JP5546807B2 - PPAR ligand agent - Google Patents
PPAR ligand agent Download PDFInfo
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- JP5546807B2 JP5546807B2 JP2009157200A JP2009157200A JP5546807B2 JP 5546807 B2 JP5546807 B2 JP 5546807B2 JP 2009157200 A JP2009157200 A JP 2009157200A JP 2009157200 A JP2009157200 A JP 2009157200A JP 5546807 B2 JP5546807 B2 JP 5546807B2
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- Prior art keywords
- ppar
- compound
- extract
- ppar ligand
- obesity
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Description
本発明は、ＰＰＡＲリガンド剤に関する。より具体的には、肥満、肥満に伴い発症するインスリン抵抗性、高脂血症、高血圧または糖尿病を予防および／または改善する作用を有するＰＰＡＲα、δおよび／またはγのリガンド剤に関する。さらに、ＰＰＡＲα、δおよび／またはγのリガンド作用を有する新規化合物に関する。 The present invention relates to a PPAR ligand agent. More specifically, the present invention relates to a ligand agent for PPARα, δ and / or γ having an action of preventing and / or improving obesity, insulin resistance that develops with obesity, hyperlipidemia, hypertension or diabetes. Furthermore, the present invention relates to a novel compound having a ligand action of PPARα, δ and / or γ.
ペルオキシソーム増殖剤応答性受容体（Ｐｅｒｏｘｉｓｏｍｅ ｐｒｏｌｉｆｅｒａｔｏｒ−ａｃｔｉｖａｔｅｄ ｒｅｃｅｐｔｏｒｓ：ＰＰＡＲs）は、リガンド依存的に転写を制御する核内受容体で、ＰＰＡＲα、ＰＰＡＲδ（ＰＰＡＲβ）、ＰＰＡＲγの３種のサブタイプの存在が知られている。 Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate transcription in a ligand-dependent manner and are known to have three subtypes: PPARα, PPARδ (PPARβ), and PPARγ. It has been.
ＰＰＡＲαの主要調節臓器は肝臓であり、ＰＰＡＲαが活性化することにより、肝臓における脂肪の燃焼が促進され、血中・肝臓・骨格筋の中性脂肪含量が減少し、インスリン抵抗性が改善される。 The main regulatory organ of PPARα is the liver, and activation of PPARα promotes the burning of fat in the liver, reduces the triglyceride content in blood, liver and skeletal muscle, and improves insulin resistance .
ＰＰＡＲδはＰＰＡＲβとも呼ばれ、特に骨格筋を中心とした強力なエネルギー代謝促進作用、脂肪酸燃焼促進作用をつかさどっていることが明らかとなっている。ＰＰＡＲδアゴニスト（ＧＷ５０１５１６）を用いた実験では、ＰＰＡＲδの活性化により、骨格筋の脂肪酸酸化が亢進し、高脂肪食による肥満やインスリン抵抗性も抑制されたことが示されている。 PPARδ is also referred to as PPARβ, and it has been clarified that it particularly has a strong energy metabolism promoting action mainly on skeletal muscles and a fatty acid combustion promoting action. Experiments using a PPARδ agonist (GW501516) show that activation of PPARδ promotes fatty acid oxidation of skeletal muscle and suppresses obesity and insulin resistance due to a high fat diet.
ＰＰＡＲγの主要調節臓器は脂肪組織である。ＰＰＡＲγのアゴニストであるチアゾリジン誘導体は、ＰＰＡＲγを介して肥大脂肪細胞のアポトーシスと前駆脂肪細胞から小型脂肪細胞への分化による生成より、肥大脂肪細胞を小型脂肪細胞に置き換えることにより、インスリン抵抗性を改善することが報告されている（非特許文献１）。 The main regulatory organ of PPARγ is adipose tissue. Thiazolidine derivatives, agonists of PPARγ, improve insulin resistance by replacing hypertrophic adipocytes with small adipocytes rather than PPARγ via apoptosis of hypertrophic adipocytes and generation from preadipocytes to small adipocytes It has been reported (Non-Patent Document 1).
このように、ＰＰＡＲsは生体内の糖、脂質代謝の制御に関与しているのみならず、肥満、高脂血症、高血圧、糖尿病などの生活習慣病、癌、炎症性疾患、動脈硬化症などの疾患の発症への関与が明らかとなっている（非特許文献２）。 Thus, PPARs are not only involved in the regulation of sugar and lipid metabolism in the body, but also include lifestyle-related diseases such as obesity, hyperlipidemia, hypertension, diabetes, cancer, inflammatory diseases, arteriosclerosis, etc. Involvement in the onset of other diseases has been clarified (Non-patent Document 2).
メタボリックシンドロームにおいて、肥満は他のリスクファクター、インスリン抵抗性、高脂血症、高血圧、糖尿病などの上流に位置しており、したがって、肥満を改善することにより、他のリスクファクターをも改善することが可能である。すなわち、ＰＰＡＲのリガンド剤はＰＰＡＲを活性化することにより、生体内における脂質代謝を促進し、蓄積した脂肪を減少させることにより、肥満を予防および改善し、さらに肥満に伴い発症するインスリン抵抗性、高脂血症、高血圧、糖尿病を予防および改善することが可能である（非特許文献３）。 In the metabolic syndrome, obesity is located upstream of other risk factors, such as insulin resistance, hyperlipidemia, hypertension, diabetes, etc. Therefore, improving other obesity factors by improving obesity Is possible. That is, the ligand agent of PPAR activates PPAR, promotes lipid metabolism in the living body, reduces and accumulates fat, prevents and improves obesity, and further, insulin resistance that develops with obesity, It is possible to prevent and improve hyperlipidemia, hypertension, and diabetes (Non-patent Document 3).
ウリ科植物の抽出物の抗肥満作用が報告されている（特許文献１）。その内容は、タワシヘチマ(Ｌｕｆｆａ ｃｙｌｉｎｄｒｉｃａ Ｌ．)由来の、インスリン分泌促進作用やサイクリックＡＭＰホスホジエステラーゼ阻害作用による肥満および糖尿病の予防および治療効果である。また、ウリ科植物、タワシヘチマ由来の有効成分であるデヒドロジコニフェリルアルコールが、ＰＰＡＲαおよびδの働きを活性化させ、脂肪前駆細胞からの脂肪生成を抑制すると報告されている（特許文献２および３）。 An anti-obesity effect of an extract of the Cucurbitaceae plant has been reported (Patent Document 1). Its content is the effect of preventing and treating obesity and diabetes derived from Tuffet loach ( Luffa cylindrica L.) by promoting insulin secretion and inhibiting cyclic AMP phosphodiesterase. In addition, it has been reported that dehydrodiconiferyl alcohol, which is an active ingredient derived from the cucurbitaceae plant and Tawahishi Hima, activates the functions of PPARα and δ and suppresses adipogenesis from adipose precursor cells (Patent Documents 2 and 3). ).
ウリ科の植物であるトカドヘチマ（Ｌｕｆｆａ ａｃｕｔａｎｇｕｌａ Ｒｏｘｂ．）は、インドから東南アジア、中国南部にかけて広く栽培され、未熟果実を野菜として利用している。果実ジュースのエーテル抽出物に細胞毒性を示すククルビタシン類（ｃｕｃｕｒｂｉｔａｃｉｎｓ）が存在するという報告（非特許文献４）、幼苗、根、完熟種子はククルビタシン類を含むという報告がある（非特許文献５）。しかし、トカドヘチマ抽出物がＰＰＡＲリガンド作用を示すことは知られていない。 The cucurbitaceae plant Luffa acutangula Roxb. Is widely cultivated from India to Southeast Asia and southern China, and uses immature fruits as vegetables. There are reports that cucurbitacins that exhibit cytotoxicity exist in the ether extract of fruit juice (Non-patent Document 4), and that seedlings, roots, and mature seeds contain cucurbitacins (Non-patent Document 5). However, it is not known that Tocadohetima extract exhibits PPAR ligand action.
ＰＰＡＲリガンド剤は、肥満を予防および／または改善することが期待され、さらにはメタボリックシンドロームのリスクファクターであるインスリン抵抗性、高脂血症、高血圧または糖尿病などを予防および／または改善することが期待される。しかし、既存のＰＰＡＲリガンド剤は、医薬品の長期投与による副作用などが危惧されるほか、食品由来のポリフェノール類などには、十分なＰＰＡＲリガンド作用が得られないなどの問題点がある。 PPAR ligand agents are expected to prevent and / or improve obesity, and further prevent and / or improve insulin resistance, hyperlipidemia, hypertension, diabetes, etc., which are risk factors of metabolic syndrome Is done. However, existing PPAR ligand agents have problems such as side effects due to long-term administration of pharmaceuticals, and food-derived polyphenols cannot obtain sufficient PPAR ligand action.
本発明の目的は、安全で、優れたＰＰＡＲリガンド剤を提供することである。 An object of the present invention is to provide a safe and excellent PPAR ligand agent.
本発明者らは、上記課題を解決するため、長期摂取しても安全で副作用の少ないＰＰＡＲリガンドを天然由来の４２０種類の植物に求め、鋭意探索した結果、トカドヘチマの抽出物に高いＰＰＡＲリガンド活性があることを見出した。さらに、トカドヘチマ抽出物中から新規化合物である式（１）： In order to solve the above problems, the present inventors have sought 420 kinds of naturally-derived PPAR ligands that are safe and have few side effects even when ingested for a long period of time, and as a result of diligent search, the extract of Tocadohetica has high PPAR ligand activity. Found that there is. Furthermore, the formula (1), which is a novel compound from Tocadohetima extract:
（Ｒは糖である）
で表わされる化合物を精製し、この化合物が強いＰＰＡＲリガンド作用を有することを見出した。本発明はこれらの知見に基づいて完成したものである。
(R is sugar)
The compound represented by (2) was purified and found to have a strong PPAR ligand action. The present invention has been completed based on these findings.
すなわち本発明は、次の［１］〜［７］である。
［１］ トカドヘチマの溶媒抽出物を有効成分とするＰＰＡＲα、δおよび／またはγのリガンド剤。
［２］ 溶媒がアルコール類または含水アルコール類である、［１］記載のＰＰＡＲα、δおよび／またはγのリガンド剤。
［３］ 有効成分として、式（１）：
That is, the present invention includes the following [1] to [7].
[1] A ligand agent of PPARα, δ and / or γ containing a solvent extract of tocadohetima as an active ingredient.
[2] The ligand agent for PPARα, δ and / or γ according to [1], wherein the solvent is an alcohol or a hydrous alcohol.
[3] As an active ingredient, the formula (1):
（ＲはＨまたは糖である）
で表される化合物を含む、［１］または［２］記載のＰＰＡＲα、δおよび／またはγのリガンド剤。
［４］ 肥満、肥満に伴い発症するインスリン抵抗性、高脂血症、高血圧または糖尿病を予防および／または改善するための、［１］〜［３］のいずれかに記載のＰＰＡＲα、δおよび／またはγのリガンド剤。
［５］ 飲食品の形態である、［４］記載のＰＰＡＲα、δおよび／またはγのリガンド剤。
［６］ 医薬品の形態である、［４］記載のＰＰＡＲα、δおよび／またはγのリガンド剤。
［７］ 式（１）：
(R is H or sugar)
A PPARα, δ and / or γ ligand agent according to [1] or [2], which comprises a compound represented by the formula:
[4] PPARα, δ and / or [1] for preventing and / or improving obesity, insulin resistance, hyperlipidemia, hypertension or diabetes that develops with obesity Or a ligand agent for γ.
[5] The PPARα, δ and / or γ ligand agent according to [4], which is in the form of a food or drink.
[6] The PPARα, δ and / or γ ligand agent according to [4], which is in the form of a pharmaceutical product.
[7] Formula (1):
（Ｒは糖である）
で表される化合物。
(R is sugar)
A compound represented by
本発明のＰＰＡＲリガンド剤は、ＰＰＡＲα、δおよびγに対して優れたリガンド活性を示し、かつ、食物として摂取されている植物由来であり、安全性が高い。したがって、本発明により、優れたＰＰＡＲリガンド剤が提供され、肥満、肥満に伴うインスリン抵抗性、高脂血症、高血圧、糖尿病などを予防および/または改善に有効な飲食物、医薬品の形態であるＰＰＡＲリガンド剤が提供される。 The PPAR ligand agent of the present invention exhibits excellent ligand activity for PPARα, δ, and γ, and is derived from a plant that is ingested as food, and has high safety. Therefore, according to the present invention, an excellent PPAR ligand agent is provided, which is a form of food, beverage, or medicine effective for preventing and / or improving obesity, insulin resistance associated with obesity, hyperlipidemia, hypertension, diabetes and the like. A PPAR ligand agent is provided.
以下、本発明の実施の形態について、詳細に説明する。
＜ＰＰＡＲリガンド剤＞
本発明のＰＰＡＲリガンド剤は、トカドヘチマ抽出物または該抽出物中の特定の化合物を有効成分として含有する。
Hereinafter, embodiments of the present invention will be described in detail.
<PPAR ligand agent>
The PPAR ligand agent of the present invention contains a tocadohetima extract or a specific compound in the extract as an active ingredient.
トカドヘチマ抽出物
原料となるトカドヘチマ（Ｌｕｆｆａ ａｃｕｔａｎｇｕｌａ Ｒｏｘｂ．）はウリ科の植物である。トカドヘチマはインドから東南アジア、中国南部にかけて広く栽培され、未熟果実を野菜として利用している（世界有用植物事典 平凡社 p. 637、熱帯の野菜 農林水産省熱帯農業研究センター p. 37-39）。
Tocadohetima ( Luffa acutangula Roxb.), Which is a raw material for Tokadohema extract , is a plant of the Cucurbitaceae family. Tokadohema is widely cultivated from India to Southeast Asia and southern China, and uses immature fruits as vegetables (World useful plant encyclopedia Heibonsha p. 637, Tropical vegetable research center for tropical agriculture, Ministry of Agriculture, Forestry and Fisheries p. 37-39).
トカドヘチマ抽出物の原料は、未熟果実を用いるのが好ましいが、これら以外の部位、果皮、葉、花、地上部、全草などのいずれかを、またはいずれも用いることができる。
抽出に用いる溶媒としては、炭素数１〜４の低級アルコール類（たとえばメタノール、エタノール、プロパノール、ブタノールなど）、液状多価アルコール（例えば、１，３−ブチレングリコール、プロピレングリコール、グリセリンなど）、ケトン類（たとえば、アセトン、メチルエチルケトンなど）、エステル類（例えば、酢酸エチル、酢酸ブチルなど）などが挙げられる。これらは、単独または２種以上を混合して用いることもできる。本発明においては、含水アルコール類またはアルコール類を用いるのが好ましく、特に含水低級アルコール類または低級アルコール類が好ましい。
It is preferable to use immature fruits as the raw material for the Tocadohetima extract, but any part other than these, such as fruit skin, leaves, flowers, above-ground parts, whole grasses, etc. can be used.
Solvents used for extraction include lower alcohols having 1 to 4 carbon atoms (for example, methanol, ethanol, propanol, butanol, etc.), liquid polyhydric alcohols (for example, 1,3-butylene glycol, propylene glycol, glycerin, etc.), ketones (For example, acetone, methyl ethyl ketone, etc.), esters (for example, ethyl acetate, butyl acetate, etc.) and the like. These may be used alone or in combination of two or more. In the present invention, water-containing alcohols or alcohols are preferably used, and water-containing lower alcohols or lower alcohols are particularly preferable.
溶媒抽出する場合、トカドヘチマは生のまま、または乾燥させたもののいずれを用いても良く、抽出する際の植物体は原型のまま、切断したもの、粉砕したもの、粉末化したものなどいずれを用いても良い。抽出温度は５〜８０℃の範囲で適宜に、更に加圧、減圧などの条件も適宜に設定することが可能であるが、抽出溶媒の安全性、抽出成分の安定性の点から、温度としては室温が好ましい。抽出時間は０．１時間〜１ヶ月の範囲で適宜に設定することが可能であるが、好ましくは０．５時間〜７日である。植物体と抽出溶媒の比率は１〜1０００倍（Ｗ/Ｖ）の範囲で任意に設定することが可能であるが、好ましくは１〜１００倍（Ｗ/Ｖ）である。 When solvent extraction is performed, either the raw tokadohema may be used as it is or dried, and the plant body used for extraction may be the original, cut, crushed, powdered, etc. May be. The extraction temperature can be appropriately set within the range of 5 to 80 ° C., and further conditions such as pressurization and decompression can be set as appropriate. However, from the viewpoint of the safety of the extraction solvent and the stability of the extraction components, Is preferably room temperature. The extraction time can be appropriately set in the range of 0.1 hour to 1 month, preferably 0.5 hour to 7 days. Although the ratio of a plant body and an extraction solvent can be arbitrarily set in the range of 1 to 1000 times (W / V), it is preferably 1 to 100 times (W / V).
２−アリルベンゾフラン類縁体
本発明のリガンド剤は、式（１）
2-allylbenzofuran analog The ligand agent of the present invention has the formula (1)
（ＲはＨまたは糖である）
で表される２−アリルベンゾフラン類縁体を含む。
Ｒ部分の糖は、３炭糖〜７炭糖のいずれであってもよく、また単糖に限らず複数個結合した糖であってもよい。好ましい例としては、構成糖としてはグルコース、ラムノース、アラビノース、キシロース、またはガラクトースであり、それらが１〜８個結合したものが挙げられる。特に好ましくは、糖はグルコースである。
(R is H or sugar)
The 2-allyl benzofuran analog represented by these is included.
The sugar at the R moiety may be any of tricarbon sugar to 7 carbon sugar, and is not limited to a monosaccharide but may be a sugar in which a plurality of sugars are bonded. Preferable examples include glucose, rhamnose, arabinose, xylose, or galactose as constituent sugars, and those in which 1 to 8 of them are bound. Particularly preferably, the sugar is glucose.
Ｒが糖の場合、糖中のいずれのＯＨ基が結合した化合物であってもよいが、Ｃ−１位のＯＨ基が結合したものが好ましい。
上記化合物は、トカドヘチマから抽出・精製することにより得ることができる。抽出・精製方法は、当業者の知識に基づいて適宜実施することができる。例示としては、抽出物を実施例８〜１２に示す方法で精製することにより得ることができる。
When R is a saccharide, it may be a compound to which any OH group in the saccharide is bonded, but a compound having an OH group at the C-1 position is preferable.
The above compound can be obtained by extraction and purification from tocadohecima. The extraction / purification method can be appropriately performed based on the knowledge of those skilled in the art. For example, the extract can be obtained by purifying the extract by the methods shown in Examples 8 to 12.
上記化合物は、強いＰＰＡＲα、δおよびγリガンド作用を有する。
なお、ＷＯ ２００３０５１８６０には、本発明に用いられる２−アリルベンゾフラン類縁体と構造類似のＣＡＳ ５５１００２−３３−６が開示されている。しかし、該物質のエストロジェン作用を標榜しており、ＰＰＡＲリガンド作用や抗肥満効果に関しては開示されていない。また、ＷＯ ２００９０６４２５１には、２−アリルベンゾフラン類縁体（ＲがＨ）が開示されている。しかし、該物質を部分構造とするプロスタグランジンＥ合成酵素阻害作用を標榜しており、ＰＰＡＲリガンド作用や抗肥満効果に関しては開示されていない。
The above compounds have strong PPARα, δ and γ ligand actions.
WO 2003051860 discloses CAS 551002-33-6, which is structurally similar to the 2-allylbenzofuran analog used in the present invention. However, the estrogen action of the substance is advocated and no PPAR ligand action or anti-obesity effect is disclosed. WO 2009064251 discloses a 2-allylbenzofuran analog (R is H). However, the prostaglandin E synthase inhibitory action with the substance as a partial structure is advocated, and no PPAR ligand action or anti-obesity effect is disclosed.
ＰＰＡＲリガンド活性の評価
ＰＰＡＲリガンド活性は、当業者が通常用いる方法で測定することができる。たとえば、培養細胞にＰＰＡＲα、δまたはγを発現させると同時に、ＰＰＡＲの活性化に反応して蛍光シグナル等の測定用シグナルを発する系を発現させ、試験物を投与して、測定用シグナルの強度を測定することにより、ＰＰＡＲリガンド活性を定量化することができる。具体的には、実施例１〜３に示す方法で評価することができる。
Evaluation of PPAR Ligand Activity PPAR ligand activity can be measured by methods commonly used by those skilled in the art. For example, PPARα, δ, or γ is expressed in cultured cells, and at the same time, a system that emits a measurement signal such as a fluorescence signal in response to PPAR activation is expressed. Can be used to quantify PPAR ligand activity. Specifically, it can be evaluated by the methods shown in Examples 1 to 3.
ＰＰＡＲリガンド剤
本発明のＰＰＡＲリガンド剤は、ＰＰＡＲの生体内分布や生理活性に応じて、ペルオキシソーム増殖剤応答性受容体が関連する疾患の予防および／または改善のために用いることができる。具体的には、本発明のＰＰＡＲリガンド剤は、肥満、肥満に伴い発症するインスリン抵抗性、高脂血症、高血圧または糖尿病の予防および／または改善に有効である。
PPAR Ligand Agent The PPAR ligand agent of the present invention can be used for prevention and / or improvement of diseases associated with peroxisome proliferator-responsive receptors, depending on the biodistribution and physiological activity of PPAR. Specifically, the PPAR ligand agent of the present invention is effective for the prevention and / or improvement of obesity, insulin resistance that develops with obesity, hyperlipidemia, hypertension or diabetes.
本発明において、肥満の予防とは、肥満または肥満症であるとされる状態になるのを防ぐ又は遅らせることをいう。また、肥満の改善とは、肥満または肥満症であるとされる状態を改善することをいう。 In the present invention, prevention of obesity refers to preventing or delaying the occurrence of obesity or obesity. Moreover, the improvement of obesity means improving the state considered to be obesity or obesity.
本発明において、インスリン抵抗性とは、肝臓・脂肪細胞・骨格筋で、インスリンの主な作用である糖の吸収促進作用が弱っている状態をいう。インスリン抵抗性の予防とは、ＳＳＰＧ（Steady-state plasma glucose）法などによるインスリン抵抗性の指標となる値がより悪化するのを防ぐ又は遅らせることを指す。インスリン抵抗性の改善とは、上記のインスリン抵抗性の指標となる値をより改善することをいう。 In the present invention, insulin resistance refers to a state where the absorption promotion action of sugar, which is the main action of insulin, is weak in the liver, adipocytes, and skeletal muscle. Prevention of insulin resistance refers to preventing or delaying further deterioration of a value serving as an index of insulin resistance by the SSPG (Steady-state plasma glucose) method or the like. Improvement of insulin resistance means improvement of a value that serves as an index of insulin resistance.
本発明において、高脂血症の予防とは、高脂血症の状態又は境界域の状態になるのを防ぐ又は遅らせることをいう。また、高脂血症の改善とは、上記に示す高脂血症の状態または境界域の状態から、正常域と定義している状態に近づけることをいう。 In the present invention, prevention of hyperlipidemia refers to preventing or delaying hyperlipidemia or borderline conditions. Further, the improvement of hyperlipidemia refers to bringing the state of hyperlipidemia or boundary region described above closer to the state defined as the normal region.
本発明において、高血圧の予防とは、高血圧とされる状態または境界域の状態になるのを防ぐ又は遅らせることをいう。また、高血圧の改善とは、高血圧とされる状態または境界域の状態から、正常域と定義している状態に近づけることをいう。 In the present invention, prevention of hypertension refers to preventing or delaying the occurrence of hypertension or borderline conditions. In addition, improvement of hypertension refers to bringing a state defined as a normal range closer to a state defined as a normal range from a state considered to be high blood pressure or a state of a boundary region.
本発明において、糖尿病の予防とは、糖尿病の状態または境界域の状態になるのを防ぐ又は遅らせることをいう。また、糖尿病の改善とは、糖尿病の状態または境界域の状態から、正常域と定義している状態に近づけることをいう。 In the present invention, prevention of diabetes refers to preventing or delaying diabetic state or borderline state. Further, the improvement of diabetes refers to the approach of a state defined as a normal range from a diabetic state or a boundary state.
本発明のＰＰＡＲリガンド剤は、ＰＰＡＲα、δ、γのいずれをも活性化する効果を有する。本発明のＰＰＡＲリガンド剤は、ＰＰＡＲγに対してもリガンド作用を有することから、トカドヘチマ抽出物の作用はタワシヘチマの作用と明確に区別される。 The PPAR ligand agent of the present invention has an effect of activating any of PPARα, δ, and γ. Since the PPAR ligand agent of the present invention also has a ligand action on PPARγ, the action of Tocadohetima extract is clearly distinguished from the action of Tawashi loofah.
本発明のＰＰＡＲリガンド剤は、飲食品および医薬品として利用することができるが、その形態は限定されず、健康食品、栄養補助食品、栄養機能食品、特定保健用食品などの飲食品および医薬品として用いることができる。 The PPAR ligand agent of the present invention can be used as foods and drinks and pharmaceuticals, but the form is not limited, and is used as foods and drinks and pharmaceuticals such as health foods, nutritional supplements, functional nutritional foods, and foods for specified health use. be able to.
飲食品としては、チューインガム、チョコレート、キャンディー、ゼリー、ビスケット、クラッカーなどの菓子類、アイスクリーム、氷菓などの冷菓類、 茶、清涼飲料、栄養ドリンク、美容ドリンクなどの飲料、うどん、中華麺、スパゲティー、即席麺などの麺類、蒲鉾、竹輪、はんぺんなどの練り製品、ドレッシング、マヨネーズ、ソースなどの調味料、マーガリン、バター、サラダ油などの油脂類、パン、ハム、スープ、レトルト食品、冷凍食品など、すべての飲食品に使用することができる。これら肥満、肥満に伴い発症するインスリン抵抗性、高脂血症、高血圧、糖尿病を予防および／または改善する組成物を摂取する場合、その摂取量は当該抽出物として成人一人一日当たり、好ましくは０．０１〜１０００ｍｇ／ｋｇ体重、より好ましくは１〜３００ｍｇ／ｋｇ体重である。 Foods and drinks include chewing gum, chocolate, candy, jelly, biscuits, crackers and other confectionery, ice cream, frozen desserts such as ice confectionery, tea, soft drinks, nutrition drinks, beauty drinks, udon, Chinese noodles, spaghetti , Noodles such as instant noodles, kneaded products such as rice cakes, bamboo rings, hampen, seasonings such as dressing, mayonnaise, sauces, fats and oils such as margarine, butter, salad oil, bread, ham, soup, retort food, frozen food, etc. Can be used for food and drink. When the composition for preventing and / or improving obesity, insulin resistance, hyperlipidemia, hypertension, and diabetes that develops due to obesity is ingested, the amount of intake is per adult day, preferably 0 as the extract. 0.01 to 1000 mg / kg body weight, more preferably 1 to 300 mg / kg body weight.
医薬品として用いる場合は、その剤形は特に限定されず、例えば、カプセル剤、錠剤、顆粒剤、注射剤、座薬、貼付剤などが挙げられる。製剤化においては、薬剤学的に許容される他の製剤素材、例えば、賦形剤、崩壊剤、滑沢剤、結合剤、酸化防止剤、着色剤、凝集防止剤、吸収促進剤、溶解補助剤、安定化剤などを適宜添加して調製することができる。これら製剤を当該抽出物換算で成人一人一日当たり、好ましくは０．０１〜１０００ｍｇ／ｋｇ体重、より好ましくは１〜３００ｍｇ／ｋｇ体重を１回ないし数回に分けて投与する。 When used as a pharmaceutical, the dosage form is not particularly limited, and examples thereof include capsules, tablets, granules, injections, suppositories, and patches. In formulation, other pharmaceutically acceptable formulation materials such as excipients, disintegrants, lubricants, binders, antioxidants, colorants, anti-aggregation agents, absorption enhancers, solubilizers An agent, a stabilizer and the like can be added as appropriate. These preparations are administered in an amount of from 0.01 to 1000 mg / kg body weight, more preferably from 1 to 300 mg / kg body weight per day per adult, in terms of the extract.
＜新規化合物＞
本発明は、トカドヘチマから得られる新規化合物に関する。具体的には、
式（１）：
<New compound>
The present invention relates to a novel compound obtained from tocadohecima. In particular,
Formula (1):
（Ｒは糖である）
で表される化合物である。
Ｒ部分の糖は、３炭糖〜７炭糖のいずれであってもよく、また単糖に限らず複数個結合した糖であってもよい。好ましい例としては、構成糖としてはグルコース、ラムノース、アラビノース、キシロース、またはガラクトースであり、それらが１〜８個結合したものが挙げられる。特に好ましくは、糖はグルコースである。
(R is sugar)
It is a compound represented by these.
The sugar at the R moiety may be any of tricarbon sugar to 7 carbon sugar, and is not limited to a monosaccharide but may be a sugar in which a plurality of sugars are bonded. Preferable examples include glucose, rhamnose, arabinose, xylose, or galactose as constituent sugars, and those in which 1 to 8 of them are bound. Particularly preferably, the sugar is glucose.
Ｒ部分が糖である化合物は、化学的に合成することができる。たとえば、Ｎ，Ｎ‘−ジシクロヘキシルカルボジイミド（ＤＣＣ）中、２、３、４、６−テトラ−Ｏ−ベンジル−Ｄ−グルコピラノースをＲ部分がＨの化合物とカップリングさせたのち、通常の水素化分解によってベンジル基を除去する。例えば、酢酸やアルコールなどのプロトン性極性溶媒中で、あるいはベンゼン、トルエン、酢酸エチルなどの非極性溶媒中で、パラジウム炭素やパラジウム黒、あるいはプラチナ炭素やプラチナ黒などを触媒として水素の存在で脱ベンジル化し、Ｒ部分がグルコースの化合物に導くことができる。 A compound in which the R moiety is a sugar can be chemically synthesized. For example, in N, N′-dicyclohexylcarbodiimide (DCC), 2, 3, 4, 6-tetra-O-benzyl-D-glucopyranose is coupled with a compound in which the R moiety is H, followed by conventional hydrogenation. The benzyl group is removed by decomposition. For example, in a protic polar solvent such as acetic acid or alcohol, or in a nonpolar solvent such as benzene, toluene, or ethyl acetate, palladium carbon or palladium black, or platinum carbon or platinum black is used as a catalyst to remove hydrogen. Benzylated and the R moiety can lead to a glucose compound.
Ｒ部分の糖は、糖中のいずれのＯＨ基が結合した化合物であってもよいが、Ｃ−１位のＯＨ基が結合したものが好ましい。
上記化合物は、トカドヘチマから抽出・精製することにより得ることができる。抽出・精製方法は、当業者の知識に基づいて適宜実施することができる。例示としては、抽出物を実施例８〜１２に示す方法で精製することにより得ることができる。また、化学合成によっても得ることができる。
The saccharide at the R moiety may be a compound to which any OH group in the saccharide is bonded, but preferably has a OH group at the C-1 position bonded thereto.
The above compound can be obtained by extraction and purification from tocadohecima. The extraction / purification method can be appropriately performed based on the knowledge of those skilled in the art. For example, the extract can be obtained by purifying the extract by the methods shown in Examples 8 to 12. It can also be obtained by chemical synthesis.
上記化合物は、強いＰＰＡＲα、δおよびγリガンド作用を有する。
以下に本発明を実施例により詳細に説明するが、本発明はこれらに限定されるものではない。
The above compounds have strong PPARα, δ and γ ligand actions.
EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.
実施例１ ＰＰＡＲγリガンド活性の測定方法
ＰＰＡＲγリガンド活性測定用ＣＨＯ細胞を以下の方法で取得した。
ＰＰＡＲレポータープラスミド（ｐＰＰＲＥ-Ｌｕｃ）は、ＳＶ４０プロモーター遺伝子、蛍ルシフェラーゼ遺伝子を含むレポータープラスミド ｐＧＬ３（Ｐｒｏｍｅｇａ社）のＳＶ４０プロモーター遺伝子の上流にＰＰＡＲ応答配列(ＰＰＲＥ)を３回組み込んだレポータープラスミドである。ＰＰＡＲγ発現プラスミド（ｐＫＤ-ｒＰＰＡＲγ）はＳＶ４０プロモーターによる哺乳類細胞用発現プラスミドにラットＰＰＡＲγ遺伝子を組み込んだプラスミドである。 ｐＰＰＲＥ-ＬｕｃとｐＫＤ-ｒＰＰＡＲγを、Ｌｉｐｏｆｅｃｔａｍｉｎｅ（Ｉｎｖｉｔｏｒｇｅｎ社）を用いてＣＨＯ（ｄｈｆｒ-）細胞（チャイニーズハムスター卵巣由来細胞ジヒドロ葉酸還元酵素欠損株）にコトランスフェクションした。チミジンをほとんど含有しない透析ウシ胎児血清（Ｇｉｂｃｏ社）を含むＤＭＥＭ培地（Ｄｕｌｂｅｃｃｏ‘ｓ Ｍｏｄｉｆｉｅｄ Ｅａｇｌｅ Ｍｅｄｉｕｍ、Ｇｉｂｃｏ社）で細胞を培養することにより、ｐＰＰＲＥ-Ｌｕｃ と ｐＫＤ-ｒＰＰＡＲγを保持する安定形質転換株(ＣＨＯ/ＰＰＡＲγ/ＰＰＲＥ)を取得した。
Example 1 Method for Measuring PPARγ Ligand Activity CHO cells for measuring PPARγ ligand activity were obtained by the following method.
The PPAR reporter plasmid (pPPRE-Luc) is a reporter plasmid in which the PPAR response element (PPRE) is incorporated three times upstream of the SV40 promoter gene of the reporter plasmid pGL3 (Promega) containing the SV40 promoter gene and the firefly luciferase gene. The PPARγ expression plasmid (pKD-rPPARγ) is a plasmid in which the rat PPARγ gene is incorporated into an expression plasmid for mammalian cells using the SV40 promoter. pPPRE-Luc and pKD-rPPARγ were co-transfected into CHO (dhfr-) cells (Chinese hamster ovary-derived cell dihydrofolate reductase-deficient strain) using Lipofectamine (Invitrogen). A stable transformant that retains pPPRE-Luc and pKD-rPPARγ by culturing cells in DMEM medium (Dulbecco's Modified Eagle Medium, Gibco) containing dialyzed fetal calf serum (Gibco) containing almost no thymidine (CHO / PPARγ / PPRE) was obtained.
上記細胞を９６穴培養プレートに１ｘ１０４ Ｃｅｌｌｓ／ｗｅｌｌ となるように播種し、３７℃、５％ ＣＯ2条件下で２４時間培養した。培地には、１０％ ＦＢＳ（ウシ胎仔血清；Ｅｑｕｉｔｅｃｈ−Ｂｉｏ社）、０．３ｇ／ｌ−Ｇｌｕｔａｍｉｎｅ（日水製薬）、１０ｍｌ/ｌ ＭＥＭ用非必須アミノ酸溶液（大日本住友製薬）を含むＤＭＥＭ（日水製薬）を用いた。２４時間培養後、試験物を含む培地に交換し、２４時間培養した。溶媒対照にはジメチルスルホキシドを用い、培地に１／１００量添加した。細胞をリン酸緩衝生理食塩水（ＰＢＳ−）で洗浄した後、細胞溶解液（Ｃｅｌｌ Ｃｕｌｔｕｒｅ Ｌｙｓｉｓ Ｒｅａｇｅｎｔ:Ｐｒｏｍｅｇａ社）で細胞を溶解させ、Ｌｕｃｉｆｅｒａｓｅ Ａｓｓａｙ Ｒｅａｇｅｎｔ（Ｐｒｏｍｅｇａ社）を添加してマルチラベルカウンター（Ｗａｌｌａｃ社）にてルシフェラーゼの発光強度を測定した。また、ＰＰＡＲγの合成アゴニストであるシグリチゾン（Ｃｉｇｌｉｔｉｚｏｎｅ）（Ｓｉｇｍａ社、濃度２５μＭ）をポジティブコントロールとして用いた。リガンド活性の評価は、コントロール（溶媒対照）の発光強度に対する試験物の発光強度の比を試験物のＰＰＡＲγリガンド活性発光度比とし、１．３以上を示したものについて、ＰＰＡＲγのリガンド活性があると判断した。 The cells were seeded in a 96-well culture plate at 1 × 10 4 Cells / well and cultured at 37 ° C. and 5% CO 2 for 24 hours. The medium includes 10% FBS (fetal calf serum; Equitech-Bio), 0.3 g / l-Glutamine (Nissui Pharmaceutical), 10 ml / l MEM containing a non-essential amino acid solution for MEM (Dainippon Sumitomo Pharma) Nissui Pharmaceutical) was used. After culturing for 24 hours, the medium was replaced with a medium containing the test substance, and cultured for 24 hours. Dimethyl sulfoxide was used as a solvent control, and 1/100 amount was added to the medium. After the cells were washed with phosphate buffered saline (PBS-), the cells were lysed with a cell lysis solution (Cell Culture Lysis Reagent: Promega), Luciferase Assay Reagent (Promega) was added, and a multi-label counter (Promega) was added. The luminescence intensity of luciferase was measured by Wallac). In addition, ciglitisone (Sigma, concentration 25 μM), a synthetic agonist of PPARγ, was used as a positive control. Evaluation of the ligand activity is based on the ratio of the luminescence intensity of the test substance to the luminescence intensity of the control (solvent control) as the PPARγ ligand activity luminescence intensity ratio of the test article. It was judged.
実施例２ ＰＰＡＲδリガンド活性の測定方法
ＨｅｐＧ２細胞（ヒト肝臓癌由来の培養細胞）を９６穴培養プレートに１ｘ１０４ ｃｅｌｌｓ／ｗｅｌｌとなるように播種し、３７℃、５％ ＣＯ２条件下で２４時間培養した。培地には、１０％ ＦＢＳ（ウシ胎仔血清；Ｅｑｕｉｔｅｃｈ−Ｂｉｏ社）、０．３ｇ／ｌ Ｌ−Ｇｌｕｔａｍｉｎｅ（日水製薬）を含むＲＰＭＩ１６４０（日水製薬）を用いた。その細胞をＯＰＴＩ−ＭＥＭ（Ｇｉｂｃｏ社）で洗浄した後、ｐＢＩＮＤ／ＧＡＬ４：：ｍＰＰＡＲδとｐＧ５ｌｕｃ（Ｐｒｏｍｅｇａ社）を用いてトランスフェクションした。なお、ｐＢＩＮＤ／ＧＡＬ４：：ｍＰＰＡＲδは、酵母由来転写因子ＧＡＬ４融合タンパク発現プラズミドであるｐＢＩＮＤ（Ｐｒｏｍｅｇａ社）にマウスＰＰＡＲδ遺伝子を挿入したプラスミドであり、ｐＧ５ｌｕｃはルシフェラーゼ遺伝子の上流にＧＡＬ４の応答配列（ＵＡＳ）を５回組み込んだレポーター・プラスミドである（Ｃｅｌｌ，１９９５年，８３巻，８０３〜８１２頁などに記載の方法で作成可能）。トランスフェクションの約２４時間後、試験物を含む培地に交換し、２４時間培養した。溶媒対照にはジメチルスルホキシドを用い、培地に１／１００量添加した。細胞をリン酸緩衝生理食塩水（ＰＢＳ−）で洗浄した後、細胞溶解液（Ｃｅｌｌ Ｃｕｌｔｕｒｅ Ｌｙｓｉｓ Ｒｅａｇｅｎｔ：Ｐｒｏｍｅｇａ社）で細胞を溶解させ、Ｌｕｃｉｆｅｒａｓｅ Ａｓｓａｙ Ｒｅａｇｅｎｔ（Ｐｒｏｍｅｇａ社）を添加してマルチラベルカウンター（Ｗａｌｌａｃ社）にてルシフェラーゼの発光強度を測定した。また、ＰＰＡＲδの合成アゴニストであるＬ−１６５０４１（Ｓｉｇｍａ社、濃度２５μＭ）をポジティブコントロールとして用いた。リガンド活性の評価は、コントロール（溶媒対照）の発光強度に対する試験物の発光強度の比を試験物のＰＰＡＲδリガンド活性発光度比とし、１．３以上を示したものについて、ＰＰＡＲδのリガンド活性があると判断した。
Example 2 Method for Measuring PPARδ Ligand Activity HepG2 cells (cultured cells derived from human liver cancer) were seeded in a 96-well culture plate so as to be 1 × 10 4 cells / well, and the condition was maintained at 37 ° C. and 5% CO 2 for 24 hours. Cultured. RPMI1640 (Nissui Pharmaceutical) containing 10% FBS (fetal bovine serum; Equitech-Bio), 0.3 g / l L-Glutamine (Nissui Pharmaceutical) was used as the medium. The cells were washed with OPTI-MEM (Gibco) and then transfected with pBIND / GAL4 :: mPPARδ and pG5luc (Promega). PBIND / GAL4 :: mPPARδ is a plasmid in which the mouse PPARδ gene is inserted into pBIND (Promega), a yeast-derived transcription factor GAL4 fusion protein expression plasmid, and pG5luc is a GAL4 response element (UAS) upstream of the luciferase gene. ) Is incorporated 5 times (can be prepared by the method described in Cell, 1995, 83, 803-812, etc.). About 24 hours after transfection, the medium was replaced with a medium containing the test substance and cultured for 24 hours. Dimethyl sulfoxide was used as a solvent control, and 1/100 amount was added to the medium. After washing the cells with phosphate buffered saline (PBS-), the cells were lysed with a cell lysis solution (Cell Culture Lysis Reagent: Promega), Luciferase Assay Reagent (Promega) was added, and a multi-label counter (Promega) was added. The luminescence intensity of luciferase was measured by Wallac). Moreover, L-165041 (Sigma, concentration 25 μM), which is a synthetic agonist of PPARδ, was used as a positive control. Evaluation of the ligand activity is based on the ratio of the luminescence intensity of the test substance to the luminescence intensity of the control (solvent control) as the PPARδ ligand activity luminescence intensity ratio of the test article. It was judged.
実施例３ ＰＰＡＲαリガンド活性の測定方法
実施例２に記載の方法のうち、融合タンパク発現プラスミドとして、ｐＢＩＮＤ／ＧＡＬ４：：ｍＰＰＡＲδの代わりに、ｐＢＩＮＤ／ＧＡＬ４：：ｍＰＰＡＲαを用いる以外は、実施例２と同様に実施し、ＰＰＡＲαリガンド活性の測定を行った。なお、ｐＢＩＮＤ／ＧＡＬ４：：ｍＰＰＡＲαとは、ｐＢＩＮＤ（Ｐｒｏｍｅｇａ社）にマウスＰＰＡＲα遺伝子を挿入したプラスミドである。また、ＰＰＡＲαの合成アゴニストであるＷＹ−１４６４３（Ｓｉｇｍａ社、濃度２５μＭ）をポジティブコントロールとして用いた。リガンド活性の評価は、コントロール（溶媒対照）の発光強度に対する試験物の発光強度の比を試験物のＰＰＡＲαリガンド活性発光度比とし、１．３以上を示したものについて、ＰＰＡＲαのリガンド活性があると判断した。
Example 3 Method for Measuring PPARα Ligand Activity Of the methods described in Example 2, except that pBIND / GAL4 :: mPPARα is used instead of pBIND / GAL4 :: mPPARδ as a fusion protein expression plasmid, In the same manner, PPARα ligand activity was measured. Note that pBIND / GAL4 :: mPPARα is a plasmid in which the mouse PPARα gene is inserted into pBIND (Promega). Moreover, WY-14463 (Sigma, concentration 25 μM), which is a synthetic agonist of PPARα, was used as a positive control. The evaluation of the ligand activity is based on the ratio of the luminescence intensity of the test substance to the luminescence intensity of the control (solvent control) as the PPARα ligand activity luminescence intensity ratio of the test article. It was judged.
実施例４ 試験物のＰＰＡＲリガンド活性
植物４２０種の乾燥物をそれぞれ破砕し、破砕物１gに対して１０倍量の７０容量％エタノールに浸し、室温下、１日１回撹拌操作を加えて７日間抽出した。遠心分離後の上澄みを減圧濃縮後、凍結乾燥し、抽出物を得た。抽出物をジメチルスルホキシドに溶かして１０ｍｇ／ｍｌとし、実施例１−３の方法に従ってＰＰＡＲリガンド活性を測定した。セイヨウニワトコ（Ｓａｍｂｕｃｕｓ ｎｉｇｒａ Ｌ．（花））、アギタケ（Ｐｌｅｕｒｏｔｕｓ ｆｅｒｕｌａｅ（子実体））、アシュワガンダ（Ｗｉｔｈａｎｉａ ｓｏｍｎｉｆｅｒａ Ｄｕｎａｌ（根））、アニス（Ｐｉｍｐｉｎｅｌｌａ ａｎｉｓｕｍ Ｌ．（種子））、ギョリュウモドキ（Ｃａｌｌｕｎａ ｖｕｌｇａｒｉｓ（Ｌ．）Ｈｕｌｌ．（花））、サクナ（Ｐｅｕｃｅｄａｎｕｍ ｊａｐｏｎｉｃｕｍ Ｔｈｕｎｂ．（地上部））、セイヨウサンザシ（Ｃｒａｔａｅｇｕｓ ｍｏｎｏｇｙｎａ Ｊａｑｕｉｎ ｅｍｅｎｄ．Ｌｉｎｄｍａｎ（果実））、セキガイチャ（Ａｄｉｎａｎｄｒａ ｎｉｔｉｄａ（葉））、タワシヘチマ（Ｌｕｆｆａ ｃｙｌｉｎｄｒｉｃａ Ｌ．（果実））、チャボトケイソウ（Ｐａｓｓｉｆｌｏｒａ ｉｎｃａｒｎａｔｅ Ｌ．（地上部））、トカドヘチマ（Ｌｕｆｆａ ａｃｕｔａｎｇｕｌａ Ｒｏｘｂ．（果実））、ハリエンジュ（Ｒｏｂｉｎｉａ ｐｓｅｕｄｏａｃａｃｉａ Ｌ．（花））、マンシュウウコギ（Ａｃａｎｔｈｏｐａｎａｘ ｓｅｓｓｉｌｉｆｌｏｒｕｓ（Ｒｕｐｒ．ｅｔ Ｍａｘｉｍ．）Ｓｅｅｍ．（葉））に活性が認められた。中でも、トカドヘチマ抽出物が活性スペクトル上、とくに優れていた。結果を表１に示す。
Example 4 420 dry samples of PPAR ligand-active plants as test samples were each crushed, soaked in 10 volumes of 70% by volume ethanol with respect to 1 g of the crushed product, and stirred at room temperature once a day to add 7 Extracted for days. The supernatant after centrifugation was concentrated under reduced pressure and lyophilized to obtain an extract. The extract was dissolved in dimethyl sulfoxide to 10 mg / ml, and PPAR ligand activity was measured according to the method of Example 1-3. Sambucus nigra (Sambucus nigra L. (flower)), Agitake (Pleurotus ferulae (fruiting bodies)), Ashwagandha (Withania somnifera Dunal (root)), anise (Pimpinella anisum L. (seed)), Calluna (Calluna vulgaris (L .) Hull. (Hana)), Peucedanum japonicum (Peucedanum japonicum Thunb. (above-ground part)), hawthorn (Crataegus monogyna Jaquin emend.Lindman (fruit)), Adinandra nitida (Adinandra nitida (leaf)), Tawashihechima (Luffa cylindrica L. (fruit)), passiflora passion flower (passiflora in arnate L. (above-ground)), Luffa Acutangula (Luffa acutangula Roxb. (fruit)), locust (Robinia pseudoacacia L. (flower)), Man Shu Acanthopanax (Acanthopanax sessiliflorus (Rupr.et Maxim.) Seem. to (leaves)) Activity was observed. Among them, the tocadohetima extract was particularly excellent on the activity spectrum. The results are shown in Table 1.
実施例５ トカドヘチマ抽出物の部位の違いによるＰＰＡＲリガンド活性
２３６（ＩＤ２３８０）未熟果実（９月収穫）、４２１（ＩＤ２３７９）根、茎、葉（９月収穫）、４３３（ＩＤ４７１５）根、茎、葉（１０月下旬収穫）の乾燥物をブレンダー（ラボミルサーＬＭ−ＰＬＵＳ，大阪ケミカル株式会社製）で粉砕後、１５ｇに５倍量のメタノールを添加し、室温で一週間浸漬した。東洋ろ紙Ｎｏ．２で吸引ろ過し、ろ液を減圧乾固し、抽出物を得た。固形分回収率は、それぞれ６．２％、４．１％、３．１％であった。抽出物をジメチルスルホキシドに溶かして１０ｍｇ／ｍｌとし、実施例１−３の方法に従ってＰＰＡＲリガンド活性を測定した。結果を表２〜４及び図１〜３に示す。
Example 5 PPAR Ligand Activity 236 (ID2380) Immature Fruit (September Harvest), 421 (ID2379) Root, Stem, Leaf (September Harvest), 433 (ID4715) Root, Stem, Leaf The dried product (harvested in late October) was pulverized with a blender (Lab Miller LM-PLUS, manufactured by Osaka Chemical Co., Ltd.), 5 times the amount of methanol was added to 15 g, and the mixture was immersed at room temperature for one week. Toyo Filter Paper No. The mixture was suction filtered through 2, and the filtrate was dried under reduced pressure to obtain an extract. The solid content recovery rates were 6.2%, 4.1%, and 3.1%, respectively. The extract was dissolved in dimethyl sulfoxide to 10 mg / ml, and PPAR ligand activity was measured according to the method of Example 1-3. The results are shown in Tables 2 to 4 and FIGS.
最大用量の１００μｇ/ｍｌでは細胞障害性を示したが、根・茎・葉および未熟果実にほぼ同等の活性が観察された。
実施例６ トカドヘチマ抽出物の抽出溶媒の違いによるＰＰＡＲリガンド活性
トカドヘチマ乾燥物をブレンダーで粉砕後、熱水、７０容量％エタノール、メタノールの３種類の溶媒で抽出した。抽出条件（固形分収率）は、熱水：１０倍量、８０℃、３０分（２８％）、７０容量％エタノール：１０倍量、室温一週間（２１％）、メタノール：５倍量、室温一週間（６％）である。得られた乾燥抽出物をジメチルスルホキシドに溶かして１０ｍｇ／ｍｌとし、実施例１−３の方法に従ってＰＰＡＲリガンド活性を測定した。結果を表５〜７及び図４〜６に示す。
The maximum dose of 100 μg / ml showed cytotoxicity, but almost the same activity was observed in roots, stems, leaves and immature fruits.
Example 6 PPAR Ligand-Activated Tocadohetima Dried Product Due to Difference in Extraction Solvent of Tocadohetima Extract After pulverizing with a blender, it was extracted with three kinds of solvents: hot water, 70 vol% ethanol, and methanol. Extraction conditions (solid content yield) are as follows: hot water: 10 times, 80 ° C., 30 minutes (28%), 70 vol% ethanol: 10 times, room temperature for one week (21%), methanol: 5 times, Room temperature for one week (6%). The obtained dried extract was dissolved in dimethyl sulfoxide to 10 mg / ml, and PPAR ligand activity was measured according to the method of Example 1-3. The results are shown in Tables 5 to 7 and FIGS.
実施例７ トカドヘチマ抽出物の抽出条件の違いによるＰＰＡＲリガンド活性
トカドヘチマ乾燥物をブレンダーで粉砕後、２gに対して１０倍量の含水量の異なるエタノール（１０容量％、３０容量％、５０容量％、７０容量％、９０容量％エタノール）を添加し、室温で抽出した。１日後、３日後、５日後、７日後に遠心分離し、抽出液を得た。それぞれの抽出液を減圧濃縮、凍結乾燥し、固形分を得た。７０容量％エタノール、７日間浸漬条件の固形分抽出効率（１７．６％）を１．００とした相対抽出効率を求めた。結果を表８に示す。また、得られた乾燥抽出物をジメチルスルホキシドに溶かして５０ｍｇ／ｍｌとし、実施例１−３の方法に従ってＰＰＡＲリガンド活性を測定した。結果を表９〜１１に示す。
Example 7 PPAR Ligand-Activated Tocadohetima Dried Product Due to Differences in Extraction Conditions of Tocadohetima Extract After grinding with a blender, ethanol (10 vol%, 30 vol%, 50 vol%, 70 volume%, 90 volume% ethanol) was added and extracted at room temperature. Centrifugation was performed after 1 day, 3 days, 5 days, and 7 days to obtain an extract. Each extract was concentrated under reduced pressure and lyophilized to obtain a solid content. The relative extraction efficiency was determined with a solid content extraction efficiency (17.6%) of 70 vol% ethanol and 7 days immersion conditions being 1.00. The results are shown in Table 8. Further, the obtained dried extract was dissolved in dimethyl sulfoxide to give 50 mg / ml, and PPAR ligand activity was measured according to the method of Example 1-3. The results are shown in Tables 9-11.
実施例８
成分の分画
トカドヘチマのメタノールエキス３１０ｍｇにメタノール４ｍｌを添加した試料をＢｏｎｄ−Ｅｌｕｔ−Ｃ８ １ｍｌ（Ｖａｒｉａｎｓ社）５本に分けて負荷し、それぞれメタノール２ｍｌ、アセトニトリル１ｍｌで溶出し、湿重量２９０ｍｇを得た。この前処理ののち、ジメチルスルホキシド２００μｌ、メタノール１００μｌを添加した試料をパックドカラムに付し、５ｍｌ/０．５分ずつ採取した。結果を図７に示す。
Example 8
A sample obtained by adding 4 ml of methanol to 310 mg of the component fraction Tocadochema methanol extract was loaded into 5 parts of Bond-Elut-C8 (Varians) and eluted with 2 ml of methanol and 1 ml of acetonitrile, respectively, to obtain a wet weight of 290 mg. It was. After this pretreatment, a sample to which 200 μl of dimethyl sulfoxide and 100 μl of methanol were added was applied to a packed column and sampled at a rate of 5 ml / 0.5 minutes. The results are shown in FIG.
分取条件
システム：Ｇｉｌｓｏｎ（登録商標）３０５型および３０３型
カラム：ＤｅｖｅｌｏｓｉｌＴＭ Ｃ３０−ＵＧ−５（２０＊２５０ｍｍ＋２０＊５０ｍｍ、野村化学株式会社製）
移動相：Ａ：蒸留水、Ｂ：アセトニトリル
プログラム：０分（０％ Ｂ）、７６分（１００％ Ｂ）、１１４分（１００％ Ｂ）
流速：１０ｍｌ/分
検出波長：２８０ｎｍ
フラクションコレクター：Ｇｉｌｓｏｎ（登録商標） ＦＣ２０４型
実施例９ 分画物のＰＰＡＲリガンド活性測定
実施例８で得られたフラクション８１−１３０から各々２００μｌ採取し、減圧濃縮してジメチルスルホキシド１００μｌに再溶解した。実施例１−３の方法にしたがって測定した結果、フラクション９３、９４、１２４―１２７に活性が認められた（図８）。
Preparative conditions System: Gilson <(R)> 305 and 303 columns: Develosil < TM > C30-UG-5 (20 * 250 mm + 20 * 50 mm, manufactured by Nomura Chemical Co., Ltd.)
Mobile phase: A: distilled water, B: acetonitrile program: 0 min (0% B), 76 min (100% B), 114 min (100% B)
Flow rate: 10 ml / min Detection wavelength: 280 nm
Fraction collector: Gilson (registered trademark) FC204 type
Example 9 Measurement of PPAR Ligand Activity of Fractions 200 μl of each fraction was collected from fractions 81-130 obtained in Example 8, concentrated under reduced pressure, and redissolved in 100 μl of dimethyl sulfoxide. As a result of measurement according to the method of Example 1-3, the activity was recognized in fractions 93, 94, and 124-127 (FIG. 8).
実施例１０ 成分のＰＰＡＲリガンド活性
実施例８で得られた活性画分のうち、フラクション９３、９４、および１２４、１２５の用量反応性を実施例１−３の方法にしたがって測定した。結果を表１２および図９〜１２に示す。活性を示す最大有効希釈倍率はフラクション９３、９４では１３００倍、１２４、１２５では１２０００倍であった。アッセイ時に用いた試料はフラクションを２倍濃縮したものなので、もとの試料ではそれぞれ６５０倍、６０００倍希釈となる。該当フラクションを減圧濃縮、凍結乾燥し、得られた重量が０．２ｍｇであることを考慮すると、有効濃度は、
フラクション９３、９４：０．２ｍｇ/１０ｍｌ/６５０＝０．００００３ｍｇ/ｍｌ＝０．０３μｇ/ｍｌ
フラクション１２４、１２５：０．２ｍｇ/１０ｍｌ/６０００＝０．０００００３ｍｇ/ｍｌ＝０．００３μｇ/ｍｌ
Example 10 PPAR Ligand Activity of Components Of the active fraction obtained in Example 8, the dose responsiveness of fractions 93, 94, and 124, 125 was measured according to the method of Example 1-3. The results are shown in Table 12 and FIGS. The maximum effective dilution factor showing activity was 1300 times for fractions 93 and 94, and 12000 times for 124 and 125. Since the sample used at the time of the assay is a fraction concentrated twice, the original sample is diluted 650 times and 6000 times, respectively. Considering that the relevant fraction is concentrated under reduced pressure and lyophilized and the weight obtained is 0.2 mg, the effective concentration is
Fraction 93, 94: 0.2 mg / 10 ml / 650 = 0.00003 mg / ml = 0.03 μg / ml
Fraction 124, 125: 0.2 mg / 10 ml / 6000 = 0.000003 mg / ml = 0.003 μg / ml
実施例１１ 精製物の活性
実施例８で得られたフラクョン１２４，１２５をＤｅｖｅｌｏｓｉｌＴＭ Ｃ３０−ＵＧ−５に付し、５０Ｖ/Ｖ％アセトニトリル−０．１％ギ酸で溶出し、化合物Ａ（ＲはＨ）を得た（図１５）。また、実施例８で得られたフラクョン９３，９４をＤｅｖｅｌｏｓｉｌＴＭ Ｃ３０−ＵＧ−５に付し、３０Ｖ/Ｖ％アセトニトリル−０．１％ギ酸で溶出し、化合物Ｂ（ＲはＧｌｃ）を得た（図１６）。化合物Ａ（ＲはＨ）の極大吸収は２５１ｎｍおよび３０４ｎｍ、化合物Ｂ（ＲはＧｌｃ）の極大吸収は２５６ｎｍおよび３０４ｎｍであった（図１３，１４）。ＰＰＡＲリガンド活性を測定した結果を表１３に示す。
Example 11 Activity of Purified Product Fractions 124 and 125 obtained in Example 8 were subjected to Develosil ™ C30-UG-5 and eluted with 50 V / V% acetonitrile-0.1% formic acid to obtain compound A (R is H) was obtained (FIG. 15). Further, fractions 93 and 94 obtained in Example 8 were subjected to Develosil ™ C30-UG-5 and eluted with 30 V / V% acetonitrile-0.1% formic acid to obtain compound B (R is Glc). (FIG. 16). The maximum absorption of Compound A (R is H) was 251 nm and 304 nm, and the maximum absorption of Compound B (R was Glc) was 256 nm and 304 nm (FIGS. 13 and 14). The results of measuring the PPAR ligand activity are shown in Table 13.
糖部分の無い物質（アグリコン）よりも配糖体の方が吸収されやすいことが知られている。例えば、ケルセチン配糖体の方が糖部分のないケルセチンよりも生物学的利用率が高いことが知られている（Ｆｒｅｅ Ｒａｄｉｃ． Ｒｅｓ． ３１（６）：５６９−５７３； １９９９）。また、糖部分の無い物質（アグリコン）よりも配糖体の方が極性が高く、より水に溶けやすいという性質を有する。これらの性質からも、化合物Ｂは優れたＰＰＡＲリガンド剤であるといえる。 It is known that glycosides are more easily absorbed than substances without sugar moieties (aglycones). For example, it is known that quercetin glycoside has a higher bioavailability than quercetin without a sugar moiety (Free Radic. Res. 31 (6): 569-573; 1999). In addition, glycosides are more polar than substances without a sugar moiety (aglycone), and are more soluble in water. From these properties, it can be said that Compound B is an excellent PPAR ligand agent.
実施例１２ 精製物の質量分析
Ｑ−ＴＯＦ Ｐｒｅｍｉｅｒ（Ｍｉｃｒｏｍａｓｓ社製、ＵＫ）を用いて、以下の条件で精密質量分析(ＬＣ−ＭＳおよびＬＣ−ＭＳ／ＭＳ)を行った；
カラム：ＤｅｖｅｌｏｓｉｌＴＭ Ｃ３０−ＵＧ−５（３ｍｍ＊１５０ｍｍ、野村化学株式会社製）、カラム温度：４０℃
移動相：５０Ｖ/Ｖ％アセトニトリル−０．１％ギ酸、流速：０．２５ｍｌ/分
イオン化法：ＥＳＩ、イオンソース；Ｚ−スプレー
Ｃａｐｉｌｌａｒｙ ｖｏｌｔａｇｅ：２．７ｋＶ（ネガティブ、Ｖモード）、３．０ｋＶ（ポジティブ、Ｖモード、）
Ｃｏｎｅ ｖｏｌｔａｇｅ：
３８Ｖ｛ネガティブモード、化合物Ａ（ＲはＨ）のＭＳおよび化合物Ａ（ＲはＨ）のｍ／ｚ ２６７．０７のＭＳ／ＭＳ測定時｝
４０Ｖ｛ポジティブモード、化合物Ａ（ＲはＨ）のＭＳおよび化合物Ａ（ＲはＨ）のｍ／ｚ ２６９．０８のＭＳ／ＭＳ測定時｝
２４Ｖ｛ネガティブモード、化合物Ｂ（ＲはＧｌｃ）のＭＳ測定時｝
２０Ｖ｛ネガティブモード、化合物Ｂ（ＲはＧｌｃ）のｍ／ｚ ４２９．１２のＭＳ／ＭＳ測定時｝
Ｃｏｌｌｉｓｉｏｎ ｅｎｅｒｇｙ：
２０−３０ｅＶ｛ネガティブモード、化合物Ａ（ＲはＨ） の ｍ／ｚ ２６７．０７のＭＳ／ＭＳ測定時｝
２５−３０ｅＶ｛ポジティブモード、化合物Ａ（ＲはＨ） の ｍ／ｚ ２６９．０８のＭＳ／ＭＳ測定時｝
２０ ｅＶ｛ネガティブモード、化合物Ｂ（ＲはＧｌｃ） の ｍ／ｚ ４２９．１２のＭＳ／ＭＳ測定時｝
Ｓｏｕｒｃｅ Ｔｅｍｐ：１００℃（ネガティブモード、ポジティブモード）
Ｄｅｓｏｌｖａｔｉｏｎ Ｔｅｍｐ：３００℃（ネガティブモード、ポジティブモード）
ロックスプレーによる質量補正を行い、リファレンスにはロイシンエンケファリン（ｍ／ｚ ５５４．２６１５（ネガティブモード）、ｍ／ｚ ５５６．２７７１（ポジティブモード））を用いた。
＜化合物Ａ＞（ＲはＨ）
ネガティブモード：
ＭＳ：ｍ／ｚ ２６７．０６５０［Ｍ−Ｈ］−、Ｃ１６Ｈ１１Ｏ４（理論ｍ／ｚ ２６７．０６５７、誤差―２．６ｐｐｍ）
ＭＳ／ＭＳ（プレカーサーイオン ｍ／ｚ ２６７．０７）：
フラグメントイオン ｍ／ｚ ２０８．０５２６、ｍ／ｚ ２２３．０７５６
ポジティブモード：
ＭＳ：ｍ／ｚ ２６９．０８０８［Ｍ＋Ｈ］＋、Ｃ１６Ｈ１３Ｏ４（理論ｍ／ｚ ２６９．０８１４、誤差−２．２ｐｐｍ）
ＭＳ／ＭＳ（プレカーサーイオンｍ／ｚ ２６９．０８）：
フラグメントイオンｍ／ｚ １６５．０７０３、ｍ／ｚ １８１．０６５６、
ｍ／ｚ １９５．０８００、ｍ／ｚ ２０９．０６０６、ｍ／ｚ ２２３．０７６０、ｍ／ｚ ２４１．０８５８
＜化合物Ｂ＞（ＲはＧｌｃ）
ネガティブモード：
ＭＳ：ｍ／ｚ ４２９．１１８５［Ｍ−Ｈ］−、Ｃ２２Ｈ２１Ｏ９（理論ｍ／ｚ ４２９．１１８６、誤差−０．２ｐｐｍ）
ＭＳ／ＭＳ（プレカーサーイオン ｍ／ｚ ４２９．１２）：
フラグメントイオン ｍ／ｚ ２２３．０７５６、ｍ／ｚ ２６７．０６４０
ポジティブモードの精密質量のＭＳとＭＳ／ＭＳは分析せず。
Example 12 Mass Spectrometry of Purified Product Using Q-TOF Premier (Micromass, UK), accurate mass spectrometry (LC-MS and LC-MS / MS) was performed under the following conditions;
Column: Develosil ™ C30-UG-5 (3 mm * 150 mm, manufactured by Nomura Chemical Co., Ltd.), column temperature: 40 ° C.
Mobile phase: 50 V / V% acetonitrile-0.1% formic acid, flow rate: 0.25 ml / min Ionization method: ESI, ion source; Z-spray Capillary voltage: 2.7 kV (negative, V mode), 3.0 kV ( Positive, V mode,)
Cone voltage:
38 V {negative mode, MS of compound A (R is H) and MS / MS of compound A (R is H) m / z 267.07}
40V {positive mode, MS of compound A (R is H) and MS / MS of compound A (R is H) m / z 269.08}
24V {Negative mode, MS measurement of compound B (R is Glc)}
20 V {in negative mode, MS / MS measurement of m / z 429.12 of compound B (R is Glc)}
Collision energy:
20-30 eV {in negative mode, MS / MS measurement of m / z 267.07 of compound A (R is H)}
25-30 eV {positive mode, compound A (R is H) m / z 269.08 MS / MS measurement}
20 eV {negative mode, Compound B (R is Glc) m / z 429.12 MS / MS measurement}
Source Temp: 100 ° C (negative mode, positive mode)
Desolation Temp: 300 ° C (negative mode, positive mode)
The mass was corrected by rock spray, and leucine enkephalin (m / z 554.2615 (negative mode), m / z 556.2771 (positive mode)) was used as a reference.
<Compound A> (R is H)
Negative mode:
MS: m / z 267.0650 [M−H] − , C 16 H 11 O 4 (theoretical m / z 267.0657, error −2.6 ppm)
MS / MS (Precursor ion m / z 267.07):
Fragment ions m / z 208.0526, m / z 223.0756
Positive mode:
MS: m / z 269.0808 [M + H] + , C 16 H 13 O 4 (theoretical m / z 269.814, error −2.2 ppm)
MS / MS (Precursor ion m / z 269.08):
Fragment ion m / z 165.0703, m / z 181.0656,
m / z 195.0800, m / z 209.0606, m / z 223.0760, m / z 241.0858
<Compound B> (R is Glc)
Negative mode:
MS: m / z 429.1185 [M−H] − , C 22 H 21 O 9 (theoretical m / z 429.1186, error −0.2 ppm)
MS / MS (Precursor ion m / z 429.12):
Fragment ions m / z 223.0756, m / z 267.0640
MS and MS / MS of positive mass in positive mode are not analyzed.
実施例１３ 構造解析
実施例１１で得られた化合物Ａ，化合物Ｂの試料をメタノール−Ｄ４に溶解し、溶媒を内部標準として、ＤＭＸ−７５０ ｓｐｅｃｔｒｏｍｅｔｅｒ（ＢＲＵＫＥＲ ＢＩＯＳＰＩＮ， Ｇｅｒｍａｎｙ)を用いて測定した。測定項目は１Ｈ ＮＭＲ、１Ｈ｛１３Ｃ｝−ＨＳＱＣ、１Ｈ｛１３Ｃ｝−ＨＭＢＣ、ＴＯＣＳＹ、ＤＱＦ−ＣＯＳＹ、ＮＯＥＳＹおよびＲＯＥＳＹである。
化合物Ａ（ＲはＨ）： ２−（４−ｍｅｔｈｏｘｙｐｈｅｎｙｌ）ｂｅｎｚｏｆｕｒａｎ−５−ｃａｒｂｏｘｙｌｉｃ ａｃｉｄ
δＨ（Ｈｚ）：８．１８（Ｃ−４Ｈ，１Ｈ、ｄ、Ｊ＝１．４）、７．９２（Ｃ−６Ｈ，１Ｈ、ｄｄ、Ｊ＝８．５，１．４）、７．８３（Ｃ−２‘Ｈ，Ｃ−６’Ｈ、２Ｈ、ｄ、Ｊ＝８．８）、７．４３（Ｃ−７Ｈ，１Ｈ、ｄ、Ｊ＝８．５）、７．０６（Ｃ−３Ｈ，１Ｈ、ｓ）、７．０２（Ｃ−３‘Ｈ，Ｃ−５’Ｈ，２Ｈ、ｄ、Ｊ＝８．８）、３．８６（Ｃ−４’−ＯＣＨ３、３Ｈ、ｓ）
δＣ： １５７．６（Ｃ２）、１０１.１（Ｃ３）、１３４．４（Ｃ３ａ）、１２３．４（Ｃ４），１３０．４（Ｃ５）、１２６．７（Ｃ６）、１１０．５（Ｃ７）、１５７．４（Ｃ７ａ）、１６７．９（Ｃ８）、１２４.５（Ｃ１‘）、１２７.４（Ｃ２’,Ｃ６‘）、１１５（Ｃ３’,Ｃ５‘）、１６１．７（Ｃ４’）、５６（Ｃ４‘−ＯＣＨ３）
化合物Ｂ（ＲはＧｌｃ）： ５−［（β−Ｄ−ｇｌｕｃｏｐｙｒａｎｏｓｙｌｏｘｙ）ｃａｒｂｏｎｙｌ］−２−（４−ｍｅｔｈｏｘｙｐｈｅｎｙｌ）ｂｅｎｚｏｆｕｒａｎ
ＧｌｃのＣ−１位の水素（Ｃ−１”Ｈ、δH５．７５）とカルボキシル基の炭素（Ｃ−８、δｃ１６７）とのつながりを示す１Ｈ｛１３Ｃ｝−ＨＭＢＣスペクトルデータから、ＧｌｃのＣ−１位のＯＨが結合していると結論した。また、グルコース Ｃ−１位の水素（Ｃ−１”Ｈ、δH５．７５）の結合定数、Ｊ＝８．１ Ｈｚであることから、β結合であることが分かった。
δＨ（Ｈｚ）：８．３７（Ｃ−４Ｈ，１Ｈ、ｄ、Ｊ＝１．７）、８．０４（Ｃ−，１Ｈ、ｄｄ、Ｊ＝８．６，１．７）、７．８６（Ｃ−２‘Ｈ，Ｃ−６’Ｈ，２Ｈ、ｄ、Ｊ＝８．８）、７．６０（Ｃ−７Ｈ，１Ｈ、ｄ、Ｊ＝８．６）、７．１４（Ｃ−３Ｈ，１Ｈ、ｓ）、７．０４（Ｃ−３‘Ｈ，Ｃ−５’Ｈ，２Ｈ、ｄ、Ｊ＝８．８）、３．５６（Ｃ４’−ＯＣＨ３，３Ｈ、ｓ）； ５．７５（Ｃ−１“Ｈ，１Ｈ、ｄ、Ｊ＝８．１）、３．８７（Ｃ−６”Ｈ，１Ｈ、ｄｄ、Ｊ＝１２．３、２．０）、３．７２（Ｃ−６“Ｈ，１Ｈ、ｄｄ、Ｊ＝１２．３、５．２）、３．５５（Ｃ−２”Ｈ，１Ｈ、ｄｄ、Ｊ＝９．１、８．１）、３．５１（Ｃ−３“Ｈ、１Ｈ、Ｊ＝９．１、８．７）、３．４７（Ｃ−５”Ｈ、１Ｈ、ｍ）、３．４３（Ｃ−４“Ｈ、１Ｈ、ｄｄ、Ｊ＝９．６、８．７）
δＣ：１５９．５（Ｃ２）、１０１（Ｃ３）、１３１（Ｃ３ａ）、１２４．５（Ｃ４），１２６（Ｃ５）、１２７（Ｃ６）、１１２（Ｃ７）、１５９（Ｃ７ａ）、１６７（Ｃ８）、１２４（Ｃ１‘）、１２８（Ｃ２’,Ｃ６‘）、１１６（Ｃ３’,Ｃ５‘）、１６２（Ｃ４’）、５６（Ｃ４‘−ＯＣＨ３）；９６（Ｃ１“）、７４（Ｃ２”）、７８（Ｃ３“）、７１（Ｃ４”）、７９（Ｃ５“）、６２．４（Ｃ６”）
Example 13 Structural Analysis Example Compound obtained in 11 A, a sample of compound B was dissolved in methanol -D 4, the solvent as internal standard, was measured using a DMX-750 spectrometer (BRUKER BIOSPIN, Germany). Measurement items are 1 H NMR, 1 H { 13 C} -HSQC, 1 H { 13 C} -HMBC, TOCSY, DQF-COSY, NOESY, and ROESY.
Compound A (R is H) : 2- (4-methoxyphenyl) benzofuran-5-carboxylic acid
δ H (Hz): 8.18 (C-4H, 1H, d, J = 1.4), 7.92 (C-6H, 1H, dd, J = 8.5, 1.4), 7. 83 (C-2′H, C-6′H, 2H, d, J = 8.8), 7.43 (C-7H, 1H, d, J = 8.5), 7.06 (C− 3H, 1H, s), 7.02 (C-3′H, C-5′H, 2H, d, J = 8.8), 3.86 (C-4′-OCH3, 3H, s)
δ C : 157.6 (C2), 101.1 (C3), 134.4 (C3a), 123.4 (C4), 130.4 (C5), 126.7 (C6), 110.5 (C7) ), 157.4 (C7a), 167.9 (C8), 124.5 (C1 ′), 127.4 (C2 ′, C6 ′), 115 (C3 ′, C5 ′), 161.7 (C4 ′) ), 56 (C4′-OCH3)
Compound B (R is Glc) : 5-[(β-D-glucopyranosyloxy) carbonyl] -2- (4-methoxyphenyl) benzofuran
From 1 H { 13 C} -HMBC spectrum data showing the connection between hydrogen at C-1 position of Glc (C-1 ″ H, δ H 5.75) and carbon of carboxyl group (C-8, δc 167), It was concluded that the OH at the C-1 position of Glc was bonded, and the binding constant of hydrogen at the C-1 position (C-1 ″ H, δ H 5.75) at J = 8.1 Hz. There was a β bond.
δ H (Hz): 8.37 (C-4H, 1H, d, J = 1.7), 8.04 (C-, 1H, dd, J = 8.6, 1.7), 7.86 (C-2′H, C-6′H, 2H, d, J = 8.8), 7.60 (C-7H, 1H, d, J = 8.6), 7.14 (C-3H , 1H, s), 7.04 (C-3′H, C-5′H, 2H, d, J = 8.8), 3.56 (C4′-OCH3, 3H, s); 5.75 (C-1 “H, 1H, d, J = 8.1), 3.87 (C-6” H, 1H, dd, J = 12.3, 2.0), 3.72 (C-6 “H, 1H, dd, J = 12.3, 5.2), 3.55 (C-2” H, 1H, dd, J = 9.1, 8.1), 3.51 (C-3 “H, 1H, J = 9.1, 8.7), 3.47 (C-5” H, 1H, m), 3.43 (C-4 “H, 1H, d) d, J = 9.6, 8.7)
δ C: 159.5 (C2), 101 (C3), 131 (C3a), 124.5 (C4), 126 (C5), 127 (C6), 112 (C7), 159 (C7a), 167 (C8 ), 124 (C1 ′), 128 (C2 ′, C6 ′), 116 (C3 ′, C5 ′), 162 (C4 ′), 56 (C4′-OCH3); 96 (C1 ″), 74 (C2 ″) ), 78 (C3 "), 71 (C4"), 79 (C5 "), 62.4 (C6")
本発明により、優れたＰＰＡＲリガンド剤が提供され、肥満、肥満に伴うインスリン抵抗性、高脂血症、高血圧、糖尿病などの予防および/または改善に有効な飲食物、医薬品の形態であるＰＰＡＲリガンド剤が提供される。 INDUSTRIAL APPLICABILITY According to the present invention, an excellent PPAR ligand agent is provided, and is a PPAR ligand that is in the form of food, beverage, or medicine effective in preventing and / or improving obesity, insulin resistance associated with obesity, hyperlipidemia, hypertension, diabetes, etc. An agent is provided.
Claims (4)
で表される化合物を含む、ＰＰＡＲα、δおよび／またはγのリガンド剤。 As an active ingredient, the formula (1):
A ligand agent for PPARα, δ and / or γ, which comprises a compound represented by:
で表される化合物。
Formula (1):
A compound represented by
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