JP5673091B2 - New resveratrol derivatives - Google Patents
New resveratrol derivatives Download PDFInfo
- Publication number
- JP5673091B2 JP5673091B2 JP2010290547A JP2010290547A JP5673091B2 JP 5673091 B2 JP5673091 B2 JP 5673091B2 JP 2010290547 A JP2010290547 A JP 2010290547A JP 2010290547 A JP2010290547 A JP 2010290547A JP 5673091 B2 JP5673091 B2 JP 5673091B2
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- JP
- Japan
- Prior art keywords
- resveratrol
- novel
- ferulic acid
- resveratrol derivative
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Images
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- Coloring Foods And Improving Nutritive Qualities (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Description
本発明は、新規レスベラトロール誘導体及び該新規レスベラトロール誘導体の製造方法、並びに前記新規レスベラトロール誘導体を含有するアンジオテンシン変換酵素阻害剤、血圧降下剤、心血管病治療剤および抗癌剤に関するものである。 The present invention relates to a novel resveratrol derivative, a method for producing the novel resveratrol derivative, an angiotensin converting enzyme inhibitor, a blood pressure lowering agent, a cardiovascular disease therapeutic agent and an anticancer agent containing the novel resveratrol derivative. is there.
ブドウ果皮に含有されるスチルベン誘導体であるレスベラトロールについて、画期的な研究成果が明らかにされつつある。レスベラトロールは本来ブドウが病原菌から自己を守るファイトアレキシンとして存在する抗菌作用を有する化合物であり、赤系、白系を問わずブドウ果皮に含まれることが知られている。最近の研究で、レスベラトロールは哺乳動物に対しても有用な効果を有していることが明らかになりつつある。いわゆる「フレンチパラドックス」と言われる赤ワインの有用な生理効果は、レスベラトロールの抗酸化能を始めとして各種の生理活性機能が一因であるとされている。さらに、レスベラトロールには多くの疾病に効果があることが明らかにされつつあり（非特許文献１）、その一つにレスベラトロールは強い抗癌作用を有することが報告されている（非特許文献２）。
また、前記レスベラトロールの誘導体として、天然にはレスベラトロールの重合体、例えばε−ビニフェリン（二量体）、α−ビニフェリン（三量体）、バチカノールＣ（四量体）等が数々報告されている。非天然型のレスベラトロール誘導体についての報告も数々あるが（例えば特許文献１）、本発明の新規化合物を特定し生理活性を詳細に報告した例は見られない。
Breakthrough research results are being revealed for resveratrol, a stilbene derivative contained in grape skin. Resveratrol is a compound having an antibacterial action that originally exists as a phytoalexin that protects grapes from pathogenic bacteria and is known to be contained in grape skins regardless of whether they are red or white. Recent studies are revealing that resveratrol has a useful effect on mammals as well. The useful physiological effect of red wine called so-called “French paradox” is attributed to various physiologically active functions including the antioxidant ability of resveratrol. Furthermore, resveratrol is being clarified to be effective for many diseases (Non-patent Document 1), and one of them is reported that resveratrol has a strong anticancer activity (non-patent document 1). Patent Document 2).
In addition, as a derivative of resveratrol, a number of resveratrol polymers such as ε-viniferin (dimer), α-viniferin (trimer), and vaticanol C (tetramer) have been reported in nature. Has been. Although there are many reports on non-natural type resveratrol derivatives (for example, Patent Document 1), no example of identifying the novel compound of the present invention and reporting the physiological activity in detail has been found.
フェルラ酸は、樹木の主成分であるリグニンやリグナンの前駆体にもなっており、天然界に比較的多く存在する成分で、米糠やジャガイモの皮層部に多く含まれている。フェルラ酸について、その生理機能が報告されている。例えば、フェルラ酸を有効成分とする細胞分化促進剤（特許文献２）、フェルラ酸を有効成分とする美白用皮膚外用薬（特許文献３）、フェルラ酸を有効成分とする酸化防止剤（特許文献４）、フェルラ酸とニコチン酸アミドからなる魚卵の発色助剤（特許文献５）、フェルラ酸を有効成分とする抗菌剤（特許文献６）、フェルラ酸のアルツハイマー病予防効果（非特許文献３）が知られている。
また、また、フェルラ酸誘導体に関連した先行技術としては、例えば、フェルラ酸エステル誘導体を有効成分とする紫外線吸収剤（特許文献７）、フィトステロール類のフェルラ酸エステルを有効成分とする皮膚外用薬（特許文献８）が知られている。フェルラ酸レスベラトロールについての化合物も知られているが（特許文献９）、本発明の化合物とは異なったものである。
Ferulic acid is also a precursor of lignin and lignan, which are the main components of trees, and is a relatively large component in the natural world, and is abundant in the skin layer of rice bran and potato. The physiological function of ferulic acid has been reported. For example, a cell differentiation promoting agent containing ferulic acid as an active ingredient (Patent Document 2), a skin whitening external preparation containing ferulic acid as an active ingredient (Patent Document 3), an antioxidant containing ferulic acid as an active ingredient (Patent Document 2) 4) A coloring aid for fish eggs composed of ferulic acid and nicotinamide (Patent Document 5), an antibacterial agent containing ferulic acid as an active ingredient (Patent Document 6), and an Alzheimer's disease preventive effect of ferulic acid (Non-Patent Document 3) )It has been known.
In addition, as prior arts related to ferulic acid derivatives, for example, an ultraviolet absorber (fermented from Patent Document 7) containing a ferulic acid ester derivative as an active ingredient, and a topical skin drug containing a ferulic acid ester of phytosterols as an active ingredient ( Patent document 8) is known. Although the compound about the resveratrol ferulic acid is also known (patent document 9), it differs from the compound of this invention.
このように、レスベラトロールやフェルラ酸は食経験の豊かな天然物質であり、生体調節機能に優れた安全な化合物である。よって多岐に渡る各々の誘導体についての取り組みも多い。 Thus, resveratrol and ferulic acid are natural substances with rich dietary experience and are safe compounds with excellent bioregulatory functions. Therefore, there are many efforts for various derivatives.
フェルラ酸、レスベラトロール、それらの誘導体は、優れた有用性を示すものが多いことから、原料やリード化合物としてのこれらを効率的に製造する技術開示もなされている。フェルラ酸の製造方法の例としては、バニリンとマロン酸の縮合反応による製造（非特許文献４）、米糠からの製造方法（特許文献１０）、オイゲノールを原料とした菌体での製造法（特許文献１１）、コニフェリルアルデヒドからの酵素での製造法（特許文献１２）等が知られている。また、レスベラトロールについては、食品中のレスベラトロール濃度を高める取り組みがされており、紫外線照射によりレスベラトロール濃度を高めた後にレスベラトロール含有抽出物を得て、その抽出物を食品に添加した食品が提案されている（特許文献１３）。 Since many of ferulic acid, resveratrol, and derivatives thereof exhibit excellent utility, a technical disclosure for efficiently producing these as raw materials and lead compounds has been made. Examples of ferulic acid production methods include production by condensation reaction of vanillin and malonic acid (Non-patent Document 4), production method from rice bran (Patent Document 10), and production method using eugenol as a raw material (patent) Document 11), a production method using an enzyme from coniferyl aldehyde (Patent Document 12) and the like are known. In addition, with regard to resveratrol, efforts are being made to increase the resveratrol concentration in foods, and after increasing the resveratrol concentration by ultraviolet irradiation, a resveratrol-containing extract is obtained and the extract is used as a food. An added food has been proposed (Patent Document 13).
食生活の変化からの生活習慣病が大きな問題となっている。例えば、塩分の過剰摂取、糖類や脂肪の過剰摂取、運動不足などの各種要因により高血圧症患者数が増大している。高血圧は、それ単独でも危険因子であるが、心血管病の危険因子のうちの一つにもなっている（日本高血圧学会高血圧治療ガイドライン作成委員会編「高血圧治療ガイドライン２０００年版」より）。また、メタボリックシンドロームの診断基準における危険因子の一つにもなっている（日本内科学会合同委員会によるメタボリックシンドロームの概念と診断基準より）。すなわち、高血圧症やこれが関与する各種合併症を治療するためには血圧を降下させることが重要であることは言うまでもない。したがって医薬品においては既に様々な作用機序に基づく降圧剤が知られている。中でも、アンジオテンシン変換酵素阻害薬は第一選択薬として用いられることも多いポピュラーな薬剤である。さらに、アンジオテンシン変換酵素阻害薬は、単に血圧を降下させるだけでなく、血管内皮機能を改善し様々な心血管病の治癒にも効果があることが知られており、心不全にも用いられるなど実地臨床においても広く活用されている。ただし、空咳や頭痛など副作用が出現することがあり、本薬剤の課題となっている。 Lifestyle-related diseases resulting from changes in dietary habits are a major problem. For example, the number of hypertensive patients is increasing due to various factors such as excessive intake of salt, excessive intake of sugars and fats, and lack of exercise. Although hypertension is a risk factor by itself, it is also one of the risk factors for cardiovascular disease (from the “High Blood Pressure Treatment Guidelines 2000 Edition” edited by the Japanese Society for Hypertension Treatment Guidelines). It is also one of the risk factors in the diagnostic criteria for metabolic syndrome (from the concept of metabolic syndrome and diagnostic criteria by the Japan Internal Medicine Meeting Committee). That is, it goes without saying that it is important to lower blood pressure in order to treat hypertension and various complications related thereto. Therefore, antihypertensive agents based on various mechanisms of action are already known in pharmaceuticals. Among these, angiotensin converting enzyme inhibitors are popular drugs that are often used as first-line drugs. In addition, angiotensin converting enzyme inhibitors are known not only to lower blood pressure but also to improve vascular endothelial function and cure various cardiovascular diseases, and are also used for heart failure. It is also widely used in clinical practice. However, side effects such as dry cough and headache may appear, which is a problem for this drug.
医薬品に限らず、降圧機能を付加した「特定保険用食品」が認可され販売されている。アンジオテンシン変換酵素阻害活性を作用機序とした商品が多く、関与成分は多くの場合オリゴペプチドである。同様に血圧降下作用のみならず、血管内皮機能改善作用についても報告され（非特許文献５）、効果面では有効なものであり、副作用も医薬品とは異なり特に報告されていない。ただし、オリゴペプチドはアミノ酸同士がペプチド結合されている所以に、熱、酸、アルカリ、プロテアーゼなどにより分解されやすいという欠点をそもそも有している。したがって、製品加工時や経口摂取後の安定性の面で課題が残されている。食品分野において、非ペプチド性のアンジオテンシン変換酵素阻害剤は殆ど知られておらず、現在ではフラボノイド配糖体が知られているが、その活性は弱いものである（非特許文献６）。そこで、日常的に摂取できる安全で、且つ有効性の高い安定な非ペプチド性のアンジオテンシン変換酵素阻害剤の開発が望まれている。 Not only medicinal products but also “food for specified insurance” with an antihypertensive function approved and sold. Many products have angiotensin converting enzyme inhibitory activity as a mechanism of action, and the components involved are often oligopeptides. Similarly, not only a blood pressure lowering action but also a vascular endothelial function improving action has been reported (Non-patent Document 5), which is effective in terms of effectiveness, and side effects are not particularly reported unlike pharmaceutical products. However, oligopeptides originally have the disadvantage that they are easily decomposed by heat, acid, alkali, protease, etc., because amino acids are peptide-bonded. Therefore, problems remain in terms of stability during product processing and after oral intake. In the food field, non-peptide angiotensin converting enzyme inhibitors are hardly known, and flavonoid glycosides are currently known, but their activity is weak (Non-patent Document 6). Therefore, development of a safe and highly effective non-peptide angiotensin converting enzyme inhibitor that can be ingested on a daily basis is desired.
一方、厚生労働省の調べによると、平成２０年の日本人の死亡原因の３０％が悪性新生物つまり癌である。多くの癌が、医療技術や薬の発達により発生数は、横這い又は減少しているのに対し、現在でも増加している癌の１つが口腔癌であり癌発生の５％を占めている。また、２０１５年には現在の４倍の罹患数になると予想されている。現在の研究では、日常的に摂取できる天然物由来の化合物としては、ルテオリンが知られている。（非特許文献７）
しかし、より抗癌活性が強く、日常的に摂取できる安全な癌、特に口腔癌の治療薬、予防薬の開発が望まれている。
On the other hand, according to a survey by the Ministry of Health, Labor and Welfare, 30% of the causes of death in 2008 in Japan are malignant neoplasms or cancer. While many cancers are leveling off or decreasing due to the development of medical technology and drugs, one of the increasing cancers is oral cancer, accounting for 5% of cancer occurrences. In 2015, the number of affected cases is expected to be four times the current number. In the current research, luteolin is known as a natural product-derived compound that can be ingested on a daily basis. (Non-patent document 7)
However, it is desired to develop a therapeutic or preventive agent for safe cancer, particularly oral cancer, which has stronger anticancer activity and can be taken on a daily basis.
本発明者らは、レスベラトロールやフェルラ酸に関する前記の状況を鑑みて、新規な生理活性または、強力な生理活性を有するレスベラトロール誘導体の探索と、その製造方法を確立すべく鋭意検討した結果、意外にもレスベラトロールとフェルラ酸を金属塩存在下で加熱処理するという簡便且つ安全な方法により、レスベラトロール、フェルラ酸、市販のレスベラトロール誘導体及びルテオリンに比べて優れた抗癌活性、特に口腔癌に対する活性を有し、アンジオテンシン変換酵素阻害活性を有する新規なレスベラトロール誘導体を製造することに成功し、本発明を完成するに至った。 In view of the above-mentioned situation concerning resveratrol and ferulic acid, the present inventors have intensively studied to search for a novel physiological activity or a resveratrol derivative having a strong physiological activity and to establish a production method thereof. As a result, surprisingly superior anti-cancer compared to resveratrol, ferulic acid, commercially available resveratrol derivatives and luteolin by a simple and safe method of heat-treating resveratrol and ferulic acid in the presence of metal salt The present invention was completed by successfully producing a novel resveratrol derivative having an activity, particularly an activity against oral cancer, and having an angiotensin converting enzyme inhibitory activity.
したがって、本発明は、レスベラトロール、フェルラ酸、市販のレスベラトロール誘導体及びルテオリンより強力な抗癌活性、特に口腔癌に対する活性を有し、アンジオテンシン変換酵素阻害活性を有する新規レスベラトロール誘導体を提供し、さらに該新規レスベラトロール誘導体を、効率よく、安全に生成する方法を提供することを目的とする。
また、本発明は、前記新規レスベラトロール誘導体を含有することを特徴とする抗癌剤、血圧降下剤、心血管病治療剤さらには食品、医薬品、医薬部外品を提供することを目的とする。
Accordingly, the present invention provides a novel resveratrol derivative having resveratrol, ferulic acid, a commercially available resveratrol derivative and luteolin having a stronger anticancer activity, particularly an oral cancer, and an angiotensin converting enzyme inhibitory activity. It is another object of the present invention to provide a method for efficiently and safely producing the novel resveratrol derivative.
Another object of the present invention is to provide an anticancer agent, an antihypertensive agent, a cardiovascular disease therapeutic agent, a food, a pharmaceutical product, and a quasi-drug, characterized by containing the novel resveratrol derivative.
本発明の要旨は、
〔１〕式（１）：
The gist of the present invention is as follows:
[1] Formula (1):
で示される新規レスベラトロール誘導体又はその薬学的に許容可能な塩、
〔２〕前記〔１〕記載の新規レスベラトロール誘導体又はその薬学的に許容可能な塩を含有するアンジオテンシン変換酵素阻害剤、
〔３〕前記〔１〕記載の新規レスベラトロール誘導体又はその薬学的に許容可能な塩を含有する血圧降下剤、
〔４〕前記〔１〕記載の新規レスベラトロール誘導体又はその薬学的に許容可能な塩を含有する心血管病治療剤、
〔５〕前記〔１〕記載の新規レスベラトロール誘導体又はその薬学的に許容可能な塩を含有する抗癌剤、
〔６〕前記〔１〕記載の新規レスベラトロール誘導体又はその薬学的に許容可能な塩を含有する口腔癌細胞に対する抗癌剤、
〔７〕前記〔１〕記載の新規レスベラトロール誘導体又はその薬学的に許容可能な塩を含有する食品、
〔８〕前記〔１〕記載の新規レスベラトロール誘導体又はその薬学的に許容可能な塩を含有する医薬品または医薬部外品、
〔９〕レスベラトロールとフェルラ酸を金属塩存在下で１１０℃以上に加熱処理することにより、目的の化合物を生成することを特徴とする前記〔１〕記載の新規レスベラトロール誘導体又はその薬学的に許容可能な塩の製造方法
に関する。
A novel resveratrol derivative represented by or a pharmaceutically acceptable salt thereof,
[2] An angiotensin converting enzyme inhibitor containing the novel resveratrol derivative according to [1] or a pharmaceutically acceptable salt thereof ,
[3] An antihypertensive agent comprising the novel resveratrol derivative of [1] or a pharmaceutically acceptable salt thereof ,
[4] A therapeutic agent for cardiovascular disease comprising the novel resveratrol derivative or the pharmaceutically acceptable salt thereof according to [1],
[5] An anticancer agent comprising the novel resveratrol derivative or the pharmaceutically acceptable salt thereof according to [1],
[6] An anticancer agent for oral cancer cells containing the novel resveratrol derivative or the pharmaceutically acceptable salt thereof according to [1],
[7] above [1] new resveratrol derivative according or a pharmaceutically foods containing acceptable salts,
[8] A pharmaceutical or quasi-drug containing the novel resveratrol derivative or the pharmaceutically acceptable salt thereof according to [1],
[ 9 ] The novel resveratrol derivative or the pharmacology thereof according to [1], wherein the target compound is produced by heat-treating resveratrol and ferulic acid to 110 ° C. or higher in the presence of a metal salt. Relates to a process for producing a chemically acceptable salt .
本発明の新規レスベラトロール誘導体又はその薬学的に許容可能な塩（以下、新規レスベラトロール誘導体という）は、レスベラトロール、フェルラ酸、市販のレスベラトロール誘導体及びルテオリンと比べて、抗癌活性、特に抗口腔癌活性に優れていることから、新規な抗癌剤として有用である。さらに、レスベラトロールやフラボノイド配糖体と比べて優れたアンジオテンシン変換酵素阻害活性を有することから、新規な血圧降下剤、心血管治療剤として有用である。
また、本発明の新規レスベラトロール誘導体は、前記のような生理活性に優れることに加えて、安全性にも優れることから、食品、医薬品および医薬部外品に配合することができる。
The novel resveratrol derivative of the present invention or a pharmaceutically acceptable salt thereof ( hereinafter referred to as a novel resveratrol derivative) is more anticancer than resveratrol, ferulic acid, commercially available resveratrol derivatives and luteolin. It is useful as a novel anticancer agent because of its excellent activity, particularly anti-oral cancer activity. Furthermore, since it has an angiotensin converting enzyme inhibitory activity superior to resveratrol and flavonoid glycosides, it is useful as a novel antihypertensive agent and cardiovascular therapeutic agent.
Moreover, since the novel resveratrol derivative of this invention is excellent also in safety | security in addition to being excellent in the above physiological activities, it can be mix | blended with a foodstuff, a pharmaceutical, and a quasi-drug.
以下、本発明について詳細に説明する。
本発明の新規レスベラトロール誘導体は、式（１）：
Hereinafter, the present invention will be described in detail.
The novel resveratrol derivative of the present invention has the formula (1):
で示される新規レスベラトロール誘導体又はその薬学的に許容可能な塩である。
Or a pharmaceutically acceptable salt thereof .
前記新規レスベラトロール誘導体において、炭素−炭素２重結合は、トランスまたはシスであってよく、シス体とトランス体との混合物を含む。 In the novel resveratrol derivative, the carbon-carbon double bond may be trans or cis, and includes a mixture of a cis isomer and a trans isomer.
前記新規レスベラトロール誘導体の薬学的に許容可能な塩としては、例えば、リチウム塩、ナトリウム塩、カリウム塩等のアルカリ金属塩；マグネシウム塩、カルシウム塩、バリウム塩等のアルカリ土類金属塩；アルミニウム塩；アルミニウムヒドロキシド塩等の金属ヒドロキシド塩；アルキルアミン塩、ジアルキルアミン塩、トリアルキルアミン塩、アルキレンジアミン塩、シクロアルキルアミン塩、アリールアミン塩、アラルキルアミン塩、複素環式アミン塩等のアミン塩；α−アミノ酸塩、ω−アミノ酸塩等のアミノ酸塩；ペプチド塩又はそれらから誘導される第１級、第２級、第３級若しくは第４級アミン塩等が挙げられる。これらの薬理的に許容し得る塩は、単独で又は２種以上を混合して用いることができる。 Examples of the pharmaceutically acceptable salt of the novel resveratrol derivative include alkali metal salts such as lithium salt, sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt, calcium salt and barium salt; aluminum Metal hydroxide salt such as aluminum hydroxide salt; alkylamine salt, dialkylamine salt, trialkylamine salt, alkylenediamine salt, cycloalkylamine salt, arylamine salt, aralkylamine salt, heterocyclic amine salt, etc. Amin salts; amino acid salts such as α-amino acid salts and ω-amino acid salts; peptide salts or primary, secondary, tertiary or quaternary amine salts derived therefrom. These pharmacologically acceptable salts can be used alone or in admixture of two or more.
以上のような構造を有する本発明の新規レスベラトロール誘導体は、当該分野で周知の方法に従って化学合成することも可能ではあるが、反応工程が複雑であり、有害な試薬や工程を必要とする。また、化学合成では不純物を除去する煩雑さもあり、さらに安全性の観点から、新規レスベラトロール誘導体の精製を徹底する必要もあり、工業的には不向きな方法である。 The novel resveratrol derivative of the present invention having the structure as described above can be chemically synthesized according to a method well known in the art, but the reaction process is complicated and requires harmful reagents and processes. . In addition, chemical synthesis is complicated to remove impurities, and from the viewpoint of safety, it is necessary to thoroughly purify a novel resveratrol derivative, which is an industrially unsuitable method.
そこで、本発明者らは、鋭意検討した結果、レスベラトロールとフェルラ酸を金属塩存在下で加熱処理することで、前記の化学合成法のように有害な試薬や工程を必要とせずに、新規レスベラトロール誘導体を効率的で安全に製造することができることを見出した。以下に、本発明の新規レスベラトロール誘導体の製造方法（以下、本発明の製造方法）について具体的に説明する。 Therefore, as a result of intensive studies, the present inventors conducted heat treatment of resveratrol and ferulic acid in the presence of a metal salt, without requiring harmful reagents and steps as in the chemical synthesis method described above, It has been found that a novel resveratrol derivative can be produced efficiently and safely. Below, the manufacturing method (henceforth the manufacturing method of this invention) of the novel resveratrol derivative | guide_body of this invention is demonstrated concretely.
本発明の製造方法では、前駆体としてレスベラトロールを用いる。レスベラトロールにはトランス体とシス体の構造異性体が存在するが、加熱や紫外線によってトランス体とシス体の変換が一部生じる。したがって、レスベラトロールとしては、トランス体でもシス体でも、あるいはトランス体とシス体の混合物であってもよい。レスベラトロールは、ブドウ果皮から抽出・精製した天然由来のものであっても、化学合成された純度の高い化成品であっても良い。天然由来のレスベラトロールを用いる場合は、完全に精製されたものである必要はなく、後述のように所望の生成反応が進み最終的に本発明の新規レスベラトロール誘導体が得られるから、レスベラトロール以外の成分を含む混合物も使用できる。また、レスベラトロールには、塩、エーテル、エステル等の誘導体もあるが、本発明の製造方法では、これらの誘導体も原料として使用することができる。
ただし、新規レスベラトロール誘導体の回収率の観点からは、レスベラトロール換算で１重量％以上含有された混合物が原料として望ましい。
前記レスベラトロールとしては、ブドウ果皮、ピーナッツなどの原料からの抽出物、凍結乾燥品などを使用してもよい。
In the production method of the present invention, resveratrol is used as a precursor. Resveratrol has structural isomers of trans form and cis form, but some conversion of trans form and cis form occurs by heating or ultraviolet rays. Therefore, resveratrol may be a trans isomer, a cis isomer, or a mixture of a trans isomer and a cis isomer. Resveratrol may be a naturally derived product extracted and purified from grape skin, or a chemically synthesized chemical product synthesized with high purity. When natural resveratrol is used, it does not need to be completely purified, and the desired production reaction proceeds as described later, and finally the novel resveratrol derivative of the present invention is obtained. Mixtures containing ingredients other than veratrol can also be used. Resveratrol also includes derivatives such as salts, ethers and esters, but these derivatives can also be used as raw materials in the production method of the present invention.
However, from the viewpoint of the recovery rate of the novel resveratrol derivative, a mixture containing 1% by weight or more in terms of resveratrol is desirable as a raw material.
As the resveratrol, an extract from a raw material such as grape skin or peanut, a freeze-dried product, or the like may be used.
また、本発明の製造方法では、前駆体としてフェルラ酸も必要である。フェルラ酸は、天然由来のものであっても、化学合成された純度の高い化成品であっても良い。天然由来のフェルラ酸を用いる場合は、完全に精製されたものである必要はなく、後述のように所望の生成反応が進み最終的に本発明の新規レスベラトロール誘導体が得られるから、フェルラ酸以外の成分を含む混合物も使用できる。
ただし、新規レスベラトロール誘導体の回収量の観点からは、フェルラ酸が１重量％以上含有された混合物が原料として望ましい。このような原料としては、米糠抽出物又は食品添加物としてのフェルラ酸、先行技術に示されるような微生物発酵によるフェルラ酸含有培養液、酵素反応後のフェルラ酸含有溶液等が挙げられる。
In the production method of the present invention, ferulic acid is also required as a precursor. Ferulic acid may be of natural origin or may be a chemically synthesized chemical product with high purity. When natural ferulic acid is used, it does not need to be completely purified, and the desired production reaction proceeds as described later, and finally the novel resveratrol derivative of the present invention is obtained. Mixtures containing other ingredients can also be used.
However, from the viewpoint of the recovered amount of the novel resveratrol derivative, a mixture containing 1% by weight or more of ferulic acid is desirable as a raw material. Examples of such raw materials include ferulic acid as a rice bran extract or food additive, a ferulic acid-containing culture solution by microbial fermentation as shown in the prior art, and a ferulic acid-containing solution after an enzymatic reaction.
本発明の製造方法では、レスベラトロール、フェルラ酸、またはレスベラトロールとフェルラ酸との混合物を適切な溶媒に溶解させる。この際、溶媒が水のみであればレスベラトロールやフェルラ酸の溶解度が著しく低いために、水と有機溶媒の混合液や、有機溶媒のみに溶解させればよい。水と有機溶媒の配合比や、有機溶媒の種類に特に制限はなく、レスベラトロールやフェルラ酸が十分に溶解すれば良い。中でも、メタノールやエタノールのみの溶媒や、水とメタノール、水とエタノールの混合液を使用することが、安全性やコスト面から好ましい。新規レスベラトロール誘導体を含む反応後組成物に対して最終的な精製を十分に適用せずに食品に使用する場合には、安全性や法規面から溶媒としてエタノールや含水エタノールを使用することが望ましい。
得られるレスベラトロール、フェルラ酸、またはレスベラトロールとフェルラ酸との混合物を含有する溶液中のレスベラトロールおよびフェルラ酸の濃度に制限はない。それぞれの濃度が高いほど、溶媒使用量が少ない等のメリットもあるため、レスベラトロールおよびフェルラ酸の濃度は各々の溶媒に対しレスベラトロールおよびフェルラ酸がそれぞれ飽和する濃度近くが好ましい。
また、レスベラトロール、フェルラ酸は前記溶液中において生成反応前に完全に溶解していなくともよい。例えば、レスベラトロール含有溶液とフェルラ酸含有溶液とを混合する場合、それぞれの溶液中のレスベラトロール濃度、フェルラ酸濃度が飽和濃度以上であっても、混合液とした場合には、飽和濃度近くになるように調整しておけばよい。
In the production method of the present invention, resveratrol, ferulic acid, or a mixture of resveratrol and ferulic acid is dissolved in a suitable solvent. At this time, if the solvent is only water, the solubility of resveratrol and ferulic acid is remarkably low. There is no restriction | limiting in particular in the compounding ratio of water and an organic solvent, and the kind of organic solvent, and resveratrol and ferulic acid should just fully melt | dissolve. Among them, it is preferable from the viewpoint of safety and cost to use a solvent containing only methanol or ethanol, or a mixed solution of water and methanol or water and ethanol. When using a post-reaction composition containing a new resveratrol derivative in foods without fully applying final purification, ethanol or hydrous ethanol may be used as a solvent for safety and legal reasons. desirable.
There is no limitation on the concentration of resveratrol and ferulic acid in the resulting solution containing resveratrol, ferulic acid, or a mixture of resveratrol and ferulic acid. The higher the respective concentrations are, the more advantageous is that the amount of the solvent used is smaller. Therefore, the concentration of resveratrol and ferulic acid is preferably close to the concentration at which resveratrol and ferulic acid are saturated with respect to each solvent.
Resveratrol and ferulic acid may not be completely dissolved in the solution before the formation reaction. For example, when resveratrol-containing solution and ferulic acid-containing solution are mixed, even if resveratrol concentration and ferulic acid concentration in each solution are equal to or higher than saturation concentration, Adjust it so that it is close.
次に、前記レスベラトロールおよびフェルラ酸を含有する溶液（以下、レスベラトロール、フェルラ酸含有溶液）のｐＨを８未満に調整することが好ましい。調整方法として、例えば、レスベラトロール、フェルラ酸含有溶液を調製した後にｐＨ調整剤を添加してｐＨを調整しても良いし、前記溶液の調製時に前もって溶媒のｐＨを調整しておいても良い。レスベラトロール、フェルラ酸含有溶液の反応開始時のｐＨは８．０以上であれば、他の反応や目的化合物の分解も一方で生じるために最終的な新規レスベラトロール誘導体の回収量が低下する。したがって、反応開始時のｐＨは３以上８未満が望ましい。 Next, it is preferable to adjust the pH of the solution containing resveratrol and ferulic acid (hereinafter referred to as resveratrol and ferulic acid-containing solution) to less than 8. As an adjustment method, for example, after preparing a solution containing resveratrol and ferulic acid, the pH may be adjusted by adding a pH adjusting agent, or the pH of the solvent may be adjusted in advance when preparing the solution. good. If the pH at the start of the reaction of the resveratrol / ferulic acid-containing solution is 8.0 or more, other reactions and decomposition of the target compound may occur on the other hand, resulting in a reduction in the final recovered amount of the resveratrol derivative To do. Therefore, the pH at the start of the reaction is desirably 3 or more and less than 8.
本発明の製造方法では、前記レスベラトロール、フェルラ酸含有溶液中に金属塩を添加する。前記金属塩としては、酸性塩、塩基性塩、正塩のいずれでもよく、また、単塩、複塩、錯塩のいずれでもよい。さらに、金属塩は１種類であっても、複数種類の混合物であってもよい。金属塩の例としては、食品添加物として認可されているものが安全性の面で好ましい。例えば、食品に添加することが認められているマグネシウム塩、カルシウム塩、ナトリウム塩、カリウム塩、亜鉛塩、銅塩などが挙げられる。
また、前記金属塩の混合物としては、例えば、ミネラルプレミックス（田辺製薬株式会社、グルコン酸亜鉛、クエン酸鉄アンモニウム、乳酸カルシウム、グルコン酸銅、リン酸マグネシウムを主成分としたミネラル混合物）のように金属塩を数種類含む物質が挙げられる。また、複数の金属塩を含む混合物として、ミネラルウォーターも挙げることができる。
なお、前記金属塩の含有量としては、新規レスベラトロール誘導体を生成可能な量であればよく、特に限定はない。
In the production method of the present invention, a metal salt is added to the resveratrol and ferulic acid-containing solution. The metal salt may be any of an acid salt, a basic salt, and a normal salt, and may be any of a single salt, a double salt, and a complex salt. Furthermore, the metal salt may be one kind or a mixture of plural kinds. As an example of the metal salt, those approved as food additives are preferable in terms of safety. For example, magnesium salt, calcium salt, sodium salt, potassium salt, zinc salt, copper salt and the like that are permitted to be added to foods can be mentioned.
In addition, as a mixture of the metal salts, for example, a mineral premix (Tanabe Seiyaku Co., Ltd., a mineral mixture mainly composed of zinc gluconate, ammonium iron citrate, calcium lactate, copper gluconate, and magnesium phosphate) In addition, substances containing several kinds of metal salts are listed. Moreover, mineral water can also be mentioned as a mixture containing a some metal salt.
In addition, as content of the said metal salt, what is necessary is just the quantity which can produce | generate a novel resveratrol derivative, and there is no limitation in particular.
次に、金属塩存在下、レスベラトロール、フェルラ酸含有溶液を加熱処理する。この加熱処理により、新規レスベラトロール誘導体の生成反応を行う。生成反応を効率的に進ませるために、レスベラトロール、フェルラ酸含有溶液の加熱温度は１１０℃以上に調整することが好ましい。また、使用する溶媒の沸点から考え、加圧加温が望ましい。例えば、開放容器にレスベラトロール、フェルラ酸含有溶液を入れ、溶媒の沸点を超える高温で前記容器を加温する、密閉容器にレスベラトロール、フェルラ酸含有溶液を入れて前記容器を加温する、レトルト装置やオートクレーブを用いて加圧加温する等、少なくとも部分的に溶液温度が１１０℃以上に達するように加熱することが好ましい。回収効率面から、溶液温度が均一に１１０℃〜１５０℃になることが、さらに好ましい。加熱時間も加熱温度と同様に限られたものではなく、効率的に目的の反応が進行する時間条件とすればよい。特に、加熱時間は加熱温度との兼ね合いによるものであり、加熱温度に応じた加熱時間にすることが望ましい。例えば、１３０℃付近で加熱する場合は、５分〜６０分の加熱時間が望ましい。また、加熱は、一度でも良いし、複数回に分けて繰り返し加熱しても良い。複数回に分けて加熱する場合、溶媒を新たに追加して行うことが好ましい。 Next, the resveratrol and ferulic acid-containing solution is heat-treated in the presence of a metal salt. By this heat treatment, a formation reaction of a novel resveratrol derivative is performed. In order to promote the production reaction efficiently, it is preferable to adjust the heating temperature of the resveratrol and ferulic acid-containing solution to 110 ° C. or higher. Further, considering the boiling point of the solvent to be used, pressure heating is desirable. For example, resveratrol and ferulic acid-containing solution are put in an open container, and the container is heated at a high temperature exceeding the boiling point of the solvent. Resveratrol and ferulic acid-containing solution is put in a sealed container and the container is heated. It is preferable to heat the solution so that the solution temperature reaches 110 ° C. or higher, for example, by heating under pressure using a retort device or an autoclave. From the viewpoint of recovery efficiency, it is more preferable that the solution temperature be 110 ° C. to 150 ° C. uniformly. The heating time is not limited as in the case of the heating temperature, and may be a time condition in which the target reaction efficiently proceeds. In particular, the heating time depends on the heating temperature, and it is desirable to set the heating time according to the heating temperature. For example, when heating near 130 ° C., a heating time of 5 to 60 minutes is desirable. Further, the heating may be performed once or may be repeated repeatedly in a plurality of times. When heating in multiple steps, it is preferable to add a new solvent.
前記加熱処理による新規レスベラトロール誘導体の生成反応の終了は、例えば、ＨＰＬＣによる成分分析により新規レスベラトロール誘導体の生成量を確認して判断すればよい。 The completion of the production reaction of the novel resveratrol derivative by the heat treatment may be judged by confirming the production amount of the novel resveratrol derivative by component analysis by HPLC, for example.
得られる反応液中には、本発明の新規レスベラトロール誘導体が含有されている。
また、安全な原料のみを用いた工程で新規レスベラトロール誘導体を製造した場合には、前記新規レスベラトロール誘導体を含む混合物の状態で食品、医薬品または医薬部外品に使用することが可能である。例えば、天然由来のレスベラトロール、フェルラ酸を含水エタノール溶媒に溶解し、ミネラルウォーターやミネラルプレミックスを用い、加熱処理した場合には、得られる反応液を食品原料の一つとして使用することが可能である。
The resulting reaction solution contains the novel resveratrol derivative of the present invention.
In addition, when a new resveratrol derivative is produced by a process using only safe raw materials, it can be used in foods, pharmaceuticals or quasi drugs in the state of a mixture containing the new resveratrol derivative. is there. For example, when a naturally occurring resveratrol and ferulic acid are dissolved in a water-containing ethanol solvent and heated with mineral water or a mineral premix, the resulting reaction solution may be used as one of the food ingredients. Is possible.
また、風味面での改良やさらなる高機能化を望む場合は、前記反応液を濃縮して新規レスベラトロール誘導体の濃度を高める、あるいは前記反応液を精製し新規レスベラトロール誘導体の純品を得ることができる。濃縮、精製は、公知の方法で実施可能である。例えば、クロロホルム、酢酸エチル、エタノール、メタノール等の溶媒抽出法や炭酸ガスによる超臨界抽出法等で抽出して新規レスベラトロール誘導体を濃縮できる。また、カラムクロマトグラフィーを利用して濃縮や精製を施すことも可能である。再結晶法や限外ろ過膜等の膜処理法も適用可能である。 Also, if you want to improve the flavor and further enhance the functionality, concentrate the reaction solution to increase the concentration of the new resveratrol derivative, or purify the reaction solution to obtain a pure product of the new resveratrol derivative. Can be obtained. Concentration and purification can be performed by a known method. For example, the novel resveratrol derivative can be concentrated by extraction with a solvent extraction method such as chloroform, ethyl acetate, ethanol, methanol or the like or a supercritical extraction method with carbon dioxide gas. It is also possible to perform concentration and purification using column chromatography. A membrane treatment method such as a recrystallization method or an ultrafiltration membrane can also be applied.
また、前記反応液から式（１）で表される新規レスベラトロール誘導体を分離して回収する場合には、カラムクロマトグラフィー、ＨＰＬＣ等を用いてもよい。 In addition, when the novel resveratrol derivative represented by the formula (1) is separated and recovered from the reaction solution, column chromatography, HPLC, or the like may be used.
前記濃縮物や精製物を、必要に応じて、減圧乾燥や凍結乾燥して溶媒除去することで、粉末状の新規レスベラトロール誘導体を得ることができる。 A powdered novel resveratrol derivative can be obtained by removing the solvent from the concentrate or purified product by drying under reduced pressure or lyophilization, if necessary.
また、得られた新規レスベラトロール誘導体は、必要に応じて、当該分野で公知の方法により、新規レスベラトロール誘導体の塩としたり、新規レスベラトロール誘導体のヒドロキシ基をエーテル化またはエステル化してもよい。 Further, the obtained new resveratrol derivative can be converted into a salt of the new resveratrol derivative or the etherified or esterified hydroxy group of the new resveratrol derivative by a method known in the art, if necessary. Also good.
以上のようにして得られる本発明の新規レスベラトロール誘導体は、レスベラトロール、フェルラ酸、市販のレスベラトロール誘導体及びルテリオンに比べて、極めて優れた抗癌活性を有する。また、レスベラトロールやフラボノイド配糖体と比べて、極めて優れたアンジオテンシン変換酵素阻害活性を有する。したがって、新規レスベラトロール誘導体を有効成分として含有する抗癌剤、アンジオテンシン変換酵素阻害剤、血圧降下剤又は心血管病治療剤を提供することができる。 The novel resveratrol derivative of the present invention obtained as described above has extremely excellent anticancer activity as compared with resveratrol, ferulic acid, commercially available resveratrol derivatives and luterion. In addition, it has extremely superior angiotensin converting enzyme inhibitory activity compared to resveratrol and flavonoid glycosides. Therefore, an anticancer agent, an angiotensin converting enzyme inhibitor, an antihypertensive agent or a cardiovascular disease therapeutic agent containing the novel resveratrol derivative as an active ingredient can be provided.
なお、本発明で得られた新規レスベラトロール誘導体が持つさらなる効果効能は、得られた生理活性データより類推できる範囲で使用できる。 In addition, the further effect efficacy which the novel resveratrol derivative | guide_body obtained by this invention has can be used in the range which can be estimated from the obtained physiological activity data.
原料であるレスベラトロールおよびフェルラ酸の安全性が確認されていることから、本発明の新規レスベラトロール誘導体の安全性も同様に優れたものであると考えられる。 Since the safety of resveratrol and ferulic acid as raw materials has been confirmed, the safety of the novel resveratrol derivative of the present invention is considered to be excellent as well.
また、本発明の新規レスベラトロール誘導体は、前記のような生理活性を奏することから、食品、医薬品、医薬部外品等に配合して使用することができる。 Moreover, since the novel resveratrol derivative of the present invention exhibits the physiological activity as described above, it can be used by blending it with foods, pharmaceuticals, quasi drugs and the like.
前記食品としては、例えば、飲料、アルコール飲料、ゼリー、菓子等、どのような形態でもよく、菓子類の中でも、その容量等から保存や携帯に優れた、ハードキャンディ、ソフトキャンディ、グミキャンディ、タブレット等が挙げられるが、特に限定はない。また、新規レスベラトロール誘導体をワインに添加することで、ワインの健康機能効果をさらに増強した新規なワインとすることもできる。この新規なワインのように、嗜好性と健康機能効果の双方を持ち合わせた飲食品は、社会ニーズの非常に高い分野であり、これに応えることが可能である。また、新規レスベラトロール誘導体は、後述のように、癌、中でも口腔癌に対する優れた抗癌活性を有することから、現在問題になっている口腔癌に対する予防を目的に、容易に摂取できるキャンディー、グミキャンディ、タブレットなどとしても有用である。さらに、新規レスベラトロール誘導体は、後述のように、アンジオテンシン変換酵素阻害活性を有することから、現在問題になっている高血圧症や心血管病予防を目的に、容易に摂取できるキャンディー、グミキャンディ、タブレットなどとしても有用である。なお、食品には、機能性食品、健康食品、健康志向食品等も含まれる。 The food may be in any form such as beverage, alcoholic beverage, jelly, confectionery, etc., and among confectionery, hard candy, soft candy, gummy candy, tablet that is excellent in storage and carrying due to its capacity etc. There are no particular limitations. Further, by adding a novel resveratrol derivative to wine, it is possible to obtain a new wine that further enhances the health function effect of the wine. Like this new wine, food and drink with both palatability and health function effects is a field with very high social needs and can respond to this. In addition, as described below, the novel resveratrol derivative has excellent anticancer activity against cancer, especially oral cancer, and therefore can be easily ingested for the purpose of preventing oral cancer, which is currently a problem, It is also useful as a gummy candy or tablet. Furthermore, since the novel resveratrol derivative has angiotensin converting enzyme inhibitory activity as will be described later, it can be easily ingested for the purpose of preventing hypertension and cardiovascular disease which are currently problematic, It is also useful as a tablet. The food includes functional food, health food, health-oriented food, and the like.
前記医薬品としては、散剤、錠剤、丸剤、カプセル剤、細粒剤、顆粒剤等の固形製剤、水剤、懸濁剤、乳剤等の液剤、ゲル剤等が挙げられる。錠剤、丸剤、顆粒剤、顆粒を含有するカプセル剤の顆粒は、必要により、ショ糖等の糖類、マルチトール等の糖アルコールで糖衣を施したり、ゼラチン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース等でコーティングを施したりすることもできる。または胃溶性若しくは腸溶性物質のフィルムで被覆してもよい。また、製剤の溶解性を向上させるために、公知の可溶化処理を施すこともできる。常法に基づいて、注射剤、点滴剤に配合して使用してもよい。 Examples of the pharmaceutical include solid preparations such as powders, tablets, pills, capsules, fine granules and granules, liquids such as liquids, suspensions and emulsions, gels and the like. If necessary, the granules of capsules containing tablets, pills, granules, granules can be sugar-coated with sugars such as sucrose, sugar alcohols such as maltitol, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. It can also be coated. Alternatively, it may be covered with a film of gastric or enteric material. Moreover, in order to improve the solubility of a formulation, a well-known solubilization process can also be performed. Based on a conventional method, it may be used in an injection or a drip.
医薬部外品としては、口腔に用いられる医薬部外品、例えば、歯磨き、マウスウオッシュ、マウスリンスが挙げられる。 Examples of quasi drugs include quasi drugs used in the oral cavity, such as toothpaste, mouthwash, and mouth rinse.
本発明の新規レスベラトロール誘導体を用いて食品、医薬品または医薬部外品を調製する場合、本発明の効果が損なわれない範囲内で食品、医薬品または医薬部外品に通常用いられる成分を適宜任意に配合することができる。
例えば、食品の場合には、水、アルコール、澱粉室、蛋白質、繊維質、糖質、脂質、ビタミン、ミネラル、着香料、着色料、甘味料、調味料、安定剤、防腐剤のような食品に通常配合される原料または素材と組み合わせることができる。
医薬部外品の場合には、主剤、基材、界面活性剤、起泡剤、湿潤剤、増粘剤、透明剤、着香料、着色料、安定剤、防腐剤、殺菌剤等組み合わせ、常法に基づいて、液状、軟膏状あるいはスプレー噴射可能な最終形態等にすることができる。
特に、本発明の新規レスベラトロール誘導体の生理活性分野を考慮すると、癌および高血圧等の心血管病予防・治療等の健康維持増進、さらには疾病治癒分野において用いることが好ましい。
When preparing foods, pharmaceuticals or quasi drugs using the novel resveratrol derivative of the present invention, the components usually used in foods, drugs or quasi drugs are appropriately selected within the range that does not impair the effects of the present invention. It can mix | blend arbitrarily.
For example, in the case of food, food such as water, alcohol, starch chamber, protein, fiber, sugar, lipid, vitamin, mineral, flavoring, coloring, sweetener, seasoning, stabilizer, preservative Can be combined with raw materials or materials usually blended in
In the case of quasi-drugs, combinations of main ingredients, base materials, surfactants, foaming agents, wetting agents, thickeners, clearing agents, flavoring agents, coloring agents, stabilizers, preservatives, bactericides, etc. Based on the law, it can be made into a liquid, ointment-like or sprayable final form.
In particular, considering the physiologically active field of the novel resveratrol derivative of the present invention, it is preferably used in the field of health maintenance and promotion such as prevention and treatment of cardiovascular diseases such as cancer and hypertension, and further in the field of disease healing.
本発明の新規レスベラトロール誘導体を食品に添加する場合には、該食品中に対して、通常は０．００１〜２０重量％添加することが好ましい。 When the novel resveratrol derivative of the present invention is added to food, it is usually preferable to add 0.001 to 20% by weight based on the food.
本発明の新規レスベラトロール誘導体を医薬用途で使用する場合、例えば、その摂取量は、所望の改善、治療又は予防効果が得られるような量であれば特に制限されず、通常その態様、患者の年齢、性別、体質その他の条件、疾患の種類並びにその程度等に応じて適宜選択される。１日当たり約０．１ｍｇ〜１，０００ｍｇ程度とするのがよく、これを１日に１〜４回に分けて摂取することができる。 When the novel resveratrol derivative of the present invention is used for pharmaceutical purposes, for example, the amount of intake thereof is not particularly limited as long as the desired improvement, treatment or prevention effect is obtained. It is appropriately selected according to the age, sex, constitution and other conditions, the type and degree of disease. About 0.1 mg to about 1,000 mg per day is preferable, and this can be taken in 1 to 4 times a day.
本発明の新規レスベラトロール誘導体を医薬部外品に添加する場合には、該医薬部外品中に、通常０．００１〜３０重量％添加するのが好ましい。 When the novel resveratrol derivative of the present invention is added to a quasi drug, it is usually preferable to add 0.001 to 30% by weight in the quasi drug.
また、本発明の新規レスベラトロール誘導体は、安全性に優れたものであるので、ヒトに対してだけでなく、例えば、非ヒト動物、例えば、ラット、マウス、モルモット、ウサギ、ヒツジ、ブタ、ウシ、ウマ、ネコ、イヌ、サル、チンパンジー等の哺乳類、鳥類、両生類、爬虫類等の治療剤または飼料に配合してもよい。飼料としては、例えばヒツジ、ブタ、ウシ、ウマ、ニワトリ等に用いる家畜用飼料、ウサギ、ラット、マウス等に用いる小動物用飼料、ウナギ、タイ、ハマチ、エビ等に用いる魚介類用飼料、イヌ、ネコ、小鳥、リス等に用いるペットフードが挙げられる。 Further, since the novel resveratrol derivative of the present invention is excellent in safety, not only for humans, for example, non-human animals such as rats, mice, guinea pigs, rabbits, sheep, pigs, You may mix | blend with mammals, such as a cow, a horse, a cat, a dog, a monkey, a chimpanzee, birds, amphibians, a reptile, etc., or a feed. As feed, for example, livestock feed used for sheep, pigs, cattle, horses, chickens, etc., feed for small animals used for rabbits, rats, mice, etc. The pet food used for a cat, a small bird, a squirrel, etc. is mentioned.
次に、本発明を実施例に基づいて詳細に説明するが、本発明はかかる実施例にのみ限定されるものではない。 EXAMPLES Next, although this invention is demonstrated in detail based on an Example, this invention is not limited only to this Example.
（実施例１：新規レスベラトロール誘導体の生成方法検討）
トランス−レスベラトロール（東京化成工業（株）製）１００ｍｇ、フェルラ酸（和光純薬工業（株）製）１００ｍｇをエタノール２ｍＬに溶解し、（１）ミネラルウォーター（商品名「ゲロルシュタイナー」サッポロ飲料（株）製）２ｍＬ、（２）ミネラルプレミックス１００ｍｇ、水２ｍＬ、（３）リン酸マグネシウム・３水和物（和光純薬工業（株）製、ミネラルプレミックスの主成分）１００ｍｇ、水２ｍＬをそれぞれ加えて、レスベラトロール、フェルラ酸含有溶液（ｐＨ：（１）４．８、（２）５．２、（３）５．４）を３種類調製した。このレスベラトロール、フェルラ酸含有溶液をオートクレーブ（三洋電機（株）製、「ＳＡＮＹＯ ＬＡＢＯ ＡＵＴＯＣＬＡＶＥ」）にて１３０℃、３０分間加熱した。得られた反応溶液のうち１ｍＬをメタノールにて５０ｍＬにメスアップし、このうちの１０μＬをＨＰＬＣにより分析した。
(Example 1: Examination of production method of novel resveratrol derivative)
100 mg of trans-resveratrol (manufactured by Tokyo Chemical Industry Co., Ltd.) and 100 mg of ferulic acid (manufactured by Wako Pure Chemical Industries, Ltd.) are dissolved in 2 mL of ethanol, and (1) mineral water (trade name “Gerol Steiner” Sapporo Beverage ( Co., Ltd.) 2 mL, (2) mineral premix 100 mg,
ＨＰＬＣ分析は以下条件にて行った。
カラム：逆相用カラム「Ｄｅｖｅｌｏｓｉｌ（登録商標）Ｃ−３０−ＵＧ−５」（４．６ｍｍｉ．ｄ．×２５０ｍｍ）
移動相：Ａ・・・Ｈ2Ｏ（０．１％トリフルオロ酢酸（ＴＦＡ））， Ｂ・・・アセトニトリル（０．１％ＴＦＡ）
流速：１ｍＬ／ｍｉｎ
注入：１０μＬ
検出：２５４ｎｍ
勾配（容量％）：８０％Ａ／２０％Ｂから２０％Ａ／８０％Ｂまで３０分間、２０％Ａ／８０％Ｂから１００％Ｂまで５分間、１００％Ｂで１０分間（全て直線）
HPLC analysis was performed under the following conditions.
Column: Column for reverse phase “Develosil (registered trademark) C-30-UG-5” (4.6 mm.d. × 250 mm)
Mobile phase: A: H 2 O (0.1% trifluoroacetic acid (TFA)), B: Acetonitrile (0.1% TFA)
Flow rate: 1 mL / min
Injection: 10 μL
Detection: 254 nm
Gradient (% by volume): 30 minutes from 80% A / 20% B to 20% A / 80% B, 5 minutes from 20% A / 80% B to 100% B, 10 minutes at 100% B (all linear)
得られたクロマトグラムを図１に示す。上から、反応前、（１）、（２）、（３）の反応溶液のクロマトグラムをそれぞれ示している。反応後には、レスベラトロールやフェルラ酸以外のピークが検出され、複数の化合物が生成されていることが確認された。
例えば、図中、Ｂのピークは、フェルラ酸の分解物であり、それ以外で、反応前後で生成量に顕著な差があったのが、後述する新規レスベラトロール誘導体であるＡのピークである。なお、（１）、（２）、（３）の反応溶液の間では、Ａのピーク成分の生成量の差は殆どなく、つまり、今回用いた金属塩の種類による新規レスベラトロール誘導体の生成量の差は小さかった。
The obtained chromatogram is shown in FIG. From the top, the chromatograms of the reaction solutions (1), (2), and (3) are shown before the reaction. After the reaction, peaks other than resveratrol and ferulic acid were detected, and it was confirmed that a plurality of compounds were produced.
For example, in the figure, the peak of B is a decomposition product of ferulic acid, and other than that, there was a significant difference in the amount of production before and after the reaction, the peak of A being a new resveratrol derivative described later. is there. In addition, there is almost no difference in the amount of peak component A generated between the reaction solutions (1), (2), and (3), that is, the production of a novel resveratrol derivative depending on the type of metal salt used this time. The difference in quantity was small.
（実施例２：新規レスベラトロール誘導体の大量生成）
トランス−レスベラトロール１ｇ、フェルラ酸１ｇをエタノール２０ｍＬに溶解し、ミネラルウォーター２０ｍＬを加えて、レスベラトロール、フェルラ酸含有溶液（ｐＨ＝４．８）を得た。このレスベラトロール、フェルラ酸含有溶液をオートクレーブにて１３０℃、９０分間加熱した。得られた反応溶液のうち１ｍＬをメタノールにて５０ｍＬにメスアップし、実施例１と同様にＨＰＬＣにより分析し、実施例１と同様のクロマトグラムが確認できた。
(Example 2: Mass production of novel resveratrol derivative)
1 g of trans-resveratrol and 1 g of ferulic acid were dissolved in 20 mL of ethanol, and 20 mL of mineral water was added to obtain a resveratrol and ferulic acid-containing solution (pH = 4.8). This resveratrol and ferulic acid-containing solution was heated in an autoclave at 130 ° C. for 90 minutes. 1 mL of the obtained reaction solution was made up to 50 mL with methanol and analyzed by HPLC in the same manner as in Example 1, and the same chromatogram as in Example 1 was confirmed.
（実施例３：新規レスベラトロール誘導体の単離・構造決定）
実施例２で得られた反応物のうち、図１のＡで示したピークに含まれる化合物を分取ＨＰＬＣにより単離し、常法により乾燥したところ新規化合物（以下ＵＨＡ１１２４）を６０ｍｇ得た。単離精製したＵＨＡ１１２４は、褐色粉末状物質となった。
(Example 3: Isolation and structure determination of a novel resveratrol derivative)
Among the reactants obtained in Example 2, the compound contained in the peak indicated by A in FIG. 1 was isolated by preparative HPLC and dried by a conventional method to obtain 60 mg of a new compound (hereinafter referred to as UHA1124). The isolated and purified UHA1124 became a brown powdery substance.
次いで、前記ＵＨＡ１１２４の分子量を高分解能電子イオン化質量分析法（Ｅｌｅｃｔｒｏｎ Ｉｏｎｉｚａｔｉｏｎ−Ｍａｓｓ Ｓｐｅｃｔｒｏｍｅｔｒｙ）にて測定したところ、測定値は３７８．４１７６であり、理論値との比較から、以下の分子式を得た。
理論値Ｃ２３Ｈ２２Ｏ５（Ｍ+）：３７８．４１７８
分子式Ｃ23Ｈ22Ｏ5
Next, when the molecular weight of the UHA1124 was measured by high resolution electron ionization-mass spectrometry, the measured value was 378.4176, and the following molecular formula was obtained from comparison with the theoretical value.
Theoretical value C23H22O5 (M + ): 378.4178
Molecular formula C 23 H 22 O 5
次に、前記ＵＨＡ１１２４を核磁気共鳴（ＮＭＲ）測定に供し、１Ｈ−ＮＭＲ、１３Ｃ−ＮＭＲ及び各種２次元ＮＭＲデータの解析から、前記ＵＨＡ１１２４が式（１）で表される構造を有することを確認した。式（１）で表される新規レスベラトロール誘導体は本発明の方法で効率的に生成できることが示された。 Next, the UHA1124 was subjected to nuclear magnetic resonance (NMR) measurement, and it was confirmed from analysis of 1H-NMR, 13C-NMR and various two-dimensional NMR data that the UHA1124 had a structure represented by the formula (1). did. It was shown that the novel resveratrol derivative represented by the formula (1) can be efficiently produced by the method of the present invention.
ＮＭＲ測定値について、ＵＨＡ１１２４を For NMR measurements, UHA1124
として、その1Ｈ核磁気共鳴スペクトル、13Ｃ核磁気共鳴スペクトルを表１に示す。
値はδ、ｐｐｍで、溶媒はメタノール−ｄ3で測定した。
Table 1 shows the 1 H nuclear magnetic resonance spectrum and 13 C nuclear magnetic resonance spectrum.
The values were δ and ppm, and the solvent was measured with methanol-d 3 .
また、ＵＨＡ１１２４の物理化学的性状は、以下のようになった。
（性状）
褐色粉末
（溶解性）
水：難溶
メタノール：溶解
エタノール：溶解
ＤＭＳＯ：溶解
クロロホルム：溶解
酢酸エチル：溶解
Moreover, the physicochemical properties of UHA1124 were as follows.
(Properties)
Brown powder (soluble)
Water: Slightly soluble methanol: Dissolved ethanol: Dissolved DMSO: Dissolved chloroform: Dissolved ethyl acetate: Dissolved
（実施例４：ＵＨＡ１１２４の抗癌作用）
次に癌細胞に対する各化合物の効果を見るため、ＳＣＣ−４細胞（ヒト口腔癌細胞細胞、ＡＴＣＣ）を用いた癌細胞増殖抑制作用について試験した。
(Example 4: Anticancer activity of UHA1124)
Next, in order to see the effect of each compound on cancer cells, the cancer cell proliferation inhibitory action using SCC-4 cells (human oral cancer cell cells, ATCC) was tested.
ＳＣＣ−４細胞の培養には、４００ｎｇ／ｍＬヒドロコルチソン（Ｈｙｄｒｏｃｏｒｔｉｓｏｎｅ、シグマアルドリッチジャパン社製）、１%アンチバイオティック−アンチマイコティック（Ａｎｔｉｂｉｏｔｉｃ-Ａｎｔｉｍｙｃｏｔｉｃ、ギブコ（ＧＩＢＣＯ）社製）、１０％ＦＢＳ（Ｆｏｅｔａｌ Ｂｏｖｉｎｅ Ｓｅｒｕｍ、ＡＴＣＣ社製）を含むＤＭＥＭ／Ｆ−１２（１：１）培地（ギブコ社製）を使用した。試験には細胞培養用コラーゲンＩコート９６ウェルプレート（日本ＢＤ社製）を用い、５×１０5ｃｅｌｌｓ／ｍLとなるように細胞数を調整したＳＣＣ−４細胞を１ウェルあたり１００μｌずつ播種した。これを３７℃、５％ＣＯ2条件下で２４時間培養し、８０％コンフルエント以上の状態で試験に使用した。 For culturing SCC-4 cells, 400 ng / mL hydrocortisone (Hydrocortisone, manufactured by Sigma-Aldrich Japan), 1% antibiotic-antimycotic (manufactured by Antibiotic-Antilytic, Gibco (GIBCO)), 10% FBS A DMEM / F-12 (1: 1) medium (Gibco) containing (Foetal Bovine Serum, manufactured by ATCC) was used. In the test, a collagen I-coated 96-well plate for cell culture (manufactured by Japan BD) was used, and 100 μl of SCC-4 cells adjusted to 5 × 10 5 cells / mL were seeded per well. This was cultured for 24 hours under conditions of 37 ° C. and 5% CO 2 , and used for testing in a state of 80% confluence or higher.
試料は、レスベラトロールとフェルラ酸、本発明品であるＵＨＡ１１２４、ＳＣＣ−４細胞に対して抗癌作用の報告があるルテオリン（和光純薬社製）および市販のレスベラトロール誘導体であるε―ビニフェリン（和光純薬社製）の５種類を用いた。試料調製は、各々の化合物をジメチルスルホキシド（ＤＭＳＯ、和光純薬社製）にて溶解し、０．６３ｍM、１．２５ｍM、２．５ｍM、５ｍM、１０ｍMとなるように調製した。これをＳＣＣ−４細胞培養液中の最終濃度がそれぞれ６．３μＭ、１２．５μＭ、２５μＭ、５０μＭ、及び１００μＭとなるように添加して試験を開始した。なお溶媒であるＤＭＳＯのみを同量添加したものをネガティブコントロールとした。 Samples are resveratrol and ferulic acid, UHA1124 which is the product of the present invention, luteolin (manufactured by Wako Pure Chemical Industries) which has a report of anticancer activity against SCC-4 cells, and commercially available resveratrol derivative ε- Five types of biniferin (manufactured by Wako Pure Chemical Industries, Ltd.) were used. For sample preparation, each compound was dissolved in dimethyl sulfoxide (DMSO, manufactured by Wako Pure Chemical Industries, Ltd.) to prepare 0.63 mM, 1.25 mM, 2.5 mM, 5 mM, and 10 mM. This was added so that the final concentrations in the SCC-4 cell culture were 6.3 μM, 12.5 μM, 25 μM, 50 μM, and 100 μM, respectively, and the test was started. A negative control was prepared by adding the same amount of DMSO as a solvent.
生存細胞数の定量は「Ｃｅｌｌ ｃｏｕｎｔｉｎｇ ｋｉｔ−８」（同仁化学社製）を用いたＭＴＴ法にて行った。試験開始より４８時間後、各ウェルにＣｅｌｌ ｃｏｕｎｔｉｎｇ ｋｉｔ−８溶液を１０μL添加し、よく攪拌した。３７℃、５％ＣＯ2条件下で１時間の遮光反応後にプレートリーダー（「ＢＩＯ−ＲＡＤ Ｍｏｄｅｌ ６８０」、バイオ・ラッドラボラトリーズ社製）を用いて測定波長４５０ｎｍの吸光度測定を行い、得られたデータをもとに細胞生存率を算出した。細胞生存率とは、溶媒であるＤＭＳＯのみを添加した培養液の生存細胞数を１００％とし、各化合物の濃度下における細胞の生存細胞数を相対値として算出した値である。各化合物濃度と細胞生存率の関係から、細胞増殖を５０％抑制する濃度ＩＣ50（５０％阻害濃度：ｈａｌｆ ｍａｘｉｍａｌ ｉｎｈｉｂｉｔｏｒｙ ｃｏｎｃｅｎｔｒａｔｉｏｎ）を算出した（表２）。これらの結果から、ＵＨＡ１１２４には、強い癌細胞増殖抑制能、特に口腔癌細胞増殖抑制能が認められた。この効果は、レスベラトロールおよびフェルラ酸には全く認められず、さらにルテオリンおよびε―ビニフェリンよりも高い活性を示した。したがってレスベラトロールとフェルラ酸を新規レスベラトロール誘導体に変換する有意性が強く示唆された。 The number of viable cells was quantified by the MTT method using “Cell counting kit-8” (manufactured by Dojindo). 48 hours after the start of the test, 10 μL of the cell counting kit-8 solution was added to each well and stirred well. Data obtained by measuring absorbance at a measurement wavelength of 450 nm using a plate reader (“BIO-RAD Model 680”, manufactured by Bio-Rad Laboratories) after light-shielding reaction at 37 ° C. and 5% CO 2 for 1 hour. Based on the above, the cell viability was calculated. The cell viability is a value calculated by setting the number of viable cells in a culture solution to which only DMSO as a solvent is added as 100% and the number of viable cells in each compound concentration as a relative value. From the relationship between the concentration of each compound and the cell viability, a concentration IC 50 (50% inhibitory concentration) that suppresses cell proliferation by 50% was calculated (Table 2). From these results, UHA1124 was observed to have a strong ability to suppress cancer cell growth, particularly an ability to suppress oral cancer cell growth. This effect was not observed at all for resveratrol and ferulic acid, and was more active than luteolin and ε-biniferin. Therefore, the significance of converting resveratrol and ferulic acid into novel resveratrol derivatives was strongly suggested.
（実施例５：ＵＨＡ１１２４のアンジオテンシン変換酵素阻害作用）
つぎにアンジオテンシン変換酵素（ＡＣＥ）に対する阻害作用を評価するために、「ＡＣＥ Ｋｉｔ−ＷＳＴ」（商品名、同仁化学社製）を用いた阻害実験をこのキットに添付の取り扱い説明書に準じて行った。
(Example 5: Angiotensin converting enzyme inhibitory action of UHA1124)
Next, in order to evaluate the inhibitory action on angiotensin converting enzyme (ACE), an inhibition experiment using “ACE Kit-WST” (trade name, manufactured by Dojin Chemical Co., Ltd.) was performed according to the instruction manual attached to this kit. It was.
試料は、レスベラトロールと本発明品であるＵＨＡ１１２４の２種類を用いた。試料調製は、各々の化合物を０．１ｍM、０．５ｍM、１ｍM、５ｍM、及び１０ｍMとなるようにＤＭＳＯにて調製し、これをさらに３μＭ、１５μＭ、３０μＭ、１５０μＭ、及び３００μＭとなるように超純水で希釈した。この試料希釈液を酵素反応液に、最終濃度がそれぞれ１μＭ、５μＭ、１０μＭ、５０μＭ、及び１００μＭとなるように添加して試験を開始した。なおコントロールはＤＭＳＯのみとし、これを同様に調製した。 Two types of samples, resveratrol and UHA1124 which is the product of the present invention, were used. For sample preparation, each compound was prepared in DMSO to be 0.1 mM, 0.5 mM, 1 mM, 5 mM, and 10 mM, and this was further increased to 3 μM, 15 μM, 30 μM, 150 μM, and 300 μM. Diluted with pure water. The sample dilution was added to the enzyme reaction solution so that the final concentrations were 1 μM, 5 μM, 10 μM, 50 μM, and 100 μM, respectively, and the test was started. The control was DMSO only, and this was prepared in the same manner.
試験方法はキットに添付の取り扱い説明書に記載の使用方法に沿って行った。つまり、９６ウェルマイクロプレート（アズワン社製）の各ウェルに、超純水で調製したＡＣＥとアミノアシラーゼとの混合液２０μＬ、基質溶液（３−Ｈｙｄｒｏｘｙｂｕｔｙｌ−Ｇｌｙ−Ｇｌｙ−Ｇｌｙ、３ＨＢ−ＧＧＧ）２０μＬ、試料希釈液２０μＬを混合し、３７℃で1時間反応させた。これに、３−ヒドロキシブチル酸デヒドロゲナーゼと補酵素の混合液２００μＬを添加して10分間室温で反応させた。反応後、プレートリーダー（「ＢＩＯ−ＲＡＤ Ｍｏｄｅｌ ６８０」）を用いて測定波長４５０ｎｍの吸光度測定を行い、得られたデータをもとに阻害率を算出した。阻害率の算出にはキット記載の下記の式にて算出した。
阻害率＝[（Ａblank1−Ａsample）／（Ａblank1−Ａblank2）]×１００
ｂｌａｎｋ１：コントロール（ＡＣＥ阻害なし）
ｂｌａｎｋ２：試薬ブランク
The test method was performed in accordance with the method of use described in the instruction manual attached to the kit. That is, 20 μL of a mixed solution of ACE and aminoacylase prepared with ultrapure water and a substrate solution (3-Hydroxybutyl-Gly-Gly-Gly, 3HB-GGG) 20 μL are added to each well of a 96-well microplate (manufactured by ASONE). The sample diluent 20 μL was mixed and reacted at 37 ° C. for 1 hour. To this, 200 μL of a mixture of 3-hydroxybutyrate dehydrogenase and coenzyme was added and allowed to react at room temperature for 10 minutes. After the reaction, absorbance was measured at a measurement wavelength of 450 nm using a plate reader (“BIO-RAD Model 680”), and the inhibition rate was calculated based on the obtained data. The inhibition rate was calculated by the following formula described in the kit.
Inhibition rate = [(A blank1 -A sample ) / (A blank1 -A blank2 )] × 100
blank1: Control (no ACE inhibition)
blank2: Reagent blank
その結果、ＵＨＡ１１２４にＡＣＥ阻害作用が見出された（表３）。レスベラトロールには活性が認められないことから、レスベラトロールとフェルラ酸をＵＨＡ１１２４に変換する有意性が強く示唆された。また、前記非特許文献６のフラボノイド類のＡＣＥ阻害活性が数百μMであることから、ＵＨＡ１１２４にＡＣＥ阻害作用は、非ペプチド化合物の中でも顕著に強いものであることか明らかになった。 As a result, ACE inhibitory action was found in UHA1124 (Table 3). Since resveratrol was not active, the significance of converting resveratrol and ferulic acid to UHA1124 was strongly suggested. In addition, since the ACE inhibitory activity of the flavonoids of Non-Patent Document 6 is several hundred μM, it has been clarified that UHA1124 has a remarkably strong ACE inhibitory action among non-peptide compounds.
（実施例６：加熱温度によるＵＨＡ１１２４の生成量の違い）
レスベラトロール１００ｍｇ、フェルラ酸１００ｍｇ、エタノール２ｍＬ、ミネラルウォーター２ｍＬの混合溶液（ｐＨ＝４．８）を、オートクレーブにて７０℃、９０℃、１１０℃、１３０℃の各温度条件で２０分間加熱した。それぞれの温度条件で得られた反応後組成物１ｍＬをメタノールにて５０ｍＬにメスアップし、実施例１と同様にＨＰＬＣにより分析した。
(Example 6: Difference in production amount of UHA1124 depending on heating temperature)
A mixed solution (pH = 4.8) of resveratrol 100 mg, ferulic acid 100 mg,
その結果、１１０℃以上でＵＨＡ１１２４の生成は確認できた。レスベラトロールおよびフェルラ酸の合計量からの生成比率（重量％）は、７０℃、９０℃が非生成、１１０℃が極微量、１３０℃が３％となり、１３０℃での加熱がもっとも多くＵＨＡ１１２４が生成していた。 As a result, the formation of UHA1124 was confirmed at 110 ° C. or higher. The production ratio (% by weight) from the total amount of resveratrol and ferulic acid is 70 ° C., 90 ° C. is not produced, 110 ° C. is extremely small, 130 ° C. is 3%, and heating at 130 ° C. is the most, UHA1124 Was generated.
（実施例７：ＵＨＡ１１２４含有エキスの調製）
ブドウ果皮抽出エキスパウダー（レスベラトロール原料）１０ｇ、フェルラ酸（食品添加物、築野ライスファインケミカル（株）製）１ｇ、エタノール１０ｍＬ、ミネラルウォーターを１０ｍＬ加えて調製した混合溶液を、オートクレーブにて１３０℃、６０分間加熱した。得られた反応溶液を減圧加熱させて乾固し、ＵＨＡ１１２４含有エキスを１２ｇ得た。得られたＵＨＡ１１２４エキス１２ｇ中には、実施例３と同様の手法で確認したところＵＨＡ１１２４が０．０３６ｇ含有されていた。必要に応じてこの作業を繰り返した。
(Example 7: Preparation of UHA1124-containing extract)
Grape peel extract powder (resveratrol raw material) 10 g, ferulic acid (food additive, manufactured by Tsukino Rice Fine Chemical Co., Ltd.) 1 g, ethanol 10 mL, and 10 mL of mineral water were added to prepare a mixed solution of 130 in an autoclave. Heated at 60 ° C. for 60 minutes. The obtained reaction solution was heated under reduced pressure to dryness to obtain 12 g of an extract containing UHA1124. In 12 g of the obtained UHA1124 extract, it was confirmed by the same method as in Example 3 and 0.036 g of UHA1124 was contained. This work was repeated as necessary.
（実施例８：ＵＨＡ１１２４を含有する食品）
実施例７で得たＵＨＡ１１２４含有エキス１ｇをあらかじめ１００ｍＬのエタノールに溶解させ、これに砂糖５００ｇ、水飴４００ｇを混合溶解し、生クリーム１００ｇ、バター２０ｇ、練乳７０ｇ、乳化剤１．０ｇを混合した後、真空釜にて−５５０ｍｍＨｇ減圧させ、１１５℃の条件下で濃縮し、水分値３．０重量％のミルクハードキャンディを得た。このミルクハードキャンディは、菓子として食べ易いものであることはもちろん、癌患者における癌の拡散のリスクを低減したり、癌の発症のリスクを低減したり、癌の予防を期待した機能性食品としても利用できる。また、高血圧症の患者における血圧降下作用により、高血圧症や心血管病などの予防を期待した機能性食品として利用できる。
(Example 8: Food containing UHA1124)
1 g of UHA1124-containing extract obtained in Example 7 was dissolved in 100 mL of ethanol in advance, 500 g of sugar and 400 g of starch syrup were mixed and dissolved therein, and after mixing 100 g of fresh cream, 20 g of butter, 70 g of condensed milk, and 1.0 g of emulsifier, The pressure was reduced by −550 mmHg in a vacuum kettle and concentrated under a condition of 115 ° C. to obtain a milk hard candy having a moisture value of 3.0% by weight. This milk hard candy is easy to eat as a confectionery, as well as reducing the risk of cancer spread in cancer patients, reducing the risk of developing cancer, and as a functional food that is expected to prevent cancer. Can also be used. Moreover, it can be used as a functional food that is expected to prevent hypertension, cardiovascular disease and the like due to the blood pressure lowering effect in patients with hypertension.
（実施例９：ＵＨＡ１１２４を含有する医薬品）
実施例２，３と同様の方法で得たＵＨＡ１１２４をエタノールに溶解し、これを微結晶セルロースに添加して吸着させた後に、減圧乾燥させた。この吸着物を用いて常法に従い、打錠品を得た。処方は、ＵＨＡ１１２４を１０重量部、コーンスターチ２３重量部、乳糖１２重量部、カルボキシメチルセルロース８重量部、微結晶セルロース３２重量部、ポリビニルピロリドン４重量部、ステアリン酸マグネシウム３重量部、タルク８重量部の通りである。本打錠品は、癌や高血圧症などの心血管病の治癒を目的とする医薬品として有効に利用できる。
(Example 9: Drug containing UHA1124)
UHA1124 obtained in the same manner as in Examples 2 and 3 was dissolved in ethanol, added to microcrystalline cellulose and adsorbed, and then dried under reduced pressure. Using this adsorbent, a tableted product was obtained according to a conventional method. The formulation is 10 parts by weight of UHA1124, 23 parts by weight of corn starch, 12 parts by weight of lactose, 8 parts by weight of carboxymethyl cellulose, 32 parts by weight of microcrystalline cellulose, 4 parts by weight of polyvinylpyrrolidone, 3 parts by weight of magnesium stearate, 8 parts by weight of talc. Street. This tableted product can be effectively used as a pharmaceutical for the purpose of healing cardiovascular diseases such as cancer and hypertension.
（実施例１０：ＵＨＡ１１２４を含有する医薬部外品）
実施例２、３の方法で得たＵＨＡ１１２４ １．２ｇを１０ｍＬのエタノールに溶解し、タウリン２０ｇ、ビタミンＢ１硝酸塩０．１２ｇ、安息香酸ナトリウム０．６ｇ、クエン酸４ｇ、砂糖６０ｇ、ポリビニルピロリドン１０ｇを全て精製水に溶解させ、１０００ｍＬにメスアップした。なお、ｐＨは、希塩酸を用いて３．２に調整した。得られた溶液１０００ｍＬのうち５０ｍＬをガラス瓶に充填し、８０℃で３０分間滅菌して、医薬部外品であるドリンク剤を完成させた。本ドリンク剤は、栄養補給の目的に加えて、癌患者における癌の拡散のリスクを低減したり、癌の発症のリスクを低減したり、癌の予防や高血圧症などの心血管病の予防を目的とする医薬部外品として有効に利用できる。
(Example 10: Quasi-drug containing UHA1124)
1.2 g of UHA1124 obtained by the method of Examples 2 and 3 was dissolved in 10 mL of ethanol, 20 g of taurine, 0.12 g of vitamin B1 nitrate, 0.6 g of sodium benzoate, 4 g of citric acid, 60 g of sugar, and 10 g of polyvinylpyrrolidone. All were dissolved in purified water and made up to 1000 mL. The pH was adjusted to 3.2 using dilute hydrochloric acid. 50 ml of 1000 ml of the obtained solution was filled in a glass bottle and sterilized at 80 ° C. for 30 minutes to complete a quasi-drug drink. In addition to nutritional purposes, this drink reduces the risk of cancer spread in cancer patients, reduces the risk of developing cancer, prevents cancer, and prevents cardiovascular diseases such as hypertension. It can be effectively used as the intended quasi-drug.
Claims (9)
The novel resveratrol derivative according to claim 1, or a pharmaceutically acceptable product thereof, wherein the target compound is produced by heat-treating resveratrol and ferulic acid to 110 ° C or higher in the presence of a metal salt. Method for producing salt .
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