TW200823219A - ACAT inhibitor - Google Patents

Abstract

An acyl-CoA cholesterol acyltransferase inhibitor comprising at least one member selected from the group consisting of 3'-acetoxy-4'-tigloyloxy-3'-4'-dihydroseselin, a derivative thereof and a pharmaceutically acceptable salt of the compound or the derivative as an active ingredient. The inhibitor or a pharmaceutical, food or animal feed comprising the inhibitor is effective for hyperlipemia, arterial sclerosis or a disease associated with these diseases. Particularly, the food is useful as a functional food which has an inhibitory activity on acyl-CoA cholesterol acyltransferase and is effective for the maintenance of homeostasis in vivo.

Description

200823219 IX. Description of the Invention: [Technical Field] The present invention relates to a kind of natural substance which is useful for treating or preventing arteriosclerosis, hyperlipidemia, etc., having a thiol-based coA cholesterol thiol transferase inhibitory action. The ingredients. [Prior Art]

In recent years, 'the moxibustion of a diet with a large intake of high-calorie or high-cholesterol foods or an increase in the average age has led to an increase in 'arteriosclerosis, hyperlipidemia, hypertension, diabetes, etc.' Living habits have rapidly increased and become a major social problem. The initial consumption of atherosclerosis can be seen as a patchy or linear fat deposit called a fat strip. This change is mainly due to the accumulation of foamed macrophages on the vascular endothelium. The blistering of giant pythons and cells is caused by the ingestion of moxibustion by L. sinensis and the production of free cholesterol, which is caused by the accumulation of thiol c〇a cholesterol thiol transferase. At the beginning (4), the cytopathic lesions develop into a complex lesion containing foaming of vascular smooth muscle cells. The fat line soon becomes a fibrous hard spot and protrudes on the blood vessel wall, and if the lesion develops, it is accompanied by calcification and thrombus adhesion, and the blood vessel cavity is narrowed or the hard spot is broken to cause a recording blockage. It is also known that hard spots which are easily broken include many fat f components such as cholesterol vinegar. Therefore, it is expected that the activity of the thiol-based C 〇 A cholesterol thiol transferase will be stabilized and stabilized, and the onset or recurrence of acute coronary heart disease based on arteriosclerosis or hyperlipidemia may be reduced. Further, it is known that by inhibiting the activity of the brewing-based CoA cholesterol thiol transferase, the vinegar bond of the cholesterol in the human intestine which forms the cholesterol ester formed by the foot in the liver is reduced: Small-key, ,,. And reduce the absorption of cholesterol, less ash in the cholesterol, blood neutral fat. Therefore, the scientific name of the peony wind-proof system is to be reduced. In the water bud family, the original defense (four) anum japoni_ (the former Japanese genus) is a perennial herb of the genus M., growing on the rocks or grassland of the coast. Go out and go... 〇~100 cm, if it is 6~9 in the flowering period, it will be opened to 1 salty: white. As far as its physiological activity is concerned, it recognizes the mu in the origin of Okinawa: two S', fatigue recovery, nourishment and strong effect, since ancient times, a system has been attached to the recent research and also learned that the peony wind has the effect of (For example, Non-Patent Document 1), a disaccharide-degrading enzyme is inhibited (for example, Patent Document U, antioxidant action (for example, Patent Document, Non-Patent Document 2), cell activation (for example, Patent Document 2), and U-production In the case of the characteristic chemical components contained in the peony wind, it is known that a variety of coumarins have been studied for their cancer promoters (for example, Non-Patent Document 3). Patent Document 1: Japanese Patent Laid-Open Publication No. 2003-26694. Patent Document 2. Japanese Patent Laid-Open No. 2004-26697. Non-Patent Document 1 · T. Morioka Other 8th, Caneer Letters, 2004, Volume 2G5, 133] 41 pages Non-Patent Document 2: M. Hisamoto Other 2, J. Agric. Food Chem·' 2004, Vol. 52, pp. 445_45 Non-Patent Document 3: B.Fan Other 5, journai of japanese

Botany, 200G, Vol. 75, No. 4, pp. 257.261 123192.doc 200823219 [Summary of the Invention] If the present invention is summarized, the first invention of the present invention relates to a sulfhydryl group.

a CoA cholesterol thiol transferase inhibitor characterized by comprising a component selected from the group consisting of 3'-ethoxycarbonyl 4'-isopreneoxy 3 丨, 4, _ dioxin, One or more of the derivatives and the salt compositions of the above-mentioned salts and pharmaceutically acceptable substances are used as active ingredients. A second invention of the present invention relates to a medicine according to the invention of the present invention, which comprises the wine-based COA cholesterol cyclylase inhibitor. The third invention of the invention relates to a food or beverage characterized by comprising the brewing-based coA cholesterol-based conversion inhibitor of the invention of the invention. [Embodiment] The present invention relates to a medicine, a food or a feed which is capable of being safely and easily ingested, and (d) a substance having a thiol-based cholesterol-based transferase inhibitory action as a raw material or a pharmaceutical raw material. i according to the present invention 'providing a thiol-based coA cholesterol thiol transferase inhibitor, a pharmaceutical, food or medicinal material containing the same, the ceramide c〇a cholesterol thiotransferase inhibitor is selected from the group consisting of One or more of the components consisting of the 3'-acetoxy group of isoamyloxy oxy-3,4,-dihydroartemisia (four), its derivatives, and the salts permitted by the pharmacy As an active ingredient. The above inhibitor, medicine, food or feed is useful for hyperlipidemia, dipulmonary sclerosis, and diseases caused by the above, wherein the food buckle of the present invention has a pair of thiol-based CoA cholesterol thiol transferase inhibitory effects. It is useful to maintain the organism as a useful functional food. 123192.doc 200823219 Stuffed CoA cholesterol thiol transferase (alias, also known as thiol c〇a ·• cholesterol basal transferase; ACAT) is an enzyme that transfers long-chain fatty acid from brewed-based CoA to cholesterol and catalyzes the synthesis of cholesterol ester. The ACAT inhibitory action can be easily determined by using the assay system described in Example 1 below. Mixing the test substance with an enzyme source containing ACAT' and treating the Oleoyl-CoA from the radioactive label to cholesterol

Oleoyl-based transfer was evaluated and the acat inhibitory effect was easily determined. The following formula (I) represents a structural formula of 3f-acetoxy-4,-prenyloxy-3,4,-dihydromethanone (hereinafter, referred to as a compound of the present invention). . [Chemical 1]

The compound of hai is a substance of 3 in peony or peucedanum praerupt rum, and it has been initially confirmed to have acat inhibitory action in the present invention. That is, as an active ingredient of the present invention, 3,_ethoxycarbonyl-4, isopentenyloxy_3', 4»-dihydroartemisinide, a derivative thereof and/or a pharmacy is used. These salts are allowed (hereinafter, these are all referred to as active ingredients of the present invention). The method for producing the compound of the present invention is not particularly limited, and it can be used as a raw material for the use of fighting water or peucedanum praer叩t〇 um. 123192.doc 200823219 For example, as described in Preparation 1, it can be protected from wind by peony. The ethanol extract is obtained by various chromatographic methods. Further, in the case of using peony windproof as a raw material, there is no particular limitation, and fruits, seeds, seed coats, flowers, leaves, stems, roots, rhizomes, and/or whole plants can be directly used, but it is preferred to use leaves and/or Or stem. Further, in the case of synthesizing the compound of the present invention, it can also be obtained by a combination of known methods.

Furthermore, in the present specification, 3,_ethoxycarbonyl 4,-prenyl decyloxydihydrolactone, even for all optical isomers, __enol tautomers Various isomers such as geometric isomers can be used in the present invention as long as they have an ACAT inhibitory action. In the specification, in the specification, as a derivative, for example, in the above 3'_ethyl decyloxyisoprenyloxy group _3,4, _ dihydrogen artemisia vinegar skeleton has various substitutions The effect of the desired effect is not particularly limited. Examples of the substituent include a linear aliphatic group such as an aliphatic group (10), an ethyl group, a n-propyl group, or a branched fat such as an isopropyl group, an isobutyl group or an isoprene group: a geranyl group. Family group), aromatic group (phenyl, decyl, biphenyl, base, (tetra), etc.), aliphatic (group, phenethyl, etc.), (d), several groups, sulfate, decanoic acid A group, a thiol group, an amine group, or a succinyl group: a calcined base (methoxy group, etc.), a decyloxy group (such as an ethyl group), a _ element (a gas, a fluorine, or the like). Further, for example, a substance which can be metabolized by administering the compound of the present invention to mammals is also included in the derivative of the present invention. 1下马本本发明一一一一一乳丞-4 - isoprene 峨 丞〇.,, 一风邪高中酯 or its street & & _ _ _ _ _ _ _ _ _ _ _ . As for the use of the present invention, for example, an alkali metal salt, a base 123192.doc 200823219 metal salt, a salt formed by an organic test, and the like can be exemplified. Further, the salt which is allowed in the music used in the present invention means a salt of a compound which is substantially non-toxic to the living body and which has an ACAT inhibitory action. As the salt, for example, sodium, potassium, xenon, town, money or protonated star compound _,-di-glyethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, sugar A salt of an amine (8) methyl glucosamine), phenenthr (tetrakis-phenylethylamine), pyrazine or a phase-butanol (2-amino-2-hydroxymethyl q, % propylene glycol).

Derivatives of the compounds of the invention can be prepared by methods well known in the art. Further, the salt of the compound or derivative of the present invention can be easily produced by any method known to those skilled in the art. The active ingredient of the present invention is a synthetic compound having acat inhibiting effect (for example, the following FR179254) which has been known since the ancient times--the compound contained in the peony wind-proof edible xiao, which has a high safety and is not In particular, it is found that the toxicity is as follows, and there is no need to worry about side effects. Further, it is possible to treat or prevent diseases safely and appropriately. Therefore, an ACAT inhibitor containing the active ingredient (hereinafter referred to as an acat inhibitor of the present invention) is effective for treating or preventing a disease requiring an ACAT inhibitory action, and is useful as a raw material of the following medicine, food or feed. Further, the ACAT inhibitor of the present invention is also useful for the treatment or prevention of a disease requiring an ACAT inhibitory action, such as atherosclerosis or hyperlipidemia, and drug screening for diseases caused by such diseases. Further, the ACAT inhibitor is also useful for studying the mechanism of formation of a phosphitol ester or a mechanism related to the development of the above-mentioned diseases such as hyperlipidemia and arteriosclerosis. The ACAT inhibitor of the present invention is not particularly limited as long as it contains 123192.doc -11-200823219, and can be directly used as the active ingredient of the present invention. Composition. In other words, the content of the above-mentioned effective component in the ACAT inhibitor is not particularly limited as long as it is an amount which exhibits the desired effect of the present invention. The content of the active ingredient in the ACAT inhibitor of the present invention is about 1 to 1 〇〇 weight 〇 /0. Further, the amount of the ACAT inhibitor to be used is not particularly limited as long as it exhibits the desired effect of the present invention, and when it is administered to a living organism, it is preferred that The amount of the active ingredient to be administered in the pharmaceutical composition of the present invention may be administered in an amount of the active ingredient. The administration method is not particularly limited, and may be appropriately set in the same manner as the following medicine. Further, the form of use is not particularly limited, and may be produced in an appropriate form depending on the intended use. Further, the present invention also provides a medicine (hereinafter, also referred to as a medicine of the present invention) containing the ACAT inhibitor of the present invention. The medicine of the present invention is useful for a disease requiring ACAT inhibition in the treatment or prevention, and the disease is not particularly limited, and examples thereof include hyperlipidemia, hypercholesterolemia, hyperglyceridemia, and metabolic synthesis. Syndrome, multiple risk factors syndrome, atherosclerosis, ischemic heart disease, acute myocardial infarction, unstable angina, ischemic sudden death, cerebrovascular disease, chronic obstructive atherosclerosis, myocardial infarction, angina pectoris, cerebral infarction, Subarachnoid hemorrhage, obesity, or diseases caused by such diseases (for example, reference to 〇, R〇urke et al., j.

Biol Chem et al, 2002, 277 (45), pp. 42557-42562, Ohishi et al, Biol Pharm. Bull, 2003, 26(8), pp. 1125-1128, and Ohishi et al., Chem Pharm Bull·, 2001, 49(7), 830-839 123192.doc -12- 200823219). The pharmaceutical of the present invention is prepared by combining the above-mentioned effective component used as the acAT inhibitor of the present invention with a known pharmaceutical carrier. Further, as the medicine of the present invention, the active ingredient of the present invention may be formulated with other ingredients which can be used for the same purpose as the above-mentioned active ingredient. The manufacture of the γ2 invention is usually carried out by blending the above-mentioned active ingredient with a pharmaceutically acceptable liquid or solid carrier, and a solvent, a dispersant, an emulsifier, a buffer, and a stabilizer may be added according to the requirement. , shape 2, adhesive, disintegrant, lubricant, etc., into tablets, granules, powder: powder, capsules and other solid agents, usually made into liquid, suspension, = liquid agent. X ' can also be prepared by adding a suitable carrier before use to a dry product of a second form or a form or other external preparation. For example, when the corn can also be flow-medicinal carrier, it can be prepared according to the dosage form and the form of the preparation, and the preparation can be made into a tablet composition composed of a solid composition, and the preparation can be made into a pill, a capsule, a powder, Fine granules, granules, etc. " Lithium, white sugar, mannitol m cellulose, inorganic salts and other pharmaceutical carriers. Further, in the case of preparing an oral agent, a booster or a bridge-like agent, in the case of a tablet or a sugar-coated or a stomach, a candied sugar, a gelatin, or a (tetra)-based cellulose can be used from a thin layer of a liquid combination substance. Coating. In the case of the oral preparation of the composition of the milk and the gas, it can be made into a pharmacy (2) 192.doc ^suspension agent, syrup, etc., for example, using purified-13-200823219 water, ethanol, etc. As a carrier. ^ . m ^ can also be added as required: such as moisturizing agent: auxiliaries 'sweeteners, seasoning swords, preservatives, etc. = on the one hand, ^ when made into a non-oral preparation, by The above-mentioned active ingredient of the present invention_water, physiological food whole::::::: as a sweeping agent for injection of sesame oil, peanut oil 'soybean oil=,: liquid two-shot vegetable oil, medium, iP aunt two... %, polyethylene glycol, etc. are to be added with a fungicide, a stabilizer, an isotonic agent, an analgesic agent, etc. = a solid composition is prepared in 2 bacillus, and the solid composition is cold-dissolved in a non-reading water or a sterile injection before use. Used as a solvent, as a topical agent, containing a solid, semi-solid, H-mucosal membrane for administration in a cavity (intra-sigma, nasal, or sputum), or a liquid preparation. Also, including For example, it can be used as an emulsion for emulsions and lotions, and for liquid preparations such as F (iv), oily ointment, and hydrophilic. Soft sputum, etc. = 'membrane sword, patch, paste, etc. for transdermal administration or two kinds of patching agents, etc. 1 together with = various forms of preparation of medicines' can use known medicines, respectively, appropriately In accordance with the conventional method, the amount of the medicine is considered to be the form of administration, the method of administration, etc., and the effect is as follows: The content of the active ingredient in the medical treatment is usually from 1 to 10. The method of the medicine according to the form of the preparation according to the form of the preparation is not particularly limited, and for example, it can be used internally or externally. In the case of administering the medicine of the present invention by injection, 123192.doc -14. 200823219, administered subcutaneously, intradermally, etc., as an external preparation such as a suppository, may be, for example, intravenously or intramuscularly When it is administered by external use, for example, it is administered via a method suitable for its administration. This: The dosage of the medicine of Ming is based on the form of the preparation, the prescription of the disease, and the use of ^ The object is the appropriate setting of the patient's age, weight, and symptoms. , is not fixed. On the top, f ancient ^ 4 \, and a, based on the dosage of the above-mentioned active ingredients contained in the preparation, it is better to be a warrior's mother's day is 〇·1 ton~5 ΓΓ 1,2 g/kg body weight, more preferably 1. (4): g weight. Of course, the amount of administration varies depending on various conditions, and thus the amount of the above-mentioned agent 1 may be sufficient, or sometimes it must exceed the range. The trr is expected to be administered in a single dose within a range of days, or;: to be administered. The administration time is also arbitrary. X, the medical beam of the present invention can be directly administered orally. It is a daily intake of any food. 2 In another aspect of the present invention, there is provided a method of using the above-mentioned medicine for the treatment of π. The treatment method of the disease is characterized in that the medicine containing the above-mentioned active ingredient is administered to hyperlipidemia, hypercholesterolemia, q-glyceraldehyde monophosphateemia, metabolic syndrome, and multiple risk factors for comprehensive atherosclerosis. , ischemic heart disease, acute myocardial infarction, instability, human pain, ischemic sudden death, cerebrovascular disease, chronic obstructive arteriosclerosis, sacral infarction, angina pectoris, cerebral infarction, subarachnoid hemorrhage, obesity or The temple is a patient with a disease caused by the cause. Furthermore, the technical and various conditions of the medical treatment can be applied in accordance with the disclosure of the above-mentioned pharmaceutical investment. 123192.doc -15- 200823219 Two kinds of _ made... ^, pentyl lactate-3,, 4,_ dihydroeridate lactone ^ t , as 3,-acetoxy-4, _ different The pentenoloxy-3,4,-dihydrogen scorpion 酉曰' contains the above-mentioned salts of the above-mentioned street organisms and pharmacy. ACm provides a food or forage (in the present specification, a food of the present invention; or a feed) containing the above-described acat# preparation of the present invention. The food or feed of the present invention is produced by the present invention:::acat>; for the treatment or prevention, acat == disease, that is, the above various diseases applicable to the medicine of the present invention;; Extremely useful. Namely, the food of the present invention is used as a pre-use. : The functional food for the purpose of the above-mentioned diseases (Special Health Care 2: etc.) is extremely useful 'for those who are worried about blood cholesterol levels, those who are worried about the mouth' are worried about body fat. In the specification of the present patent application, "the so-called food also includes a drinker" is used in the food or feed of the present invention, and "containing" means containing or diluting. Here, "contains" means food or feed: the package: the aspect of the active ingredient used in the invention, and the "addition" aspect, the raw material used for adding the food or feed to the active ingredient used for dilution The food to be used in the present invention is not particularly limited, and examples thereof include: the starch-containing product..., the processed product of the product (the processed wheat flour, the alpha product, the noodle, the macaroni, the bread) 123192.doc -16 - 200823219 Flavor (soy sauce (beef cover rice food, etc.) Mai Yi Yi I instant instant coffee, cooking drinks, categories, museums, wheat, bran, rice noodles, fans, packaging cakes, etc.) , oil processing, (plastic oil, tempura oil, salad oil, mayonnaise, salad dressing, etc.), processed soybean products (tofu, miso, natto, etc.), processed meat products (ham, enzyme meat, Italian raw Ham, sausage, etc.), aquatic products (cold bunched fish, fish plate, bamboo wheel, fish meat word cake, fried fish fillet, life ball, skin fish paste, fish ham, sausage, bonito, fish print processing Products, canned aquatic products, sea Flavored vegetables, etc., dairy products (raw milk, emulsifiable concentrate, sour milk road, cream, milk, condensed milk, milk powder, ice cream, etc.), vegetables, processed fruits (sauce, jam, pickles, fruit drinks) , vegetable drinks, mixed drinks, etc.), snacks (chocolate, biscuits, pastries, cakes, cakes, rice crackers, etc.), alcoholic beverages (曰本酒, Chinese wine, wine, whiskey, shochu, vodka, brandy , gin, liqueur, beer: 酉, clear: alcoholic beverages, fruit wine, liqueur, etc., hobby drinks. Green tea, black tea, oolong tea, coffee, refreshing drinks, lactic acid drinks, etc.), sauces, sauces, Vinegar, cooking wine, etc.), canned, bottled, bagged food, small steel painted rice, red bean glutinous rice, curry, other kinds of hen, semi-dry or concentrated food (liver mud, other spread food, smashing soup, etc.) ), dry foods (bubble, instant curry, juice powder, powder soup, ready-to-eat bean sauce, cooking food, lamb soup, etc.), frozen food (Japanese beef hot pot, steamed egg, slow-fried fish fillet, Burger Stew, siu mei, dumplings, various sticks, assorted fruits, etc., solid foods, liquid foods (soups), spicy seasonings, and the like, agricultural products, processed products, processed products, aquatic products, etc. The food is contained, added, and/or diluted separately or plurally. 123192.doc -17- 200823219 The above-mentioned effective ingredient 'the content is equivalent to the amount necessary for expressing ACAT inhibition', and the shape thereof is not particularly limited. Also included in the form of a powder, a tablet, a granule, a capsule, or the like which can be orally ingested. Further, the food of the present invention may be directly the active ingredient of the present invention or may be suitably emulsified. The food or the excipients and the like are appropriately mixed. The foods can be eaten directly or mixed with water to prepare a beverage. Further, in the case of the food of the present invention, the active ingredient of the present invention can also be used with various plants ( Juices of vegetables or fruits are mixed to make a healthy drink. For example, the active ingredient of the present invention may be diluted with water, or it may be combined with Peony wind, Peucedanum praeruptorum, tomorrow leaf, parsley, celery, licorice, mandarin, small pine, kohlrabi, Chinese cabbage, tomato, orange, #棣, grapefruit, kiwi, spinach, carrot, radish, cabbage, broccoli &cabbage; lettuce, leeks, okra, sweet pepper, cucumber, four seasons, hair, peas, corn, garlic, arugula Juices such as sputum, summer orange, sweet summer orange, etc., or mixed with cow's milk, soymilk, etc. to make a healthy drink with AC AT inhibition. Further, as a food aspect of the present invention, 3, _ ethoxylated oxime is an active ingredient (participating component), and includes the following aspects: A plant-treated product such as a peony wind-proof extract or a pulverized product, a squeezed juice, or the like, which directly produces an effect of the active ingredient of the present invention, for example, a food for a specific health care. - The content of the above-mentioned active ingredient of the food towel of the present invention is not particularly limited, and may be appropriately selected from the viewpoints of its functional and performance activities, for example, the active ingredient of the present July in the food, preferably 0.00001% by weight or more. 123192.doc -18- 200823219 More preferably, it is 0.0001 to 10% by weight, more preferably 〇〇〇〇6 to 6% by weight. The method for producing the food of the present invention is not particularly limited. For example, the preparation, the conditioning, the processing, and the like may be carried out according to the method for producing a general food, and may be produced by using the above-described production methods, and the obtained food may contain the above-mentioned effective component of the present invention having an ACAT inhibitory action. The food of the present invention, for example, is preferably 〇·i called 〜5 g/kg body weight, more preferably 1 〜2 g/kg body weight, more preferably 〜1 g/kg body weight. The active ingredient of the present invention may be used. Moreover, the present invention provides a biological feed comprising the above-mentioned active ingredient, that is, containing, adding and/or diluting the above-mentioned active ingredient, which has an ACAT inhibitory action; further, as another aspect, a biological feeding method is also provided. It is characterized in that the above active ingredient is administered to a living being. Further, as another aspect of the present invention, there is provided a biological feeding agent characterized by comprising the above active ingredient. In the present specification, the organism is not limited, and examples thereof include culture animals, pet animals, and the like. As for farmed animals, animals such as horses, cattle, pigs, sheep, goats, camels, llamas, experimental animals such as mice, rats, guinea pigs, rabbits, chickens, ducks, turkeys, ostriches, etc., fish, Crustaceans or shellfish. As for pet animals, dogs, cats, and the like can be exemplified. As for the feed, a feed for maintaining and/or improving the body condition can be exemplified. As the biological feeding agent, an impregnation agent, a feed additive, and a beverage additive can be exemplified. According to the inventions, in the organisms as exemplified above, the ACAT inhibitory action of the above-mentioned active ingredient used in the present invention can be expected to exhibit the same effects as the above-mentioned medicine of the present invention. That is, the 123192.doc -19-200823219 of the present invention feeds a disease requiring acat inhibition in the treatment or prevention of the organism, such as atherosclerosis or hyperlipidemia, and the disease caused by the disease can be treated. Or preventive effects. The above-mentioned effective ingredients used in the present invention are usually preferably 0.1 to 5 g/kg body weight per day, more preferably Si 2 to 2 g/kg body weight, more preferably 10 times to 丨g/ The kg body weight was administered. The administration can be carried out, for example, by mixing and mixing the active ingredient in the raw material of the artificially-prepared feed of the donor organism or by mixing it with the powder raw material of the human-controlled feed, and then adding and mixing it to the other raw material. χ, the content of the above-mentioned active ingredient in the feed is not particularly limited, and may be appropriately set according to the purpose. For example, it is preferably 〇01% by weight or more, more preferably 〇〇〇〇1 to 1〇 by weight. %, i is 〇·〇_~6 wt%. The content of the active ingredient of the present invention in the substance-raising agent may be set to the same level. The method for producing the feed of the present invention is not particularly limited, and may be formulated in accordance with the method for producing a conventional feed. The raw ingredient of the present invention having an ACAT inhibitory action may be contained in the feed to be produced. The biological feeding agent can also be prepared in the same manner. In the present invention, for example, a feed containing the above-mentioned active ingredient used in the present invention having an ACAT inhibitory action is ingested, or a target organism is impregnated with the above-mentioned active ingredient contained in the present invention (for example, I will be described). The impregnation agent is dissolved in the water, whereby the physical state of the cockroach, the experimental animal, the pheasant, the dragon animal, and the like can be well maintained or improved. Furthermore, the sadness is the result of the method of feeding the living organism of the present invention. The above-mentioned effective ingredient ' used in the present invention will not be found to be toxic even if it is administered in an effective amount to 123192.doc -20-200823219. For example, in the case of oral administration, 'even if 1 g/kg body weight of 3'-B-oxy-oxymoxy-3,4,-dihydroartemisia (4) is administered to mice in a single case. . Further, when the active ingredient was administered orally to the rats, no death was observed even if the phantom g/kg body weight was administered early. EXAMPLES The present invention will be more specifically illustrated by the examples, but the present invention is not limited by the scope of the invention. Furthermore, the caution record indicates "capacity%". If the preparation is not specifically prepared, 丨31-B, ethoxylated _4, _ isoflavone, oxygen, m-lactone, preparation f, i (1), smashed the cold stalk of the peony leaf blade 2 L of 60% ethanol was added to 〇〇g, and the mixture was extracted and extracted at room temperature for about 3 minutes, and the mixture was separated into an extract and a residue by suction. Then, the residue was repeatedly subjected to an extraction operation using 2 L of the same solvent. The extract obtained was collected, concentrated by a rotary evaporator, and extracted for removal of sugar: 40% ethanol, and the obtained extract was concentrated again. Finally, it was dissolved in 50 mL of 20% ethanol to obtain a peony windproof 6〇% ethanol extract. (7) The peony windproof 60% ethanol extract obtained from the preparation of the sample (1) was separated by reverse phase chromatography. As the resin, Cosmosil 75C18-〇PN (200 mL, manufactured by Nacalai Co., Ltd.) equilibrated with 2% by weight of ethanol was used. After the peony windproof 60% ethanol extract is added to the resin, it is in the order of 2〇〇% ethanol, 3.4 L of 40% ethanol, 16 L of 6〇% ethanol, and JB 8〇% ethanol. Dissolution is carried out. 123192.doc -21 - 200823219 (3) The i 6 l to 2 L portion and the 2 L to 2.4 L portion of the 40% ethanol eluate obtained in Preparation Example 1-(2) were concentrated by a rotary evaporator. Finally, it was dissolved in 5 mL of 40% ethanol to prepare peony windproof c〇sm〇sU: part-1, peony windproof Cosmosil separation part-2. (4) The peony wind-proof Cosmosi 丨 separation part _丨 and the peony wind-proof c〇sm〇sU separation part obtained in the preparation example i_(3) were separated by reverse phase chromatography. TSK gel 〇DS-80Ts (20 mmx25 em, manufactured by Tosoh Corporation) was used for the column. The solvent was distilled water: acetonitrile = 30: 7 Torr (capacity ratio), dissolution rate was 5 mL/min, and detection was carried out under the conditions of UV: 215 nm. The eluate was separated by ultraviolet absorption of the eluate as an index. (5) The fraction obtained in Preparation Example 1-(4) containing a peak having a holding time of 33.3 minutes was concentrated by a rotary evaporator. Finally, it is dissolved in dimethyl sulfoxide of i〇 to obtain a separation part of the peony windproof reverse phase column. (6) Using a nuclear magnetic resonance (NMR) spectroscopy apparatus (avance type 6 ,, manufactured by Bmker Biospin Co., Ltd.), various separations of the peony windproof reverse phase column obtained in Preparation Example 1-(5) were carried out. Spectrometry. Further, mass spectrometry was measured by an ion spray method using a mass spectrometer (API3000, manufactured by Applied Biosystems). According to the results of NMR spectroscopy and mass spectrometry analysis, it was confirmed that the separated part of the peony windproof reverse phase column was 3,_acetoxy-4'-isopentenyloxy_3', 4' represented by the above formula (1). - Dihydrogenella vinegar (3'-ACet〇xy-4'-tigl〇yl〇Xy_3,, 4,-dihydr〇SeSelin). Example 1 (1) Preparation of microsomes of rats Four Sprague-Dawley rats were reared and then sacrificed, immediately 123192.doc -22-200823219 The liver was removed and gently washed with cold saline, and then impregnated (25 mL). /l only) in sucrose buffer (0.3 sucrose, 50 mM tris-HCl, 1 mM EDTA, 50 mM NaCl, pH 7.4). The obtained liver was homogenized, centrifuged at 10,000 x g for 30 minutes, and the precipitate was removed, and the operation was repeated twice. The obtained supernatant was centrifuged at 10,00 Torr x for 70 minutes, and the precipitate was collected and suspended in an appropriate amount of 100 mM phytic acid buffer (pH 7.4). The suspension was again suspended in a phosphate buffer to have a protein concentration of 10 mg/mL, and EDTA was added to have a final concentration of 1 mM, and then stored at -80 ° C until use. (2) Measurement of ACAT inhibitory activity The enzyme activity of ACAT was measured in accordance with the method of Lee et al. (Planta Med, 2004, 70, pp. 678-679) and was partially modified. An aqueous solution containing 1.5 pL of rat liver microsomes prepared in Example 1 -(1) in a 1.5 mL eppendorf tube (microcentrifuge tube) (0.05 Μ acid-depleted, 1 mM disulfide) Add 1 g of 3'-acetoxy-4'-isopentene prepared in Preparation Example 1 with threitol, 9 mg/mL fatty acid-free bovine serum albumin, 200 pg/mL cholesterol, pH 7.4) The methoxy-3',4'-dihydroeridate lactone dimethyl hydrazine solution was brought to a final concentration of 14 pg/mL, and incubated at 37 ° C for 30 minutes. Further, as a control portion, a portion in which a compound is added only with a dimercaptosulfoxide solution is added, and as a positive control, a compound FR179254 (final concentration: 10 μM, manufactured by Merck, 344235) to which ACAT inhibitory activity is known is added. section. Thereafter, 2 μί 0.05 μCi/mL of Oleoyl Coenzyme A [oleoyl-9,10_3H]_ (Morman® Molyse Biochemicals, MT1649) and 5 pL of 0.2123192.doc -23-200823219 mg/mL of Oleoyl Coenzyme A ( A mixed solution of ICN Co., Ltd., 591-20521) was added to each tube and mixed, and then kept at 37 ° C for 5 minutes. Thereafter, the reaction was stopped by adding 0.5 mL of a solution of isopropyl alcohol: heptane = 4:1 (capacity ratio) to each tube. Add 0.2 mL of 0.1 Μ potassium phosphate solution (pH 7.4) and 0.3 mL of heptane to each tube and stir for 15 seconds, then centrifuge for 15 seconds, and use the upper layer 15 μμΕ to obtain ULTIMA GOLD. (PerkinElmer Life Sciences Co., Ltd., 6013329) As a scintillation counter, the radioactivity was measured using a liquid Scintillation Counter LS6500 (manufactured by Beckman Co., Ltd.). Further, each reaction system was subjected to secondary radioactivity, and the average value was calculated. The AC AT inhibitory activity (%) of the test sample was calculated by adding the positive control, i.e., FR179254 of 1 〇, to 1 〇〇〇/0 by the following formula. Inhibitory activity (%) =={([radiation activity (cpm)H of the control part of the test sample added part of the radioactivity (cpm)]) / ([Control part of the radioactivity (cpm) MlO μΜ of the FR179254 addition part Radioactivity (cprn)]) χΙΟΟ As a result, the inhibitory activity of 3'-acetoxy-4'-isopreneoxy-3,4,-dihydroartemisinide was 164%, and it was found Significant ACAT inhibitory activity. According to the invention 'providing an ACAT inhibitor comprising 3'-acetoxy-4,-prenyl decyl diterpene lactone, a derivative thereof and/or a pharmaceutically acceptable salt thereof, Contains medicines, foods or feeds. This medicine is useful as a therapeutic or prophylactic agent for atherosclerosis or hyperlipidemia, and diseases caused by such diseases. Further, the food can be improved or prevented by the ingestion as a regular food. Therefore, the food containing the active ingredient of the present invention containing 123192.doc -24-200823219 is a functional food which is useful for maintaining the constantity of the living body by its ACAT inhibitory action. 123192.doc -25-

Claims (1)

200823219 X. Patent application scope: 1. 2. 2. - A sulfhydryl-based COA cholesterol thiol transferase inhibitor, characterized by: containing a methoxy-3, which is selected from 3,-ethyloxybutanyl 4,_Dihydrolactone, a derivative thereof, and a salt of the pharmaceutically acceptable salt: one or more of them as an active ingredient. The inhibitor of this. (4) A medicine according to claim 1, characterized in that it contains a food or feed according to claim 1, which is characterized in that it contains 123192.doc 200823219 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 123192.doc