JP4840845B2 - Novel ellagic acid derivatives and xanthine oxidase inhibitors - Google Patents
Novel ellagic acid derivatives and xanthine oxidase inhibitors Download PDFInfo
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Description
本発明は、新規エラグ酸誘導体及びそれを含有するキサンチンオキシダーゼ阻害剤等に関する。 The present invention relates to a novel ellagic acid derivative and a xanthine oxidase inhibitor containing the same.
哺乳動物の肝臓、小腸粘膜、乳汁中に多く含まれるキサンチンオキシダーゼは、プリン化合物分解経路の最終段階においてヒポキサンチンからキサンチンを経て尿酸を生成する。
血中における尿酸濃度の上昇は、高尿酸血症としての痛風等の様々な疾病を引き起こすため、高尿酸血症を是正すべく臨床的に尿酸生成阻害剤つまりキサンチンオキシダーゼ阻害剤の投与が行われており、キサンチンオキシダーゼの活性を抑制し得る生理活性物質の開発が注視されている。
ところで、今日までキサンチンオキシダーゼ阻害作用を有する数多くの化合物が報告されているが、それらの多くは化学的手法により合成されたものであり、人体に対する安全性が高いとは決して言えなかった。また最近では、このような人体に対する安全性の観点から天然物由来のキサンチンオキシダーゼ阻害剤も開示されるようになってきたが（例えば、特許文献１，２，３，４，５参照）、これらのキサンチンオキシダーゼ阻害効果は充分満足できるものではなかった。
Xanthine oxidase, which is abundant in mammalian liver, small intestinal mucosa and milk, generates uric acid from hypoxanthine via xanthine in the final stage of the purine compound degradation pathway.
Since an increase in blood uric acid concentration causes various diseases such as gout as hyperuricemia, clinical administration of a uric acid production inhibitor, that is, a xanthine oxidase inhibitor, was performed to correct hyperuricemia. Therefore, the development of physiologically active substances capable of suppressing the activity of xanthine oxidase is closely watched.
By the way, many compounds having an xanthine oxidase inhibitory action have been reported to date, but many of them have been synthesized by a chemical method and have never been said to be highly safe for the human body. In addition, recently, xanthine oxidase inhibitors derived from natural products have been disclosed from the viewpoint of safety to human bodies (see, for example, Patent Documents 1, 2, 3, 4, and 5). The xanthine oxidase inhibitory effect of was not fully satisfactory.
本発明は、新規エラグ酸誘導体及びキサンチンオキシダーゼ活性阻害剤の提供を課題とするものである。 An object of the present invention is to provide a novel ellagic acid derivative and an xanthine oxidase activity inhibitor.
本発明者らは、前記の課題を解決するために、既に多年にわたって食用に供され人体に対する安全性が確認されているザクロから、新規エラグ酸誘導体を見出し、さらに該新規エラグ酸誘導体がキサンチンオキシダーゼ阻害剤として有用であることを見出し、本発明を完成した。すなわち、本発明は、以下に関する。 In order to solve the above-mentioned problems, the present inventors have found a novel ellagic acid derivative from pomegranate that has been used for food for many years and has been confirmed to be safe for the human body, and further, the novel ellagic acid derivative is xanthine oxidase. The present invention was completed by finding it useful as an inhibitor. That is, the present invention relates to the following.
（１）化１に記載の新規エラグ酸誘導体。
（２）上記（１）記載の新規エラグ酸誘導体を有効成分として含有するキサンチンオキシダーゼ阻害剤。
（３）上記（１）記載の新規エラグ酸誘導体を有効成分として含有する高尿酸血症の予防又は治療剤。
（４）ザクロから抽出された成分であることを特徴とする、上記（１）記載の新規エラグ酸誘導体。
(1) The novel ellagic acid derivative described in Chemical formula 1.
(2) A xanthine oxidase inhibitor containing the novel ellagic acid derivative according to (1) as an active ingredient.
(3) A prophylactic or therapeutic agent for hyperuricemia containing the novel ellagic acid derivative according to (1) as an active ingredient.
(4) The novel ellagic acid derivative according to (1) above, which is a component extracted from pomegranate.
本発明の各種剤に有効成分として含まれる化１記載の新規エラグ酸誘導体は、キサンチンオキシダーゼ阻害活性を示す。従って、それを使用することによって、高尿酸血症の予防・改善に対して優れた効果が期待される。また、この有効成分を含む各種剤、飲食品、医薬品及び化粧品を経済的に提供することが可能となる。 The novel ellagic acid derivative described in Chemical Formula 1 contained as an active ingredient in various agents of the present invention exhibits xanthine oxidase inhibitory activity. Therefore, by using it, an excellent effect is expected for prevention and improvement of hyperuricemia. In addition, it is possible to economically provide various agents, foods and drinks, pharmaceuticals and cosmetics containing this active ingredient.
１．新規エラグ酸誘導体
本発明は、化１記載の新規エラグ酸誘導体（以下、「本新規エラグ酸誘導体」という。）である。
本新規エラグ酸誘導体は、エラグ酸を出発物質とする化学合成法、植物を出発材料とする抽出法等により得ることができる。抽出法の出発材料となる植物としては、ザクロが好適である。この場合、まず、ザクロ（Ｐｕｎｉｃａ ｇｒａｎａｔｕｍ）果実を乾燥させた後に粉砕し、次いで６０から９５％エタノール水（熱水を含む）を用いて抽出し、得られた抽出物を酸加水分解する。酸加水分解物をクロマトグラフィー技術によって分離精製することにより本新規エラグ酸誘導体が得られる。
1. Novel ellagic acid derivative The present invention is a novel ellagic acid derivative described in Chemical Formula 1 (hereinafter referred to as “the present novel ellagic acid derivative”).
The novel ellagic acid derivative can be obtained by a chemical synthesis method using ellagic acid as a starting material, an extraction method using a plant as a starting material, or the like. Pomegranate is suitable as a plant used as a starting material for the extraction method. In this case, first, the pomegranate ( Punica granatum ) fruit is dried and then pulverized, then extracted with 60 to 95% ethanol water (including hot water), and the resulting extract is acid hydrolyzed. The novel ellagic acid derivative can be obtained by separating and purifying the acid hydrolyzate by chromatographic techniques.
２．キサンチンオキシダーゼ阻害剤
本新規エラグ酸誘導体は、キサンチンオキシダーゼ阻害活性を有しており、キサンチンオキシダーゼ阻害剤として有用である。
2. Xanthine oxidase inhibitor The novel ellagic acid derivative has xanthine oxidase inhibitory activity and is useful as a xanthine oxidase inhibitor.
３．高尿酸血症の予防又は治療剤
本新規エラグ酸誘導体は、キサンチンオキシダーゼ阻害活性を通じて、生体内における尿酸の生成を抑制するので、高尿酸血症の予防又は治療剤として有用である。さらに、痛風など高尿酸血症に起因して生じる様々な疾患の予防及び治療に利用することができ、更には炎症、老化、発癌、動脈硬化、脳障害など活性酸素に起因して生じる様々な疾患の予防及び治療にも効果を発揮する。
3. Preventive or therapeutic agent for hyperuricemia Since the novel ellagic acid derivative suppresses the production of uric acid in vivo through xanthine oxidase inhibitory activity, it is useful as a preventive or therapeutic agent for hyperuricemia. Furthermore, it can be used for the prevention and treatment of various diseases caused by hyperuricemia such as gout, and furthermore, various diseases caused by active oxygen such as inflammation, aging, carcinogenesis, arteriosclerosis, and brain damage. Also effective in preventing and treating diseases.
４．本発明の剤の使用法
本発明のキサンチンオキシダーゼ阻害剤、及び高尿酸血症の予防又は治療剤は、医薬品、医薬部外品、化粧品、食品、飲料などとして使用することができる。例えば、キサンチンオキシダーゼ阻害作用、あるいは高尿酸血症の予防又は治療効果を有するザクロジュースとして提供することもできる。
剤型としては、凍結乾燥或いは噴霧乾燥等により乾燥させて乾燥粉末とすることもできるし、また液剤、錠剤、散剤、顆粒、糖衣錠、カプセル、懸濁液、液剤、乳剤、アンプル、注射剤等とすることもできる。
また、本新規エラグ酸誘導体のみを単独でキサンチンオキシダーゼ阻害剤、あるいは高尿酸血症の予防又は治療剤の有効成分とすることもできるが、その他キサンチンオキシダーゼ阻害作用を有する食品、あるいは抗高尿酸血症剤として知られているアロプリノールやアロキサンチン、尿酸利尿剤として知られるプロベネシド、ベンズブロマロンなどを併用すれば一層効果を高めることができる。
4). Usage of the Agent of the Present Invention The xanthine oxidase inhibitor and the prophylactic or therapeutic agent for hyperuricemia of the present invention can be used as pharmaceuticals, quasi drugs, cosmetics, foods, beverages and the like. For example, it can be provided as a pomegranate juice having an inhibitory action on xanthine oxidase or an effect of preventing or treating hyperuricemia.
The dosage form can be dried by freeze-drying or spray-drying to obtain a dry powder, and can also be a liquid, tablet, powder, granule, dragee, capsule, suspension, liquid, emulsion, ampoule, injection, etc. It can also be.
In addition, the novel ellagic acid derivative alone can be used alone as an active ingredient of a xanthine oxidase inhibitor, or a prophylactic or therapeutic agent for hyperuricemia, but other foods having xanthine oxidase inhibitory action or antihyperuricemia If allopurinol and alloxanthin, which are known as symptomatic agents, and probenecid, benzbromarone, which are known as uric acid diuretics, are used in combination, the effect can be further enhanced.
本新規エラグ酸誘導体の投与量は、投与方法と症状の程度、患者の年齢、体重等により異なるが、通常、成人一日あたりの有効成分として０．０１〜２０ｇ、好ましくは０．５〜１０ｇの範囲で選ばれる。また、本新規エラグ酸誘導体を、他の医薬品等と適宜混合して使用することも可能である。本新規エラグ酸誘導体を機能性食品として用いる場合、そのままで、又は他の食品に添加して使用することができる。本新規エラグ酸誘導体を他の食品に添加する場合、食品中に混合する方法、食品表面に塗布する方法等が例示される。その場合は、食品１ｋｇ当たり０．０１ｇ以上、好ましくは、０．５〜１０ｇ程度添加すればよい。
適用できる食品としては、醤油、味噌、つゆ等の調味料、カマボコ、チクワ等の水産練り製品、ハム、ソーセージ等の畜肉加工品、日本酒、洋酒、果実酒等の酒類、清涼飲料、果実飲料等の飲料類、ケーキ、プリン、饅頭等の菓子類が例示される。さらに、本発明物質を、果実、野菜類、缶詰類、惣菜食品等に添加して用いることも可能である。
The dosage of the novel ellagic acid derivative varies depending on the administration method and the degree of symptoms, the patient's age, weight, etc., but is usually 0.01 to 20 g, preferably 0.5 to 10 g as an active ingredient per day for an adult. Is selected within the range. In addition, the novel ellagic acid derivative can be used by appropriately mixing with other pharmaceuticals and the like. When the novel ellagic acid derivative is used as a functional food, it can be used as it is or added to other foods. When this novel ellagic acid derivative is added to other foods, examples thereof include a method of mixing in foods and a method of applying to the food surface. In that case, 0.01 g or more, preferably about 0.5 to 10 g may be added per 1 kg of food.
Applicable foods include seasonings such as soy sauce, miso and soup, marine products such as kamaboko and chikuwa, processed meat products such as ham and sausage, alcoholic beverages such as sake, Western liquor, fruit liquor, soft drinks, fruit beverages, etc. Examples include beverages, cakes, pudding, buns and other confectionery. Furthermore, the substance of the present invention can be used by adding to fruits, vegetables, canned foods, prepared foods and the like.
（ザクロの抽出及び精製）
図1に示す工程でザクロの抽出及び精製を行い、各分画について後述する測定方法によってキサンチンオキシダーゼ阻害活性を測定した。
カリフォルニア産ザクロ果実全体を強制的に十分乾燥させ、これを粉砕してよく混合した。このサンプル８ｇに４００ｍｌの８０％エタノールを加え、常温で一晩攪拌、抽出した。次に、得られた抽出液に終濃度１Ｍになるように塩酸を加え７０℃で一晩攪拌し、酸加水分解を行い、得られた抽出液をエバポレーターで濃縮、乾燥させ、ザクロ酸加水分解物を得た。
(Pomegranate extraction and purification)
Pomegranate was extracted and purified in the process shown in FIG. 1, and xanthine oxidase inhibitory activity was measured for each fraction by the measurement method described later.
The entire California pomegranate fruit was forced to dry thoroughly and then ground and mixed well. To 8 g of this sample, 400 ml of 80% ethanol was added, and the mixture was stirred and extracted overnight at room temperature. Next, hydrochloric acid is added to the resulting extract to a final concentration of 1 M, and the mixture is stirred overnight at 70 ° C. to perform acid hydrolysis. The resulting extract is concentrated and dried with an evaporator, and then hydrolyzed with pomegranate. I got a thing.
ザクロにはエラジタンニンが豊富に含まれており、これらの成分は酸加水分解することによりエラグ酸を生成することが知られている。また、このエラグ酸には強いキサンチンオキシダーゼ阻害活性があることがすでに知られている。そこで、このザクロ酸加水分解物中のエラグ酸含量を測定し、後述する測定方法でキサンチンオキシダーゼ阻害活性を調べた。結果を図２に示す。このザクロ酸加水分解物は約７０％前後のエラグ酸しか含有していなかったが、図２に示すように純品（含量１００％）のエラグ酸と比較しても優れたキサンチンオキシダーゼ阻害活性を有していることが判明した。この効果は、ザクロ抽出物に含まれるエラグ酸以外の成分も寄与することによるものである。
Pomegranate is rich in ellagitannins, and these components are known to generate ellagic acid by acid hydrolysis. Moreover, it is already known that this ellagic acid has a strong xanthine oxidase inhibitory activity. Therefore, the ellagic acid content in the hydrolyzate of pomegranate was measured, and the xanthine oxidase inhibitory activity was examined by the measurement method described later. The results are shown in FIG. This pomegranate hydrolyzate contained only about 70% ellagic acid. However, as shown in FIG. 2, it has excellent xanthine oxidase inhibitory activity as compared with pure ellagic acid (
次にエラグ酸以外の関与成分を同定するため高速液体クロマトグラフィーを用い、ザクロ酸加水分解物を分画し、各分画物についてキサンチンオキシダーゼ阻害活性を測定することとした。
カラムは資生堂社製ＣＡＰＣＥＬＬ ＰＡＫ Ｃ１８ ＵＧ１２０ ５ｍｍ ４．６ｍｍ×１５０ｍｍを使用し、１００％Ｈ２Ｏ（０．１％ＴＦＡ含有）から１時間後に５０％アセトニトリル（０．１％ＴＦＡ含有）のグラジエントモード、室温条件下、流速１ｍｌ／ｍｉｎで流した。溶出した成分は紫外部吸収２５０ｎｍでモニタリングした。ピーク又は時間で溶出液を、フラクションコレクターを用いて、それぞれ分画し、濃縮後、凍結乾燥により乾燥物を得た。図３には高速液体クロマトグラフィーで分画した際の紫外吸収２５０ｎｍでの溶出パターンを、また、図４に、得られたフラクションのキサンチンオキシダーゼ阻害活性を示した。ピークＮＯ．１を含むフラクション３、及びピークＮＯ．２を含むフラクション４に強いキサンチンオキシダーゼ阻害活性が測定された。図４のエラグ酸、ザクロ酸加水分解物の濃度は０．２μｇ／ｍｌでキサンチンオキシダーゼ阻害活性を測定した。
Next, in order to identify components other than ellagic acid, high-performance liquid chromatography was used to fractionate the hydrolyzate of pomegranate, and the xanthine oxidase inhibitory activity of each fraction was measured.
The column uses a CAPCELL PAK C18 UG120 5 mm 4.6 mm × 150 mm manufactured by Shiseido Co., Ltd., and a gradient mode of 50% acetonitrile (containing 0.1% TFA) after 1 hour from 100% H 2 O (containing 0.1% TFA). The flow rate was 1 ml / min at room temperature. The eluted component was monitored by ultraviolet absorption at 250 nm. The eluate was fractionated using a fraction collector at a peak or time, concentrated, and then dried to obtain a dried product. FIG. 3 shows the elution pattern at 250 nm of ultraviolet absorption when fractionated by high performance liquid chromatography, and FIG. 4 shows the xanthine oxidase inhibitory activity of the obtained fraction. Peak No. 1 containing fraction 3, and peak NO. Strong xanthine oxidase inhibitory activity was measured in fraction 4 containing 2. The xanthine oxidase inhibitory activity was measured at a concentration of ellagic acid and zacurate hydrolyzate in FIG. 4 of 0.2 μg / ml.
（構造解析）
ピークＮＯ．１及びＮＯ．２の物性を以下に示す。
ピークＮＯ．１
性状；黄色粉末
融点（℃）；＞３６０℃（分解）
分子量及び分子式；３０２．２０、Ｃ１４Ｈ６Ｏ８
マススペクトル；ｍ／ｚ ３０１（Ｍ−Ｈ）
ＡＰＣＩ Ｎｅｇａｔｉｖｅモード、ＪＥＯＬ Ｂｕ−３０ （日本電子社製）
１Ｈ−ＮＭＲスペクトル；ＤＭＳＯ―ｄ６中、５００ＭＨｚ、Ｂｒｕｋｅｒ ＡＶＡＮＣＥ ５００ Ｓｐｅｃｔｒｏｍｅｔｅｒ（Ｂｒｕｋｅｒ社製）δ（ｐｐｍ） ７．４５、
１３Ｃ−ＮＭＲスペクトル ； ＤＭＳＯ ―ｄ６、１２５ＭＨｚ、δ（ｐｐｍ）１０７．３、１１０．１、１１２．２、１３６．３、１３９．７、１４８．１、１５９．２
ＵＶスペクトル；ＤＭＳＯ溶液中、２５１、３６７ｎｍに吸収
ピークＮＯ．２
性状；褐色粉末
分子量及び分子式；４５４．３０、Ｃ２１Ｈ１０Ｏ１２
マススペクトル；ｍ／ｚ ４５３、３０１（Ｍ−Ｈ）
ＡＰＣＩ Ｎｅｇａｔｉｖｅモード、ＪＥＯＬ Ｂｕ−３０（日本電子社製）
１Ｈ−ＮＭＲスペクトル；ＤＭＳＯ―ｄ６中、５００ＭＨｚ、Ｂｒｕｋｅｒ ＡＶＡＮＣＥ ５００ Ｓｐｅｃｔｒｏｍｅｔｅｒ（Ｂｒｕｋｅｒ社製）δ（ｐｐｍ） ７．０９、７．１２、７．７３
１３Ｃ−ＮＭＲスペクトル；ＤＭＳＯ―ｄ６、１２５ＭＨｚ、δ（ｐｐｍ）１０７．７、１０９．６、１０９．７、１１７．０、１１７．３、１１７．８、１１９．７、１３６．９、１３９．５、１３９．９、１４０．６、１４３．５、１４５．９、１４６．１、１５８．３、１６４．１
ＵＶスペクトル；ＤＭＳＯ溶液中、２４７、３５５ｎｍに吸収
(Structural analysis)
Peak No. 1 and NO. The physical properties of 2 are shown below.
Peak No. 1
Properties: Yellow powder Melting point (° C);> 360 ° C (decomposition)
Molecular weight and molecular formula; 302.20, C 14 H 6 O 8
Mass spectrum; m / z 301 (MH)
APCI Negative mode, JEOL Bu-30 (manufactured by JEOL Ltd.)
1H-NMR spectrum: in DMSO-d6, 500 MHz, Bruker AVANCE 500 Spectrometer (manufactured by Bruker) δ (ppm) 7.45,
13C-NMR spectrum; DMSO-d6, 125 MHz, δ (ppm) 107.3, 110.1, 112.2, 136.3, 139.7, 148.1, 159.2
UV spectrum; absorption peak NO. 2
Properties: Brown powder Molecular weight and molecular formula: 454.30, C 21 H 10 O 12
Mass spectrum; m / z 453, 301 (M−H)
APCI Negative mode, JEOL Bu-30 (manufactured by JEOL Ltd.)
1H-NMR spectrum: DMSO-d6, 500 MHz, Bruker AVANCE 500 Spectrometer (manufactured by Bruker) δ (ppm) 7.09, 7.12, 7.73
13C-NMR spectrum; DMSO-d6, 125 MHz, δ (ppm) 107.7, 109.6, 109.7, 117.0, 117.3, 117.8, 119.7, 136.9, 139.5 139.9, 140.6, 143.5, 145.9, 146.1, 158.3, 164.1
UV spectrum; absorbed at 247, 355 nm in DMSO solution
上記機器分析の結果より、ピークＮＯ．１は従来キサンチンオキシダーゼ活性阻害活性を有するといわれているエラグ酸と同一であることがわかった。そこで、ピークＮＯ．１のエラグ酸以外で、特にキサンチンオキシダーゼ活性阻害活性が強かったピークＮＯ．２に分画された成分ついてＮＭＲ及びマススペクトルを用いて機器分析したところ、化１記載の新規エラグ酸誘導体（エラグ酸−４−没食子酸エステル）であると同定できた。 From the result of the instrumental analysis, the peak NO. 1 was found to be the same as ellagic acid, which is conventionally said to have xanthine oxidase activity inhibitory activity. Therefore, peak NO. In addition to the ellagic acid of No. 1, the peak NO. When the component fractionated into 2 was subjected to instrumental analysis using NMR and mass spectrum, it could be identified as the novel ellagic acid derivative (Elagic acid-4-gallate) described in Chemical Formula 1.
（キサンチンオキシダーゼ阻害活性の試験方法）
キサンチンオキシダーゼ阻害活性の試験方法は、ＣＨＥＭ．Ｐｈａｒｍ．Ｂｕｌｌ． ３８， １２２４−１２２９ （１９９０）に従って測定した。すなわち、試験管に７２０μｌの０．１Ｍリン酸緩衝液（ｐＨ７．５）、３５２μｌの蒸留水、４８μｌのジメチルスルホキシドに溶解した試料溶液に加え混合後、８０μｌの０．１Ｍリン酸緩衝液に溶解したキサンチンオキシダーゼ（Ｒｏｃｈｅ社製、０．０４ｕｎｉｔ／ｍｌ）を加えて、３７℃で１０分間プレインキュベーションした。次に、１２００μｌの０．１ｍＭキサンチン(和光純薬社製)水溶液を基質として加えて３７℃で３０分間反応させた。２００μｌの１Ｎ ＨＣｌを加えることで反応を停止させ、生成した尿酸をＨＰＬＣにて測定した。
ＨＰＬＣによる尿酸測定は、以下のように行った。カラムはＣＡＰＣＥＬＬ ＰＡＫ Ｃ１８ ＵＧ１２０ ５ｍｍ×４．６ｍｍ×１５０ｍｍ （資生堂社製）を用い、溶離液５０ｍＭ ＮＨ４Ｈ２ＰＯ４を流速１．０ｍｌ／ｍｉｎで通液し、尿酸を２８０ｎｍで検出した。
キサンチンオキシダーゼの阻害活性は、コントロールとしてサンプルの変わりにＤＭＳＯを添加した場合の尿酸量を１００％として、サンプル添加による尿酸量の減少量により計算した。
対照として、市販のエラグ酸（和光純薬社製）、キサンチンオキシダーゼ阻害剤であるアロプリノール(ＲＯＣＨＥ社製)を使用した。
(Test method for xanthine oxidase inhibitory activity)
The test method for xanthine oxidase inhibitory activity is described in CHEM. Pharm. Bull. 38, 1224-1229 (1990). That is, 720 μl of 0.1M phosphate buffer (pH 7.5), 352 μl of distilled water, and 48 μl of dimethyl sulfoxide were mixed in a test tube and mixed, and then dissolved in 80 μl of 0.1 M phosphate buffer. The xanthine oxidase (Roche, 0.04 unit / ml) was added and preincubated at 37 ° C. for 10 minutes. Next, 1200 μl of 0.1 mM xanthine (Wako Pure Chemical Industries, Ltd.) aqueous solution was added as a substrate and reacted at 37 ° C. for 30 minutes. The reaction was stopped by adding 200 μl of 1N HCl, and the produced uric acid was measured by HPLC.
The uric acid measurement by HPLC was performed as follows. CAPCELL PAK C18 UG120 5 mm × 4.6 mm × 150 mm (manufactured by Shiseido Co., Ltd.) was used as the column, and eluent 50 mM NH 4 H 2 PO 4 was passed at a flow rate of 1.0 ml / min, and uric acid was detected at 280 nm.
The inhibitory activity of xanthine oxidase was calculated from the amount of decrease in the amount of uric acid due to the addition of the sample, with the amount of uric acid when DMSO was added instead of the sample as a control as 100%.
As controls, commercially available ellagic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and allopurinol (manufactured by ROCHE) which is a xanthine oxidase inhibitor were used.
（キサンチンオキシダーゼ阻害活性の測定）
本新規エラグ酸誘導体のキサンチンオキシダーゼに対するＩＣ５０を測定したところ、純品のエラグ酸よりも約６倍キサンチンオキシダーゼ阻害活性が強いことが判明した（表１）。表１では、エラグ酸純品、ピークＮＯ．２の精製品である本新規エラグ酸誘導体（エラグ酸−４−没食子酸エステル）及びアロプリノール（ａｌｌｏｐｕｒｉｎｏｌ）のキサンチンオキシダーゼに対するＩＣ５０を示した。ＩＣ５０とはキサンチンオキシダーゼの活性を５０％とするために必要な濃度（μＭ）を表す。
(Measurement of xanthine oxidase inhibitory activity)
When the IC 50 of the novel ellagic acid derivative to xanthine oxidase was measured, it was found that the inhibitory activity of xanthine oxidase was about 6 times stronger than that of pure ellagic acid (Table 1). In Table 1, pure ellagic acid, peak NO. The IC 50 for xanthine oxidase of this novel ellagic acid derivative (ellagic acid-4-gallate) and allopurinol, which are purified products of No. 2, was shown. IC 50 represents a concentration (μM) necessary to bring the activity of xanthine oxidase to 50%.
実施例１で使用した、本新規エラグ酸誘導体は、以下のようにして、飲食品、医薬品又は化粧品に添加し、これらにキサンチンオキシダーゼ阻害作用、或いは高尿酸血症の予防又は治療作用を付与することができる。 The novel ellagic acid derivative used in Example 1 is added to foods, drinks, pharmaceuticals, or cosmetics as follows, and imparts xanthine oxidase inhibitory action or hyperuricemia preventive or therapeutic action to them. be able to.
（錠剤タイプの内服剤又は機能性食品）
本新規エラグ酸誘導体５０ｍｇ、乳糖８０ｍｇ、結晶セルロース６０ｍｇ、ショ脂肪酸エステル１０ｍｇ、以上を１錠分として常法により錠剤化する。この錠剤は、内服用の医薬品又は機能性食品として使用できる。
(Tablet type oral medicine or functional food)
The novel ellagic acid derivative 50 mg,
（乳化液剤タイプ内服剤又は機能性食品）
本新規エラグ酸誘導体５０ｍｇ、中鎖飽和脂肪酸トリグリセリド７０ｍｇ、ビタミンＥ１ｍｇ、オレンジ油２０ｍｇ、デカグリセリンモノステアレート３０ｍｇ、グリセリン７５０ｍｇ、ブドウ糖１０ｇ、クエン酸１ｇ、アスコルビン酸５００ｍｇ、以上を水に加えて全量を１００ｍｌとし、常法により分散乳化処理して、乳化液剤とする。この液剤は、内服用の医薬品又は機能性食品として使用できる。
(Emulsified liquid type oral medicine or functional food)
This novel ellagic acid derivative 50 mg, medium-chain saturated
（散剤及び顆粒剤タイプの内服剤又は機能性食品）
本新規エラグ酸誘導体５０ｍｇ、トウモロコシデンプン１．１ｇ、乳糖０．８ｇ、以上を一包分とする散剤又は顆粒剤を常法に従い調製する。この散剤又は顆粒剤は、内服剤又は機能性食品として使用できる。
(Powder and granule type internal medicine or functional food)
A powder or granule containing 50 mg of the novel ellagic acid derivative, 1.1 g of corn starch, 0.8 g of lactose and the above as one package is prepared according to a conventional method. This powder or granule can be used as an internal preparation or a functional food.
（注射剤）
本新規エラグ酸誘導体５０ｍｇ、界面活性剤８％、生理食塩水９０％、以上を重量比で含む混合液を加熱滅菌して注射剤とする。
(Injection)
A mixture containing 50 mg of the novel ellagic acid derivative, 8% surfactant, 90% physiological saline, and the above in a weight ratio is heat sterilized to give an injection.
（キャンディータイプ健康志向食品）
本新規エラグ酸誘導体５０ｍｇ、砂糖４３ｇ、水飴４２ｇ、水７ｇ、果汁３ｇ、増粘剤４ｇ、アスコルビン酸１ｇ、香料０．１ｇ、ビタミンＥ０．１ｇを常法に従い、５ｇ／個のキャンディーとする。
(Candy type health-oriented food)
The novel ellagic acid derivative 50 mg, sugar 43 g, starch syrup 42 g, water 7 g, fruit juice 3 g, thickener 4 g, ascorbic acid 1 g, fragrance 0.1 g, and vitamin E 0.1 g are converted into 5 g / candy according to a conventional method.
（飲料タイプ健康志向食品）
本新規エラグ酸誘導体５０ｍｇ、オレンジジュース（果汁１００％）９９９．９５ｇをミキサーにて混合して均一な飲料とする。
(Beverage type health-oriented food)
The novel ellagic acid derivative 50 mg and orange juice (
Claims (4)
で示される新規エラグ酸誘導体。 The following formula
A novel ellagic acid derivative represented by
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