JP5672963B2 - New 4-vinylphenol polymerization compound - Google Patents
New 4-vinylphenol polymerization compound Download PDFInfo
- Publication number
- JP5672963B2 JP5672963B2 JP2010242673A JP2010242673A JP5672963B2 JP 5672963 B2 JP5672963 B2 JP 5672963B2 JP 2010242673 A JP2010242673 A JP 2010242673A JP 2010242673 A JP2010242673 A JP 2010242673A JP 5672963 B2 JP5672963 B2 JP 5672963B2
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- JP
- Japan
- Prior art keywords
- vinylphenol
- novel
- acceptable salt
- pharmaceutically acceptable
- coumaric acid
- 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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Description
本発明は、新規４−ビニルフェノール重合化合物及びその製造方法、前記新規４−ビニルフェノール重合化合物を含むリパーゼ阻害剤、抗肥満剤、皮膚疾患治療剤、抗癌剤、チロシナーゼ阻害剤、美白剤、食品、医薬品、又は化粧品に関するものである。 The present invention relates to a novel 4-vinylphenol polymer compound and a method for producing the same, a lipase inhibitor containing the novel 4-vinylphenol polymer compound, an anti-obesity agent, a skin disease therapeutic agent, an anticancer agent, a tyrosinase inhibitor, a whitening agent, a food, It relates to pharmaceuticals or cosmetics.
ｐ−クマル酸は植物の二次代謝産物の一つであり、例えば樹木の主成分であるリグニンやリグナンの前駆体となるほか、フラボノイドなどの機能性成分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ある。また、ｐ−クマル酸としては、プラムをはじめとして、多くの果物の果実や果皮、プロポリスなどにも含まれていることが知られている。これらは全て食経験がある植物であるため、ｐ−クマル酸は、人に対する安全性も高い成分である。 p-coumaric acid is one of the secondary metabolites of plants. For example, it is a precursor of lignin and lignan, which are the main components of trees, and a precursor of functional components such as flavonoids. It is a component that exists relatively in the field. In addition, it is known that p-coumaric acid is contained in the fruits, peels and propolis of many fruits including plums. Since these are all plants that have dietary experience, p-coumaric acid is a highly safe ingredient for humans.
ｐ−クマル酸については、その生理機能に関連した先行技術がある。例えば、ｐ−クマル酸をはじめ、桂皮酸類を有効成分とする抗ヘリコバクター・ピロリ剤（特許文献１）、フェルラ酸及び／又はｐ−クマル酸を有効成分とする皮膚改善剤（特許文献２）、クマル酸をはじめ、プロポリスの抽出物に含まれる桂皮酸類を有効成分とする血管新生抑制剤（特許文献３）が挙げられる。
また、ｐ−クマル酸誘導体に関連した先行技術がある。例えば、クマル酸を化学合成させたリグニン類を有効成分とする抗菌剤（特許文献４）、カフェイン酸アミド誘導体又はエステル誘導体を有効成分とするアディポネクチン産生増強剤（特許文献５）、ｐ−クマル酸二量体を原料とした抗菌剤であるベンゾフランカルボキサミド誘導体の合成方法（特許文献６）が挙げられる。
また、ｐ−クマル酸誘導体やｐ−クマル酸誘導体は、植物中にも多く含まれていることから、リンゴ、ナシ又はモモの未熟果実の果実ポリフェノールとして、ｐ−クマル酸誘導体やｐ−クマル酸誘導体などを含む酸化防止剤、血圧降下剤、抗変異原性作用剤、アレルギー抑制剤、抗う蝕剤及び消臭剤（特許文献７）が挙げられる。
このようにｐ−クマル酸やｐ−クマル酸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ｐ−クマル酸やｐ−クマル酸誘導体を効率的に製造する技術開示もなされている。例えば、組み換え体を用いた微生物によるｐ−ヒドロキシ桂皮酸（ｐ−クマル酸）などの製造法方（特許文献８）が示される。
Regarding p-coumaric acid, there is a prior art related to its physiological function. For example, p-coumaric acid, anti-Helicobacter pylori agent containing cinnamic acid as an active ingredient (Patent Document 1), skin improving agent containing ferulic acid and / or p-coumaric acid as an active ingredient (Patent Document 2), Examples thereof include an angiogenesis inhibitor (Patent Document 3) containing cinnamic acid contained in a propolis extract including coumaric acid as an active ingredient.
There is also prior art related to p-coumaric acid derivatives. For example, an antibacterial agent containing a lignin chemically synthesized from coumaric acid as an active ingredient (Patent Document 4), an adiponectin production enhancer containing a caffeic acid amide derivative or an ester derivative as an active ingredient (Patent Document 5), p-coumaru A method for synthesizing a benzofurancarboxamide derivative that is an antibacterial agent using an acid dimer as a raw material (Patent Document 6) can be mentioned.
In addition, since many p-coumaric acid derivatives and p-coumaric acid derivatives are also contained in plants, p-coumaric acid derivatives and p-coumaric acid are used as fruit polyphenols of immature fruits of apples, pears or peaches. Examples include antioxidants including derivatives, antihypertensive agents, antimutagenic agents, allergy inhibitors, anti-cariogenic agents, and deodorants (Patent Document 7).
As described above, since many p-coumaric acids and p-coumaric acid derivatives exhibit excellent usefulness, technical disclosure for efficiently producing p-coumaric acid and p-coumaric acid derivatives as raw materials and lead compounds. It has also been made. For example, a method for producing p-hydroxycinnamic acid (p-coumaric acid) or the like by a microorganism using a recombinant is disclosed (Patent Document 8).
このような状況から、有用なｐ−クマル酸関連化合物である４−ビニルフェノール重合化合物を容易に工業化できる効率的な生成方法の確立が望まれていた。 Under such circumstances, establishment of an efficient production method capable of easily industrializing a 4-vinylphenol polymerization compound which is a useful p-coumaric acid-related compound has been desired.
本発明者らは、ｐ−クマル酸及びｐ−クマル酸誘導体に関する前記の状況を鑑みて、新規な生理活性を有するｐ−クマル酸関連化合物の探索と、その製造方法を確立すべく鋭意検討した結果、驚くべきことにｐ−クマル酸をアルカリ条件下で加熱処理することで、前記ｐ−クマル酸関連化合物である新規４−ビニルフェノール重合化合物を生成できることを初めて見出し、さらに前記新規４−ビニルフェノール重合化合物が原料であるｐ−クマル酸には認められない優れた抗癌活性、リパーゼ阻害活性及びチロシナーゼ阻害活性を有することを明らかにし、本発明を完成するに至った。 In view of the above-described situation regarding p-coumaric acid and p-coumaric acid derivatives, the present inventors have conducted intensive studies to search for a p-coumaric acid-related compound having a novel physiological activity and to establish a production method thereof. As a result, it was surprisingly found for the first time that a novel 4-vinylphenol polymerized compound which is a p-coumaric acid-related compound can be produced by heat-treating p-coumaric acid under alkaline conditions. It was clarified that the phenol polymerization compound has excellent anticancer activity, lipase inhibitory activity and tyrosinase inhibitory activity which are not recognized in p-coumaric acid as a raw material, and the present invention has been completed.
したがって、本発明は、優れた抗癌活性、リパーゼ阻害活性及びチロシナーゼ阻害活性を有する新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩及び該新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩を効率よく製造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４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩を含有するリパーゼ阻害剤、抗肥満剤、皮膚疾患治療剤、抗癌剤、チロシナーゼ阻害剤及び美白剤、さらには前記新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩を含有する食品、医薬品、又は化粧品を提供することを目的とする。
Therefore, the present invention provides a novel 4-vinylphenol polymerized compound or a pharmaceutically acceptable salt thereof having excellent anticancer activity, lipase inhibitory activity and tyrosinase inhibitory activity, and the novel 4-vinylphenol polymerized compound or pharmaceutically acceptable salt thereof. It is an object of the present invention to provide a method for efficiently producing an acceptable salt.
The present invention also provides a lipase inhibitor, an anti-obesity agent, a skin disease therapeutic agent, an anticancer agent, a tyrosinase inhibitor and a whitening agent containing the novel 4-vinylphenol polymerization compound or a pharmaceutically acceptable salt thereof, It is an object of the present invention to provide a food, medicine or cosmetic containing the novel 4-vinylphenol polymerization compound or a pharmaceutically acceptable salt thereof.
本発明の要旨は、
〔１〕下記式（１）：
The gist of the present invention is as follows:
[1] The following formula (1):
で表される新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩、
〔２〕前記〔１〕記載の新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩からなるリパーゼ阻害剤、
〔３〕前記〔１〕記載の新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩からなる抗肥満剤、
〔４〕前記〔１〕記載の新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩からなる皮膚疾患治療剤、
〔５〕前記〔１〕記載の新規４−ビニルフェノール重合化合物及びその薬学的に許容可能な塩からなる抗癌剤、
〔６〕前記〔１〕記載の新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩からなるチロシナーゼ阻害剤、
〔７〕前記〔１〕記載の新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩からなる美白剤、
〔８〕前記〔１〕記載の新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩を含有することを特徴とする食品、
〔９〕前記〔１〕記載の新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩を含有することを特徴とする医薬品、
〔１０〕前記〔１〕記載の新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩を含有することを特徴とする化粧品、
〔１０〕ｐ−クマル酸をアルカリ条件下で１１０℃以上に加熱処理することにより前記式（１）で表される新規４−ビニルフェノール重合化合物を生成することを特徴とする式（１）で表される新規４−ビニルフェノール重合化合物又は薬学的に許容可能な塩の製造方法
に関する。
A novel 4-vinylphenol polymerization compound represented by the formula:
[2] A lipase inhibitor comprising the novel 4-vinylphenol polymerization compound according to [1] or a pharmaceutically acceptable salt thereof,
[3] An anti-obesity agent comprising the novel 4-vinylphenol polymerized compound according to [1] or a pharmaceutically acceptable salt thereof,
[4] A skin disease therapeutic agent comprising the novel 4-vinylphenol polymerized compound or the pharmaceutically acceptable salt thereof according to [1],
[5] An anticancer agent comprising the novel 4-vinylphenol polymerization compound according to [1] and a pharmaceutically acceptable salt thereof,
[6] A tyrosinase inhibitor comprising the novel 4-vinylphenol polymerization compound according to [1] or a pharmaceutically acceptable salt thereof,
[7] A whitening agent comprising the novel 4-vinylphenol polymerization compound according to [1] or a pharmaceutically acceptable salt thereof,
[8] above [1] novel 4-vinylphenol polymer compound according or foods, characterized by containing a pharmaceutically acceptable salt thereof,
[9] A pharmaceutical comprising the novel 4-vinylphenol polymerization compound or the pharmaceutically acceptable salt thereof according to [1],
[10] A cosmetic comprising the novel 4-vinylphenol polymer compound or a pharmaceutically acceptable salt thereof according to [1],
[ 10 ] In formula (1), p-coumaric acid is heated to 110 ° C. or higher under alkaline conditions to produce a novel 4-vinylphenol polymerized compound represented by formula (1). The present invention relates to a method for producing a novel 4-vinylphenol polymerized compound or a pharmaceutically acceptable salt.
本発明の前記式（１）で表される新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩は、原料のｐ−クマル酸が持たないリパーゼ阻害活性、抗癌活性、チロシナーゼ阻害活性を有することから、リパーゼ阻害剤、抗癌剤、チロシナーゼ阻害剤を提供することができる。また、これらの作用を奏することから、本発明により、優れた抗肥満剤、皮膚疾患治療剤、抗癌剤及び美白剤を提供することができる。
また、本発明の新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩は、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、又は化粧品に配合することができる。
The novel 4-vinylphenol polymerization compound represented by the formula (1) of the present invention or a pharmaceutically acceptable salt thereof has a lipase inhibitory activity, an anticancer activity, and a tyrosinase inhibitory activity that the starting p-coumaric acid does not have. Therefore, a lipase inhibitor, an anticancer agent, and a tyrosinase inhibitor can be provided. In addition, because of these effects, the present invention can provide excellent antiobesity agents, skin disease treatment agents, anticancer agents and whitening agents.
In addition, the novel 4-vinylphenol polymer compound of the present invention or a pharmaceutically acceptable salt thereof is excellent in safety in addition to being excellent in physiological activity as described above. Can be blended.
以下、本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明の新規４−ビニルフェノール重合化合物は、式（１）： The novel 4-vinylphenol polymerization compound of the present invention has the formula (1):
で表される構造を有する。 It has the structure represented by these.
本発明では、前記式（１）で表される新規４−ビニルフェノール重合化合物は、薬学的に許容可能な塩でもよい。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。 In the present invention, the novel 4-vinylphenol polymerization compound represented by the formula (1) may be a pharmaceutically acceptable salt. Examples of the pharmaceutically acceptable salt 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 salt; aluminum hydroxide salt and the like Metal amine salts of; amine salts such as alkylamine salts, dialkylamine salts, trialkylamine salts, alkylenediamine salts, cycloalkylamine salts, arylamine salts, aralkylamine salts, heterocyclic amine salts; α-amino acid salts And amino acid salts such as 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.
前記式（１）で表される新規４−ビニルフェノール重合化合物又は薬学的に許容可能な塩（以下、本発明の新規４−ビニルフェノール重合化合物と略する）は、前駆体であるｐ−クマル酸には認められない強いリパーゼ阻害活性、抗癌活性、チロシナーゼ阻害活性を有する化合物である。 The novel 4-vinylphenol polymerized compound represented by the formula (1) or a pharmaceutically acceptable salt (hereinafter abbreviated as the novel 4-vinylphenol polymerized compound of the present invention) is p-coumaru which is a precursor. It is a compound having strong lipase inhibitory activity, anticancer activity, and tyrosinase inhibitory activity that is not found in acids.
本発明の新規４−ビニルフェノール重合化合物は、ｐ−クマル酸を含有する組成物を、アルカリ条件下で加熱処理することで、生成することができる。 The novel 4-vinylphenol polymerization compound of the present invention can be produced by heat-treating a composition containing p-coumaric acid under alkaline conditions.
本発明の新規４−ビニルフェノール重合化合物は、ｐ−クマル酸以外の原料を用いて化学合成することも可能ではあるが、その場合有害な触媒や溶媒、反応副産物等の不純物を除去するための徹底した精製工程が必要であり、産業化する上でコスト面において大きな障害がある。これに対して、本発明の製造方法は、比較的安価に入手できるｐ−クマル酸をアルカリ条件下で加熱処理する工程を有する方法であるため、化学合成方法のように有害な試薬や、危険な工程を必要としない効率的で安全な製造方法である。 Although the novel 4-vinylphenol polymerization compound of the present invention can be chemically synthesized using raw materials other than p-coumaric acid, in that case, impurities for removing harmful catalysts, solvents, reaction byproducts and the like are removed. A thorough refining process is required, and there are significant cost barriers for industrialization. On the other hand, the production method of the present invention is a method having a step of heat-treating p-coumaric acid, which can be obtained at a relatively low cost, under alkaline conditions. It is an efficient and safe manufacturing method that does not require a complicated process.
本発明の製造方法では、新規４−ビニルフェノール重合化合物の前駆体としてｐ−クマル酸が必要である。ｐ−クマル酸は、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p−クマル酸を用いる場合は、完全に精製されたものである必要はなく、その後の所望の反応が進み最終的に本発明の新規４−ビニルフェノール重合化合物が得られるから、混合物であっても問題ない。ただし、回収量の観点からは、ｐ−クマル酸が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、様々な果実やジュース、濃縮果汁、又は、破棄されることの多い果皮の抽出物、プロポリス又はその抽出物あるいは前記特許文献８等に記載される先行技術に示されるような微生物発酵によるｐ−クマル酸含有培養液等が挙げられる。 In the production method of the present invention, p-coumaric acid is required as a precursor of a novel 4-vinylphenol polymerization compound. The p-coumaric acid may be naturally derived or may be a chemically synthesized chemical product with high purity. When natural p-coumaric acid is used, it does not need to be completely purified, and the desired reaction proceeds thereafter to finally obtain the novel 4-vinylphenol polymerization compound of the present invention. But there is no problem. However, from the viewpoint of the recovery amount, a mixture containing 1% by weight or more of p-coumaric acid is desirable as a raw material. Examples of such raw materials include various fruits and juices, concentrated fruit juices, extracts of peels that are often discarded, propolis or extracts thereof, and the prior art described in Patent Document 8 and the like. And p-coumaric acid-containing culture solution produced by simple microbial fermentation.
本発明の製造方法では、前記ｐ−クマル酸の純品又はｐ−クマル酸含有混合物を、適切な溶媒に溶解させる。この際、溶媒が水のみであればｐ−クマル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、有機溶媒の種類には特に制限はなく、ｐ−クマル酸が十分に溶解する溶媒であれば良いが、メタノールやエタノールのみか、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望ましい。特に、最終的な精製を十分に適用せずに得られた生成物を食品に使用する場合には、安全性や法規面からエタノールや含水エタノールの使用が望ましい。 In the production method of the present invention, the pure p-coumaric acid or the p-coumaric acid-containing mixture is dissolved in an appropriate solvent. At this time, if the solvent is only water, the solubility of p-coumaric acid is remarkably low. Therefore, the solvent may be dissolved only in a mixed solution of water and an organic solvent or in an organic solvent. The mixing ratio of water and organic solvent and the type of organic solvent are not particularly limited and may be any solvent that can sufficiently dissolve p-coumaric acid, but only methanol or ethanol, water and methanol, or water and ethanol. Use of a mixed solution is desirable from the viewpoint of safety and cost. In particular, when a product obtained without sufficiently applying final purification is used for food, it is desirable to use ethanol or hydrous ethanol from the viewpoint of safety and legal regulations.
上記で得られたｐ−クマル酸含有溶液を、アルカリ性に調整する。例えば、ｐ−クマル酸含有溶液を調製した後にｐＨ調整剤を添加しｐＨを調整しても良いし、前述のｐ−クマル酸含有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。ｐＨは最終的に７．１以上であれば生成反応が進むが、ｐＨ１３．０を超えると生成反応と同時に、他の化合物の生成反応や目的化合物の分解も一方で生じるために本発明の４−ビニルフェノール重合化合物の最終的な回収量が低下する。したがって、本発明の製造方法において生成反応開始時のｐ−クマル酸含有溶液のｐＨは７．０〜１３．０が望ましい。 The p-coumaric acid-containing solution obtained above is adjusted to be alkaline. For example, after preparing a p-coumaric acid-containing solution, a pH adjuster may be added to adjust the pH, or the pH of the solvent may be adjusted in advance during the preparation of the aforementioned p-coumaric acid-containing solution. . If the pH is finally 7.1 or more, the formation reaction proceeds. However, if the pH exceeds 13.0, the formation reaction of the other compound and the decomposition of the target compound occur at the same time as the formation reaction. -The final recovery amount of the vinylphenol polymerization compound is lowered. Accordingly, the pH of the p-coumaric acid-containing solution at the start of the production reaction in the production method of the present invention is preferably 7.0 to 13.0.
また、ｐ−クマル酸含有溶液中のｐ−クマル酸の濃度に制限はない。中でも、ｐ−クマル酸の濃度が高いほど、溶媒使用量が少ない等のメリットがあるため、前記濃度は各々の溶媒に対しｐ−クマル酸が飽和する濃度近辺が好ましい。また、ｐ−クマル酸を飽和する濃度以上で含有させてもよい。この場合、生成反応前の時点では、ｐ−クマル酸は前記溶媒中に完全に溶解していなくともよい。溶解していないｐ−クマル酸は生成反応が進むにつれて徐々に溶解することになる。 Moreover, there is no restriction | limiting in the density | concentration of p-coumaric acid in a p-coumaric acid containing solution. Among them, the higher the concentration of p-coumaric acid is, the more advantageous is that the amount of solvent used is smaller, and therefore the concentration is preferably near the concentration at which p-coumaric acid is saturated with respect to each solvent. Moreover, you may make it contain more than the density | concentration which saturates p-coumaric acid. In this case, p-coumaric acid may not be completely dissolved in the solvent before the production reaction. Undissolved p-coumaric acid gradually dissolves as the production reaction proceeds.
ｐ−クマル酸含有溶液をアルカリ性に調整するために使用できるｐＨ調整剤としては、特に制限はないが、安全性、効率及びコスト面からは、水酸化ナトリウム、水酸化カリウム、炭酸水素ナトリウム等が望ましい。また、生成反応時のｐ−クマル酸含有溶液のｐＨ変化を極力抑える場合には、緩衝溶液を用いても良い。 The pH adjuster that can be used to adjust the p-coumaric acid-containing solution to alkalinity is not particularly limited. desirable. Moreover, when suppressing the pH change of the p-coumaric acid containing solution at the time of production | generation reaction as much as possible, you may use a buffer solution.
本発明の製造方法では、前記アルカリ性に調整されたｐ−クマル酸含有溶液を加熱処理する。所望の生成反応を効率的に進ませるために、ｐ−クマル酸含有溶液の加熱温度は９０℃以上が必要である。溶媒の沸点から考え、加圧加温処理を行うことが望ましい。例えば、開放容器にｐ−クマル酸含有溶液を入れ高温で容器を加温する、密閉容器にｐ−クマル酸含有溶液を入れ加温する、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ｐ−クマル酸含有溶液の温度が９０℃以上に達することが必要である。また、回収効率面から、溶液温度が均一に９０℃〜１５０℃になることがさらに好ましい。加熱温度が１５０℃を超えると、所望の生成反応以外の反応が行われるため、回収効率が低くなる。加熱時間も加熱温度と同様に限られたものではなく、効率的に目的の生成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ｐ−クマル酸含有溶液の加熱処理をする場合は、５分〜３００分の加熱時間が望ましい。また、加熱処理の回数は、一度でも良いし、複数回に分けて繰り返し加熱しても良く、効率面から回数を判断すればよい。 In the production method of the present invention, the alkaline p-coumaric acid-containing solution is heat-treated. In order to efficiently advance a desired production reaction, the heating temperature of the p-coumaric acid-containing solution needs to be 90 ° C. or higher. Considering the boiling point of the solvent, it is desirable to perform the pressure heating treatment. For example, p-coumaric acid-containing solution is put into an open container and the container is heated at a high temperature, p-coumaric acid-containing solution is put into a sealed container and heated, and heated under pressure using a retort device or an autoclave. It is necessary that the temperature of the p-coumaric acid-containing solution at least partially reaches 90 ° C. or higher. Further, from the viewpoint of recovery efficiency, it is more preferable that the solution temperature is uniformly 90 ° C to 150 ° C. When the heating temperature exceeds 150 ° C., a reaction other than the desired production reaction is performed, so that the recovery efficiency is lowered. The heating time is not limited as in the case of the heating temperature, and may be a time condition in which the target production reaction proceeds efficiently. 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 the p-coumaric acid-containing solution is heated at around 130 ° C., a heating time of 5 minutes to 300 minutes is desirable. In addition, the number of heat treatments may be one, or may be repeatedly heated in a plurality of times, and the number of times may be determined from the viewpoint of efficiency.
前記のようにしてｐ−クマル酸含有溶液をアルカリ条件下で加熱処理することで、本発明の４−ビニルフェノール重合化合物を含有した混合物が得られる。特に、安全な原料のみを用いて本発明の４−ビニルフェノール重合化合物が得られた場合には、前記混合物の状態で使用することが可能である。例えば、天然由来のｐ−クマル酸をエタノール溶媒に溶解し炭酸水素ナトリウムを加え、加熱反応させた場合には、混合物として食品原料の一つとして使用が可能である。 A mixture containing the 4-vinylphenol polymerization compound of the present invention is obtained by heat-treating the p-coumaric acid-containing solution under alkaline conditions as described above. In particular, when the 4-vinylphenol polymerization compound of the present invention is obtained using only safe raw materials, it can be used in the state of the mixture. For example, when p-coumaric acid derived from nature is dissolved in an ethanol solvent and sodium hydrogen carbonate is added and reacted by heating, the mixture can be used as one of food ingredients.
また、風味面での改良やさらなる高機能化を望む場合は、前記混合物を濃縮して本発明の４−ビニルフェノール重合化合物の濃度を高める、あるいは精製し純品を得ることができる。前記濃縮、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前記混合物から本発明の４−ビニルフェノール重合化合物を抽出して濃縮できる。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。濃縮物や精製物から最後に減圧乾燥や凍結乾燥により溶媒除去すると、粉末状の前記式（１）で表される新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩の純品を得ることができる。 In addition, in the case where improvement in flavor and further enhancement of functionality are desired, the mixture can be concentrated to increase the concentration of the 4-vinylphenol polymerization compound of the present invention, or purified to obtain a pure product. The concentration and purification can be performed by a known method. For example, the 4-vinylphenol polymerization compound of the present invention can be extracted and concentrated from the mixture by a solvent extraction method such as chloroform, ethyl acetate, ethanol, or methanol, or a supercritical extraction method using 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. When the solvent is finally removed from the concentrate or purified product by drying under reduced pressure or freeze drying, a pure 4-vinylphenol polymerized compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof is obtained. Can be obtained.
前記式（１）で表される新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩は、後述のように、優れたリパーゼ阻害活性、抗癌活性、及びチロシナーゼ阻害活性を有するために、本化合物を有効成分として含有する抗肥満剤、皮膚疾患治療剤、抗癌剤及び美白剤を提供することができる。また、前記抗肥満剤、皮膚疾患治療剤、抗癌剤及び美白剤では、他の有効成分を含有しても良い。 Since the novel 4-vinylphenol polymerization compound represented by the formula (1) or a pharmaceutically acceptable salt thereof has excellent lipase inhibitory activity, anticancer activity, and tyrosinase inhibitory activity as described later. Further, an antiobesity agent, a skin disease treatment agent, an anticancer agent and a whitening agent containing the present compound as an active ingredient can be provided. The anti-obesity agent, skin disease treatment agent, anti-cancer agent and whitening agent may contain other active ingredients.
また、前記式（１）で表される新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩は、前記抗肥満効果、皮膚疾患治療効果、抗癌効果、美白効果を目的として、液状、ペースト状、ゲル状、及び固形状の食品、医薬品、又は化粧品等として使用することができる。 Moreover, the novel 4-vinylphenol polymerization compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is liquid for the purpose of the anti-obesity effect, skin disease treatment effect, anti-cancer effect, and whitening effect. It can be used as a paste, gel, and solid food, medicine, cosmetic, or the like.
例えば、食品の場合には、水、アルコール、澱粉質、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又は素材と組み合わせて、また医薬品の場合には、担体、賦形剤、希釈剤、安定剤と組み合わせて、前記式（１）で表される新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩を使用することが出来る。特に、本化合物の生理活性分野を考慮すると、抗肥満効果によるメタボリックシンドロームなどの生活習慣病の予防、癌予防・癌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。またニキビ治療や予防、美白を目的とした美容分野における化粧品などで用いることが望ましい。 For example, in the case of food, food such as water, alcohol, starch, protein, fiber, carbohydrate, lipid, vitamin, mineral, flavoring, coloring, sweetener, seasoning, stabilizer, preservative A novel 4-vinylphenol polymerization compound represented by the above formula (1) in combination with a raw material or a material usually blended in a drug, or in the case of a pharmaceutical, in combination with a carrier, an excipient, a diluent and a stabilizer. Alternatively, a pharmaceutically acceptable salt thereof can be used. In particular, in view of the physiologically active field of the present compound, it is preferably used in the field of prevention of lifestyle-related diseases such as metabolic syndrome due to anti-obesity effect, health maintenance and promotion such as cancer prevention / treatment, and disease healing. It is also desirable to use it in cosmetics in the beauty field for the purpose of acne treatment and prevention, and whitening.
前記式（１）で表される新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩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。 The further effect and efficacy of the novel 4-vinylphenol polymerized compound represented by the formula (1) or a pharmaceutically acceptable salt thereof can be used within a range that can be analogized from the obtained physiological activity data.
前記式（１）で表される新規４−ビニルフェノール重合化合物又は薬学的に許容可能な塩を医薬用途で使用する場合、例えば、本化合物の摂取量は、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。例えば、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 4-vinylphenol polymerized compound represented by the formula (1) or a pharmaceutically acceptable salt is used for pharmaceutical purposes, for example, the intake of this compound has a desired improvement, therapeutic or preventive effect. It is not particularly limited as long as it is an amount that can be obtained, and it is usually selected appropriately according to the form, age, sex, constitution and other conditions of the patient, the type and degree of disease, and the like. For example, it may be about 0.1 mg to 1,000 mg per day, and this can be taken in 1 to 4 times a day.
前記式（１）で表される新規４−ビニルフェノール重合化合物又はその薬学的に許容可能な塩は、機能性食品、健康食品、健康志向食品等の食品に使用することができる。食品の形態としては、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、例えば、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。 The novel 4-vinylphenol polymer compound represented by the formula (1) or a pharmaceutically acceptable salt thereof can be used for foods such as functional foods, health foods, health-oriented foods and the like. The form of the food may be any form such as a beverage, alcoholic beverage, jelly, confectionery, etc. For example, among confectionery, hard candy, soft candy, gummy that is excellent in storage and carrying due to its capacity, etc. Examples include candy and tablets, but there is no particular limitation.
また、前記式（１）で表される新規４−ビニルフェノール重合化合物又は薬学的に許容可能な塩を医薬品又は食品として経口から投与又は摂取する場合には、常法に基づいて、錠剤、丸剤、カプセル剤、細粒剤、顆粒剤等としてもよい。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し、胃溶性も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、前記錠剤、丸剤、顆粒剤、顆粒を含有するカプセル剤の顆粒等には公知の可溶化処理を施すこともできし、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。 In addition, when the novel 4-vinylphenol polymerized compound represented by the above formula (1) or a pharmaceutically acceptable salt is orally administered or ingested as a pharmaceutical product or food, it is based on a conventional method. It may be an agent, capsule, fine granule, granule or 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. A coating may be applied, or it may be covered with a film of a gastric or enteric substance. In addition, in order to improve the solubility of the preparation, the tablet, pill, granule, granule of the capsule containing the granule and the like can be subjected to a known solubilization treatment. You may mix | blend and use for an injection and a drip.
前記化粧品としては、ローション、乳液、クリーム、パック剤、仕上げ化粧品、頭髪用化粧品、洗顔剤、浴剤、制汗剤等が挙げられる。これらの化粧品では、リパーゼ阻害効果からニキビ治癒、チロシナーゼ阻害効果から美白作用に特に効果が期待され、美白及びニキビ予防・治癒等の目的で利用することができる。 Examples of the cosmetics include lotions, emulsions, creams, packs, finished cosmetics, hair cosmetics, facial cleansers, bath agents, and antiperspirants. These cosmetics are expected to be particularly effective for acne healing due to lipase inhibitory effect and whitening action due to tyrosinase inhibitory effect, and can be used for the purpose of whitening and acne prevention / curing.
前記医薬品又は食品は、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、爬虫類等の治療剤又は飼料に配合してもよい。 Since the pharmaceutical or food is excellent in safety, not only for humans, for example, non-human animals such as rats, mice, guinea pigs, rabbits, sheep, pigs, cows, horses, cats, You may mix | blend with therapeutic agents or feed, such as mammals, such as a dog, a monkey, and a chimpanzee, birds, amphibians, and reptiles.
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４−ビニルフェノール重合化合物の生成）
ｐ−クマル酸（和光純薬工業（株）製）５００ｍｇをエタノール１０ｍｌに溶解し、５％炭酸水素ナトリウム水溶液（和光純薬業（株）製）１０ｍｌを加えた混合液（ｐH＝７．５）をオートクレーブ（商品名「ＳＡＮＹＯ ＬＡＢＯ ＡＵＴＯＣＬＡＶＥ」、三洋電機（株）製）にて１３０℃、４０分間加熱した。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、このうちの１０μｌをＨＰＬＣにより分析した。
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）
(Example 1: Production of novel 4-vinylphenol polymerization compound)
500 mg of p-coumaric acid (manufactured by Wako Pure Chemical Industries, Ltd.) is dissolved in 10 ml of ethanol, and a mixed solution (pH = 7.5) containing 10 ml of 5% aqueous sodium hydrogen carbonate solution (manufactured by Wako Pure Chemical Industries, Ltd.) is added. ) Was heated in an autoclave (trade name “SANYO LABO AUTOCLAVE”, manufactured by Sanyo Electric Co., Ltd.) at 130 ° C. for 40 minutes. 1 ml of the obtained composition after the reaction was made up to 50 ml with methanol, and 10 μl of this was analyzed by HPLC.
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。上図が生成反応前の溶液中のｐ−クマル酸、下図が生成反応後の溶液のクロマトグラムを示している。生成反応によりｐ−クマル酸が減少し、増大したピークがいくつか確認されたことから、複数の化合物が生成されていることが確認された。中でも、Ａのピークで示された化合物は、ｐ−クマル酸から、生成されていることがわかる。 The obtained chromatogram is shown in FIG. The upper figure shows p-coumaric acid in the solution before the production reaction, and the lower figure shows the chromatogram of the solution after the production reaction. Since p-coumaric acid was reduced by the production reaction and several increased peaks were confirmed, it was confirmed that a plurality of compounds were produced. Especially, it turns out that the compound shown by the peak of A is produced | generated from p-coumaric acid.
（実施例２：新規４−ビニルフェノール重合化合物の単離・構造決定）
実施例１で得られた反応物における図１のＡで示したピークに含まれる化合物を、分取ＨＰＬＣにより単離した。常法に従って、乾燥したところ、Ａから黄色粉末状の新規４−ビニルフェノール重合化合物（以下、ＵＨＡ７０１１）が３２ｍｇ得られた。
(Example 2: Isolation and structure determination of a novel 4-vinylphenol polymerization compound)
The compound contained in the peak shown by A in FIG. 1 in the reaction product obtained in Example 1 was isolated by preparative HPLC. When dried according to a conventional method, 32 mg of a novel 4-vinylphenol polymerization compound (hereinafter referred to as UHA7011) in the form of a yellow powder was obtained from A.
次いで、前記ＵＨＡ７０１１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３６０．４４５８であり、理論値との比較から、以下の分子式を得た。
ＵＨＡ７０１１
理論値Ｃ２４Ｈ２４Ｏ３（Ｍ+）： ３６０．４４５６
分子式Ｃ24Ｈ24Ｏ3
Subsequently, when the molecular weight of the UHA7011 was measured by high resolution electron ionization-mass spectrometry, the measured value was 360.4458, and the following molecular formula was obtained from comparison with the theoretical value.
UHA7011
Theoretical value C24H24O3 (M + ): 360.4456
Molecular formula C 24 H 24 O 3
次に、前記ＵＨＡ７０１１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、ＵＨＡ７０１１が前記式（１）で表される構造を有することを確認した。このことから、式（１）で表される新規４−ビニルフェノール重合化合物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 UHA7011 is subjected to nuclear magnetic resonance (NMR) measurement, and it is confirmed from analysis of 1H-NMR, 13C-NMR and various two-dimensional NMR data that the UHA7011 has a structure represented by the formula (1). did. From this, it was shown that the novel 4-vinylphenol polymerization compound represented by the formula (1) can be efficiently produced by the method of the present invention.
なお、ＮＭＲ測定値について、式（１）で表されるＵＨＡ７０１１の各部位を In addition, about each NMR measurement value, each site | part of UHA7011 represented by Formula (1) is represented.
とし、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で示す。
値はδ、ｐｐｍで、メタノール−ｄ３で測定した値である。
1H nuclear magnetic resonance spectrum and 13C nuclear magnetic resonance spectrum are shown in Table 1.
Values are δ and ppm, measured with methanol-d3.
また、ＵＨＡ７０１１の物理化学的性状は、以下のようになった。
（性状）
黄色粉末
（溶解性）
水： 不溶
メタノール： 可溶
エタノール： 可溶
ＤＭＳＯ： 可溶
クロロホルム： 可溶
酢酸エチル： 可溶
Moreover, the physicochemical properties of UHA7011 were as follows.
(Properties)
Yellow powder (soluble)
Water: Insoluble methanol: Soluble ethanol: Soluble DMSO: Soluble chloroform: Soluble ethyl acetate: Soluble
（実施例３：ＵＨＡ７０１１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、ＨＬ−６０細胞（Ｈｕｍａｎ ｐｒｏｍｙｅｌｏｃｙｔｉｃ ｌｅｏｋｅｍｉａ ｃｅｌｌｓ：ヒト骨髄球性白血病細胞）を用いた癌細胞増殖抑制作用について試験した。
(Example 3: Anticancer activity of UHA7011)
Next, in order to see the effect of each compound on cancer cells, the cancer cell proliferation inhibitory action using HL-60 cells (Human proneolytic leukemia cells: human myeloid leukemia cells) was tested.
ＨＬ−６０細胞の培養には、４ｍＭグルタミン（Ｌ−Ｇｌｕｔａｍｉｎｅ、シグマアルドリッチジャパン（株）製）、１０％ＦＢＳ（ウシ胎児血清、バイオロジカルインダストリー社製）を含む高栄養培地ＲＰＭＩ−１６９０（シグマアルドリッチジャパン（株）製）を使用した。試験には細胞培養用９６ウェルプレート（コーニングジャパン（株）製）を用い、５×１０5ｃｅｌｌｓ／ｍｌとなるように細胞数を調整したＨＬ−６０細胞を１ウェルあたり１００μｌずつ播種した。 For the culture of HL-60 cells, a high nutrient medium RPMI-1690 (Sigma Aldrich) containing 4 mM glutamine (L-Glutamine, manufactured by Sigma Aldrich Japan Co., Ltd.) and 10% FBS (fetal bovine serum, manufactured by Biological Industry). Japan Co., Ltd.) was used. In the test, a 96-well plate for cell culture (manufactured by Corning Japan Co., Ltd.) was used, and HL-60 cells, the number of cells of which was adjusted to 5 × 10 5 cells / ml, were seeded at 100 μl per well.
試料は、ｐ−クマル酸（和光純薬工業（株）製）と、本発明品であるＵＨＡ７０１１の2種類を用いた。試料調製については、各々の化合物をＤＭＳＯ（ジメチルスルホキシド、和光純薬工業（株）製）にて溶解し、ＨＬ−６０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となるように調整し、試験を開始した。 Two types of samples, p-coumaric acid (manufactured by Wako Pure Chemical Industries, Ltd.) and UHA7011, which is the product of the present invention, were used. For sample preparation, each compound was dissolved in DMSO (dimethyl sulfoxide, manufactured by Wako Pure Chemical Industries, Ltd.), and the final concentrations in the HL-60 cell culture solution were 6.3 μM, 12.5 μM, and 25 μM, respectively. The test was started after adjusting to 50 μM and 100 μM.
生存細胞数の定量は「Ｃｅｌｌ ｃｏｕｎｔｉｎｇ ｋｉｔ−８」（商品名、ドージンドー・モレキュラー・テクノロジー（株）製）を用いたＭＴＴ法にて行った。試験開始より２４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。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（株）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（図２）。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、ＵＨＡ７０１１には、強い癌細胞増殖抑制能が認められた。この効果は、ｐ−クマル酸には全く認められず、ｐ−クマル酸をｐ−クマル酸重合化合物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” (trade name, manufactured by Dojin Dou Molecular Technology Co., Ltd.). After 24 hours from the start of the test, 10 μl of Cell counting kit-8 solution was added to each well and stirred well. After a light-shielding reaction for 1 hour, the absorbance at a measurement wavelength of 450 nm is measured using a plate reader (“BIO-RAD Model 680”, manufactured by Bio-Rad Laboratories), and the cell viability is calculated based on the obtained data. Calculated (FIG. 2). 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, UHA7011 was recognized to have a strong ability to suppress cancer cell growth. This effect was not observed at all in p-coumaric acid, and the significance of converting p-coumaric acid into a p-coumaric acid polymerized compound was strongly suggested.
（実施例４：ＵＨＡ７０１１のリパーゼ阻害作用）
リパーゼに対する各化合物の阻害作用を見るため、ラット腸由来リパーゼを用いての阻害作用試験を行った。
リパーゼは、ラット由来腸アセトンパウダー（シグマアルドリッチジャパン（株）製）１００ｍｇを１００ｍＭクエン酸バッファー（ｐＨ６．０）１ｍｌに懸濁して４℃で１時間撹拌し、これを遠心分離（１５０００ｒｐｍ、４５分間、４℃）した上清を１５００倍希釈したものをリパーゼ溶液として使用した。
(Example 4: Lipase inhibitory action of UHA7011)
In order to see the inhibitory action of each compound on lipase, an inhibitory action test using rat intestinal lipase was performed.
The lipase was obtained by suspending 100 mg of rat-derived intestinal acetone powder (manufactured by Sigma Aldrich Japan) in 1 ml of 100 mM citrate buffer (pH 6.0) and stirring at 4 ° C. for 1 hour, followed by centrifugation (15000 rpm, 45 minutes) A supernatant obtained by diluting 1500 times (4 ° C.) was used as a lipase solution.
試料は、ｐ−クマル酸と、本発明品であるＵＨＡ７０１１の２種類を用いた。試料調製については、各々の化合物をＤＭＳＯ（ジメチルスルホキシド、和光純薬工業（株）製）にて溶解し、０．1ｍＭ、０．５ｍＭ、１ｍＭ、２ｍＭ、４ｍＭに調製したものを使用した。 Two types of samples, p-coumaric acid and UHA7011, which is the product of the present invention, were used. For sample preparation, each compound was dissolved in DMSO (dimethyl sulfoxide, manufactured by Wako Pure Chemical Industries, Ltd.) and prepared to 0.1 mM, 0.5 mM, 1 mM, 2 mM, 4 mM.
活性測定には「リパーゼキットＳ」（商品名、大日本製薬（株）製）を使用した。まず、リパーゼキットＳのカタログに記載の調製法に従い発色液を調製した。発色液を７０μｌ、エステラーゼ阻害剤を２μｌ、リパーゼ溶液を１０μｌ、試料を１０μｌ（終濃度１０μＭ、５０μＭ、１００μＭ、２００μＭ、４００μＭ）混合した反応液を調製し、３０℃で５分間プレインキュベートした後に基質溶液を８μｌ添加して反応を開始した。１０分間の反応後、リパーゼキットＳのカタログに記載の調製法に従い調製した反応停止液を１５０μｌ添加して反応を停止した。これを測定波長４１５ｎｍの吸光度測定をおこなった。試料の溶媒であるＤＭＳＯのみを添加した反応液をポジティブコントロールとし、リパーゼ溶液の代わりに１００ｍＭクエン酸バッファー（ｐＨ６．０）１０μｌを添加したものをネガティブコントロールとした。これらから得られたデータを基に算出したリパーゼ阻害率と各化合物濃度の関係から、リパーゼ活性を５０％阻害する濃度ＩＣ50（５０％阻害濃度：ｈａｌｆ ｍａｘｉｍａｌ ｉｎｈｉｂｉｔｏｒｙ ｃｏｎｃｅｎｔｒａｔｉｏｎ）を算出した（表３）。
これらの結果からＵＨＡ７０１１には高いリパーゼ阻害活性が認められた。この効果はｐ−クマル酸では認められないことから，ｐ−クマル酸をｐ−クマル酸重合化合物に変換する有意性が強く示唆された。
For the activity measurement, “Lipase Kit S” (trade name, manufactured by Dainippon Pharmaceutical Co., Ltd.) was used. First, a color developing solution was prepared according to the preparation method described in the catalog of the lipase kit S. Prepare a reaction solution by mixing 70 μl of color developing solution, 2 μl of esterase inhibitor, 10 μl of lipase solution, and 10 μl of sample (
From these results, high lipase inhibitory activity was observed in UHA7011. Since this effect was not observed with p-coumaric acid, the significance of converting p-coumaric acid to a p-coumaric acid polymerized compound was strongly suggested.
したがって、ＵＨＡ７０１１は優れたリパーゼ阻害作用を奏することから、抗肥満剤として、さらにはメタボリックシンドローム予防剤として有用であると考えられる。また、皮膚におけるリパーゼ阻害はニキビ予防・治癒に有効であるから、ニキビ予防・治癒などの皮膚疾患治療剤としても有用であると考えられる。 Therefore, since UHA7011 has an excellent lipase inhibitory action, it is considered useful as an anti-obesity agent and further as a preventive agent for metabolic syndrome. Moreover, since lipase inhibition in the skin is effective for preventing and curing acne, it is considered useful as a therapeutic agent for skin diseases such as acne prevention and healing.
（実施例５：ＵＨＡ７０１１のチロシナーゼ阻害作用）
チロシナーゼに対する各化合物の阻害作用を見るため、マッシュルーム由来チロシナーゼ（シグマアルドリッチジャパン（株）製）を用いての阻害作用試験を行った。
(Example 5: Tyrosinase inhibitory action of UHA7011)
In order to see the inhibitory action of each compound on tyrosinase, an inhibitory action test using mushroom-derived tyrosinase (manufactured by Sigma-Aldrich Japan) was performed.
試料は、ｐ−クマル酸と、本発明品であるＵＨＡ７０１１の２種類を用いた。試料調製については、各々の化合物をＤＭＳＯ（ジメチルスルホキシド、和光純薬工業（株）製）にて溶解し、０．２５ｍＭ、１．２５ｍＭ、２．５ｍＭ、３．７５ｍＭ、５ｍＭに調製したものを使用した。 Two types of samples, p-coumaric acid and UHA7011, which is the product of the present invention, were used. For sample preparation, each compound was dissolved in DMSO (dimethyl sulfoxide, manufactured by Wako Pure Chemical Industries, Ltd.) and prepared to 0.25 mM, 1.25 mM, 2.5 mM, 3.75 mM, 5 mM. used.
測定は既存の活性検出法によって行なった。まず、Ｌ―ＤＯＰＡ（和光純薬工業（株）製）を１００ｍMリン酸ナトリウムバッファー（ｐＨ６．５）で２．４ｍＭになるように調製した。また、上記の濃度で調製した試料２０μｌと１００ｍMリン酸ナトリウムバッファー（ｐＨ６．５）３０μｌを混合した。反応液には１００ｍMリン酸ナトリウムバッファー９０μｌ、Ｌ―ＤＯＰＡ溶液４０μｌ（終濃度４８０μＭ）、試料２０μｌ（終濃度１０μＭ、５０μＭ、１００μＭ、１５０μM、２００μＭ）を混合した。これを３７℃で５分間加温し、同様に加温したチロシナーゼ溶液（１００ｍＭリン酸ナトリウムバッファーで調製）を５０μｌ（１０U／ｍｌ）添加し反応を開始した。１０分間の反応後、メラニンの吸収波長（４７５ｎｍ）の吸光度を測定した。コントロールとしてチロシナーゼ溶液の代わりに１００ｍＭリン酸ナトリウムバッファー（ｐＨ６．０）１０μｌを添加したものをネガティブコントロールとした。これらから得られたデータを基に算出したチロシナーゼ阻害率と各化合物濃度の関係から、チロシナーゼ活性を５０％阻害する濃度ＩＣ50（５０％阻害濃度）を算出した（表４）。
これらの結果からＵＨＡ７０１１には高いチロシナーゼ阻害活性が認められた。この効果はｐ−クマル酸では認められないことから，ｐ−クマル酸をｐ−クマル酸重合化合物に変換する有意性が強く示唆された。
The measurement was performed by the existing activity detection method. First, L-DOPA (manufactured by Wako Pure Chemical Industries, Ltd.) was prepared to be 2.4 mM with 100 mM sodium phosphate buffer (pH 6.5). Further, 20 μl of the sample prepared at the above concentration and 30 μl of 100 mM sodium phosphate buffer (pH 6.5) were mixed. The reaction mixture was mixed with 90 μl of 100 mM sodium phosphate buffer, 40 μl of L-DOPA solution (final concentration 480 μM), and 20 μl of sample (
From these results, high tyrosinase inhibitory activity was observed in UHA7011. Since this effect was not observed with p-coumaric acid, the significance of converting p-coumaric acid to a p-coumaric acid polymerized compound was strongly suggested.
したがって、ＵＨＡ７０１１は優れたチロシンキナーゼ作用を奏することから、メラニンの合成を抑えることによる美白剤等の化粧品として有用であると考えられる。 Therefore, UHA7011 has an excellent tyrosine kinase action, and thus is considered useful as a cosmetic product such as a whitening agent by suppressing melanin synthesis.
（実施例６：加熱温度によるＵＨＡ７０１１の生成量の違い）
ｐ−クマル酸５０ｍｇ、エタノール１ｍｌ、５％炭酸水素ナトリウム水溶液１ｍｌの混合溶液（ｐＨ＝７．５）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 UHA7011 depending on heating temperature)
A mixed solution (pH = 7.5) of 50 mg of p-coumaric acid, 1 ml of ethanol, and 1 ml of 5% aqueous sodium hydrogen carbonate solution is heated for 20 minutes at 70 ° C., 90 ° C., 110 ° C., and 130 ° C. in an autoclave. did. 1 ml of the post-reaction composition obtained under each temperature condition was made up to 50 ml with methanol and analyzed by HPLC in the same manner as in Example 1.
その結果、９０℃を超える条件下においてＵＨＡ７０１１の生成は確認できた。ｐ−クマル酸からＵＨＡ７０１１の生成比率は７０℃で非生成、９０℃で非生成、１１０℃で１重量％、１３０℃で６重量％であった。すなわち、１３０℃での加熱が最も効率的であった。 As a result, the formation of UHA7011 was confirmed under conditions exceeding 90 ° C. The production ratio of UHA7011 from p-coumaric acid was not produced at 70 ° C., not produced at 90 ° C., 1% by weight at 110 ° C., and 6% by weight at 130 ° C. That is, heating at 130 ° C. was the most efficient.
（実施例７：ＵＨＡ７０１１含有エキスの調製）
プロポリス水抽出エキス１０ｇ、エタノール１０ｍｌ、炭酸水素ナトリウム１ｇ加えて調製した混合溶液（ｐH＝８．５）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、エキスを１１ｇ得た。得られたエキス中には、実施例６と同様の手法で確認したところＵＨＡ７０１１が０．００３ｇ含有されていた。必要に応じてこの作業を繰り返してエキスの量を増やした
(Example 7: Preparation of UHA7011-containing extract)
A mixed solution (pH = 8.5) prepared by adding 10 g of propolis water extract, 10 ml of ethanol and 1 g of sodium bicarbonate was heated in an autoclave at 130 ° C. for 60 minutes. The obtained reaction solution was heated under reduced pressure to dryness to obtain 11 g of extract. In the obtained extract, it was confirmed by the same method as in Example 6 that 0.003 g of UHA7011 was contained. Repeated this work as needed to increase the amount of extract
（実施例８：ＵＨＡ７０１１を含有する食品）
実施例７で得たエキス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。本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、肥満を改善したり、肥満を予防したり、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。
(Example 8: Food containing UHA7011)
1 g of the extract obtained in Example 7 was previously dissolved in 100 mL of ethanol, 500 g of sugar and 400 g of starch syrup were mixed and dissolved in this, and 100 g of fresh cream, 20 g of butter, 70 g of condensed milk and 1.0 g of emulsifier were mixed, and then a vacuum kettle. -550 mmHg, and concentrated under the condition of 115 ° C. to obtain a milk hard candy having a moisture value of 3.0% by weight. This milk hard candy is not only easy to eat as a confectionery, but also improves obesity, prevents obesity, reduces the risk of cancer spreading in cancer patients, reduces the risk of developing cancer. It can also be used as a functional food that is expected to prevent cancer.
（実施例９：ＵＨＡ７０１１を含有する医薬品）
実施例１及び２と同様の方法で得たＵＨＡ７０１１をエタノールに溶解し、これを微結晶セルロースに吸着させた後に、減圧乾燥させた。これを常法に従い、打錠品を得た。処方は、ＵＨＡ７０１１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、肥満改善や肥満防止、癌の治癒や改善を目的とする医薬品として有効に利用できる。
(Example 9: Drug containing UHA7011)
UHA7011 obtained by the same method as in Examples 1 and 2 was dissolved in ethanol, adsorbed onto microcrystalline cellulose, and then dried under reduced pressure. This was tableted according to a conventional method. The formulation is 10 parts by weight of UHA7011, 23 parts by weight of corn starch, 12 parts by weight of lactose, 8 parts by weight of carboxymethylcellulose, 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 improving obesity, preventing obesity, and curing or improving cancer.
（実施例１０：ＵＨＡ７０１１を含有する化粧品）
テトラオレイン酸ポリオキシエチレンソルビット１重量部、ポリオキシエチレンステアリルエーテル０．５重量部、親油型モノステアリン酸グリセリン１重量部、ピルビン酸０．５重量部、ステアリルアルコール０．５重量部、アボガド油１重量部、実施例１及び２と同様の方法で得たＵＨＡ７０１１の０．１重量部を、常法に従って溶解させ、これに、乳酸ナトリウム１重量部、プロピレングリコール５重量部、カルボキシビニルポリマー０．１重量部、ごく少量の香料及び精製水８９．３重量部を加え、ホモゲナイザーにかけ乳化し、乳液を得た。本乳液は、美白やニキビなどの皮膚疾患治療や予防効果をもつ薬用化粧品として有効に利用できる。
(Example 10: Cosmetics containing UHA7011)
1 part by weight of polyoxyethylene sorbit tetraoleate, 0.5 part by weight of polyoxyethylene stearyl ether, 1 part by weight of glyceryl monostearate, 0.5 part by weight of pyruvic acid, 0.5 part by weight of stearyl alcohol,
Claims (11)
で表される新規４−ビニルフェノール重合化合物を生成することを特徴とする式（１）で表される新規４−ビニルフェノール重合化合物又は薬学的に許容可能な塩の製造方法。 By heat-treating p-coumaric acid at 110 ° C. or higher under alkaline conditions,
A method for producing a novel 4-vinylphenol polymerized compound represented by the formula (1) or a pharmaceutically acceptable salt, which comprises producing a novel 4-vinylphenol polymerized compound represented by formula (1):
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