prophylactic agent. The ACAT inhibitor is useful in the treatment or prevention of diseases requiring ACAT inhibitory action for the above-mentioned treatment or prevention, such as arteriosclerosis and hyperlipidemia, and diseases caused by these factors. The ACAT inhibitor is also useful for screening drugs for diseases that require ACAT inhibitory action for treatment or prevention. Furthermore, the ACAT inhibitor is also useful for studying the mechanism of cholesterol ester production and the mechanism for the development of the aforementioned diseases such as hyperlipidemia and arteriosclerosis. The ACAT inhibitor can also be added to foods or beverages.
本発明の有効成分には、後述するように特に毒性は認められない。また、副作用の 発生の心配もない。それゆえ、安全かつ適切に細胞の抗泡沫化作用及び Z又は A CAT阻害作用を生体内で発現させることができる。従って、当該有効成分を含んで なる本発明の医薬、食品または飼料は、治療又は予防に細胞の抗泡沫化作用及びThe active ingredient of the present invention is not particularly toxic as will be described later. In addition, there is no worry of side effects. Therefore, the cell antifoaming action and the Z or A CAT inhibitory action can be expressed in vivo safely and appropriately. Therefore, including the active ingredient The medicament, food or feed according to the present invention comprises an antifoaming action of cells and
Z又は ACAT阻害作用を要する疾患の治療または予防に有効である。 It is effective for the treatment or prevention of diseases requiring Z or ACAT inhibitory action.
[0052] また、本発明は、前記有効成分を含有してなる細胞の抗泡沫化用及び Z又は AC AT阻害用の食品又は飼料 (本明細書中において、本発明の食品又は飼料と称する ことがある）を提供する。本発明の食品または飼料は、細胞の抗泡沫化作用及び Z 又は ACAT阻害作用により、治療又は予防に細胞の抗泡沫化作用及び Z又は AC AT阻害作用を要する疾患、すなわち前述したような動脈硬化症、虚血性心疾患、急 性心筋梗塞、不安定狭心症、虚血性突然死、脳血管障害、慢性閉塞性動脈硬化症 、高コレステロール血症、高トリグリセライド血症、高脂血症、マルチプルリスクファクタ 一症候群の症状改善、予防に極めて有用である。すなわち、本発明の食品又は飲 料は上記の疾患の予防、改善又は治療を目的とすることを付した機能性食品 (特定 保健用食品等）として極めて有用であり、血中コレステロール値が気になる方、中性 脂肪が気になる方、体脂肪が気になる方にとって極めて有用な食品又は飲料となる [0052] Further, the present invention provides a food or feed for cell antifoaming and Z or ACAT inhibition comprising the active ingredient (in the present specification, referred to as the food or feed of the present invention). Provide). The food or feed of the present invention has a cell anti-foaming action and a Z or ACAT inhibitory action, thereby causing a disease that requires a cell anti-foaming action and a Z or ACAT inhibitory action for treatment or prevention, ie, arteriosclerosis as described above. Disease, ischemic heart disease, acute myocardial infarction, unstable angina, ischemic sudden death, cerebrovascular disorder, chronic obstructive arteriosclerosis, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, multiple Risk factor Very useful for improving and preventing symptoms of a syndrome. That is, the food or drink of the present invention is extremely useful as a functional food (specific health food, etc.) with the purpose of preventing, ameliorating or treating the above-mentioned diseases, and the blood cholesterol level is a concern. For those who are worried about neutral fat, those who are worried about body fat
[0053] 本発明の食品または飼料においては、本発明の有効成分と、高脂血症や動脈硬 化症の改善、治療または予防作用を有するその他の物質、例えば公知の高脂血症 や動脈硬化症の治療または予防作用を有する成分、例えばプラバスタチン、シンパ スタチン、フルパスタチン、セリバスタチン、アトルバスタチン等のスタチン系の化合物 等の HMG— CoAレダクターゼ阻害剤、フコィダン等の細胞の抗泡沫化剤、メリナミド 等の ACAT阻害剤、コレステロールエステル転送タンパク質 (CETP)抑制剤、コレス テロール吸収阻害剤、スクアレン合成酵素阻害剤、 LDL酸化抑制剤、ミクロソーマル トリグリセリドトランスファータンパク（MTP)阻害剤、アポリポタンパク質 A1産生促進 剤、 ATP—バインディングカセットサブファミリー Al (ABCA1)誘導剤、スクアレンェ ポキシダーゼ阻害剤、コレスチラミン等の胆汁酸結合榭脂、クロフイブレート等のフィ プレート系、ナイァシン等のニコチン酸系、ィコサペント酸ェチル等の中性脂肪低下 剤などと配合することで、より効果の高い食品又は飼料を製造することもできる。また 、既知の健康食品素材、例えば、ァシタパやその加工物、ペプチド、ダルコマンナン 、キトサン、植物ステロールエステル、 EPA、 DHA等と配合することもできる。 [0054] なお、本発明の食品または飼料にぉ 、て「含有」とは、含有、添加および/または 希釈を意味する。ここで、「含有」とは食品または飼料中に本発明で使用される有効 成分が含まれるという態様を、「添加」とは食品または飼料の原料に、本発明で使用 される有効成分を添加するという態様を、「希釈」とは本発明で使用される有効成分 に、食品または飼料の原料を添加すると 、う態様を 、うものである。 [0053] In the food or feed of the present invention, the active ingredient of the present invention and other substances having an action for improving, treating or preventing hyperlipidemia and arteriosclerosis, such as known hyperlipidemia and arteries. Ingredients having therapeutic or prophylactic effects on sclerosis, for example, HMG-CoA reductase inhibitors such as pravastatin, sympastatin, flupastatin, cerivastatin, atorvastatin and the like, and antifoaming agents for cells such as fucoidan, melinamide ACAT inhibitor, cholesterol ester transfer protein (CETP) inhibitor, cholesterol absorption inhibitor, squalene synthase inhibitor, LDL oxidation inhibitor, microsomal triglyceride transfer protein (MTP) inhibitor, apolipoprotein A1 production promoter, ATP—binding cassette subfamily Al (ABCA1) inducer, square More effective by combining with Renepoxidase inhibitors, bile acid-binding rosins such as cholestyramine, fiplates such as clofibrate, nicotinic acids such as niacin, and neutral fat lowering agents such as icosapentate. High food or feed can also be produced. It can also be blended with known health food materials such as ashitapa and processed products thereof, peptides, dalcomannan, chitosan, plant sterol esters, EPA, DHA and the like. [0054] The term "containing" in the food or feed of the present invention means inclusion, addition and / or dilution. Here, “containing” means that the active ingredient used in the present invention is contained in food or feed, and “addition” means that the active ingredient used in the present invention is added to the raw material of food or feed. In other words, “dilution” refers to a mode in which a raw material for food or feed is added to the active ingredient used in the present invention.
[0055] 本発明の食品または飼料の製造法に特に限定はな 、。たとえば、配合、調理、加 ェなどは一般の食品または飼料のものに従えばよぐそれらの製造法により製造する ことができ、得られた食品または飼料に細胞の抗泡沫ィ匕作用及び Z又は ACAT阻 害作用を有する本発明に係る前記有効成分が含有されて!ヽれば良 ヽ。  [0055] The method for producing the food or feed of the present invention is not particularly limited. For example, compounding, cooking, cooking, etc. can be produced by their production method according to general foods or feeds, and the resulting foods or feeds can have anti-foaming action of cells and Z or It would be good if the active ingredient according to the present invention having ACAT inhibitory action was contained!
[0056] 本発明の食品としては特に限定はないが、たとえば、本発明に係る前記有効成分 が含有されてなる、穀物加工品（小麦粉加工品、デンプン類加工品、プレミックスカロ ェ品、麵類、マカロ-類、パン類、あん類、そば類、麩、ビーフン、はるさめ、包装餅 など）、油脂加工品（可塑性油脂、てんぷら油、サラダ油、マヨネーズ類、ドレッシング など）、大豆加工品（豆腐類、味噌、納豆など）、食肉加工品（ハム、ベーコン、プレス ハム、ソーセージなど）、水産製品（冷凍すりみ、力まぼこ、ちくわ、はんぺん、さつま 揚げ、つみれ、すじ、魚肉ハム、ソーセージ、かつお節、魚卵加工品、水産缶詰、つ くだ煮など）、乳製品 (原料乳、クリーム、ヨーグルト、バター、チーズ、練乳、粉乳、ァ イスクリームなど）、野菜'果実加工品 (ペースト類、ジャム類、漬け物類、果実飲料、 野菜飲料、ミックス飲料など)、菓子類 (チョコレート、ビスケット類、菓子パン類、ケー キ、餅菓子、米菓類など）、アルコール飲料（日本酒、中国酒、ワイン、ウィスキー、焼 酎、ウォッカ、ブランデー、ジン、ラム酒、ビール、清涼アルコール飲料、果実酒、リキ ユールなど)、嗜好飲料 (緑茶、紅茶、ウーロン茶、コーヒー、清涼飲料、乳酸飲料な ど）、調味料 (しょうゆ、ソース、酢、みりんなど）、缶詰 '瓶詰め'袋詰め食品（牛飯、釜 飯、赤飯、カレー、その他の各種調理済み食品）、半乾燥または濃縮食品（レバーべ 一スト、その他のスプレッド、そば'うどんの汁、濃縮スープ類)、乾燥食品（即席麵類 、即席カレー、インスタントコーヒー、粉末ジュース、粉末スープ、即席味噌汁、調理 済み食品、調理済み飲料、調理済みスープなど)、冷凍食品 (すき焼き、茶碗蒸し、う なぎかば焼き、ハンバーグステーキ、シユウマイ、餃子、各種スティック、フルーツカク テルなど）、固形食品、液体食品 (スープなど）、香辛料類などの農産 ·林産加工品、 畜産加工品、水産加工品などが挙げられる。なお、本願明細書において、食品とは 飲料をも包含するものである。 [0056] The food of the present invention is not particularly limited. For example, a processed cereal product (processed flour product, processed starch product, premixed caloche product, rice cake, etc.) containing the active ingredient according to the present invention. , Macaro-, Bread, Anzu, Buckwheat, Rice cake, Rice noodles, Harusame, Packaging rice cake, etc.), Oil and fat processed products (Plastic oil, Tempura oil, Salad oil, Mayonnaise, Dressing, etc.), Processed soybean products (Tofu , Bean paste, natto, etc.), processed meat products (ham, bacon, pressed ham, sausage, etc.), marine products (frozen groundnut, power boiled rice cake, chikuwa, hanpen, fried fish, tsumire, streaks, fish ham, sausage Bonito, dried bonito, processed fish eggs, canned fish, boiled tsukudani, etc.), dairy products (raw milk, cream, yogurt, butter, cheese, condensed milk, powdered milk, ice cream, etc.), vegetable 'fruit processing Products (pastes, jams, pickles, fruit drinks, vegetable drinks, mixed drinks, etc.), confectionery (chocolate, biscuits, confectionery breads, cakes, rice cakes, rice confectionery, etc.), alcoholic drinks (Japanese sake, China) Liquor, wine, whiskey, shochu, vodka, brandy, gin, rum, beer, soft alcoholic beverage, fruit liquor, liquor, etc.) ), Seasonings (soy sauce, sauce, vinegar, mirin, etc.), canned 'bottled' bagged food (beef rice, kettle rice, red rice, curry, other cooked foods), semi-dried or concentrated food (lever Strikes, other spreads, buckwheat noodle soup, concentrated soups), dried foods (instant potatoes, instant curry, instant coffee, powdered juice, powdered soup, instant Miso soup, cooked food, cooked beverages, such as ready-to-eat soup), frozen food (sukiyaki, egg custard, cormorants calm grilled eel, hamburger steak, Shiyuumai, dumplings, various sticks, fruit Kaku Tel, etc.), solid foods, liquid foods (soups, etc.), spices and other agricultural / forest products, processed livestock products, processed fish products, etc. In the specification of the present application, food includes drinks.
[0057] 本発明の食品は、前記有効成分が単独もしくは複数含有、添加および Zまたは希 釈されており、その含有量が細胞の抗泡沫化作用及び Z又は ACAT阻害作用を発 現するための必要量に相当するものであれば特にその形状に限定はなぐ粉末状、 タブレット状、顆粒状、カプセル状等の経口的に摂取可能な形状物も包含する。また 、本発明の食品としては、ボタンボウフゥの処理物をそのまま、もしくは適当な乳化剤 や賦形剤等と適宜混合したものも包含される。これらの食品はそのまま、もしくは水と 混合して飲料として食することができる。 [0057] In the food of the present invention, the active ingredient is contained alone or in plural, added and Z or diluted, and the content thereof exhibits an anti-foaming action of cells and a Z or ACAT inhibitory action. If it corresponds to the required amount, the shape is not particularly limited, and includes powders, tablets, granules, capsules and the like that can be taken orally. In addition, the food of the present invention includes a processed product of button bow as it is or mixed appropriately with an appropriate emulsifier or excipient. These foods can be eaten as drinks as they are or mixed with water.
[0058] また、本発明の食品については、本発明の有効成分と、本発明に使用される植物 以外の植物 (野菜や果実等)の搾汁液と混合もしくは本発明に使用される植物と同時 に搾汁して健康飲料とすることもできる。例えば、本発明に使用される各種植物の搾 汁液を水で希釈したり、ァシタパ、パセリ、セロリ、甘草、ニンジン、小松菜、カブ、チ ンゲンサイ、トマト、ミカン、レモン、グレープフルーツ、キウイ、ほうれん草、ラディッシ ュ、大根、白菜、キャベツ、サラダ菜、レタス、ユラ、オクラ、ピーマン、キユウリ、インゲ ン、えだまめ、エンドゥ、トウモロコシ、ニン-ク、ルツコラ、ビヮ、夏みかん、甘夏等の 搾汁液や、牛乳、豆乳等と混合して細胞の抗泡沫化作用及び Z又は ACAT阻害作 用を有する健康飲料とすることができる。  [0058] Further, for the food of the present invention, the active ingredient of the present invention is mixed with the juice of a plant other than the plant used in the present invention (vegetables, fruits, etc.) or simultaneously with the plant used in the present invention. It can be squeezed into a health drink. For example, the juices of various plants used in the present invention are diluted with water, or assipida, parsley, celery, licorice, carrot, komatsuna, turnip, tomato, tangerine, lemon, grapefruit, kiwi, spinach, radish. Nuts, radish, Chinese cabbage, cabbage, salad vegetables, lettuce, yura, okra, peppers, cucumbers, green beans, edamame, endou, corn, garlic, rutcola, rice cake, summer oranges, sweet summer, milk, It can be mixed with soy milk to make a health drink with cell antifoaming action and Z or ACAT inhibitory action.
[0059] 本発明の食品中の前記有効成分の含有量は特に限定されず、その官能と活性発 現の観点力 適宜選択できるが、例えば本発明の処理物を有効成分とする場合、食 品中、好ましくは 0. 1重量％以上、より好ましくは 0. 5〜95重量％、更に好適には 1 〜90重量％である。また、有効成分として 3，—ァセトキシ— 4，—セネシオイルォキシ — 3' , 4'—ジハイドロセセリン、その誘導体及び/又は薬学的に許容されるそれら の塩を使用する場合、食品中、好ましくは 0. 00001重量％以上、より好ましくは 0. 0 001〜10重量0 /0、更【こ好適【こ ίま 0. 0006〜6重量0 /0である。 [0059] The content of the active ingredient in the food of the present invention is not particularly limited, and can be selected as appropriate in terms of its functionality and activity expression. For example, when the processed product of the present invention is used as an active ingredient, food Among them, the content is preferably 0.1% by weight or more, more preferably 0.5 to 95% by weight, and further preferably 1 to 90% by weight. In addition, when 3, -acetooxy-4, -senesioxyloxy-3 ', 4'-dihydroserine, its derivatives and / or pharmaceutically acceptable salts thereof are used as active ingredients, , preferably 0.00001% by weight or more, more preferably 0.0 001 to 10 weight 0/0, further [this preferred [this ί or 0.0006 to 6 wt 0/0.
[0060] また本発明の食品は、例えば有効成分として本発明の処理物を使用する場合、そ れらに含有される有効成分が成人 1日当り好ましくは 0. 1 μ g〜10gZkg体重、より 好ましくは 1 μ g〜5gZkg体重、さらに好ましくは 10 g〜2gZkg体重であり、また 有効成分として 3，ーァセトキシー4， 一セネシオイルォキシ 3，， 4，ージハイドロセセ リン、その誘導体及び Z又は薬学的に許容されるそれらの塩を使用する場合、成人 1日当り好ましくは 0. 1 μ g〜5gZkg体重、より好ましくは 1 μ g〜2gZkg体重、さら に好ましくは 10 g〜 lgZkg体重となるように摂取すればょ 、。 [0060] Further, in the food of the present invention, for example, when the processed product of the present invention is used as an active ingredient, the active ingredient contained therein is preferably 0.1 μg to 10 gZkg body weight per day for an adult. Preferably it is 1 μg to 5 gZkg body weight, more preferably 10 g to 2 gZkg body weight, and the active ingredient is 3, -acetooxy-4, mono-senesioxyloxy 3,4, -dihydroceserin, its derivatives and Z or pharmaceutically When using those acceptable salts, adults should preferably take 0.1 μg to 5 gZkg body weight, more preferably 1 μg to 2 gZkg body weight, more preferably 10 g to lgZkg body weight per day. Yeah.
[0061] また、本発明は、前記有効成分を含有、すなわち、含有、添加および Zまたは希釈 してなる、細胞の抗泡沫ィ匕作用及び Z又は ACAT阻害作用を有する生物用の飼料 を提供するものであり、さらに、別の一態様として、前記有効成分を生物に投与するこ とを特徴とする生物の飼育方法をも提供する。また、本発明の別の一態様として、前 記有効成分を含有することを特徴とする生物飼育用剤が提供される。  [0061] Further, the present invention provides a biological feed having an anti-foaming action of cells and an action of inhibiting Z or ACAT, comprising the above-mentioned active ingredient, that is, containing, adding and Z or diluting. Furthermore, as another aspect, there is also provided a method for breeding an organism characterized by administering the active ingredient to the organism. Moreover, as another aspect of the present invention, there is provided a biological breeding agent comprising the above-mentioned active ingredient.
[0062] 本明細書において、生物としては、限定はないが、たとえば養殖動物、ペット動物 などが挙げられる。養殖動物としてはゥマ、ゥシ、ブタ、ヒッジ、ャギ、ラタダ、ラマなど の家畜、マウス、ラット、モルモット、ゥサギなどの実験動物、 -ヮトリ、ァヒル、七面鳥、 駝鳥などの家禽、魚類、甲殻類または貝類が例示される。ペット動物としてはィヌ、ネ コなどが例示される。飼料としては体調の維持および Zまたは改善用飼料が例示さ れる。生物飼育用剤としては浸漬用剤、飼料添加剤、飲料用添加剤が例示される。  [0062] In the present specification, the organism is not limited, and examples thereof include farm animals and pet animals. As farmed animals, livestock such as horses, rushes, pigs, hidges, goats, ratadas, llamas, laboratory animals such as mice, rats, guinea pigs, magpies, etc. Examples include crustaceans or shellfish. Examples of pet animals include Inu and cats. Examples of feed include feed for maintenance and Z or improvement. Examples of biological breeding agents include soaking agents, feed additives, and beverage additives.
[0063] これらの発明によれば、それらを適用する前記例示するような生物において、本発 明に使用される前記有効成分の細胞の抗泡沫化作用及び Z又は ACAT阻害作用 に基づき、本発明の前記治療剤または予防剤によるのと同様の効果の発現が期待 できる。すなわち、本発明の飼料は、当該生物における治療又は予防に細胞の抗泡 沫化作用及び Z又は ACAT阻害作用を要する疾患、例えば動脈硬化症や高脂血 症、これらが原因因子となって起こる疾患の治療または予防効果を発揮し得る。  [0063] According to these inventions, the present invention is based on the antifoaming action and Z or ACAT inhibitory action of the cells of the active ingredient used in the present invention in the above-described organisms to which they are applied. It is expected that the same effects as those of the therapeutic agent or preventive agent will be exhibited. That is, the feed of the present invention is caused by a disease that requires an antifoaming action of cells and a Z or ACAT inhibitory action for treatment or prevention in the organism, such as arteriosclerosis and hyperlipidemia, which are caused by these factors. It can exert a therapeutic or preventive effect on the disease.
[0064] 本発明に使用される前記有効成分は通常、例えば有効成分として本発明の処理 物を使用する場合、それらに含有される有効成分が対象生物 1日当り好ましくは 0. 1 β g〜10gZkg体重、より好ましくは 1 μ g〜5gZkg体重、さらに好ましくは 10 g〜 2gZkg体重であり、また有効成分として 3'—ァセトキシ—4' セネシオイルォキシ - 3' , 4'—ジハイドロセセリン、その誘導体及び/又は薬学的に許容されるそれら の塩を使用する場合、対象生物 1日当り好ましくは 0. 1 μ g〜5gZkg体重、より好ま しくは 1 μ g〜2gZkg体重、さらに好ましくは g〜： LgZkg体重となるように投与さ れる。投与は、たとえば、当該有効成分を、対象生物に供する人工配合飼料の原料 中に添加混合しておくか、人工配合飼料の粉末原料と混合した後、その他の原料に さらに添加混合することで行うことができる。また、前記有効成分の飼料中の含有量 は特に限定されるものではなぐ目的に応じて適宜設定すれば良いが、例えば本発 明の処理物を有効成分とする場合、飼料中、好ましくは 0. 1重量％以上、より好まし くは 0. 5〜95重量％、更に好適には 1〜90重量％である。また、有効成分として 3' ーァセトキシー 4， 一セネシオイルォキシ 3，， 4，ージハイドロセセリン、その誘導体 及び Z又は薬学的に許容されるそれらの塩を使用する場合、飼料中、好ましくは 0. 00001重量0 /0以上、より好まし <ίま 0. 0001〜10重量0 /0、更【こ好適【こ ίま 0. 0006〜 6重量％である。生物飼育用剤における本発明の有効成分の含有量も同程度とすれ ばよい。 [0064] The active ingredient used in the present invention is usually, for example, when the processed product of the present invention is used as an active ingredient, the active ingredient contained therein is preferably 0.1 β g to 10 g Zkg per day of the target organism. Body weight, more preferably 1 μg to 5 gZkg body weight, still more preferably 10 g to 2 gZkg body weight, and 3′-acetoxy-4 ′ senecioyloxy-3 ′, 4′-dihydroserine as an active ingredient, When using the derivatives and / or pharmaceutically acceptable salts thereof, the target organism is preferably 0.1 μg to 5 g Zkg body weight, more preferably per day. Or 1 μg to 2 gZkg body weight, more preferably g to LgZkg body weight. The administration is performed, for example, by adding and mixing the active ingredient in the raw material of the artificially mixed feed to be provided to the target organism, or by mixing it with the powdered raw material of the artificially mixed feed and further adding and mixing it with the other raw materials. be able to. The content of the active ingredient in the feed is not particularly limited, and may be set as appropriate according to the purpose. For example, when the processed product of the present invention is used as an active ingredient, it is preferably 0 in the feed. 1% by weight or more, preferably 0.5 to 95% by weight, more preferably 1 to 90% by weight. In addition, when 3'-acetooxy-4, mono-senecyoxy3, 4, -dihydroserine, its derivatives and Z or pharmaceutically acceptable salts thereof are used as active ingredients, preferably in feed 0.00001 weight 0/0 or more, and more preferably <I or 0.0001 to 10 weight 0/0, further [this preferred [this I or 0.0006 to 6 wt%. The content of the active ingredient of the present invention in the biological breeding agent may be about the same.
[0065] 本発明の飼料の製造法に特に限定はなぐまた配合も一般の飼料に準ずるもので あればよぐ製造された飼料中に細胞の抗泡沫化作用及び Ζ又は ACAT阻害作用 を有する本発明に係る前記有効成分が含まれて ヽればよ ヽ。生物飼育用剤も同様 にして調製することができる。  [0065] The method for producing the feed of the present invention is not particularly limited, and if the formulation is similar to that of a general feed, the presently produced feed has a cell antifoaming action and a sputum or ACAT inhibitory action. It suffices if the active ingredient according to the invention is included. A biological rearing agent can be prepared in the same manner.
[0066] 本発明にお 、ては、例えば、細胞の抗泡沫化作用及び Ζ又は ACAT阻害作用を 有する本発明に使用される前記有効成分を含んでなる飼料を摂取させたり、または 細胞の抗泡沫化作用を有する本発明に使用される前記有効成分の含有液 (例えば 、前記浸漬剤を水に溶解させたもの）に対象生物を浸漬したりすることにより、家畜、 実験動物、家禽、ペット動物などの体調を良好に維持し、または、改善させたりするこ とができる。なお、これらの態様は本発明における生物の飼育方法の一態様である。  [0066] In the present invention, for example, a feed comprising the active ingredient used in the present invention having an antifoaming effect on cells and a wrinkle or ACAT inhibitory effect, or a cell anti-foaming effect is used. By immersing the target organism in a liquid containing the active ingredient used in the present invention having a foaming action (for example, a solution obtained by dissolving the immersion agent in water), livestock, laboratory animals, poultry, pets It is possible to maintain or improve the physical condition of animals and the like. In addition, these aspects are one aspect | mode of the biological breeding method in this invention.
[0067] 本発明はまた、被験体に、前記有効成分を投与することを含む、治療又は予防に ぉ 、て細胞の抗泡沫化作用及び Ζ又は ACAT阻害作用を要する疾患の治療方法 又は予防方法を提供する。  [0067] The present invention also includes a method for treating or preventing a disease requiring an anti-foaming action of cells and an anther or ACAT inhibitory action for treatment or prevention, comprising administering the active ingredient to a subject. I will provide a.
[0068] 本明細書中において被験体とは、好ましくは細胞の抗泡沫化作用及び Z又は AC AT阻害作用を必要とするヒトである力 上記のような養殖動物、ペット動物等であつ てもよい。 [0069] また、本明細書中において有効量とは、前記有効成分を上記被験体に投与した場 合に、該有効成分を投与していない被験体と比較して、細胞の抗泡沫化作用及び Z 又は ACAT阻害作用を発揮する該成分の量である。具体的な有効量としては、投与 形態、投与方法、使用目的および被験体の年齢、体重、症状等によって適宜設定さ れ一定ではないが、好ましくは、上記の医薬と同様に、例えば有効成分として本発明 の処理物を使用する場合、それらに含有される有効成分がヒト（例えば成人） 1日当り 好ましくは 0. 1 μ g〜10gZkg体重、より好ましくは 1 μ g〜5gZkg体重、さらに好ま しくは 10 g〜2gZkg体重であり、また有効成分として 3，—ァセトキシ— 4，—セネシ オイルォキシ—3' , 4'—ジノヽイドロセセリン、その誘導体及び/又は薬学的に許容 されるそれらの塩を使用する場合、ヒト（例えば成人） 1日当り好ましくは 0. 1 μ g〜5g Zkg体重、より好ましくは 1 μ g〜2gZkg体重、さらに好ましくは g〜： LgZkg体 重となるように投与される。 [0068] In the present specification, the subject is preferably a human being who requires a cell antifoaming action and a Z or ACAT inhibitory action, such as a cultured animal or a pet animal as described above. Good. [0069] Further, in the present specification, the effective amount means that when the active ingredient is administered to the subject, the antifoaming action of the cells compared to the subject not administered the active ingredient. And the amount of the component exhibiting Z or ACAT inhibitory action. The specific effective amount is appropriately set according to the administration form, administration method, purpose of use and age, weight, symptom, etc. of the subject. When the processed product of the present invention is used, the active ingredient contained therein is preferably 0.1 μg to 10 gZkg body weight, more preferably 1 μg to 5 gZkg body weight, more preferably human (eg, adult) per day. 10g ~ 2gZkg body weight and using 3, -acetoxy-4, -seneci oiloxy-3 ', 4'-dinoidoidoserine, its derivatives and / or pharmaceutically acceptable salts as active ingredients In this case, human (for example, an adult) is preferably administered at a dose of 0.1 μg to 5 g Zkg body weight, more preferably 1 μg to 2 g Zkg body weight, still more preferably g to LgZkg body weight per day.
[0070] 本発明の治療又は予防にお!、て細胞の抗泡沫ィ匕作用及び Z又は ACAT阻害作 用を要する疾患の治療方法又は予防方法にぉ 、ては、有効量の前記有効成分をそ のまま上記被験体に投与してもよぐまた、上記のような医薬、食品、又は飼料として 投与してもよい。また、投与方法にも限定はなぐ例えば、上記の医薬と同様に、経口 投与や注射等により投与すればよい。  [0070] In the treatment or prevention of the present invention, an effective amount of the active ingredient is added to the method for treating or preventing a disease requiring an antifoaming action and Z or ACAT inhibitory action of cells. It may be administered to the subject as it is, or may be administered as a pharmaceutical, food, or feed as described above. Further, there is no limitation on the administration method. For example, it may be administered by oral administration, injection or the like, as in the case of the above-mentioned medicine.
[0071] 本発明の治療方法又は予防方法によれば、前記の本発明の医薬、食品又は飼料 の対象となる疾患を治療又は予防することができ、例えば、動脈硬化症や高脂血症 、これらが原因因子となって起こる疾患の治療や予防を行う効果が発揮され得る。  [0071] According to the treatment method or the prevention method of the present invention, the target disease of the medicament, food or feed of the present invention can be treated or prevented, for example, arteriosclerosis or hyperlipidemia, An effect of treating or preventing a disease caused by these as causative factors can be exhibited.
[0072] 本発明で使用される前記有効成分は、その作用発現にとっての有効量の投与を生 体に行っても毒性は認められない。たとえば経口投与の場合、ボタンボウフゥのエタ ノール抽出物、 3，—ァセトキシ— 4，—セネシオイルォキシ—3，， 4，—ジハイドロセセ リンをそれぞれ lgZkg体重でマウスに単回投与しても死亡例は認められない。また、 前記有効成分は、ラットへの経口投与にぉ 、て lgZkg体重を経口単回投与しても 死亡例は認められない。  [0072] The active ingredient used in the present invention does not show toxicity even if the living body is administered in an effective amount for expression of the action. For example, in the case of oral administration, even if a single dose of buttonbofu ethanol extract, 3, -acetoxy-4, -senesioyloxy-3,4, -dihydroceserin at lgZkg body weight is given to mice, unacceptable. In addition, after the oral administration to rats, no mortality was observed even if the lgZkg body weight was administered orally once.
実施例  Example
[0073] 以下、実施例を挙げて、本発明を更に具体的に説明するが、本発明はこれらの記 載に何ら限定されるものではな 、。なお、実施例における％は特に記載がなければ すべて容量％を意味する。 [0073] Hereinafter, the present invention will be described more specifically with reference to examples. It is not limited to what is listed. In the examples, “%” means “volume%” unless otherwise specified.
[0074] 調製例 1 ボタンボウフゥ茎エタノール抽出画分およびボタンボウフゥ茎 70%ェタノ ール抽出画分の調製  [0074] Preparation Example 1 Preparation of ethanol extract of button bow stalk and 70% ethanol extract of button bow stalk
ボタンボウフゥ茎部の凍結乾燥物を粉砕したもの 2gに、 40mLのエタノールまたは 70%エタノールをカ卩え、 30分間室温で抽出を行い、遠心分離にて抽出液と残渣に 分けた。次いで、残渣に対して同溶媒 30mLによる抽出操作を 2回繰り返した。得ら れた抽出液を集めてロータリーエバポレーターで濃縮した。最終的にエタノール抽出 画分については lmLのジメチルスルホキシドに、 70%エタノール抽出画分について は 2mLのジメチルスルホキシドに溶解し、ボタンボウフゥ茎エタノール抽出画分およ びボタンボウフゥ茎 70%エタノール抽出画分を得た。  40 g of ethanol or 70% ethanol was added to 2 g of the pulverized lyophilized product of button bow stalk, extracted at room temperature for 30 minutes, and separated into an extract and a residue by centrifugation. Next, extraction with 30 mL of the same solvent was repeated twice on the residue. The obtained extracts were collected and concentrated by a rotary evaporator. Finally, the ethanol-extracted fraction was dissolved in 1 mL of dimethyl sulfoxide, and the 70% ethanol-extracted fraction was dissolved in 2 mL of dimethyl sulfoxide to obtain a button-bow-fu stem ethanol extract fraction and a button-bow-fu stem 70% ethanol-extracted fraction. It was.
[0075] 調製例 2 ボタンボウフゥ根エタノール抽出画分の調製  [0075] Preparation Example 2 Preparation of ethanol extract from button-bow-fu root
ボタンボウフゥ根部の凍結乾燥物を粉砕したもの 2gに、 40mLのエタノールをカロえ 、 30分間室温で抽出を行い、遠心分離にて抽出液と残渣に分けた。次いで、残渣に 対して同溶媒 30mL〖こよる抽出操作を 2回繰り返した。得られた抽出液を集めてロー タリーエバポレーターで濃縮した。最終的に lmLのジメチルスルホキシドに溶解し、 ボタンボウフゥ根エタノール抽出画分を得た。  40 g of ethanol was added to 2 g of the pulverized lyophilized product of button bow root, extracted at room temperature for 30 minutes, and separated into an extract and a residue by centrifugation. Next, extraction with 30 mL of the same solvent was repeated twice for the residue. The obtained extract was collected and concentrated with a rotary evaporator. Finally, it was dissolved in 1 mL of dimethyl sulfoxide to obtain a button-bow-fu root ethanol extract fraction.
[0076] 調製例 3 ボタンボウフゥ葉エタノール抽出画分の調製  [0076] Preparation Example 3 Preparation of ethanol fraction extracted from button bow-fu leaves
ボタンボウフゥ葉部の凍結乾燥物を粉砕したもの 2gに、 40mLのエタノールをカロえ 、 30分間室温で抽出を行い、遠心分離にて抽出液と残渣に分けた。次いで、残渣に 対して同溶媒 30mL〖こよる抽出操作を 2回繰り返した。得られた抽出液を集めてロー タリーエバポレーターで濃縮した。最終的に lmLのジメチルスルホキシドに溶解し、 ボタンボウフゥ葉エタノール抽出画分を得た。  40 g of ethanol was added to 2 g of the pulverized lyophilized product of the button bow leaf, extracted at room temperature for 30 minutes, and separated into an extract and a residue by centrifugation. Next, extraction with 30 mL of the same solvent was repeated twice for the residue. The obtained extract was collected and concentrated with a rotary evaporator. Finally, it was dissolved in 1 mL of dimethyl sulfoxide to obtain a button-boufu leaf ethanol extract fraction.
[0077] 調製例 4 ボタンボウフゥ葉エタノール抽出画分の逆相カラムによる分画  [0077] Preparation Example 4 Fractionation of button-boufu leaf ethanol extract fraction using reverse phase column
(1)ボタンボウフゥ葉部の凍結乾燥物を粉砕したもの 10gに、 200mLのエタノール を加え、 30分間室温で抽出を行い、吸引ろ過にて抽出液と残渣に分けた。次いで、 残渣に対して同溶媒 150mLによる抽出操作を 2回繰り返した。得られた抽出液を集 めてロータリーエバポレーターで濃縮した。最終的に 5mLのジメチルスルホキシドに 溶解し、ボタンボウフゥ葉エタノール抽出物を得た。 (1) To 10 g of pulverized lyophilized product of button bow leaf, 200 mL of ethanol was added, extracted at room temperature for 30 minutes, and separated into an extract and a residue by suction filtration. Next, extraction with 150 mL of the same solvent was repeated twice on the residue. The obtained extract was collected and concentrated by a rotary evaporator. To 5 mL dimethyl sulfoxide. Dissolved to obtain a button bow fu leaf ethanol extract.
[0078] (2)調製例 4一（1)で得られたボタンボウフゥ葉エタノール抽出物を逆相クロマトグ ラフィーを用いて分画した。榭脂は 20%エタノールで平衡化したコスモシール 75 C 18 -OPN (ナカライテスタ社製： 50mL)を用いた。ボタンボウフゥ葉エタノール抽出 物を榭月旨【こ添カロ後、 200mLの 200/0エタノーノレ、 600mLの 400/0エタノーノレ、 400m Lの 60%エタノールの順に溶出を行った。 (0078) (2) Preparation Example 4 The button-boufu leaf ethanol extract obtained in (1) was fractionated using reverse-phase chromatography. Cosmosil 75 C 18 -OPN (manufactured by Nacalai Testa Co., Ltd .: 50 mL) equilibrated with 20% ethanol was used as the resin. Botanboufuu leaf ethanol extract榭月after effect [This added Caro, 20 0/0 Etanonore of 200 mL, 600 mL of 40 0/0 Etanonore, eluted in order of 60% ethanol 400 meters L were performed.
[0079] (3)調製例 4 (2)で得られた 20%エタノール溶出液、 40%エタノール溶出液のう ち前半 400mL、 40%エタノール溶出液のうち後半 200mLと 60%エタノール溶出液 を合わせたもの、それぞれをロータリーエバポレーターで濃縮した。それぞれ最終的 に 5mLのジメチルスルホキシドに溶解し、ボタンボウフゥ葉エタノール抽出画分—Fr . 1、 一 Fr. 2、— Fr. 3を得た。  [0079] (3) Preparation Example 4 Of the 20% ethanol eluate and 40% ethanol eluate obtained in (2), the first half of 400 mL and the 40% ethanol eluate of the second half 200 mL and the 60% ethanol eluate were combined. Each was concentrated using a rotary evaporator. Each was finally dissolved in 5 mL of dimethyl sulfoxide to obtain button-bofu leaf ethanol-extracted fractions -Fr.1, 1 Fr.2, and -Fr.3.
[0080] 調製例 5 ボタンボウフゥ葉エタノール抽出画分—Fr. 2の逆相カラムによる分画  [0080] Preparation Example 5 Button Bow Fu Leaf Ethanol Extracted Fraction—Fr. 2 Fractionation on Reverse Phase Column
(1)調製例 4— (3)で得られたボタンボウフゥ葉エタノール抽出画分一 Fr. 2のうち 0 . 9mLを逆相クロマトグラフィーを用いて分画した。カラムは TSK gel ODS— 80T s (21. 5mm X 30cm:東ソ一社製）を用いた。溶媒は蒸留水：ァセトニトリル = 30 : 7 0、溶出速度は 5mLZ分、検出は 215nmで行った。溶出液の紫外線吸収を指標に 溶出液を分画した。  (1) Preparation Example 4—0.9 mL of Fr. 2 fraction extracted from the button-boufu leaf ethanol obtained in (3) was fractionated using reverse phase chromatography. The column used was TSK gel ODS-80Ts (21.5 mm × 30 cm: manufactured by Tosoh Corporation). The solvent was distilled water: acetonitrile = 30: 70, the elution rate was 5 mLZ, and detection was performed at 215 nm. The eluate was fractionated using the ultraviolet absorption of the eluate as an index.
[0081] (2)調製例 5—（1)で得られた保持時間 23. 7分、 35. 1分、 41. 8分のピークを含 む各画分をロータリーエバポレーターで濃縮した。それぞれ最終的に 0. 9mLのジメ チルスルホキシドに溶解し、ボタンボウフゥ葉エタノール抽出画分— Fr. 2—1、—2、 —3を得た。  [0081] (2) Fractions containing the retention times 23.7 minutes, 35.1 minutes, and 41.8 minutes obtained in Preparation Example 5- (1) were concentrated on a rotary evaporator. Each was finally dissolved in 0.9 mL of dimethyl sulfoxide to obtain button-bow-fu leaf ethanol extraction fractions—Fr. 2-1, -2, and -3.
[0082] (3)調製例 5—（2)で得られたボタンボウフゥ葉エタノール抽出画分 Fr. 2— 2の 質量スペクトル（MS)を質量分析計（API300 : Applied BioSystems/MDS Sc iex社製）により測定した結果、 mZz 387 ( [M+H] +)のシグナルを検出した。次い で、ボタンボウフゥ葉エタノール抽出画分— Fr. 2— 2を核磁気共鳴 (NMR)スぺタト ル装置（AVANCE600型：ブル力'バイオスピン社製）を用い、各種 NMRスペクトル を測定した。 MSスペクトル、各種 NMR ^ベクトル測定の結果、ボタンボウフゥ葉エタ ノール抽出画分 Fr. 2— 2は上記式（I)に示す 3'—Acetoxy—4'—senecioylox y- 3' , 4，一dihydroseselinであることが確定した。 [0082] (3) Mass spectrum (API300: Applied BioSystems / MDS Science Co., Ltd.) of the mass spectrum (MS) of Fr. 2-2 extracted from button-boufu leaf ethanol obtained in Preparation Example 5- (2) As a result, a signal of mZz 387 ([M + H] +) was detected. Subsequently, various NMR spectra were measured for the button-bow-fu leaf ethanol extraction fraction-Fr. 2-2 using a nuclear magnetic resonance (NMR) spectrum apparatus (AVANCE600 type: Bull force 'Biospin'). As a result of MS spectra and various NMR ^ vector measurements, the fraction extracted from button bow fu leaf ethanol Fr. 2-2 is 3'-Acetoxy-4'-senecioylox represented by the above formula (I). It was determined that y-3 ', 4, one dihydroseselin.
[0083] 実施例 1 マクロファージでの抗泡沫化の測定 [0083] Example 1 Measurement of antifoaming in macrophages
マクロファージは変性 LDL (ァセチル LDL (Ac-LDL)など）を細胞内に取り込み コレステロールエステルを合成し泡沫化する。各被験サンプルによるマクロファージ の抗泡沫化活性を測定した。  Macrophages take denatured LDL (such as acetyl LDL (Ac-LDL)) into cells and synthesize cholesterol esters into foam. The anti-foaming activity of macrophages by each test sample was measured.
[0084] (1)マクロファージの泡沫化  [0084] (1) Macrophage foaming
10%ゥシ胎児血清 (キャンプレックス社製)含有、ダルベッコ改良イーグル培地 (シ グマ社製、 D5796)に RAW264. 7細胞（ATCC TIB 71)を 4 X 105個/ mlにな るように懸濁し、 24穴マイクロタイタープレートのゥエルに lmLずつ加えて 5%炭酸ガ ス存在下、 37°Cでー晚培養した。次に、 UltraCHO培地（キャンプレックス社製、 B2 724)に交換し、各ゥエルに前述の調製例で調製した各被験サンプルのジメチルスル ホキシド溶液 2 /z Lをそれぞれ以下の表 1に示す濃度となるように添加した。なお、表 1中の 3，ーァセトキシー 4，一セネシオイノレォキシ一 3，， 4，ージハイドロセセリンは、 ボタンボウフゥ葉エタノール抽出画分一 Fr. 2— 2を精製したものを用いた。さらに各 ゥエルにそれぞれ終濃度 20 μ gZmLの Ac— LDL (バイオテクノロジー社製、 BT— 906)を添加し、 24時間培養した。なお、対照として Ac— LDLを添カ卩しない区分お よびジメチルスルホキシド添カ卩の区分を設定した。 Containing RAW264. 7 cells (ATCC TIB 71) at 4 x 10 5 cells / ml in Dulbecco's modified Eagle's medium (Sigma, D5796), containing 10% urine fetal serum (Camprex) After turbidity, 1 mL was added to each well of a 24-well microtiter plate and cultured at 37 ° C in the presence of 5% carbon dioxide. Next, replace with UltraCHO medium (Camprex B2 724), and each well has a concentration of dimethyl sulfoxide solution 2 / z L of each test sample prepared in the above preparation example as shown in Table 1 below. Was added as follows. In Table 1, 3, 4-acetoxy-4, 1-Senecioinoreoxy-3, 4, 4-dihydroserine were prepared by purifying Fr. Further, Ac-LDL (Biotechnology, BT-906) with a final concentration of 20 μgZmL was added to each well, and cultured for 24 hours. As a control, a category with no Ac-LDL added and a category with dimethyl sulfoxide added were set.
[0085] (2)コレステロールエステル生合成量の測定  [0085] (2) Measurement of cholesterol ester biosynthesis
マクロファージの泡沫化の指標として、細胞内の全コレステロール量及び遊離コレ ステロール量の測定を行、、コレステロールエステル量を算出した。  As an index of macrophage foaming, the amount of total cholesterol in the cell and the amount of free cholesterol were measured, and the amount of cholesterol ester was calculated.
[0086] 培養終了後、培地を除き、 0. 3% (wZv) BSA (シグマ社製、 A— 8022)含有リン 酸緩衝塩溶液で細胞を洗浄し、さらにリン酸緩衝塩溶液で洗浄した。細胞に 0. 5mL のへキサン:イソプロパノール = 3 : 2の溶媒を添加し、 30分間室温に置いた後上清を 回収した。この操作を再度繰り返し、あわせて lmLの上清を濃縮乾固した。沈殿を 3 0 μ Lのイソプロパノールに溶解後、溶液 10 μ L中に含まれる全コレステロール量を コレステロール Ε—テスト（和光純薬社製、 439— 17501)を用いて測定し、遊離コレ ステロール量を遊離コレステロール Ε—テスト（和光純薬社製、 435— 35801)を用い て測定した。また、測定は全て 2連で行った。コレステロールエステル生合成量は全 コレステロール量力 遊離コレステロール量を差し引いて求めた。また、抗泡沫化活 性は以下の式により算出した。 [0086] After completion of the culture, the medium was removed, and the cells were washed with a phosphate buffered salt solution containing 0.3% (wZv) BSA (manufactured by Sigma, A-8022), and further washed with a phosphate buffered salt solution. To the cells, 0.5 mL of hexane: isopropanol = 3: 2 solvent was added and left at room temperature for 30 minutes, after which the supernatant was collected. This operation was repeated again, and lmL supernatant was concentrated to dryness. After dissolving the precipitate in 30 μL of isopropanol, the total cholesterol content in 10 μL of the solution is measured using the Cholesterol® test (manufactured by Wako Pure Chemical Industries, Ltd., 439-17501) and the amount of free cholesterol is determined. It was measured using a free cholesterol test (Wako Pure Chemical Industries, 435-35801). All measurements were performed in duplicate. Total cholesterol ester biosynthesis Cholesterol capacity was determined by subtracting the amount of free cholesterol. The antifoaming activity was calculated by the following formula.
[0087] 抗泡沫化活性 (%) = 100- ( (被験サンプルを添カ卩したときのコレステロールエス テル生合成量）一（Ac— LDLを添カ卩しない区分のコレステロールエステル生合成量 ) ) ÷ ( (ジメチルスルホキシドを添カ卩したときのコレステロールエステル生合成量）一（ Ac— LDLを添カ卩しない区分のコレステロールエステル生合成量）） X 100  [0087] Anti-foaming activity (%) = 100- ((Cholesterol ester biosynthesis amount when test sample is added) 1 (Cholesterol ester biosynthesis amount in the case where Ac— LDL is not added)) ÷ ((Cholesterol ester biosynthesis amount when dimethyl sulfoxide is added) 1 (Cholesterol ester biosynthesis amount in the category without Ac— LDL addition)) X 100
[0088] この結果を表 1に示す。すなわち、表 1は各被験サンプルの各終濃度におけるマク 口ファージ中に蓄積されるコレステロールエステルに対する阻害活性を示すものであ り、表に記載の各サンプルに顕著な抗泡沫ィ匕活性が認められた。  [0088] The results are shown in Table 1. In other words, Table 1 shows the inhibitory activity against cholesterol ester accumulated in the Macphage phage at each final concentration of each test sample, and each sample listed in the table shows significant antifoam activity. It was.
[0089] [表 1] 被験サンプル 終濃度 (ぬ 抗泡沫化活性 ） ボタンボウフゥ茎 70%エタノ一ル抽出画分 0. 2 78  [0089] [Table 1] Test Sample Final Concentration (Nu Anti-foaming activity) Button Bow Fu Stem 70% Ethanol Extracted Fraction 0.2 78
0. 1 33  0. 1 33
ポタンボウフゥ茎エタノール抽出 W分 0. 05 86  Potambofu stem ethanol extraction W min 0. 05 86
0. 025 70  0. 025 70
ボタンボウフゥ根エタノール抽出画分 0. 0125 27 ポタンボウフゥ葉エタノ一ル抽出画分 0. 025 97  Button Bow Fu root ethanol extract fraction 0. 0 125 27 Potent Bow Fu leaf ethanol extract fraction 0. 025 97
0. 01 25 52  0. 01 25 52
ポタンボウフゥ葉エタノール抽出画分 Fr. 2 0. 1 88  Potambofu leaf ethanol extract fraction Fr. 2 0. 1 88
0. 05 34  0. 05 34
ボタンボウフゥ葉エタノール抽出両分一 Fr. 2 - - 2 Q. 2 72  Button Bow Fu Leaf Ethanol Extraction Both Fr. 2--2 Q. 2 72
0. 1 34  0. 1 34
ポタンボウフゥ葉エタノール抽出画分一 Fr. 2 - ■3 0. 2 35 被験サンプル 終濃度（ ί Μ) 抗泡沫化活性 (¾) Potambofu leaf ethanol extract fraction Fr. 2-■ 3 0. 2 35 Test sample Final concentration (ί Μ) Antifoaming activity (¾)
3 ' -ァセ卜キシ -4' -セネシオイルォキシ -3' , -1 ' - - 40 98 ジハイドロセセリン 20 19 3 '-Acetoxy-4' -Senesiyloxy-3 ', -1'--40 98 Dihydroceserin 20 19
[0090] 実施例 2 [0090] Example 2
(1)ラットミクロノームの調製  (1) Preparation of rat micronome
Spmgue— Dawleyラット 4匹を 1週間飼育後、屠殺し、直ちに肝臓を摘出し冷食塩 水で軽く洗浄後、スクロースバッファー（0. 3M スクロース、 50mM トリス HC1、 1 mM EDTA、 50mM NaCl、 pH 7. 4)に浸漬（25mLZl匹）した。得られた肝 臓をホモジナイズし、 10, 000 X g、 30分間遠心を行い沈殿を除去する操作を 2回繰 り返した。得られた上清を 105, 000 X g、 70分間遠心を行い沈殿を回収し、適当量 の lOOmM リン酸バッファー（pH 7. 4)に懸濁した。タンパク濃度が 10mg/mlに なるように再度リン酸バッファーに懸濁し、終濃度 ImMになるように EDTAを添加後 、使用するまで 80°Cで凍結保存した。 Spmgue—4 Dawley rats were raised for 1 week and sacrificed. The liver was immediately removed, washed gently with cold saline, and then sucrose buffer (0.3 M sucrose, 50 mM Tris HC1, 1 mM EDTA, 50 mM NaCl, pH 7. Immersion (25mLZl) in 4). The obtained liver was homogenized, and the operation of removing the precipitate by centrifuging at 10,000 × g for 30 minutes was repeated twice. The obtained supernatant was centrifuged at 105,000 xg for 70 minutes to collect the precipitate, and suspended in an appropriate amount of lOOmM phosphate buffer (pH 7.4). Protein concentration to 10mg / ml Then, the suspension was suspended again in a phosphate buffer, and after adding EDTA to a final concentration of ImM, it was stored frozen at 80 ° C. until use.
[0091] (2)各サンプルによる ACAT阻害活性の測定  [0091] (2) Measurement of ACAT inhibitory activity by each sample
ACATの酵素活'性 ίま Leeらの方法（Planta Med. , 2004, 70, 678— 679)に従 つて、一部改良して測定した。  The enzyme activity of ACAT was measured with some improvement according to the method of Lee et al. (Planta Med., 2004, 70, 678-679).
[0092] 1. 5mLエツペンチューブ中において実施例 2— (1)で調製したラット肝ミクロソーム 1. 5 Lを含む反応水溶液（0. 05M リン酸カリウム、 ImM ジチオスレィトール、 9 mg/mL 脂肪酸フリーゥシ血清アルブミン、 200 gZmL コレステロール、 pH7. 4) 92 Lに表 2記載の終濃度となるように各被験サンプルのジメチルスルホキシド溶 液 1 μ Lを添カ卩し 37°Cで 30分保温した。なお、表 2中の 3'—ァセトキシ—4'ーセネ シオイルォキシー3，， 4，ージハイドロセセリンは、ボタンボウフゥ葉エタノール抽出画 分 Fr. 2— 2を精製したものを用いた。また、対照区分として化合物を添加せずジメ チルスルホキシド溶液のみを添加した区分、陽性対照として ACAT阻害活性が知ら れている化合物 FR179254 (終濃度 M、メルク社製、 344235)を添加する区 分を設定した。この後、 0. 05mCiZmLの Oleoyl Coenzyme A, [oleoyl— 9, 10-Ή] - (モラベックバイオケミカルズ社製、 MT1649) 2 μ Lと 0. 2mgZmLの Oleoyl Coenzyme A (ICN社製、 591— 20521) 5 Lの混合液を各チューブに 添加し混合後、 37°Cで 5分保温した。その後イソプロパノール:ヘプタン =4 : 1の溶 液を各チューブに 0. 5mLずつ添加することで反応を停止した。各チューブに 0. 2m Lの 0. 1M リン酸カリウム溶液（pH7. 4)および 0. 3mLのヘプタンを添カ卩し 15秒間 攪拌後、 15秒間遠心分離を行い、得られた上層 150 Lを用いてウルチマゴールド (パーキンエルマ一ライフサイエンス社製、 6013329)をシンチレーシヨンカクテルと して液体シンチレーシヨンカウンター LS6500 (ベックマン社製）により放射活性を測 定した。なお、各反応は 2連で行った。各被験サンプルの ACAT阻害活性（％)は以 下の式により陽性対照である 10 μ Μの FR179254を添カ卩したときの阻害率を 100 %とすることにより算出した。  [0092] 1. Rat liver microsome prepared in Example 2 (1) in a 5 mL Eppendorf tube Reaction solution containing 1.5 L (0.05 M potassium phosphate, ImM dithiothreitol, 9 mg / mL Fatty acid serum free albumin, 200 gZmL cholesterol, pH 7.4) Add 1 μL of dimethyl sulfoxide solution of each test sample to 92 L so that the final concentration shown in Table 2 is added, and incubate at 37 ° C for 30 minutes . In Table 2, 3'-acetoxy-4'-senethioyloxy 3, 4, 4-dihydroserine used was purified from button-boufu leaf ethanol extract Fr. 2-2. In addition, as a control category, a group in which only a dimethyl sulfoxide solution was added without adding a compound, and a group in which a compound FR179254 (final concentration M, manufactured by Merck & Co., 344235) known to have ACAT inhibitory activity was added as a positive control. Set. After this, 0.05 mCiZmL Oleoyl Coenzyme A, [oleoyl— 9, 10-Ή]-(Morabek Biochemicals, MT1649) 2 μL and 0.2 mgZmL Oleoyl Coenzyme A (ICN, 591— 20521 ) 5 L of the mixture was added to each tube and mixed, and then incubated 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. Add 0.2 mL of 0.1 M potassium phosphate solution (pH 7.4) and 0.3 mL of heptane to each tube, stir for 15 seconds, and then centrifuge for 15 seconds. The radioactivity was measured with a liquid scintillation counter LS6500 (manufactured by Beckman) using Ultima Gold (Perkin Elma Life Science Co., 6013329) as a scintillation cocktail. Each reaction was performed in duplicate. The ACAT inhibitory activity (%) of each test sample was calculated by using the following formula as the inhibition rate when 10 μΜ of FR179254 as a positive control was added to 100%.
[0093] 阻害活性 (%) = ( ( [対照区分の放射活性 (cpm) ] [被験サンプル添加区分の放 射活性 (cpm) ]) / ( [対照区分の放射活性 (cpm) ]— [ 10 Mの FR179254添カロ 区分の放射活性 (cpm) ] ) ) X 100 [0093] Inhibitory activity (%) = (([Radioactivity of control category (cpm)] [Radioactivity of test sample addition category (cpm)]) / ([Radioactivity of control category (cpm)] — [10 M FR179254 Caro Category radioactivity (cpm)])) X 100
[0094] この結果を表 2に示す。すなわち、表 2は各被験サンプルの各終濃度における ACThe results are shown in Table 2. That is, Table 2 shows AC at each final concentration of each test sample.
ATに対する阻害活性を示すものであり、表に記載の各被験サンプルに顕著な ACAIt shows inhibitory activity against AT and is prominent in each test sample listed in the table.
T阻害活性が認められた。 T inhibitory activity was observed.
[0095] [表 2] 被験サンプル 終濃度 (W ACAT阻害活性 tt) ボタンボウフゥ根エタノール抽出画分 0. 1 105 [0095] [Table 2] Test Sample Final Concentration (W ACAT Inhibitory Activity tt) Button Bow Root Ethanol Extracted Fraction 0.1 5
0. 05 71  0. 05 71
0. 025 48 ボタンボウフゥ葉エタノール抽出画分 0. 1 61  0. 025 48 Button Bow Fu Leaf Ethanol Extraction Fraction 0. 1 61
0. 05 66  0. 05 66
0. 025 48 被験サンプル 終濃度（ M) ACAT阻害活性 ） 0. 025 48 Test sample Final concentration (M) ACAT inhibitory activity)
3 ' -ァセ卜キシ- 4' -セネシオイルォキシ -3' , 4' - 100 87 ジ八ィドロセセリン 50 65 3'-Acetoxy-4'-Senesiyloxy-3 ', 4'-100 100 Dioctahydroserine 50 65
25 40  25 40
産業上の利用可能性 Industrial applicability
[0096] 本発明により、ボタンボウフゥ由来の処理物、 3'—ァセトキシー 4' セネシオイル ォキシ—3' , 4'—ジハイドロセセリン、その誘導体及び/又は薬学的に許容される それらの塩を含有する治療又は予防に細胞の抗泡沫化作用及び Z又は ACAT阻 害作用を要する疾患の治療用又は予防用の医薬、食品又は飼料が提供される。該 医薬は動脈硬化症や高脂血症、これらが原因因子となって起こる疾患の治療剤又は 予防剤として有用である。また、該食品は、日常の食品として摂取することにより、上 記疾患の症状改善や予防が可能となる。従って、本発明の有効成分を含有する食 品はその細胞の抗泡沫化作用及び Z又は ACAT阻害作用により、生体の恒常性の 維持に有用な機能性食品である。  [0096] According to the present invention, a processed product derived from button bow fu, 3'-acetoxy 4 'senecioyloxy-3', 4'-dihydroserine, a derivative thereof and / or a pharmaceutically acceptable salt thereof is contained. Provided is a medicament, food, or feed for treating or preventing a disease that requires anti-foaming action of cells and Z or ACAT inhibitory action for treatment or prevention. The medicament is useful as a therapeutic or prophylactic agent for arteriosclerosis, hyperlipidemia, and diseases caused by these factors. In addition, when the food is ingested as a daily food, symptoms of the above diseases can be improved or prevented. Therefore, the food containing the active ingredient of the present invention is a functional food useful for maintaining the homeostasis of the living body by the antifoaming action of the cells and the Z or ACAT inhibitory action.

Claims

請求の範囲 The scope of the claims
[1] ボタンボウフゥ由来の処理物を有効成分として含有することを特徴とする、治療又 は予防において細胞の抗泡沫化作用及び Z又はァシル CoAコレステロールァシル トランスフェラーゼ阻害作用を要する疾患の治療剤又は予防剤。  [1] A therapeutic or prophylactic agent for a disease that requires a cell antifoaming action and a Z or acyl CoA cholesterol acyl transferase inhibitory action in treatment or prevention, comprising a processed product derived from buttonbow fu as an active ingredient Agent.
[2] ボタンボウフゥ由来の処理物力 3'ーァセトキシ 4' セネシオイルォキシ 3' , 4'—ジノ、イドロセセリン、その誘導体及び薬学的に許容されるそれらの塩からなる群 より選ばれる一種以上を含有する処理物である請求項 1記載の治療剤又は予防剤。  [2] Treatment power derived from button bow 3'-acetooxy 4 'senesioxyloxy 3', 4'-dino, idroseserine, derivatives thereof, and one or more selected from the group consisting of pharmaceutically acceptable salts thereof The therapeutic or prophylactic agent according to claim 1, which is a treated product.
[3] ボタンボウフゥ由来の処理物を有効成分として含有することを特徴とする、細胞の 抗泡沫化剤。  [3] A cell anti-foaming agent comprising a processed product derived from button bow fu as an active ingredient.
[4] ボタンボウフゥ由来の処理物力 3'ーァセトキシ 4' セネシオイルォキシ 3' , 4'—ジノ、イドロセセリン、その誘導体及び薬学的に許容されるそれらの塩からなる群 より選ばれる一種以上を含有する処理物である請求項 3記載の細胞の抗泡沫化剤。  [4] Processed power derived from button bow 3'-acetooxy 4 'senecioyloxy 3', 4'-dino, idroseserine, derivatives thereof, and one or more selected from the group consisting of pharmaceutically acceptable salts thereof 4. The antifoaming agent for cells according to claim 3, which is a treated product.
[5] ボタンボウフゥ由来の処理物を有効成分として含有することを特徴とする、ァシル C oAコレステロールァシルトランスフェラーゼ阻害剤。  [5] A acyl-CoA cholesterol acyltransferase inhibitor, comprising a processed product derived from button bow as an active ingredient.
[6] ボタンボウフゥ由来の処理物力 3'ーァセトキシ 4' セネシオイルォキシ 3' , 4'—ジノ、イドロセセリン、その誘導体及び薬学的に許容されるそれらの塩からなる群 より選ばれる一種以上を含有する処理物である請求項 5記載のァシル CoAコレステ ロールァシルトランスフェラーゼ阻害剤。  [6] Processed power derived from button bow 3'-acetooxy 4 'senecioyloxy 3', 4'-dino, idroseserine, derivatives thereof, and one or more selected from the group consisting of pharmaceutically acceptable salts thereof 6. The acyl-CoA cholesterol transferase inhibitor according to claim 5, which is a treated product.
[7] ボタンボウフゥ由来の処理物を有効成分として含有することを特徴とする、細胞の 抗泡沫化用及び Z又はァシル CoAコレステロールァシルトランスフェラーゼ阻害用 の食品又は飼料。  [7] A food or feed for anti-foaming cells and inhibiting Z or acyl CoA cholesterol acyltransferase, comprising a processed product derived from button bow as an active ingredient.
[8] ボタンボウフゥ由来の処理物力 3'ーァセトキシ 4' セネシオイルォキシ 3' , 4'—ジノ、イドロセセリン、その誘導体及び薬学的に許容されるそれらの塩からなる群 より選ばれる一種以上を含有する処理物である請求項 7記載の食品又は飼料。  [8] Processed power derived from button bow 3'-acetoxy 4 'senecioyloxy 3', 4'-dino, idroseserine, derivatives thereof, and one or more selected from the group consisting of pharmaceutically acceptable salts thereof The food or feed according to claim 7, which is a processed product.
[9] 3，—ァセトキシ— 4，—セネシオイルォキシ—3，， 4，—ジハイドロセセリン、その誘 導体及び薬学的に許容されるそれらの塩からなる群より選ばれる一種以上を有効成 分として含有することを特徴とする、治療又は予防において細胞の抗泡沫化作用及 び Z又はァシル CoAコレステロールァシルトランスフェラーゼ阻害作用を要する疾患 の治療剤又は予防剤。 [9] 3, more effective than one selected from the group consisting of: acetoxy-4, -senecylooxy-3,4, -dihydroserine, its derivatives and pharmaceutically acceptable salts thereof Diseases that require anti-foaming action of cells and inhibitory action of Z or acyl CoA cholesterol acyltransferase in treatment or prevention, characterized by containing as a component Therapeutic or prophylactic agent.
[10] 3，—ァセトキシ— 4，—セネシオイルォキシ—3，， 4，—ジハイドロセセリン、その誘 導体及び薬学的に許容されるそれらの塩からなる群より選ばれる一種以上を有効成 分として含有することを特徴とする、細胞の抗泡沫化剤。  [10] 3, more effective than one selected from the group consisting of: acetoxy-4, -senecylooxy-3,4, -dihydroserine, its derivatives and pharmaceutically acceptable salts thereof An antifoaming agent for cells, which is contained as a component.
[11] 3，—ァセトキシ— 4，—セネシオイルォキシ—3，， 4，—ジハイドロセセリン、その誘 導体及び薬学的に許容されるそれらの塩からなる群より選ばれる一種以上を有効成 分として含有することを特徴とする、ァシル CoAコレステロールァシルトランスフェラー ゼ阻害剤。 [11] 3, effective one or more selected from the group consisting of: -acetoxy-4,-senesioxyloxy-3, 4, 4-dihydroserine, its derivatives and pharmaceutically acceptable salts thereof A acyl CoA cholesterol acyltransferase inhibitor characterized by containing as a component.
[12] 3，一ァセトキシ一 4，一セネシオイルォキシ 3，， 4，一ジハイドロセセリン、その誘 導体及び薬学的に許容されるそれらの塩からなる群より選ばれる一種以上を有効成 分として含有することを特徴とする、細胞の抗泡沫ィ匕用及び Z又はァシル CoAコレス テロールァシルトランスフェラーゼ阻害用の食品又は飼料。  [12] Effectively comprises at least one selected from the group consisting of 3, 1-acetoxy-4, 1-senesioxyloxy 3, 4, 1-dihydroserine, its derivatives and pharmaceutically acceptable salts thereof. A food or feed for cell antifoam and for inhibiting Z or acyl CoA cholesterol transferase.
[13] 被験体に、有効量のボタンボウフゥ由来の処理物を投与することを含む、治療又は 予防において細胞の抗泡沫ィ匕作用及び Z又はァシル CoAコレステロールァシルトラ ンスフ ラーゼ阻害作用を要する疾患の治療方法又は予防方法。  [13] For a disease that requires a cell anti-foaming effect and a Z or acyl CoA cholesterol acyltransferase inhibitory effect in treatment or prevention, including administering to a subject an effective amount of a treatment derived from buttonbow fu Treatment or prevention method.
[14] 治療又は予防にぉ 、て細胞の抗泡沫ィ匕作用及び Z又はァシル CoAコレステロ一 ルァシルトランスフェラーゼ阻害作用を要する疾患の治療剤又は予防剤の製造のた めの、ボタンボウフゥ由来の処理物の使用。  [14] A processed product derived from button-bow fu for the manufacture of a therapeutic or prophylactic agent for diseases that require anti-foaming action of cells and Z or acyl CoA cholesterol transferase inhibitory action for treatment or prevention Use of.
[15] 被験体に、有効量の 3'—ァセトキシ—4' セネシオイルォキシ 3' , 4'—ジハイ ドロセセリン、その誘導体及び薬学的に許容されるそれらの塩力 なる群より選ばれ る一種以上を投与することを含む、治療又は予防にぉ 、て細胞の抗泡沫化作用及 び Z又はァシル CoAコレステロールァシルトランスフェラーゼ阻害作用を要する疾患 の治療方法又は予防方法。  [15] A subject selected from the group consisting of an effective amount of 3′-acetoxy-4 ′ senesioxyloxy 3 ′, 4′-dihydroserine, its derivatives, and pharmaceutically acceptable salt strength thereof A method for treating or preventing a disease requiring an antifoaming action of a cell and an inhibitory action of Z or acyl CoA cholesterol acyltransferase, for treatment or prevention, comprising administering the above.
[16] 治療又は予防にぉ 、て細胞の抗泡沫ィ匕作用及び Z又はァシル CoAコレステロ一 ルァシルトランスフェラーゼ阻害作用を要する疾患の治療剤又は予防剤の製造のた めの、 3，ーァセトキシ 4'ーセネシ才ィノレ才キシ 3' , 4'ージハイドロセセリン、そ の誘導体及び薬学的に許容されるそれらの塩からなる群より選ばれる一種以上の使 用。  [16] 3, -acetooxy 4 'for the production of a therapeutic or prophylactic agent for diseases that require anti-foaming action of cells and inhibition of Z or acyl CoA cholesterol transferase transferase in the treatment or prevention -Use of one or more selected from the group consisting of Senesi, Inore, Xi 3 ', 4'-Dihydroceserin, derivatives thereof and pharmaceutically acceptable salts thereof.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008015950A1 (en) * 2006-08-02 2008-02-07 Takara Bio Inc. Acat inhibitor
WO2009054504A1 (en) * 2007-10-24 2009-04-30 Suntory Holdings Limited Ligand agent for peroxisome proliferator-activated receptor (ppar)
JP2011184356A (en) * 2010-03-09 2011-09-22 Shiseido Co Ltd Pore-shrinking agent for oral ingestion
WO2012111643A1 (en) * 2011-02-14 2012-08-23 株式会社アミノアップ化学 Adiponectin production promoter, and medicinal composition, food, drink and feed containing adiponectin production promoter
JP7444375B2 (en) 2019-12-28 2024-03-06 株式会社 沖縄リサーチセンター Composition for improving lower urinary tract symptoms

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5666053B1 (en) * 2014-08-01 2015-02-12 株式会社 資生堂 Longevity gene expression enhancer

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60260520A (en) * 1984-06-07 1985-12-23 Takagi Koichi Drug composition
JPS60260515A (en) * 1984-06-07 1985-12-23 Takagi Koichi Pharmaceutical composition containing seselin compound as active component
WO2004096198A1 (en) * 2003-05-02 2004-11-11 Takara Bio Inc. Therapeutic agent
WO2005074906A1 (en) * 2004-02-06 2005-08-18 Takara Bio Inc. Remedy

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60260520A (en) * 1984-06-07 1985-12-23 Takagi Koichi Drug composition
JPS60260515A (en) * 1984-06-07 1985-12-23 Takagi Koichi Pharmaceutical composition containing seselin compound as active component
WO2004096198A1 (en) * 2003-05-02 2004-11-11 Takara Bio Inc. Therapeutic agent
WO2005074906A1 (en) * 2004-02-06 2005-08-18 Takara Bio Inc. Remedy

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEN I.-S.: "Coumarins and antiplatelet aggregation constituents from Formosan Peucedanum japonicum", PHYTOCHEMISTRY, vol. 41, no. 2, 1996, pages 525 - 530, XP002997573 *
DATABASE JICST-EPLUS [online] UEZU E. ET AL.: "Effects of Morus australis, Crepidiastrum lanceolatum, Peucedanum japonicum, Carica papaya, Benincasa cerifera, Abelmoschus esculentus and Artemisia princeps on plasma cholesterol levels in mice fed goat-soup dish extracts", Database accession no. (990781350) *
IGAKU TO SEIBUTSUGAKU (MEDICINE AND BIOLOGY), vol. 138, no. 6, 1999, pages 175 - 178, XP002997572 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008015950A1 (en) * 2006-08-02 2008-02-07 Takara Bio Inc. Acat inhibitor
WO2009054504A1 (en) * 2007-10-24 2009-04-30 Suntory Holdings Limited Ligand agent for peroxisome proliferator-activated receptor (ppar)
JP2011184356A (en) * 2010-03-09 2011-09-22 Shiseido Co Ltd Pore-shrinking agent for oral ingestion
WO2012111643A1 (en) * 2011-02-14 2012-08-23 株式会社アミノアップ化学 Adiponectin production promoter, and medicinal composition, food, drink and feed containing adiponectin production promoter
JPWO2012111643A1 (en) * 2011-02-14 2014-07-07 株式会社アミノアップ化学 Adiponectin production promoter, and pharmaceutical composition, food and drink, and feed comprising adiponectin production promoter
JP7444375B2 (en) 2019-12-28 2024-03-06 株式会社 沖縄リサーチセンター Composition for improving lower urinary tract symptoms

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