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 九、發明說明： 【發明所屬之技術領域】 本發明係關於-種具有醯基coA膽固醇醯基轉移酶抑制 作用之對治療或預防動脈硬化症、高脂血症等為有用之來 自天然物之成分。 【先前技術】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]

近年來’隨著大量攝取高卡路里、高膽固醇食品之飲食 的灸化或由於平均#命的延長而導致高年齡層增 加’動脈硬化症、高脂血症、高血壓症、糖尿病此類所^ 生活習慣病急速地增加，成為大的社會問題。 動脈硬化症的初期耗巾可見稱為脂料條之斑點狀或 線狀之脂肪堆積。該變化主要係由於經泡沫化之巨噬細胞 堆積於血管内皮上所致。巨嗟、細胞之泡珠化，係藉由巨嗟 ’田胞攝入灸f生LDL且生成游離膽固醇，被醯基c〇a膽固醇 醯基轉移酶酿化’再將其蓄積而引起。如此之初㈣沫化 細胞病變發展成包含血管平滑肌細胞的泡沫化之複雜病 變。脂肪線條不久變成纖維性硬斑而於血管壁上突出，進 而若病變發展則伴隨石灰化、血栓附著，而使血管腔變窄 或者使硬斑破裂而導致錄性阻塞。χ，亦已知有，易於 破裂之硬斑包含許多膽固醇醋等脂f成分。以，業者期 待藉由抑制醯基C〇A膽固醇醯基轉移酶之活性，而導致動 脈硬化病變的穩定化及消退，降低基於動脈硬化或高脂丘 症之急性冠心症的發病或復發。又，已知藉由抑制酿基 CoA膽固醇醯基轉移酶活性，而降低於肝臟中形成腳l 123192.doc 200823219 構成之膽固醇酯的人 腸中膽固醇之醋鍵：成減少VLDL合成’或者抑制於小 -鍵、、、。且降低膽固醇之吸收， 少灰中膽固醇、血中中性脂肪。 因此了』待減 牡丹防風係學名A p 」 於水芽科河原防㈣ anum japoni_(日本前胡）屬 場m 〃屬之多年生草本植物，生長於海岸的岩 ~或草地，贫之古由从、 出 门又…〇〜100 cm，若到花期之6〜9月則開 為1二咸：白色化。就其生理活性而言，於原產地沖繩認 亩：二S '、疲勞恢復、滋養強壯具有效果，自古以來一 氺制♦重視於最近的研究中亦瞭解到，牡丹防風具有 ^ “症之效果（例如，非專利文獻1)、抑制二糖類分解酶 (例如專利文獻U、抗氧化作用（例如，專利文獻 、非專利文獻2)、細胞活化作用（例如，專利文獻2)、抑 U素產生作用（例如，專利文獻2)。 料牡丹防風所含之特徵性化學成分，已知有多種香豆 素行生物’業者對其癌促進劑抑制作用等進行了研究（例 如’非專利文獻3)。 專利文獻1:日本專利特開2003-26694號公報 專利文獻2.日本專利特開2004-26697號公報 非專利文獻 1 ·· T.Morioka 其他 8 名，Caneer Letters， 2004年，第2G5卷，第133]41頁 非專利文獻 2 : M.Hisamoto 其他 2 名，J.Agric.Food Chem·’ 2004年，第 52卷，第 445_45〇 頁 非專利文獻 3 : B.Fan 其他 5 名，journai of japaneseIn 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年，第 75卷，第 4期，第 257.261 頁 123192.doc 200823219 【發明内容】 若概述本發明，則本發明之第一菸 ^發明係關於一種醯基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.

CoA膽固醇醯基轉移酶抑制劑，其特徵在於：含有選自由 3’-乙醯氧基_4’_異戊烯醯氧基_3丨，4，_二 杜 ^ 氧邪向内S旨、其衍生 物及藥學所容許的該等之鹽组成之雜 、欣之群之一種以上作為有效 成分。 本發明之第二發明係關於—種醫藥，其特徵在於：含有 , 本發明之第-發明之酿基coA膽固醇酿基轉移酶抑制劑。 、 |發明之第三發明係關於-種食品或飲料，其特徵在 於：含有本發明之第-發明之酿基coA膽固醇酿基轉 抑制劑。 【實施方式】 本發明係關於-種可安全簡便地攝取之、㈣適於作為 原材料、醫藥品原材料之具有醯基μ膽固醇酿基轉 移酶抑制作用的物質之醫藥、食品或飼料。 i 根據本發明’提供-種醯基coA膽固醇醯基轉移酶抑制 劑、含有該抑制劑之醫藥、食品或甸料，該酿基c〇a膽固 醇醯基轉移酶抑制劑含有選自由作為來自天然物的成分之 3’-乙醯氧基术異戊婦醯氧基_3,，4,_二氫邪蒿㈣、其衍生 物及藥學所容許的該等之鹽所組成之群之一種以上作為有 效成分。上述抑制劑、醫藥、食品或飼料對於高脂血症、 二脈硬化、由該等所導致之疾病為有用，其中本發明之食 扣作=具有醯基CoA膽固醇醯基轉移酶抑制作用之對生物 體匣“生維持為有用的機能性食品為有用。 123192.doc 200823219 酿基CoA膽固醇醯基轉移酶（別名，亦稱為醯基c〇a ·•膽 固醇酿基轉移酶；以下，簡稱為ACAT)係將長鏈脂肪酸 自酿基CoA轉移至膽固醇，且催化膽固醇酯合成之酶。 ACAT抑制作用，可使用如下述實施例1中記載之檢定系統 來簡便地1測定。即，可藉由將被驗物質與包含ACAT之酶 源加以混合’且對自經放射線標識之Oleoyl-CoA向膽固醇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基之轉移進行評價，而簡便地測定acat抑制作 用。 下述式（I)表示3f-乙醯氧基-4，-異戊烯醯氧基-3，，4，-二氫 邪萬内自旨（以下，稱為本發明之化合物）之結構式。 [化1]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]

-亥化合物為牡丹防風或前胡（peucedanum praerupt〇rum) 中所3之物質，於本發明中最初已明確具有acat抑制作 用。即，作為本發明之有效成分，係使用3，_乙醯氧基_4，· 異戊烯醯氧基_3’，4»_二氫邪蒿内酯、其衍生物及/或藥學所 容許的該等之鹽（以下，將該等全部稱為本發明之有效成 分）。 作為本發明之化合物之製造方法，並無特別限定，可使 用斗丹防風或剞胡（peucedanum praer叩t〇『um)作為原料， 123192.doc 200823219 例如如製備例1所記載，可由牡丹防風的乙醇萃取物進行 各種層析而獲得。再者，於使用牡丹防風作為原料之情形 時並無特別限定，可直接使用果實、種子、種皮、花、 葉、莖、根、根莖及/或植物整體，但較好的是使用葉及/ 或莖。又，於合成本發明之化合物之情形時，亦可藉由組 合公知的方法而獲得。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.

再者，於本說明書中，所謂3，_乙醯氧基_4，-異戊烯醯氧 基二氫邪蒿内酯，即使為所有的光學異構體、__烯 醇互變異構體、幾何異構體等各種異構體，只要具有 ACAT抑制作用則全部可使用於本發明。 於本專射請說明書中，作為衍生物，例如若為於上述 3’_乙醯氧基本異戊烯醯氧基_3,，4,_二氫邪蒿内醋之骨架令 職有各種取代基、且可發揮所期望之效果相無特別限 定。至於取代基，例如可舉出：脂肪族基⑽、乙基、 正丙基等直鏈狀脂肪族基或異丙基、異丁基、異戊二稀 基:香葉基等分枝狀脂肪族基），芳香族基（苯基、蔡基、 聯苯基、料基、㈣基等），料脂肪族基（节基、苯乙 基等）、㈣、幾基、硫酸基、嶙酸基、硫醇基、胺基、 石肖基:烧乳基（甲氧基等）、醯氧基（乙酿基等）、_素（氣、 演、氟等）。又，例如，腺士义 將本表明之化合物投與哺乳類而 可被代謝之物質亦包含於本發明之衍生物中。 1下馬本發明所使 一友一 乳丞-4 -異戊烯峨軋丞〇.，, 一風邪高内酯或其街& & _ 订生物之鹽，較好的是藥學所容許 I。至於本發明所使用 ^ 例如可例不鹼金屬鹽、鹼 123192.doc 200823219 類金屬鹽、與有機驗形成之鹽等。再者，所謂本發明中使 用之樂學所容許之鹽，意指對生物實質上為無毒且且有 ACAT抑制作用之化合物之鹽。至於該鹽，例如可舉出： 納、鉀、軒、鎮、錢或經質子化之节星化合物_，-二节 基乙二胺)、膽鹼、乙醇胺、二乙醇胺、乙二胺、 糖胺⑻甲基葡糖胺）、苯明㈣基苯乙胺）、派嗪或相 基丁三醇（2-胺基-2-羥甲基q，％丙二醇）之鹽。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).

本發明之化合物之衍生物可利用該領域公知的方法而製 作。又，本發明之化合物或衍生物之鹽’亦可由業者利用 該領域公知的任意方法而容易地製作。 本發明之有效成分為自古以來—直被食用之牡丹防風中 所含有之化合物’肖目前為止已知的具有acat抑制作用 之合成化合物（例如，下述FR179254)進行比較，安全性較 高、未特別發現如下述之毒性，亦無須擔心產生副作用。又 因此，可安全且適當地治療或預防疾病。因此，含有該有 效成分之ACAT抑制劑（以下，稱為本發明之acat抑制劑） 對治療或預防需要ACAT抑制作用之疾病為有效，作為下 述醫藥、食品或飼料之原材料為有用。又，本發明之 ACAT抑制劑，對於治療或預防需要ACAT抑制作用之疾 病，例如動脈硬化症或高脂血症、以該等為病因而引起之 疾病之藥物篩選亦為有用。進而，該ACAT抑制劑，對膦 固醇酯生成機制研究、或向由此引發之高脂血症、動脈硬 化症等上述疾病的發展有關之機制研究亦為有用。 作為本發明之ACAT抑制劑’若為含有上述本發明之有 123192.doc -11- 200823219 放成刀者則無特別限定，例如，可直接為本發明之有效成 为’或者含有本發明之有效成分之組合物。即，考慮該 ACAT抑制劑之使用目的等，該ACAT抑制劑中上述有效成 分之含量若為可表現本發明所期望效果之量即可，並無特 別限定。作為本發明之ACAT抑制劑中有效成分之含量， 通吊為1〜1〇〇重量〇/0左右。又，該ACAT抑制劑之使用量， 亦若為可表現本發明所期望效果之量則無特別限定，於投 與生物使用之情开> 時，較好的是，若以可於下述本發明醫 藥之有效成分投與量的範圍内投與有效成分之量而使用即 可。對於投與方法並無特別限定，若與下述醫藥同樣地適 當設定即可。又，對於使用形態並無特別限定，亦可根據 使用用途製造成適當之形態。 又’本發明亦提供一種含有本發明之ACAT抑制劑之醫 藥（以下，亦稱為本發明之醫藥）。本發明之醫藥對治療或 預防中需要ACAT抑制作用之疾病為有用，對於該疾病並 無特別限定，例如可例示：高脂血症、高膽固醇血症、高 甘油二酸酯血症、新陳代謝綜合症、多危險因素綜合症、 動脈硬化症、缺血性心臟病、急性心肌梗塞、不穩定心絞 痛、缺血性猝死、腦血管障礙、慢性阻塞性動脈硬化症、 心肌梗塞、心絞痛、腦梗塞、蜘蛛膜下出血、肥胖症或者 以該等為病因而引起之疾病（例如，參照〇，R〇urke等人，j·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·，2002,277(45)，第 42557-42562 頁，Ohishi 等 人，Biol· Pharm. Bull·，2003,26(8)，第 1125-1128 頁，及 Ohishi等人，Chem· Pharm. Bull·，2001，49⑺，第 830-839 123192.doc -12- 200823219 頁）。 作為本發明之醫藥，可舉出將作為本發明之acAT抑制 劑使用之上述有效成分與公知的醫藥用載體組合而製成製 d者。又，作為本發明之醫藥，亦可將本發明之有效成分 與可使用於與如上述之該有效成分為相同用途的其他成分 進行調配。 γ2發明之醫藥之製造，通常係藉由將上述有效成分與可 藥學所容許之液狀或固體狀載體加以調配而進行，根據要 t可添加溶劑、分散劑、乳化劑、緩衝劑、穩定劑、賦形 2、黏合劑、崩解劑、潤滑劑等，製成錠劑、顆粒劑、散 劑：粉末劑、膠囊劑等固形劑，通常製成液劑、懸浮劑、 =等液劑。X ’亦可製成於使用前添加適當的載體而成 二/文狀之乾燥品、或其他外用劑。 例如 玉米 亦可 流動 -藥用载體’可根據醫藥之投與形態及製劑形態加以選 二製成由固體組合物所構成之經口劑之情形時，可製 刈丸劑、膠囊劑、散劑、細粒劑、顆粒劑等 " 隸、白糖、甘露醇m纖維素 、無機鹽等醫藥用載體。又，當製備經口劑時 促進劑、橋味劑 机動 丸劑之情形時，於製成錠劑或 等糖衣或者胃n ’可用庶糖、明膠、㈣基纖維素 由液體組合性物質的薄臈進行包衣。於製成 許之乳、气”物所構成之經口劑之情形時，可製成藥學所办 ⑵ 192.doc ^懸濁劑、糖漿劑等，例如利用純化 -13- 200823219 水、乙醇等作為載體。 ^ . m ^ 亦可根據要求添加如濕潤 :。于叙辅助劑’甜味劑，調味劍，防腐劑等。 =一方面，^製成非經口劑之情形時，可藉由依 將本發明之上述有效成分 _水、生理食整::::::::作為掃釋劑之注射 芝麻油、花生油'大豆油=，:液二射用植物油、 中，iP姑兩 … 丙一％、聚乙二醇等 要添加殺菌劑、穩定劑、等張劑、止痛劑等而 =於2菌Γ製造固體組合物，於使用前將固體組合物 冷解於無讀水或無菌注射用溶劑中使用。 作為外用劑，包含經^^ _ 腔内）投與用之固體、半固二H黏膜（σ腔内、鼻 栓判耸η 丰固體狀或液狀製劑。又，亦包含 =。例如’可製成乳劑、洗劑等乳濁劑，外 於f投與用㈣等液狀製劑，油性軟膏、親水性軟暮等 =’膜劍、貼劑、糊劑等經皮投與用或經二 之貼附劑等。 1又齊用 用=之各種製劑形態之醫藥’可分別利用公知的醫藥 、適當地依照常法進行製造。又，該醫藥中 量’考慮其投與形態、投與方法等，較二:效 定：作為=量範圍内投與該有效成分之量則無特別限 重量%左右/之醫樂中有效成分之含量，通常為1〜10。 鱼本=之醫藥係根據製劑形態以適當的投與方法進行投 i注射推投Λ方法亦無特別限定，例如可經由内用、外用 、仃投與。於經由注射投與本發明之醫藥之情形 123192.doc -14. 200823219 皮下、皮内等投與，於 作為栓劑等外用劑，可 時’例如可經由靜脈内、肌肉内、 經由外用而投與之情形時，例如， 經由適於其之投與方法而投與。 本：明之醫藥之投與量，係根據其製劑形態、投與方 症壯而、^ +的用#對象即患者的年齡、體重、 症狀而適當設定，並非固定。一 之上、f古^ 4 \ 、又而a ，以製劑中所含有 之上述有效成分之投與量計，成 ^ 战人母天較好的是〇·1吨〜5 ΓΓ 1，2g/kg體重、更好的是1。㈣ :、g體重。當然投與量根據各種條件而變動，故而有時以 於上述劑1之量亦為充分，或者有時亦必須超過範圍。 trr望之投與量範圍内叫天内可進行單次投與、或者 ;: 進行投與。用藥時間亦為任意。X，本發明之醫 梁可直接經口投與’此外亦可添加於任意的食品中而日常 性攝取。 2為本發明之其他態樣，提供一種使用上述醫藥之疾病 之/π療方法。該疾病之治療方法之特徵在於：將含有上述 一 之有效成分之醫藥投與高脂血症、高膽固醇血症、 q甘油一酸酯血症、新陳代謝綜合症、多危險因素綜合 疒動脈硬化症、缺血性心臟病、急性心肌梗塞、不穩定 、人痛、缺血性猝死、腦血管障礙、慢性阻塞性動脈硬化 症、虮梗塞、心絞痛、腦梗塞、蜘蛛膜下出血、肥胖症 或者以兮榮 吟寺為病因所引起之疾病的患者。再者，就該醫藥 之技與之各條件而言，可依照上述醫藥投與之揭示而 施。 123192.doc -15- 200823219 二種_ 造… ^、戊稀酿乳基-3，，4，_二氫邪蒿内酯之用 ^ t ，作為3，-乙醯氧基-4，_異戊烯醯氧基-3·，4，_二氫邪 同酉曰’包含上述街生物、藥學所容許之該等之鹽。 ACm提供—種含有上述本發明之acat#制劑而成之 用食品或飼科(於本說明書中，稱為本發明之食 ;或飼料)。本發明之食品或飼料，藉由本發明之有效成 :::^acat>制作用’而對治療或預防中需要acat ==疾病、即本發明醫藥可適用之上述各種疾病的 ;=或：療極為有用。即，本發明之食品，作為以預 用入。:或療上述疾病為目的之機能性食品（特定保健 二“:等)極為有用’對擔心血中膽固醇值的人士、擔心 口 的人士 ’擔心體脂肪的人士而言係極為有用^食 ^ ，於本專利申請說明書中’所謂食品亦包含飲 再者’於本發明之食品或飼料中，所謂「含有」意指含 或稀釋。此處，所謂「含有」係指食品或飼 :包：t發明所使用之有效成分之態樣，所謂「添加」 之態樣，所謂「稀釋明所使用之有效成分 添加食品或飼料的原料所使用之有效成分中 ^為本發明之食品並無特別限定，例如可舉出：含有本 澱粉類力…、=榖物加工品(小麥粉加工品、 α工品、麵類、通心粉類、麵包 123192.doc -16 - 200823219 味料（醬油 (牛肉蓋飯 調食品等） 麥·儀I屯汁 速溶咖啡、 烹調飲料、 類、館類、筹麥類、麩、米粉、粉絲、包裝餅等）、油脂 加工，(可塑性油脂、天婦羅油、沙拉油、蛋黃醬類、沙 拉醬等）、大豆加工品（豆腐類、味增、納豆等）、肉食加工 品（火腿、酶肉、意大利生火腿、香腸等）、水產製品（冷束 磨碎的魚肉、魚板、竹輪、魚肉山字餅、炸魚片、命备丸 子、帶皮魚膏、魚肉火腿、香腸、柴魚、魚印加工品、水 產罐頭、海味小菜等）、乳製品（原料乳、乳油、酸乳路、 奶油、乳赂、煉乳、奶粉、冰溪淋等）、蔬菜.果實加工品 (醬類、果醬類、醃菜類、果實飲料、蔬菜飲料、混合飲 料等）、點心類（巧克力、餅乾類、糕點麵包類、蛋糕、糕 餅、米菓類等）、酒精飲料（曰本酒、中國酒、葡萄酒、威 士忌、燒酒、伏特加酒、白蘭地、杜松子酒、萊姆酒、啤 :酉、清：酒精飲料、果實酒、甜露酒等）、嗜好飲料。綠 茶、紅茶、烏龍茶、咖啡、清涼飲料、乳酸飲料等）、調 、醬料、醋、料理酒等）、罐裝.瓶裝.袋裝食品 小鋼繪飯、紅豆糯米飯、咖喔、其他各種亨 、半乾燥或濃縮食品（肝泥、其他塗抹食品、騫 浪縮湯類等）、乾燥食品（泡麵類、即食咖喱、 果汁粉、粉末湯料、即食豆醬汁、烹調食品、 羔調湯等）、冷凍食品（日式牛肉火鍋、蒸蛋、 緩魚烤魚片、漢堡牛排、燒賣、餃子、各種棒狀食品、什 錦水果等）、固形食品、液體食品（湯等）、香辣調味料類等 農產·林產加工品、畜產加工品、水產加工品等。 本發明之食品單獨地或者複數地含有、添加及/或稀釋 123192.doc -17- 200823219 上述有效成分’其含量若為相當於用以表現ACAT抑制作 用之必要量’則對其形狀並無特別限定，亦包含粉末狀、 錠劑狀、顆粒狀、膠囊狀等可經口攝取之形狀物。又，作 為本發明之食品’可直接為上述本發明之有效成分，或者 亦包含將其與適當的乳化劑或賦形劑等加以適當混合者。 该等食品可直接食用，或者與水混合製成飲料後食用。 又’就本發明之食品而言，亦可將本發明之有效成分與 各種植物（蔬菜或果實等）的榨汁液混合製成健康飲料。例 如，可用水稀釋本發明之有效成分，或者將其與牡丹防 風、别胡（Peucedanum praeruptorum)、明日葉、香芹、芹 菜、甘草、人蔘、小松菜、大頭菜、大白菜、西紅柿、橘 子、#棣、葡萄柚、奇異果、菠菜、紅蘿蔔、蘿蔔、白 菜甘五菜"拉菜、萵苣、韭菜、秋葵、甜椒、黃瓜、 四季旦、毛旦、豌豆、玉米、大蒜、芝麻菜、枇杷、夏 橙、甜夏橙等的榨汁液，或與牛乳、豆乳等混合而製成具 有AC AT抑制作用之健康飲料。 又作為本發明之食品之態樣，以3，_乙酿氧基卓異戍 ^醯氧基二氫邪蒿内s旨為有效成分（參與成分），亦包 含以下之態樣：將含有其之植物處理物例如牡丹防風之萃 取物或粉碎物、榨汁液等直接製錢待本發明有效成分的 效果之食品，例如特定保健用食品。 —對於本發明之食品巾上述有效成分之含量並無特別限 二’可自其官能及表現活性之觀點進行適當選擇，例如食 中之本七月之有效成分，較好的是0.00001重量％以上、 123192.doc -18- 200823219 更好的是0.0001〜10重量％、更好的是〇 〇〇〇6〜6重量％。 對於本發明之食品之製造方法並無特別限定。例如，調 配、調理、加工等，若依照一般食品之製造方法即可，可 利用該等製造方法而製造，所獲得食品中若含有具有 ACAT抑制作用之本發明之上述有效成分即可。 本發明之食品，例如若以成人每天較好的是〇 · i叫〜5 g/kg體重、更好的是1叫〜2 g/kg體重、更好的是叫〜1 g/kg體重攝取本發明之有效成分即可。 又，本發明提供一種含有上述有效成分，即含有、添加 及/或稀釋上述有效成分而成之具有ACAT抑制作用之生物 用飼料；進而，作為其他一態樣，亦提供一種生物之飼養 方法，其特徵在於：將上述有效成分投與生物。又，作為 本發明之其他一態樣，提供一種生物飼養用劑，其特徵在 於··含有上述有效成分。 於本說明書中，對於生物並無限定，例如可舉出養殖動 物、寵物動物等。至於養殖動物，可例示：馬、牛、豬、 綿羊、山羊、駱駝、美洲駝等家畜，小白鼠、大白鼠、豚 鼠、兔等實驗動物，雞、鴨、火雞、鴕鳥等家禽，魚類、 甲殼類或貝類。至於寵物動物，可例示狗、貓等。至於飼 料，可例示維持及/或改善身體狀態用飼料。至於生物飼 養用劑，可例示浸潰用劑、飼料添加劑、飲料用添加劑。 根據該等發明，於應用該等之如上述例示之生物中，基 於本發明所使用之上述有效成分之ACAT抑制作用，可期 待表現出與本發明之上述醫藥同樣之效果。即，本發明之 123192.doc -19- 200823219 飼料對該生物之治療或預防中需要acat抑制作用之疾 病，例如動脈硬化症或高脂血症、以該等為病因而引起的 疾病可發揮治療或預防效果。 本明所使用之上述有效成分，通常係以對象生物每天 較好的是0.1叩〜5 g/kg體重、更好的Si叫〜2 g/kg體重、 更好的是10叫〜丨g/kg體重進行投與。投與，例如可藉由 將該有效成分預先添加混合於供給對象生物之人工調配飼 料的原料中’或者與人卫調g己飼料的粉末原料混合後進而 添加混合於其他原料中而進行。χ，對於上述有效成分於 飼料中之含量並無特別限定，若根據目的適當設定即可， 例如，較好的是〇._01重量％以上、更好的是〇〇〇〇1〜1〇 重量％、i好的是〇·〇_〜6重量％。±物飼養用劑中本發 明之有效成分之含量若亦設為相同程度即可。 對於本發明之飼#之製造方法並無特別限定，又調配， 亦依照-般飼料之製造方法即可’若經製造之飼料中含有 具有ACAT抑制作用之本發明之上述有效成分即可。生物 飼養用劑亦可以同樣之方式製備。 於本發明中，例如攝取含有具有ACAT抑制作用之本發 明所使用之上述有效成分而成之飼料，或者將對象生物浸 潰於本發明所使用之上述有效成分之含有液（例如，將I 述浸潰用劑溶解於水中者）中，藉此可良好地維持或改善 豕畜、實驗動物、豕禽、龍物動物等之身體狀態。再者， 该荨悲樣係本發明之生物之飼養方法之_離、樣。 本發明所使用之上述有效成分’即使將對其作用表現而 123192.doc -20- 200823219 言為有效量投與生物亦不會發現有毒性。例如於經口於盘 之情形時’即使以1 g/kg體重將3’_乙酿氧基米 氧 基-3，，4，_二氫邪蒿㈣單次投與小白鼠亦不持 例。又，f將f述有效成分經口投與大白鼠時，即使幻 g/kg體重經口早次投與亦不會發現有死亡例。 實施例 舉出實施例更具體地說明本發明，但本發明並不 受該荨纟己載之任何限定。再者，眘 記載則表示「容量%」。 冑败％」若未特別 製備例丨31-乙酿氧基_4，_異戊婦酿氧m 内酯之製備 f同 i ⑴於將牡丹防風葉莖部的冷隸燥物加以粉碎者1〇〇 g 中添加2 L之60%乙醇，以3〇分鐘左右、於室溫下一面攪拌 -面储萃取，以抽氣過遽分成萃取液與殘渣。繼而，對 殘渣重複進行使用2 L相同溶劑之萃取操作。收集所庐得 之萃取液，以旋轉蒸發器進行濃縮後，為除去糖：進：： 次40%乙醇萃取，將所得萃取部分進行再次濃縮。最終溶 解於50 mL之20%乙醇中，獲得牡丹防風6〇%乙醇萃取物。 ⑺利用逆相層析法將製備例卜⑴中戶斤獲得之牡丹防風 60%乙醇萃取物進行分離。樹脂係使用以2〇%乙醇平衡化 之 Cosmosil 75C18-〇PN(200 mL，Nacalai公司製）。將牡丹 防風60%乙醇萃取物添加於樹脂中後，依8〇〇 ^^之2〇%乙 醇、3.4 L之40%乙醇、16 L之6〇%乙醇、J乙之8〇%乙醇的 順序進行溶出。 123192.doc -21 - 200823219 (3) 將製備例1-(2)中所獲得40%乙醇溶出液中之i 6 l至2 L部分及2 L至2.4 L部分以旋轉蒸發器加以濃縮。最終分別 溶解於5 mL之40%乙醇中，製成牡丹防風c〇sm〇sU分:部 分-1、牡丹防風Cosmosil分離部分-2。 (4) 利用逆相層析法將製備例i_(3)中所獲得之牡丹防風 Cosmosi丨分離部分_丨及牡丹防風c〇sm〇sU分離部分·2進= 分離。管柱係使用 TSK gel 〇DS-80Ts(20 mmx25 em， Tosoh公司製）。以溶劑為蒸餾水：乙腈=30: 7〇(容量比）、 溶出速度為5 mL/min、檢測為UV : 215 nm之條件進行。 以溶出液的紫外線吸收為指標將溶出液進行分離。 (5) 以旋轉蒸發器將製備例1-(4)中所獲得之包含保持時 間為33.3分鐘的波峰之部分加以濃縮。最終溶解於i〇 之二甲基亞砜中，獲得牡丹防風逆相管柱分離部分。 (6) 利用核磁共振（NMR)光譜裝置（avance6〇〇型， Bmker Biospin公司製），對製備例1-(5)中所獲得之牡丹防 風逆相管柱分離部分進行各種]^]^11光譜測定。又，利用質 篁分析儀（API3000，Applied Biosystems公司製）以離子喷 霧法測定質譜。根據NMR光譜、質譜解析之結果，確定牡 丹防風逆相管柱分離部分為上述式（1)所表示之3，_乙醯氧 基-4’-異戊烯醯氧基_3’，4’-二氫邪蒿内醋 (3’-ACet〇xy-4’-tigl〇yl〇Xy_3，，4，-dihydr〇SeSelin)。 實施例1 (1)大白鼠微粒體之製備 飼養4只Sprague-Dawley大白鼠，然後將其處死，立即 123192.doc -22- 200823219 摘出肝臟且以冷食鹽水輕輕清洗後，浸潰（25 mL/l只）於蔗 糖緩衝液（0.3 Μ蔗糖、50 mM tris-HCl、ImM EDTA、50 mM NaCl，pH值為7.4)中。將所獲得之肝臟進行均質化， 進行10,000xg、30分鐘之離心再除去沈澱，重複2次該操 作。將所獲得上清液進行l〇5,00〇xg、70分鐘之離心，回 收沈澱，懸浮於適當量之100 mM構酸緩衝液（pH值為7.4) 中。再次懸濁於磷酸緩衝液中以使蛋白質濃度成為10 mg/mL，添加EDTA以使最終濃度成為1 mM後，於-80°C下 冷凍保存直至使用。 (2) ACAT抑制活性之測定 ACAT之酶活性，係依照Lee等人的方法（Planta Med·， 2004,70，第678-679頁）且進行一部分改良而測定。 於1.5 mL之eppendorf管（微量離心管）中，於92 μΐ^之實施 例1-(1)中製備之含有1.5 pL大白鼠肝微粒體的反應水溶液 (0.05 Μ填酸卸、1 mM二硫蘇糖醇、9 mg/mL無脂肪酸牛 血清白蛋白、200 pg/mL膽固醇，pH值為7.4)中添加1 gL製 備例1中製備之3’-乙醯氧基-4’-異戊烯醯氧基-3’，4’-二氫邪 蒿内酯二甲基亞颯溶液以使最終濃度成為14 pg/mL，於 37°C下進行30分鐘保溫。又，作為對照部分，設定不添加 化合物僅添加二曱基亞砜溶液之部分；作為陽性對照，設 定添加已知有ACAT抑制活性之化合物FR179254(終濃度為 10 μΜ，Merck公司製，344235)之部分。之後，將2 μί之 0.05 mCi/mL 之 Oleoyl Coenzyme A[oleoyl-9,10_3H]_ (Moravek Biochemicals 公司製，MT1649)與 5 pL 之 0.2 123192.doc -23- 200823219 mg/mL之 Oleoyl Coenzyme A(ICN公司製，591-20521)的混 合液添加於各管中混合後，於37°C下保溫5分鐘。其後， 藉由將異丙醇：庚烷=4: 1(容量比）之溶液於各管中分別 添加0.5 mL，而停止反應。於各管中添加0.2 mL之0.1 Μ磷 酸鉀溶液（pH值為7.4)及0.3 mL之庚烷且攪拌15秒後，進行 15秒之離心分離，使用所獲得之上層15〇 μΕ，將ULTIMA GOLD(PerkinElmer Life Sciences公司製，6013329)作為閃 爍計數液，利用液體 Scintillation Counter LS6500 (Beckman公司製）測定放射活性。再者，各反應係進行2 次’放射活性係算出其平均值。被驗樣品之AC AT抑制活 性（％)，係利用以下式將添加陽性對照即1〇 之 FR179254時之抑制率作為1〇〇〇/0而算出。 抑制活性（％)=={([對照部分之放射活性（cpm)H被驗樣 品添加部分之放射活性（cpm)])/([對照部分之放射活性 (cpm)MlO μΜ之FR179254添加部分之放射活性（cprn)]) } χΙΟΟ 其結果，3’-乙醯氧基-4’-異戊稀醯氧基-3，，4，-二氫邪蒿内 酯之抑制活性為164%，發現有顯著的ACAT抑制活性。 根據本發明’提供一種含有3’-乙醯氧基-4，-異戊烯醯氧 基二氳邪蒿内酯、其衍生物及/或藥學所容許之該等 的鹽之ACAT抑制劑、含有其之醫藥、食品或飼料。該醫 藥作為動脈硬化症或高脂血症、以該等為病因而引起的疾 病之治療劑或預防劑為有用。又，該食品可藉由作為曰常 食品加以攝取’而改善或預防上述疾病之症狀。因此，含 123192.doc -24- 200823219 有本發明之有效成分之食品，係利用其ACAT抑制作用而 對生物體之恆常性維持為有用之機能性食品。 123192.doc -25-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 十、申請專利範圍： 1· 2. 3. -種醯基COA膽固醇醯基轉移酶抑制劑，其特徵在於： 含有選自由3，-乙酿氧基冬異戊婦醯氧基_3，，4,_二氫 内酯、其衍生物及藥學所容許的該等之鹽所組成: 一種以上作為有效成分。 的 之抑制劑。 請求項1之㈣ 一種醫藥，其特徵在於··含有如請求項1 一種食品或飼料，其特徵在於：含有如 劑0200823219 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 七、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：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.doc123192.doc