JP5122148B2 - 2-Acylphloroglucinol-4,6-di-C-β-D-glucopyranoside having antioxidant activity - Google Patents
2-Acylphloroglucinol-4,6-di-C-β-D-glucopyranoside having antioxidant activity Download PDFInfo
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- JP5122148B2 JP5122148B2 JP2007007030A JP2007007030A JP5122148B2 JP 5122148 B2 JP5122148 B2 JP 5122148B2 JP 2007007030 A JP2007007030 A JP 2007007030A JP 2007007030 A JP2007007030 A JP 2007007030A JP 5122148 B2 JP5122148 B2 JP 5122148B2
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- Prior art keywords
- glucopyranoside
- acylphloroglucinol
- compound
- antioxidant
- active ingredient
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- 239000008174 sterile solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000010902 straw Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Landscapes
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Anti-Oxidant Or Stabilizer Compositions (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Saccharide Compounds (AREA)
- Pyrane Compounds (AREA)
Description
本発明は、抗酸化作用を有し、成人病、悪性関節リウマチなど、健康維持上障害となる諸疾患、火傷などの外傷、にきび、しみなどの美容上の障害の予防、治療に効果を医薬品、化粧品、飲食品となり、劣化防止剤となる抗酸化作用を有する新規な２−アシルフロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシドを提供する。 The present invention has an antioxidant effect, and is effective for the prevention and treatment of various diseases that are impaired in health maintenance such as adult diseases, malignant rheumatoid arthritis, trauma such as burns, and cosmetic disorders such as acne and stains. Provided is a novel 2-acylphloroglucinol-4,6-di-C-β-D-glucopyranoside having an antioxidant action, which becomes a cosmetic or a food or drink, and serves as a deterioration inhibitor.
活性酸素や不飽和脂質から生成する過酸化脂質が、老化や成人病、難病の発症といった生体への悪影響を及ぼすことが近年明らかとなっており、活性酸素消去作用や過酸化脂質の生成抑制作用を有する、いわゆる抗酸化物質の探索や、動脈硬化症、高脂血症、それらにより発症する脳梗塞、悪性リウマチ、ベーチェット病、クローン病、潰瘍性大腸炎、肝炎、胃炎、パーキンソン病などの難病、農薬などの化学物質により惹起される疾患、光線過敏症、放射線障害等に対する治療薬としてのそれらの応用が一部で試みられている。また、活性酸素や過酸化脂質はしみ、そばかす、にきび、皮膚潰瘍などの成員にもなる他、食品を劣化させ嗜好的品質や栄養の低下を引き起こすことも知られてきているが、いまだにこれらの問題を十分に解決しうる物質が見出されていないのが現状である。 In recent years, it has been clarified that lipid peroxides generated from reactive oxygen and unsaturated lipids have adverse effects on the body such as aging, adult diseases, and intractable diseases. For so-called antioxidants, and atherosclerosis, hyperlipidemia, cerebral infarction caused by them, malignant rheumatism, Behcet's disease, Crohn's disease, ulcerative colitis, hepatitis, gastritis, Parkinson's disease, etc. Some of their applications as therapeutic agents for diseases caused by chemical substances such as agricultural chemicals, photosensitivity, and radiation damage have been attempted. In addition to being a member of active oxygen and lipid peroxide stains, freckles, acne, skin ulcers, etc., it has also been known to degrade foods and cause a decline in taste quality and nutrition. The present condition is that the substance which can fully solve a problem is not found.
抗酸化化合物としては、例えば、ビタミンＣ（アスコルビン酸）などの水溶性抗酸化化合物、ビタミンＥ（α−トコフェノール）などの脂溶性抗酸化化合物、ＢＨＡ（３−ｔｅｒｔ−ブチル−４−ヒドロキシアニソール）などの合成化合物が知られている。しかし、合成化合物ＢＨＡは発ガン性が報告されており、安全性の面から考えると原料として食品素材からの成分を摂取するほうが望ましい。有用な抗酸化剤が発明された場合、それは医薬品、化粧品、健康食品、食品添加物などとして利用価値のあるものである。 Examples of antioxidant compounds include water-soluble antioxidant compounds such as vitamin C (ascorbic acid), fat-soluble antioxidant compounds such as vitamin E (α-tocophenol), and BHA (3-tert-butyl-4-hydroxyanisole). Synthetic compounds such as) are known. However, since the synthetic compound BHA has been reported to be carcinogenic, it is desirable to ingest ingredients from food materials as raw materials from the viewpoint of safety. When a useful antioxidant is invented, it has utility value as a pharmaceutical, cosmetic, health food, food additive and the like.
本発明者らは、天然物由来で抗酸化作用を有する化合物を探索し、ホップを由来とする新規な２−アシルフロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシドが優れた抗酸化作用を有することを見出し、本発明を完成するに至った。 The present inventors searched for a compound derived from a natural product and having an antioxidant effect, and a novel 2-acylphloroglucinol-4,6-di-C-β-D-glucopyranoside derived from hops was excellent. It has been found that it has an antioxidant action, and has led to the completion of the present invention.
なお、特許文献１、非特許文献１〜３に各種のフロロアシルフェノン配糖体が開示されているが、本発明の２−アシルフロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシドとは構造を異にするものである。
本発明は、以下に係わるものである。
（１） 化学式［１］
The present invention relates to the following.
(1) Chemical formula [1]
（式中、Ｒはイソプロピル基、イソブチル基又はｓｅｃ−ブチル基を示す）
で表されることを特徴とする２−アシルフロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシド又は薬学的に許容されるその塩。
（２）Ｒがイソブチル基である（１）記載の２−アシルフロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシド。
（３） アサ科カラハナソウ属の植物から得られることを特徴とする（１）記載の２−アシルフロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシド。
（４） アサ科カラハナソウ属の植物がホップ（Ｈｕｍｕｌｕｓ ｌｕｐｕｌｕｓ）である（３）記載の２−アシルフロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシド。
（５） （１）記載の化合物を有効成分とする抗酸化剤。
（６） （１）記載の化合物を有効成分とする医薬品。
（７） （１）記載の化合物を有効成分とする化粧品。
（８） （１）記載の化合物を有効成分とする飲食品。
(In the formula, R represents an isopropyl group, an isobutyl group or a sec-butyl group)
2-acylphloroglucinol-4,6-di-C-β-D-glucopyranoside or a pharmaceutically acceptable salt thereof, which is represented by the formula:
(2) The 2-acylphloroglucinol-4,6-di-C-β-D-glucopyranoside according to (1), wherein R is an isobutyl group.
(3) The 2-acylphloroglucinol-4,6-di-C-β-D-glucopyranoside according to (1), which is obtained from a plant belonging to the genus Asperaceae.
(4) The 2-acylphloroglucinol-4,6-di-C-β-D-glucopyranoside according to (3), wherein the plant of the genus Asaaceae is a hop (Humulus lupulus).
(5) An antioxidant comprising the compound according to (1) as an active ingredient.
(6) A pharmaceutical comprising the compound according to (1) as an active ingredient.
(7) A cosmetic comprising the compound according to (1) as an active ingredient.
(8) A food or drink comprising the compound according to (1) as an active ingredient.
本発明の２−アシルフロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシド又は薬学的に許容されるその塩を含有する医薬品、化粧品、飲食品は、抗酸化作用を有するので、生体内に生成した活性酸素や過酸化脂質によって引き起こされる障害を抑制する効果を有する。従って、健康上の障害、美容上の障害の予防、治療に有効であり、また飲食品の安定化、保存性の向上に有用である。産業的に価値のあるものである。 Since the pharmaceuticals, cosmetics, and foods and drinks containing 2-acylphloroglucinol-4,6-di-C-β-D-glucopyranoside or a pharmaceutically acceptable salt thereof of the present invention have an antioxidant action, It has the effect of suppressing damage caused by active oxygen and lipid peroxide generated in the living body. Therefore, it is effective for the prevention and treatment of health disorders and cosmetic disorders, and it is useful for stabilizing foods and beverages and improving storage stability. It is industrially valuable.
本発明者らは、ホップ（Ｈｕｍｕｌｕｓ ｌｕｐｕｌｕｓ）より、前記一般式［１］で表される新規な２−アシルフロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシドを単離し、それに強い抗酸化活性を有することを見出し、本発明を完成した。 The present inventors isolated a novel 2-acylphloroglucinol-4,6-di-C-β-D-glucopyranoside represented by the above general formula [1] from hop (Humulus lupulus), It has been found that it has a strong antioxidant activity, and the present invention has been completed.
ホップ（Ｈｕｍｕｌｕｓ ｌｕｐｕｌｕｓ）から２−アシルフロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシドを単離する方法としては、例えばＷＯ２００４／０５２８９８号パンフレットに記載された公知方法により抽出すればよい。実施例では、前記一般式［１］のＲがイソブチル基である２−（３−メチルブチリル）フロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシドを単離したが、本発明の化合物には、Ｒがイソプロピル基の２−（２−メチルプロピル）フロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシド、ｓｅｃ−ブチル基の２−（２−メチルブチリル）フロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシドも含まれる。 As a method for isolating 2-acylphloroglucinol-4,6-di-C-β-D-glucopyranoside from hops (Humulus lupulus), for example, it can be extracted by a known method described in WO 2004/052898 pamphlet. Good. In the examples, 2- (3-methylbutyryl) phloroglucinol-4,6-di-C-β-D-glucopyranoside in which R in the general formula [1] is an isobutyl group was isolated. Examples of the compound include 2- (2-methylpropyl) phloroglucinol-4,6-di-C-β-D-glucopyranoside in which R is isopropyl group, and 2- (2-methylbutyryl) phloroglucinol in sec-butyl group. Also included is -4,6-di-C-β-D-glucopyranoside.
本発明の２−アシルフロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシドを医薬品、飲食品、化粧品として用いる場合、有利の形で用いることができるほか、薬学的に許容される塩の形で使用することもできる。 When the 2-acylphloroglucinol-4,6-di-C-β-D-glucopyranoside of the present invention is used as a pharmaceutical, food, drink or cosmetic, it can be used in an advantageous form and is pharmaceutically acceptable. It can also be used in the form of a salt.
薬学的に許容される塩としては、例えばナトリウム塩、カリウム塩、リチウム塩等のようなアルカリ金属塩、カルシウム塩、マグネシウム塩等のようなアルカリ土類金属塩、鉄塩、銅塩のような遷移金属塩、アンモニウム塩、エチルアミン類、トリエチルアミン類、ジエタノールアミン塩、トリエタノールアミン塩、ジシクロヘキシルアミン塩、ジメチルアミノエタノール、アルギニン塩またはエチレンジアミン塩等のようなアミン塩が挙げられる。 Examples of the pharmaceutically acceptable salt include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, iron salt and copper salt. Examples include transition metal salts, ammonium salts, ethylamines, triethylamines, diethanolamine salts, triethanolamine salts, dicyclohexylamine salts, dimethylaminoethanol, arginine salts, ethylenediamine salts, and the like.
これらの塩は、通常の手段で生成させることができ、例えば、塩が不溶な溶媒または溶質中で、あるいは真空乾燥又は凍結乾燥によって除去できる水のような溶媒中で、有利のフェノール酸の形にある本発明の化合物を１等量またはそれ以上の適当な塩基と反応させるか、適当なイオン交換樹脂にて、現存の塩のイオンを他のイオンに交換することにより生成させることができる。 These salts can be produced by conventional means, for example in the form of the advantageous phenolic acid in a solvent or solute in which the salt is insoluble or in a solvent such as water that can be removed by vacuum drying or freeze drying. The compound of the present invention can be produced by reacting the compound of the present invention with one equivalent or more of a suitable base, or by exchanging existing salt ions with other ions using a suitable ion exchange resin.
または、本発明の２−アシルフロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシド又はその薬学的に許容される塩は一般に使用される担体、助剤、添加剤等とともに製剤化することができ、定法に従って経口、非経口の製品として、医薬品、医薬部外品、化粧品等の分野で利用することができる。または食品素材として、混合して飲食品とすることができる。 Alternatively, 2-acylphloroglucinol-4,6-di-C-β-D-glucopyranoside or a pharmaceutically acceptable salt thereof according to the present invention is formulated with commonly used carriers, auxiliaries, additives and the like. It can be used in the fields of pharmaceuticals, quasi-drugs, cosmetics and the like as oral and parenteral products according to a standard method. Or as a food material, it can mix and it can be set as food-drinks.
医薬品は経口剤として錠剤、カプセル剤、顆粒剤、シロップ剤等が、非経口剤として軟膏剤、クリーム、水剤等の外用剤、無菌溶液剤や懸濁剤等の注射剤等がある。これらの製品を医薬として疾患に投与するときは、２ｍｇ〜５００ｍｇを１日に１ないし数回、すなわち２ｍｇ〜１０００ｍｇの全日量で投与し、十分にその効果を奏し得るものである。 Pharmaceutical products include tablets, capsules, granules, syrups and the like as oral preparations, and external preparations such as ointments, creams and liquids as parenteral preparations, and injections such as sterile solutions and suspensions. When these products are administered to a disease as a medicine, 2 mg to 500 mg can be administered once to several times a day, that is, a total daily dose of 2 mg to 1000 mg, and the effect can be sufficiently exerted.
本発明の２−アシルフロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシドまたはその薬学的に許容される塩は、生理学的に認められるベヒクル、担体、賦形剤、結合剤、安定剤、香味剤等とともに要求される単位容量をとり得る。錠剤、カプセル剤に混和される佐薬は次のようなものである。トラガントゴム、アラビアゴム、コンスターチ、ゼラチンのような結合剤、微晶性セルロースのような賦形剤、コンスターチ、前ゼラチン化澱粉、アルギン酸のような膨化剤、ステアリン酸マグネシウムのような滑沢剤、ショ糖、乳糖、サッカリンのような甘味剤、ペパーミント、アカモノ油、チェリーのような香味剤など。また、カプセル剤の混合は上記の材料に更に油脂のような液体担体を含有することができ、また、他の材料は被覆剤として、又は製剤の物理的形態を別な方法で変化させるために存在させることができる。例えば、錠剤はシェラック、砂糖で被覆することができる。シロップ又はエリキシルは活性化合物、甘味剤としてショ糖、防腐剤としてメチル又はプロピルパラベン、色素およびチェリー又はオレンジ香味のような香味剤を含有することができる。 2-acylphloroglucinol-4,6-di-C-β-D-glucopyranoside or a pharmaceutically acceptable salt thereof of the present invention is a physiologically recognized vehicle, carrier, excipient, binder, The required unit volume can be taken together with stabilizers, flavoring agents and the like. The adjuncts mixed in tablets and capsules are as follows. Binders such as gum tragacanth, gum arabic, starch, gelatin, excipients such as microcrystalline cellulose, starch, pregelatinized starch, swelling agents such as alginic acid, lubricants such as magnesium stearate, Sweeteners such as sugar, lactose, saccharin, flavoring agents such as peppermint, red mono oil, and cherry. In addition, the mixture of capsules can contain a liquid carrier such as fats and oils in addition to the above materials, and other materials can be used as coating agents or to change the physical form of the formulation in other ways. Can exist. For example, tablets can be coated with shellac, sugar. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl or propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
注射剤のための無菌組成物は、注射用水のようなベヒクル中の活性物質、ごま油、ヤシ油、落花生油、綿実油のような天然産出植物油、またはエチルオレートのような合成脂肪ベヒクルを溶解または懸濁させる通常の方法によって処方することができる。または、緩衝材、防腐剤、酸化防止剤等を必要により配合することができる。 Sterile compositions for injections dissolve or suspend active substances in vehicles such as water for injection, naturally produced vegetable oils such as sesame oil, coconut oil, peanut oil, cottonseed oil, or synthetic fat vehicles such as ethyl oleate. It can be formulated by the usual method of turbidity. Alternatively, a buffer material, an antiseptic, an antioxidant and the like can be blended as necessary.
外用剤としては基剤として、ワセリン、パラフィン、油脂類、ラノリン、マクロゴール等を用い、通常の方法によって、軟膏剤、クリーム剤等とする。 As an external preparation, petrolatum, paraffin, oils and fats, lanolin, macrogol and the like are used as a base, and an ointment, a cream and the like are obtained by a usual method.
本発明の２−アシルフロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシド又は薬学的に許容されるその塩を添加した飲食品は、上記製剤の形態でもよいが、あめ、せんべい、クッキー、ジュースなどの形態でそれぞれの食品原料に所用量を加えて、一般の製造法により加工製造する。健康食品、機能性食品としての摂取は、病気予防、健康維持に用いられるので、経口摂取として１日数回に分けて、全日量として５ｍｇ〜５００ｍｇを含む加工品として摂取される。 The food or drink to which 2-acylphloroglucinol-4,6-di-C-β-D-glucopyranoside or a pharmaceutically acceptable salt thereof of the present invention is added may be in the form of the above-mentioned preparation, but candy, rice cracker , Cookie, juice, etc., each food ingredient is added to a predetermined amount, and processed and manufactured by a general manufacturing method. Ingestion as a health food or functional food is used for disease prevention and health maintenance, so it is taken as a processed product containing 5 mg to 500 mg as a total daily dose, divided into several times a day for oral intake.
また本発明の２−アシルフロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシドは、ビタミンＣ、ビタミンＥ、補酵素Ｑｎなどの抗酸化活性を有する化合物と併用することができる。また、これらの物質は、本飲食品の安定化剤としても作用を有し、併用することが有用である。これの抗酸化物質は常用量以下で添加される。
実施例
以下実施例により本発明をさらに具体的に説明するが、本発明の範囲はこれらに限定されるものではない。
Further, the 2-acylphloroglucinol-4,6-di-C-β-D-glucopyranoside of the present invention can be used in combination with a compound having antioxidant activity such as vitamin C, vitamin E, coenzyme Qn and the like. Moreover, these substances have an effect | action also as a stabilizer of this food-drinks, and it is useful to use together. These antioxidants are added below the normal dose.
EXAMPLES The present invention will be described more specifically with reference to the following examples. However, the scope of the present invention is not limited to these examples.
２−（３−メチルブチリル）フロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシドの精製
ホップ（Ｈｕｍｕｌｕｓ ｌｕｐｕｌｕｓ）から得られる苞（以下、ホップ苞という）より既知の文献（ＷＯ２００４／０５２８９８号パンフレット）の方法に従い、ホップ苞ポリフェノール画分を調製した。すなわち、得られたホップ苞を５０％エタノールで５０℃、１０時間の条件で抽出し、遠心分離で沈殿を除去し、上清を減圧濃縮した。得られた抽出物を水に再溶解し、合成樹脂ＳＥＰＡＢＥＡＤＳ ＳＰ８５０ (三菱化学株式会社)を詰めたカラムに供し、水洗後、５０％エタノールで溶出した。この画分をスプレードライし、得られた茶色の粉末をホップ苞ポリフェノール画分とした。ホップ苞ポリフェノール画分１５０ｇを蒸留水３５０ｍｌに溶解し、ヘキサン３５０ｍｌで３回、続いて残った水層をジエチルエーテル３５０ｍｌで３回それぞれ溶媒分画した。次いで水画分を減圧、凍結乾燥することにより粉末化した。得られた粉末をＳＥＰＡＢＥＡＤＳ ＳＰ８５０樹脂カラム（三菱化学株式会社）にアプライし、水、２５％エタノール、５０％エタノールでステップワイズ溶出した。
2- (3-Methylbutyryl) phloroglucinol-4,6-di-C-β-D-glucopyranoside purified hop (Humulus lupulus) obtained from cocoon (hereinafter referred to as hop moth) (WO2004 / 052898) No. pamphlet), a hop koji polyphenol fraction was prepared. That is, the obtained hop koji was extracted with 50% ethanol at 50 ° C. for 10 hours, the precipitate was removed by centrifugation, and the supernatant was concentrated under reduced pressure. The obtained extract was redissolved in water, applied to a column packed with synthetic resin SEPABEADS SP850 (Mitsubishi Chemical Corporation), washed with water, and eluted with 50% ethanol. This fraction was spray-dried, and the resulting brown powder was used as the hop straw polyphenol fraction. 150 g of hop koji polyphenol fraction was dissolved in 350 ml of distilled water, and the solvent was fractionated three times with 350 ml of hexane, and then the remaining aqueous layer was three times with 350 ml of diethyl ether. Next, the water fraction was pulverized by lyophilization under reduced pressure. The obtained powder was applied to a SEPABEADS SP850 resin column (Mitsubishi Chemical Corporation) and stepwise eluted with water, 25% ethanol and 50% ethanol.
５０％エタノール画分を減圧濃縮、凍結乾燥した。残渣５．７ｇを下記の条件で高速液体クロマトグラフィー（ＨＰＬＣ）に供し、４５〜５０分のピークを分取精製した。
ＨＰＬＣ条件
カラム：Ｍｉｇｈｔｙｓｉｌ ＲＰ−１８ＧＰ（φ２０×２５０ｍｍ、関東化学株式会社）
流速：１０ｍｌ／ｍｉｎ
移動相：Ａ液 ０．１％ギ酸水溶液、Ｂ液 ＣＨ３ＣＮ：０．１％ギ酸水溶液＝１：１
０→７０ｍｉｎ：７０％Ａ→６０％Ａ
検出：ＵＶ２８０ｎｍ
The 50% ethanol fraction was concentrated under reduced pressure and lyophilized. 5.7 g of the residue was subjected to high performance liquid chromatography (HPLC) under the following conditions, and a peak of 45 to 50 minutes was separated and purified.
HPLC condition column: Mightysil RP-18GP (φ20 × 250 mm, Kanto Chemical Co., Inc.)
Flow rate: 10 ml / min
Mobile phase: A liquid 0.1% formic acid aqueous solution, B liquid CH 3 CN: 0.1% formic acid aqueous solution = 1: 1
0 → 70min: 70% A → 60% A
Detection: UV280nm
更に下記の条件で高速液体クロマトグラフィー（ＨＰＬＣ）に供し、４８分のピークを分取精製した。 Further, it was subjected to high performance liquid chromatography (HPLC) under the following conditions, and a 48 minute peak was separated and purified.
ＨＰＬＣ条件
カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ−３（φ２０×２５０ｍｍ、ＧＬｓｃｉｅｎｃｅｓ）
流速：１０ｍｌ／ｍｉｎ
移動相：Ａ液 ０．１％ギ酸水溶液、Ｂ液 ＣＨ３ＣＮ：０．１％ギ酸水溶液＝１：１
０→７０ｍｉｎ：６５％Ａ
検出：ＵＶ２８０ｎｍ
HPLC condition column: Inertsil ODS-3 (φ20 × 250 mm, GLsciences)
Flow rate: 10 ml / min
Mobile phase: A liquid 0.1% formic acid aqueous solution, B liquid CH 3 CN: 0.1% formic acid aqueous solution = 1: 1
0 → 70min: 65% A
Detection: UV280nm
凍結乾燥して２−（３−メチルブチリル）フロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシド１１．８ｍｇを淡黄色の粉末として得た。 Lyophilization gave 11.8 mg of 2- (3-methylbutyryl) phloroglucinol-4,6-di-C-β-D-glucopyranoside as a pale yellow powder.
２−（３−メチルブチリル）フロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシドの分子式と構造決定
精製した化合物の分子式をＴＯＦ−ＭＳ（飛行時間型質量分析）を用い、構造式をＮＭＲ（核磁気共鳴）を用いて決定した。
The molecular formula of 2- (3-methylbutyryl) phloroglucinol-4,6-di-C-β-D-glucopyranoside and the structure determination of the purified compound using TOF-MS (time-of-flight mass spectrometry) Was determined using NMR (nuclear magnetic resonance).
ＴＯＦ−ＭＳ測定
「ＵＰＬＣ／ＴＯＦ−ＭＳ条件」
ＨＰＬＣ：ＡＣＱＵＩＴＹ ＵＰＬＣ（ウォーターズ）
カラム：ＡＣＱＵＩＴＹ ＵＰＬＣ ＢＥＨ Ｃ１８（５０×２．１ＭＭ、１．７μｍ：ウォーターズ）
移動相：Ａ液−メタノール Ｂ液−０．１（Ｖ／Ｖ）％ギ酸水溶液
１０（Ｖ／Ｖ）Ａ液（０ｍｉｎ） → ５０（Ｖ／Ｖ）Ａ液（５ｍｉｎ）
流速：０．６ｍｌ／ｍｉｎ
カラム温度：４０℃
注入量：５μｌ
検出器：ＬＣＴ Ｐｒｅｍｉｅｒ（ウォーターズ）
イオン源：ＥＳＩ（ポジティブ、ネガティブ）、
コーン電圧：３０Ｖ
キャピラリー電圧：２５００Ｖ
イオン源温度：１２０℃
デソルベーション温度：３００℃
ＭＳスキャン：ｍ／ｚ１００−１０００
ポジティブイオンモードの測定で、［Ｍ＋Ｈ］＋＝５３５、ネガティブイオンモードの測定で［Ｍ−Ｈ］−＝５３３のシグナルが観測されたことから、整数分子量を５３４と決定した。また、高分解能質量分析の結果より、分子式をＣ２３Ｈ３４０１４と決定した。
TOF-MS measurement "UPLC / TOF-MS conditions"
HPLC: ACQUITY UPLC (Waters)
Column: ACQUITY UPLC BEH C18 (50 × 2.1 MM, 1.7 μm: Waters)
Mobile phase: A liquid-methanol B liquid-0.1 (V / V)% formic acid aqueous solution
10 (V / V) A liquid (0 min) → 50 (V / V) A liquid (5 min)
Flow rate: 0.6 ml / min
Column temperature: 40 ° C
Injection volume: 5 μl
Detector: LCT Premier (Waters)
Ion source: ESI (positive, negative),
Cone voltage: 30V
Capillary voltage: 2500V
Ion source temperature: 120 ° C
Desolvation temperature: 300 ° C
MS scan: m / z 100-1000
The signal of [M + H] + = 535 was observed in the positive ion mode, and the signal [M−H] − = 533 was observed in the negative ion mode. Therefore, the integer molecular weight was determined to be 534. Moreover, the molecular formula was determined as C 23 H 34 0 14 from the results of high resolution mass spectrometry.
ＮＭＲ測定
精製した化合物をＣＤ３ＯＤに溶解した。ＮＭＲ測定にはＸＷＩＮ−ＮＭＲ ＡＶ６００（Ｂｒｕｋｅｒ Ｂｉｏｓｐｉｎ）を用い、各種ＮＭＲスペクトル（１Ｈ，１３Ｃ、ＨＳＱＣ、ＨＭＢＣ）を測定した。表１に測定結果を示した。その結果、化合物を２−（３−メチルブチリル）フロログルシノール−４，６−ジ−Ｃ−β−Ｄ−グルコピラノシド（以下、ＭＢＣＧと略する場合がある）と決定した。
The compound purified by NMR measurement was dissolved in CD 3 OD. Various NMR spectra (1H, 13C, HSQC, HMBC) were measured using XWIN-NMR AV600 (Bruker Biospin) for NMR measurement. Table 1 shows the measurement results. As a result, the compound was determined to be 2- (3-methylbutyryl) phloroglucinol-4,6-di-C-β-D-glucopyranoside (hereinafter sometimes abbreviated as MBCG).
（抗酸化活性測定）
ＤＰＰＨラジカル消去活性
(Measurement of antioxidant activity)
DPPH radical scavenging activity
既知のアシルフロログルシノール一配糖体２−（２−メチルプロパノイル）フロログルシノール−１−Ｏ−β−Ｄ−グルコピラノシド（化２）、新規化合物ＭＢＣＧについて、ＤＰＰＨ（１，１−ジフェニル−２−ピクリルヒドラジル）ラジカル消去活性を測定した。すなわち、９６穴ウエルプレート中でサンプルの希釈系列を作製し、１ウエル１００μｌ）、７５０μＭ ＤＰＰＨ溶液（５０％メタノール溶液）１００μｌを加え、室温で３０分間放置した後に５５０ｎｍでの吸光度を測定した。吸光度を半減させる供試物質の最終濃度（ＩＣ５０）を求め、これを抗酸化活性の指標とした。その結果を図１に示した。ＭＢＣＧは２−（２−メチルプロパノイル）フロログルシノール−１−Ｏ−β−Ｄ−グルコピラノシドよりも強い活性を示した。（ＩＣ５０はそれぞれ０．７４ｍＭ、１．０１ｍＭ）。 For the known acylphloroglucinol monoglycoside 2- (2-methylpropanoyl) phloroglucinol-1-O-β-D-glucopyranoside (Chemical Formula 2), a novel compound MBCG, DPPH (1,1-diphenyl- (2-picrylhydrazyl) radical scavenging activity was measured. That is, a dilution series of samples was prepared in a 96-well plate, 100 μl of 1 well), 100 μl of 750 μM DPPH solution (50% methanol solution) were added, and left at room temperature for 30 minutes, and then the absorbance at 550 nm was measured. The final concentration (IC 50 ) of the test substance that reduces the absorbance by half was determined and used as an index of antioxidant activity. The results are shown in FIG. MBCG showed stronger activity than 2- (2-methylpropanoyl) phloroglucinol-1-O-β-D-glucopyranoside. (IC 50 is 0.74 mM and 1.01 mM, respectively).
これらの結果から、抗酸化作用の高い新規なアシルフロログルシノール二糖配糖体を取得できたことが明らかとなった。 From these results, it was revealed that a novel acyl phloroglucinol disaccharide glycoside having a high antioxidant action could be obtained.
（錠剤、カプセル剤）
実施例１で得られた化合物（ＭＢＣＧ） １０％
乳糖 ７５％
ステアリン酸マグネシウム １５％
上記の成分を均一に混合し、錠剤およびカプセル剤とした。
(Tablets and capsules)
Compound obtained in Example 1 (MBCG) 10%
Lactose 75%
Magnesium stearate 15%
The above ingredients were uniformly mixed to obtain tablets and capsules.
（散剤、顆粒剤）
実施例１で得られた化合物（ＭＢＣＧ） ２０％
澱粉 ３０％
乳糖 ５０％
上記の成分を均一に混合し、散剤および顆粒剤とした。
(Powder, granule)
20% of the compound (MBCG) obtained in Example 1
Starch 30%
Lactose 50%
The above ingredients were mixed uniformly to obtain a powder and granules.
（注射剤）
実施例１で得られた化合物（ＭＢＣＧ） １％
界面活性剤 ９％
生理食塩水 ９０％
上記の成分を加熱混合し、滅菌して注射剤とした。
(Injection)
Compound obtained in Example 1 (MBCG) 1%
Surfactant 9%
Saline 90%
The above ingredients were mixed by heating and sterilized to give an injection.
（クッキー）
実施例１で得られた化合物（ＭＢＣＧ）を２重量％を含む小麦粉に、食塩、ショ糖、バターなどで味付けしたものを適量の水でよく攪拌し、１９０〜２００℃で３０分間焼き上げてクッキーとした。
(cookie)
A wheat flour containing 2% by weight of the compound (MBCG) obtained in Example 1 and seasoned with salt, sucrose, butter or the like is thoroughly stirred with an appropriate amount of water, baked at 190 to 200 ° C. for 30 minutes, and cookie. It was.
（ゼリー）
寒天１３ｇを水１リットルに加熱溶解し、さらにショ糖５００ｇ、水飴１５０ｇ及び塩少々を加え、攪拌しながら加熱溶解させた後、２重量％の実施例１で得られた化合物（ＭＢＣＧ）、果汁、着色料、香料などを加えて冷却し、ゼリーとした。
(jelly)
13 g of agar was dissolved by heating in 1 liter of water, 500 g of sucrose, 150 g of starch syrup and a little salt were added, and the mixture was heated and dissolved with stirring. Then, 2% by weight of the compound (MBCG) obtained in Example 1 and fruit juice Then, coloring and flavoring were added and cooled to make a jelly.
（あめ）
ショ糖２０重量部、水飴（７５％固形分）１０量部に水１０量部を加え混合し、１５０℃に加熱攪拌後、２重量％の実施例１で得られた化合物（ＭＢＣＧ）および着色料、香料などを加え、冷却してあめとした。
(Rain)
20 parts by weight of sucrose and 10 parts by weight of starch syrup (75% solids) were added and mixed with 10 parts of water. After heating and stirring at 150 ° C., 2% by weight of the compound (MBCG) obtained in Example 1 and coloring Add fragrance, fragrance, etc. and cool to make candy.
（ハンドローション剤）
カーボンワックス１５００を１５重量部、アルコール８重量部およびプロピレングリコール９０重量部をよく混合溶解し、水５２．５重量部、実施例１で得られた化合物（ＭＢＣＧ）２重量部および香料、防腐剤を適量加え、ハンドローション剤とした。
(Hand lotion)
15 parts by weight of carbon wax 1500, 8 parts by weight of alcohol and 90 parts by weight of propylene glycol were mixed and dissolved well, 52.5 parts by weight of water, 2 parts by weight of the compound (MBCG) obtained in Example 1, and a fragrance and preservative. An appropriate amount of was added to make a hand lotion.
（外用剤）
パラオキシ安息香酸エチル０．１％、パラオキシ安息香酸ブチル０．１％、ラウロマクロゴール０．５％、セタノール１８％、白色ワセリン４０％、水３７．３％、実施例１で得られた化合物（ＭＢＣＧ）４％を混合し、定法に従って軟膏とした。
(External preparation)
Ethyl paraoxybenzoate 0.1%, butyl paraoxybenzoate 0.1%, lauromacrogol 0.5%, cetanol 18%, white petrolatum 40%, water 37.3%, the compound obtained in Example 1 ( (MBCG) 4% was mixed and made into an ointment according to a conventional method.
本発明により、抗酸化作用を有したホップ由来新規化合物を提供することができる。抗酸化作用を有するので、生体内に生成した活性酸素や過酸化脂質によって引き起こされる障害を抑制する効果を有する。従って、健康上の障害、美容上の障害の予防、治療に有効であり、医薬品、飲食品、化粧品に応用、加工ができる。 According to the present invention, a new hop-derived compound having an antioxidant action can be provided. Since it has an antioxidant action, it has an effect of suppressing damage caused by active oxygen and lipid peroxide generated in the living body. Therefore, it is effective for the prevention and treatment of health disorders and cosmetic disorders, and can be applied and processed in medicines, foods and drinks, and cosmetics.
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