JP4886879B2 - Anti-wrinkle and anti-aging cosmetics - Google Patents
Anti-wrinkle and anti-aging cosmetics Download PDFInfo
- Publication number
- JP4886879B2 JP4886879B2 JP2010136032A JP2010136032A JP4886879B2 JP 4886879 B2 JP4886879 B2 JP 4886879B2 JP 2010136032 A JP2010136032 A JP 2010136032A JP 2010136032 A JP2010136032 A JP 2010136032A JP 4886879 B2 JP4886879 B2 JP 4886879B2
- Authority
- JP
- Japan
- Prior art keywords
- residue
- ascorbic acid
- lipophilic
- ubiquinol
- ubiquinone
- 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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- 230000001153 anti-wrinkle effect Effects 0.000 title claims description 26
- 230000003712 anti-aging effect Effects 0.000 title claims description 22
- 239000002537 cosmetic Substances 0.000 title claims description 22
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- 150000000996 L-ascorbic acids Chemical class 0.000 claims description 36
- 239000003795 chemical substances by application Substances 0.000 claims description 29
- QNTNKSLOFHEFPK-UPTCCGCDSA-N ubiquinol-10 Chemical group COC1=C(O)C(C)=C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)C(O)=C1OC QNTNKSLOFHEFPK-UPTCCGCDSA-N 0.000 claims description 28
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Landscapes
- Cosmetics (AREA)
Description
この発明は、皮膚にしわの生成を予防し、またはしわの少ない皮膚に改善する抗しわ剤およびその製造方法並びに抗しわ剤を含有する抗老化性化粧料に関する。 The present invention relates to an anti-wrinkle agent that prevents the formation of wrinkles on the skin or improves the skin with less wrinkles, a method for producing the same, and an anti-aging cosmetic containing the anti-wrinkle agent.
ヒトの皮膚には、加齢によってしわ、タルミ（弛み）、くすみ、色素沈着などの老化現象が生じるが、しわやタルミといった皮膚の形態変化は、真皮マトリックスの９０％以上を占めるコラーゲンによる影響が大きいと考えられている。 Human skin undergoes aging such as wrinkles, sagging, dullness, and pigmentation due to aging, but skin morphological changes such as wrinkles and tarmi are affected by collagen, which accounts for over 90% of the dermal matrix. It is considered big.
すなわち、真皮のコラーゲンの量が加齢と共に減少すると、真皮構造の形成が不完全になり、また太陽光線に露出する機会の多い皮膚のコラーゲン量は、露出の少ない皮膚に比べて著しく少ない傾向があり、皮膚の老化と太陽光線に対する暴露がしわやタルミの大きな要因の一つとして考えられている。 That is, when the amount of collagen in the dermis decreases with age, the formation of the dermis structure becomes incomplete, and the amount of collagen in skin that is often exposed to sunlight tends to be significantly less than in skin that is less exposed. Yes, skin aging and exposure to sunlight are considered as one of the major factors for wrinkles and tarmi.
皮膚の老化による形態変化を予防するための薬剤として、油溶性有効成分であるレチノ−ルやレチノイン酸誘導体が知られており、これを有効成分としてコラーゲンおよびヒアルロン酸合成を促進させるしわ防止化粧品が知られている。
しかし、レチノ−ルやレチノイン酸誘導体は、熱や酸化に対して不安定であり、使用する際には充分に機能できない場合があった。
Retinol and retinoic acid derivatives, which are oil-soluble active ingredients, are known as drugs for preventing morphological changes due to skin aging, and wrinkle-preventing cosmetics that promote collagen and hyaluronic acid synthesis using these as active ingredients. Are known.
However, retinoic acid and retinoic acid derivatives are unstable to heat and oxidation, and may not function sufficiently when used.
また、ユビキノンおよびユビキノールはコエンザイムＱ１０とも称され、皮膚細胞中のＤＮＡ量およびヒアルロン酸生産量を増加させる作用が知られている。
これらのユビキノン、ユビキノール、レチノールは、水に難溶でかつ酸化され易いという性質を有する物質であるため、皮膚細胞に対する浸透性が低く、不安定であり製剤化が困難であり、リン酸基修飾する技術が知られている（特許文献１）。
Ubiquinone and ubiquinol are also referred to as coenzyme Q10, and are known to increase the amount of DNA and hyaluronic acid produced in skin cells.
These ubiquinones, ubiquinols, and retinol are substances that are sparingly soluble in water and easily oxidized, so they have low permeability to skin cells, are unstable and difficult to formulate, and are modified with phosphate groups. The technique which performs is known (patent document 1).
また、同様にアスコルビン酸についても、コラーゲン合成促進効果のある薬剤として知られているが、熱に対して非常に不安定で酸化しやすく、そのため使用時までに不活性になって分解することがあるため、使用する際には充分に生理作用が得られない場合があった。 Similarly, ascorbic acid is also known as a drug that has an effect of promoting collagen synthesis, but it is very unstable against heat and easily oxidized, so that it becomes inactive and decomposes before use. For this reason, there are cases where sufficient physiological effects cannot be obtained when used.
また、アスコルビン酸誘導体として、酸化されやすいＬ−アスコルビン酸のジオール部をリン酸エステル化した誘導体（特許文献２）が知られており（特許文献２）、また同部分をグルコシド化した誘導体が知られている（特許文献３）。 Moreover, as an ascorbic acid derivative, a derivative (Patent Document 2) in which the diol portion of L-ascorbic acid which is easily oxidized is phosphorylated is known (Patent Document 2), and a derivative in which the same part is glucosidated is known. (Patent Document 3).
しかし、Ｌ−アスコルビン酸誘導体や、レチノ−ル、レチノイン酸誘導体は、それぞれが熱や酸化に対して不安定であり、保存や流通に必要な経時的な安定性が不足しており、そのために使用する際にはそれぞれの安定性を高める工程が必要であり、それらの機能を高めるように複数成分を配合して製剤化するには、それぞれの安定化のための工程数が多く、コラーゲン合成促進機能やヒアルロン酸合成機能を高めて効率よく製剤化することは困難であった。 However, L-ascorbic acid derivatives, retinoic acid, and retinoic acid derivatives are unstable to heat and oxidation, respectively, and lack the stability over time necessary for storage and distribution. When using it, it is necessary to increase the stability of each component, and in order to formulate a combination of multiple components to enhance their functions, there are many steps for each stabilization and collagen synthesis. It was difficult to efficiently formulate by enhancing the promoting function and the hyaluronic acid synthesis function.
そこで、この発明の課題は、上記した問題を解決し、皮膚に処方された際には線維芽細胞のコラーゲンおよびヒアルロン酸量を増加させて優れたコラーゲン合成促進活性およびヒアルロン酸合成促進活性を有すると共に、保存のための経時的安定性の高い抗しわ剤または抗老化性化粧料であり、また上記優れたしわ改善効果を有する抗しわ剤を効率よく製造できるようにすることである。 Accordingly, the object of the present invention is to solve the above-mentioned problems and to increase the collagen and hyaluronic acid content of fibroblasts when formulated on the skin, thereby having excellent collagen synthesis promoting activity and hyaluronic acid synthesis promoting activity. At the same time, it is to make it possible to efficiently produce an anti-wrinkle agent that is an anti-wrinkle agent or an anti-aging cosmetic material that is highly stable over time and that has the above-described excellent wrinkle-improving effect.
上記の課題を解決するために、この発明においては、下記の化１の式で表わされる親油性アスコルビン酸誘導体を有効成分として含有し、前記親油性アスコルビン酸誘導体は、リン酸エステル部にレチノイル残基、ユビキノール残基またはユビキノン残基からなる親油性残基をエステル結合したＬ−アスコルビン酸−２−リン酸エステルまたはその塩である抗しわ剤としたのである。 In order to solve the above-mentioned problems, the present invention contains a lipophilic ascorbic acid derivative represented by the following formula 1 as an active ingredient, and the lipophilic ascorbic acid derivative contains a retinoyl residue in a phosphate ester part. An anti-wrinkle agent which is an L-ascorbic acid-2-phosphate ester or a salt thereof in which a lipophilic residue consisting of a group, a ubiquinol residue or a ubiquinone residue is ester-linked.
（式中、Ｒ1、Ｒ２は、水素（Ｈ）またはレチノイル残基、ユビキノール残基もしくはユビキノン残基からなる親油性残基である。ただし、Ｒ１＝Ｒ２＝水素（Ｈ）である場合を除く。） (In the formula, R 1 and R 2 are hydrogen (H) or a lipophilic residue comprising a retinoyl residue, a ubiquinol residue or a ubiquinone residue, provided that R 1 = R 2 = hydrogen (H). Except in cases.)
このようにＬ−アスコルビン酸とレチノール、ユビキノール、ならびにユビキノンを始めとした油溶性有効成分とをリン酸エステルで結合させたＬ−アスコルビン酸−２−リン酸エステルまたはその塩とすることによって、熱や酸化に不安定なＬ−アスコルビン酸や油溶性有効成分を安定化できるため、使用前の保存状態でＬ−アスコルビン酸や油溶性有効成分が分解されることを抑制できる。 Thus, L-ascorbic acid-2-phosphate ester or a salt thereof in which L-ascorbic acid and retinol, ubiquinol, and oil-soluble active ingredients such as ubiquinone are combined with a phosphate ester, In addition, since L-ascorbic acid and oil-soluble active ingredients that are unstable to oxidation can be stabilized, the decomposition of L-ascorbic acid and oil-soluble active ingredients in the storage state before use can be suppressed.
更に、使用した際には親油性残基により適度な脂溶性があって細胞内に取り込まれやすいため、皮膚に速やかに浸透し、生体内に広く分布するフォスファターゼによって効率的にリン酸部分が加水分解され、Ｌ−アスコルビン酸および油溶性有効成分（レチノール、ユビキノール、またはユビキノン）などに分解され、Ｌ−アスコルビン酸は本来の優れたコラーゲン合成促進効果を有し、一方、油溶性有効成分（レチノール、ユビキノール、またはユビキノン）は細胞賦活効果、ヒアルロン酸およびコラーゲン産生量を増加させる効果を奏するので、抗しわ剤として極めて有効である。 In addition, when used, it has a moderate lipophilicity due to the lipophilic residue and is easily taken up into cells, so that it quickly penetrates into the skin, and the phosphate moiety is efficiently hydrolyzed by phosphatase that is widely distributed in the living body. It is decomposed and decomposed into L-ascorbic acid and an oil-soluble active ingredient (retinol, ubiquinol, or ubiquinone). , Ubiquinol, or ubiquinone) is extremely effective as an anti-wrinkle agent because it has a cell activation effect and an effect of increasing hyaluronic acid and collagen production.
また、Ｌ−アスコルビン酸および油溶性有効成分は、互いに組み合わせることによって
本来の健康に有用な生理活性を阻害することなく、熱や酸化に対する安定性を高めるため、それぞれの成分に対して安定化させるための処理工程を設けて配合される製剤よりも効率よく製造できる抗親油性アスコルビン酸誘導体および抗しわ剤となる。
また、この発明の抗しわ剤の油溶性有効成分（レチノール、ユビキノール、またはユビキノン）は、細胞賦活効果、ヒアルロン酸およびコラーゲン産生量を増加させる効果を有し、すなわち「しわ」、「タルミ」の防止効果などの抗老化効果を発揮できる。
Moreover, L-ascorbic acid and an oil-soluble active ingredient are stabilized with respect to each component in order to improve the stability with respect to a heat | fever and oxidation, without inhibiting the physiological activity useful for original health by combining with each other. Therefore, it becomes an anti-lipophilic ascorbic acid derivative and an anti-wrinkle agent that can be produced more efficiently than a preparation formulated by providing a treatment step.
In addition, the oil-soluble active ingredient (retinol, ubiquinol, or ubiquinone) of the anti-wrinkle agent of the present invention has a cell activation effect, an effect of increasing hyaluronic acid and collagen production, ie, “wrinkle”, “tarmi” It can exhibit anti-aging effects such as prevention effects.
上述のように好ましい作用のあるアスコルビン酸誘導体としては、レチノイル残基が、３,７−ジメチル−９−（２,６,６−トリメチルシクロヘキセ−１−イル）ノナ−２,４,６,８−テトラエニルであり、ユビキノール残基が２,３−ジメトキシ−６−デカプレニル−ヒドロキシベンゾイルであり、ユビキノン残基が２−メトキシ−６−デカプレニル−１,４−ベンゾキノニルがあり、そのような親油性アスコルビン酸誘導体を有効成分として含有させることにより、好ましい抗しわ剤が得られる。 As described above, ascorbic acid derivatives having a preferable action include retinoyl residues of 3,7-dimethyl-9- (2,6,6-trimethylcyclohex-1-yl) nona-2,4,6, 8-tetraenyl, the ubiquinol residue is 2,3-dimethoxy-6-decaprenyl-hydroxybenzoyl, the ubiquinone residue is 2-methoxy-6-decaprenyl-1,4-benzoquinonyl, such lipophilic By including an ascorbic acid derivative as an active ingredient, a preferable anti-wrinkle agent can be obtained.
同様に、上述の好ましい作用のある親油性アスコルビン酸誘導体の塩とするために、親油性アスコルビン酸誘導体は、ナトリウム塩、カリウム塩、マグネシウム塩またはカルシウム塩であることが好ましい。 Similarly, the lipophilic ascorbic acid derivative is preferably a sodium salt, potassium salt, magnesium salt or calcium salt in order to obtain a salt of a lipophilic ascorbic acid derivative having the above-mentioned preferable action.
親油性アスコルビン酸誘導体またはその塩を有効成分として配合するには、０．０５〜８０質量％含有する上記の抗しわ剤とすることが好ましい。
さらに、上記のような抗しわ剤を含有する抗老化性化粧料としては、しわを予防または改善して抗老化性を高める化粧料とすることができる。さらにこのような抗老化性化粧料をｐＨ４．０〜９．０に調整することにより、親油性アスコルビン酸誘導体の作用をより効率よく充分に発揮させることができる。
In order to blend a lipophilic ascorbic acid derivative or a salt thereof as an active ingredient, the above-mentioned anti-wrinkle agent containing 0.05 to 80% by mass is preferable.
Furthermore, the anti-aging cosmetics containing the anti-wrinkle agent as described above can be made into cosmetics that prevent or improve wrinkles and increase anti-aging properties. Furthermore, by adjusting such an anti-aging cosmetic material to pH 4.0 to 9.0, the action of the lipophilic ascorbic acid derivative can be exhibited more efficiently and sufficiently.
このよう優れた特性のある抗しわ剤を効率よく製造するためには、下記の化２で示される親油性有機アルコールと、オキシ塩化リンとを反応させて、下記の化１０の式で示されるジクロロフォスフェートまたは化１１の式で示されるモノクロロフォスフェートを合成し、これを別途、Ｌ−アスコルビン酸とアセトンを反応させて得た５，６−Ｏ−イソプロピリデン−Ｌ−アスコルビン酸と反応させ、その後に酸加水分解することによって下記の化１２の式で表わされる親油性アスコルビン酸誘導体を得て、この親油性アスコルビン酸誘導体を有効成分として配合する抗しわ剤の製造方法を採用することができる。 In order to efficiently produce an anti-wrinkle agent having such excellent characteristics, a lipophilic organic alcohol represented by the following chemical formula 2 is reacted with phosphorus oxychloride, and the chemical formula is represented by the following chemical formula 10. A dichlorophosphate or a monochlorophosphate represented by the formula 11 was synthesized and separately reacted with 5,6-O-isopropylidene-L-ascorbic acid obtained by reacting L-ascorbic acid with acetone. Then, it is possible to obtain a lipophilic ascorbic acid derivative represented by the following formula 12 by acid hydrolysis, and to employ a method for producing an anti-wrinkle agent containing this lipophilic ascorbic acid derivative as an active ingredient. it can.
（式中、Ｒはレチノイル残基、ユビキノール残基またはユビキノン残基を示す。） (In the formula, R represents a retinoyl residue, a ubiquinol residue or a ubiquinone residue.)
（式中、Ｒはレチノイル残基、ユビキノール残基またはユビキノン残基を示す。） (In the formula, R represents a retinoyl residue, a ubiquinol residue or a ubiquinone residue.)
（式中、Ｒ1、Ｒ２は、水素（Ｈ）またはレチノイル残基、ユビキノール残基もしくはユビキノン残基を示す。ただし、Ｒ１＝Ｒ２＝水素（Ｈ）である場合を除く。） (In the formula, R 1 and R 2 represent hydrogen (H) or a retinoyl residue, ubiquinol residue or ubiquinone residue, except when R 1 = R 2 = hydrogen (H)).
（式中、Ｒ1、Ｒ２は、水素（Ｈ）またはレチノイル残基、ユビキノール残基もしくはユビキノン残基からなる親油性残基である。ただし、Ｒ１＝Ｒ２＝水素（Ｈ）である場合を除く。） (In the formula, R 1 and R 2 are hydrogen (H) or a lipophilic residue comprising a retinoyl residue, a ubiquinol residue or a ubiquinone residue, provided that R 1 = R 2 = hydrogen (H). Except in cases.)
このような親油性アスコルビン酸誘導体は、リン酸アルキルエステル部以外には変性した部分を有しないものであり、皮膚内に浸透するとエステラーゼやリパーゼがなくても、ほぼ全ての生体内組織に分布しているフォスファターゼ他の酵素等によってリン酸部分からＬ−アスコルビン酸および油溶性有効成分（レチノール、ユビキノール、またはユビキノン）に加水分解され、抗しわ作用を皮膚に及ぼすものである。 Such lipophilic ascorbic acid derivatives do not have a modified portion other than the alkyl phosphate ester portion, and when penetrating into the skin, they are distributed in almost all living tissues even without esterase or lipase. It is hydrolyzed from the phosphate moiety to L-ascorbic acid and an oil-soluble active ingredient (retinol, ubiquinol, or ubiquinone) by phosphatase and other enzymes, and has an anti-wrinkle effect on the skin.
この発明の抗しわ剤または抗老化性化粧料は、所定の化学構造を有する親油性アスコルビン酸誘導体またはその塩を有効成分として含有し、アスコルビン酸誘導体は、リン酸エステル部に所定の親油性残基を有するため、適度な脂溶性が付与されて細胞内に取り込まれやすく、しかもアスコルビン酸の不安定性の原因が排除されるので、使用前の保存状態で熱や酸化に対して安定化する。 The anti-wrinkle agent or anti-aging cosmetic of the present invention contains a lipophilic ascorbic acid derivative having a predetermined chemical structure or a salt thereof as an active ingredient, and the ascorbic acid derivative has a predetermined lipophilic residue in the phosphate ester part. Since it has a group, it is moderately lipophilic and easily taken up into cells, and the cause of instability of ascorbic acid is eliminated, so that it is stabilized against heat and oxidation in a storage state before use.
そして、抗しわ剤または抗老化性化粧料は、油溶性有効成分により皮膚に速やかに浸透し、生体内に広く分布するフォスファターゼによって効率的にリン酸部分が加水分解され、Ｌ−アスコルビン酸および油溶性有効成分（レチノール、ユビキノール、またはユビキノン）のそれぞれのコラーゲン合成促進活性およびヒアルロン酸合成促進活性を奏される。 The anti-wrinkle agent or anti-aging cosmetic composition penetrates rapidly into the skin with an oil-soluble active ingredient, and the phosphate portion is efficiently hydrolyzed by phosphatase that is widely distributed in the living body, so that L-ascorbic acid and oil Each of the soluble active ingredients (retinol, ubiquinol, or ubiquinone) exhibits collagen synthesis promoting activity and hyaluronic acid synthesis promoting activity.
このようにこの発明の抗しわ剤または抗老化性化粧料は、皮膚に処方された際に、線維芽細胞のコラーゲンおよびヒアルロン酸量を増加させて優れたコラーゲン合成促進活性およびヒアルロン酸合成促進活性を有すると共に、抗しわ剤の保存のための経時的安定性に優れ、または抗老化性化粧料となる利点がある。 As described above, the anti-wrinkle agent or anti-aging cosmetic composition of the present invention increases the collagen and hyaluronic acid content of fibroblasts when formulated on the skin, and has excellent collagen synthesis promoting activity and hyaluronic acid synthesis promoting activity. In addition to the above, there is an advantage that the anti-wrinkle agent is excellent in stability over time for storage or an anti-aging cosmetic.
また、抗しわ剤の製造方法に係る発明は、Ｌ−アスコルビン酸および油溶性有効成分であるレチノール、ユビキノールまたはユビキノンを複合的に一体化することによって、それぞれに対して安定化させるための処理を行なう場合よりも効率よく前記有利な効果を奏する抗しわ剤を製造できるという利点がある。 Moreover, the invention which concerns on the manufacturing method of an anti-wrinkle agent carries out the process for stabilizing with respect to each by combining L-ascorbic acid and the oil-soluble active ingredient which is retinol, ubiquinol, or ubiquinone complex. There is an advantage that an anti-wrinkle agent having the above-mentioned advantageous effect can be produced more efficiently than the case where it is performed.
前記化１の式で示されるＬ−アスコルビン酸リン酸エステル、すなわちモノレチノイル（ユビキノール、またはユビキノン）フォスフェートは、以下の方法で製造できる。 The L-ascorbic acid phosphate represented by the formula 1 above, that is, monoretinoyl (ubiquinol or ubiquinone) phosphate can be produced by the following method.
先ず、トルエン、クロロベンゼン、ジクロロベンゼンなどから選ばれる非極性溶媒を用いて、トリメチルアミン、トリエチルアミン、Ｎ，Ｎ−ジメチルアニリンなどから選ばれる塩基の存在下で、前記化２の式で示される親油性有機アルコールとオキシ塩化リンを−２０〜２０℃において反応させて、化３の式で示されるモノレチノイル（ユビキノール、またはユビキノン）ジクロロフォスフェートまたは化４の式で示されるジレチノイル（ユビキノール、またはユビキノン）モノクロロフォスフェートを製造する。
取り出しについては蒸留により単離するか、または上記の非極性溶媒の溶液として次工程へ進んでも良い。
First, using a nonpolar solvent selected from toluene, chlorobenzene, dichlorobenzene, etc., in the presence of a base selected from trimethylamine, triethylamine, N, N-dimethylaniline, etc., the lipophilic organic compound represented by the above formula 2 Monoretinoyl (ubiquinol or ubiquinone) dichlorophosphate represented by the chemical formula 3 or diretinoyl (ubiquinol or ubiquinone) monochlorophosphine represented by the chemical formula 4 by reacting alcohol with phosphorus oxychloride at -20 to 20 ° C. Manufacture fate.
For removal, it may be isolated by distillation or may proceed to the next step as a solution of the above nonpolar solvent.
そして、別途、Ｌ−アスコルビン酸とアセトンを反応させて得た５，６−Ｏ−イソプロピリデン−Ｌ−アスコルビン酸と反応させ、レチノイル（ユビキノール、またはユビキノン）リン酸エステル化後に該保護基を接触還元等により脱離し、定法により精製することで前記の化１の式で示されるＬ−アスコルビン酸リン酸エステルを製造できる。 Separately, it is reacted with 5,6-O-isopropylidene-L-ascorbic acid obtained by reacting L-ascorbic acid with acetone, and the protecting group is contacted after retinoyl (ubiquinol or ubiquinone) phosphoric esterification. The L-ascorbic acid phosphate represented by the above formula 1 can be produced by elimination by reduction or the like and purification by a conventional method.
前記化２の式で示される親油性有機アルコールの具体例としては、レチノイル類では３,７−ジメチル−９−（２,６,６−トリメチルシクロヘキセ−１−イル）ノナ−２,４,６,８−テトラエン−１−オール、３,７−ジメチル−９−（２,６,６−トリメチルシクロヘキセ−１−イル）ノナ−２,４,６,８−テトラエン−１−アルデヒド、ユビキノール類では２,３−ジメトキシ−５−メチル−６−デカプレニル−１,４−ジヒドロキシベンゼン、５−メチル−３−メトキシ−６−デカプレニル−１,２,４−トリヒドロキシベンゼン、５−メチル−４−メトキシ−６−デカプレニル−１,２,３−トリヒドロキシベンゼン、５−メチル−６−デカプレニル−１,２,３,４−テトラヒドロキシベンゼン、５−メチル−１,２−メトキシ−６−デカプレニル−３,４−ジヒドロキシベンゼン、５−メチル−１,３−メトキシ−６−デカプレニル−２,４−ジヒドロキシベンゼン、３−ヒドロキシ−５−メチル−２−メトキシ−６−デカプレニル−３,４−ジヒドロキシベンゼン、ユビキノン類では２−ヒドロキシ−３−メトキシ−５−メチル−６−デカプレニル−１,４−ベンゾキノン、３−ヒドロキシ−２−メトキシ−５−メチル−６−デカプレニル−１,４−ベンゾキノン、２,３−ジヒドロキシ−５−メチル−６−デカプレニル−１,４−ベンゾキノン、１−ヒドロキシ−２,３−ジメトキシ−５−メチル−６−デカプレニル−ベンゾセミキノン、４−ヒドロキシ−２,３−ジメトキシ−６−メチル−５−デカプレニル−ベンゾセミキノンなどが挙げられる。 Specific examples of the lipophilic organic alcohol represented by the formula 2 include 3,7-dimethyl-9- (2,6,6-trimethylcyclohex-1-yl) nona-2,4, for retinoyls. 6,8-tetraen-1-ol, 3,7-dimethyl-9- (2,6,6-trimethylcyclohex-1-yl) nona-2,4,6,8-tetraene-1-aldehyde, ubiquinol 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-dihydroxybenzene, 5-methyl-3-methoxy-6-decaprenyl-1,2,4-trihydroxybenzene, 5-methyl-4 -Methoxy-6-decaprenyl-1,2,3-trihydroxybenzene, 5-methyl-6-decaprenyl-1,2,3,4-tetrahydroxybenzene, 5-methyl-1,2-methoxy-6-decaprenyl -3,4 In dihydroxybenzene, 5-methyl-1,3-methoxy-6-decaprenyl-2,4-dihydroxybenzene, 3-hydroxy-5-methyl-2-methoxy-6-decaprenyl-3,4-dihydroxybenzene, ubiquinones 2-hydroxy-3-methoxy-5-methyl-6-decaprenyl-1,4-benzoquinone, 3-hydroxy-2-methoxy-5-methyl-6-decaprenyl-1,4-benzoquinone, 2,3-dihydroxy- 5-methyl-6-decaprenyl-1,4-benzoquinone, 1-hydroxy-2,3-dimethoxy-5-methyl-6-decaprenyl-benzosemiquinone, 4-hydroxy-2,3-dimethoxy-6-methyl- 5-Decaprenyl-benzosemiquinone and the like can be mentioned.
５，６−Ｏ−イソプロピリデン−Ｌ−アスコルビン酸は、Ｌ−アスコルビン酸をアセチルクロライドもしくは発煙硫酸などの脱水剤の存在下で、−３０℃〜２０℃においてアセトンと反応させ、濾過などの方法により単離される。 5,6-O-isopropylidene-L-ascorbic acid is prepared by reacting L-ascorbic acid with acetone at −30 ° C. to 20 ° C. in the presence of a dehydrating agent such as acetyl chloride or fuming sulfuric acid. Isolated by
上記で得られた５，６−Ｏ−イソプロピリデン−Ｌ−アスコルビン酸をトルエン、クロロベンゼン、ジクロロベンゼンなどから選ばれる非極性溶媒下に、トリメチルアミン、トリエチルアミン、Ｎ，Ｎ−ジメチルアニリンなどから選ばれる塩基存在下、化３の式で示されるモノレチノイル（ユビキノール、またはユビキノン）ジクロロフォスフェートもしくは化４の式で示されるジレチノイル（ユビキノール、またはユビキノン）モノクロロフォスフェートと−２０℃〜２０℃において反応させた後、塩酸、硫酸、酢酸などから選ばれる酸によって−１０〜５０℃において加水分解する。 5,6-O-isopropylidene-L-ascorbic acid obtained above is a base selected from trimethylamine, triethylamine, N, N-dimethylaniline and the like in a nonpolar solvent selected from toluene, chlorobenzene, dichlorobenzene and the like. After reaction with monoretinoyl (ubiquinol or ubiquinone) dichlorophosphate represented by the formula 3 or diretinoyl (ubiquinol or ubiquinone) monochlorophosphate represented by the formula 4 at −20 ° C. to 20 ° C. Hydrolysis at −10 to 50 ° C. with an acid selected from hydrochloric acid, sulfuric acid, acetic acid and the like.
このとき、残存する塩基を除去するために塩酸、硫酸、酢酸などの酸や塩化ナトリウム、塩化カリウム、塩化アンモニウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウムなどの無機塩の水溶液により洗浄し、非極性溶媒を留去するが、より高品質を要求される場合にはカラムクロマトなどにより、前記化６の式で示されるＬ−アスコルビン酸リン酸エステルを単離する。またはエタノール、グリセロールなどの溶液で取り出しても良い。このように、この発明のアスコルビン酸誘導体の単離精製方法は、一般的方法に従えばよく、特に制限する必要はない。 At this time, in order to remove the remaining base, it is washed with an aqueous solution of an acid such as hydrochloric acid, sulfuric acid or acetic acid or an inorganic salt such as sodium chloride, potassium chloride, ammonium chloride, sodium carbonate, potassium carbonate or sodium hydrogen carbonate, and is nonpolar. The solvent is distilled off, but when higher quality is required, L-ascorbic acid phosphate ester represented by the formula 6 is isolated by column chromatography or the like. Or you may take out with solutions, such as ethanol and glycerol. As described above, the method for isolating and purifying the ascorbic acid derivative of the present invention may follow a general method and is not particularly limited.
前記化１の式で示されるこの発明のアスコルビン酸誘導体の具体的な化合物の例としては、Ｌ−アスコルビン酸レチノイルエステルとしては２−[９,１３−ジメチル−１５−（１７,１７,２１−トリメチルシクロヘキセ−７−イル）ノナ−８,１０,１２,１４−テトラエン]−Ｌ−アスコルビルフォスフェート、２−[９,１３−ジメチル−１５−（１７,１７,２１−トリメチルシクロヘキセ−７−イル）ノナ−８,１０,１２,１４−テトラエンアルデヒド]−Ｌ−アスコルビルフォスフェートが挙げられ、Ｌ−アスコルビン酸ユビキノールエステルとしては２−（８,９−ジメトキシ−１０−メチル−１１−デカプレニル−ヒドロキシベンゼン）−Ｌ−アスコルビルフォスフェート、２−（８−ヒドロキシ−１０−メチル−１１−デカプレニル−ジヒドロキシベンゼン）−Ｌ−アスコルビルフォスフェート、２−（８,９−ジヒドロキシ−１０−メチル−１１−デカプレニル−ヒドロキシベンゼン）−Ｌ−アスコルビルフォスフェート、２−（８−ヒドロキシ−１０−メチル−９−メトキシ−１１−デカプレニル−ヒドロキシベンゼン）−Ｌ−アスコルビルフォスフェート、２−（９−ヒドロキシ−１０−メチル−８−メトキシ−１１−デカプレニル−ヒドロキシベンゼン）−Ｌ−アスコルビルフォスフェート、Ｌ−アスコルビン酸ユビキノンエステルとしては２−（１２−メトキシ−９−メチル−１０−デカプレニル−８,１１−ベンゾキノン）−Ｌ−アスコルビルフォスフェート、２−（１２−メトキシ−１０−メチル−９−デカプレニル−８,１１−ベンゾキノン）−Ｌ−アスコルビルフォスフェート、２−（２,３−ジメトキシ−６−メチル−５−デカプレニル−ベンゾセミキノン基）−Ｌ−アスコルビルフォスフェート、２−（２,３−ジメトキシ−５−メチル−６−デカプレニル−ベンゾセミキノン）−Ｌ−アスコルビルフォスフェートなどが挙げられる。 As an example of a specific compound of the ascorbic acid derivative of the present invention represented by the formula 1, the L-ascorbic acid retinoyl ester is 2- [9,13-dimethyl-15- (17,17,21 -Trimethylcyclohex-7-yl) nona-8,10,12,14-tetraene] -L-ascorbyl phosphate, 2- [9,13-dimethyl-15- (17,17,21-trimethylcyclohexe) 7-yl) nona-8,10,12,14-tetraenaldehyde] -L-ascorbyl phosphate, and L-ascorbic acid ubiquinol ester is 2- (8,9-dimethoxy-10-methyl-11). -Decaprenyl-hydroxybenzene) -L-ascorbyl phosphate, 2- (8-hydroxy-10-methyl-11-decaprenyl-dihydride) Xylbenzene) -L-ascorbyl phosphate, 2- (8,9-dihydroxy-10-methyl-11-decaprenyl-hydroxybenzene) -L-ascorbyl phosphate, 2- (8-hydroxy-10-methyl-9-methoxy) -11-decaprenyl-hydroxybenzene) -L-ascorbyl phosphate, 2- (9-hydroxy-10-methyl-8-methoxy-11-decaprenyl-hydroxybenzene) -L-ascorbyl phosphate, L-ascorbic acid ubiquinone ester As 2- (12-methoxy-9-methyl-10-decaprenyl-8,11-benzoquinone) -L-ascorbyl phosphate, 2- (12-methoxy-10-methyl-9-decaprenyl-8,11-benzoquinone ) -L-Ascorbylphos Fate, 2- (2,3-dimethoxy-6-methyl-5-decaprenyl-benzosemiquinone group) -L-ascorbyl phosphate, 2- (2,3-dimethoxy-5-methyl-6-decaprenyl-benzosemi Quinone) -L-ascorbyl phosphate and the like.
また、この発明においては、これらアスコルビン酸誘導体の塩も使用可能であり、例えばナトリウム塩、カリウム塩等のアルカリ金属塩、カルシウム塩、マグネシウム塩等のアルカリ土類金属塩、アルギニン等の塩基性アミノ酸、トリエタノールアミン等の有機アミンを用いることができる。 In the present invention, salts of these ascorbic acid derivatives can also be used. For example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and basic amino acids such as arginine. Organic amines such as triethanolamine can be used.
この発明に係るアスコルビン酸誘導体は、有効成分として含有され抗老化剤として応用される他、皮膚外用剤に配合して、皮膚の線維芽細胞においてコラーゲンおよびヒアルロン酸合成促進作用を発揮して、コラーゲンおよびヒアルロン酸合成促進作用によるしわの改善効果等の抗老化作用などの機能を持つ、抗老化用皮膚外用剤などに調製することができる。 The ascorbic acid derivative according to the present invention is contained as an active ingredient and applied as an anti-aging agent. In addition, the ascorbic acid derivative is blended with an external preparation for skin, and exhibits collagen and hyaluronic acid synthesis promoting action in skin fibroblasts. And anti-aging skin external preparations having functions such as an anti-aging action such as a wrinkle improving effect by hyaluronic acid synthesis promoting action.
この発明に係るアスコルビン酸誘導体を配合して皮膚外用剤として使用する場合、これらの１種又は２種以上が配合され、その配合量は、皮膚外用剤全量中０．０５〜８０質量％、好ましくは、０．５〜５０質量％である。 When the ascorbic acid derivative according to the present invention is blended and used as a skin external preparation, one or more of these are blended, and the blending amount is 0.05 to 80% by mass, preferably in the total amount of the skin external preparation Is 0.5-50 mass%.
この発明の美白化粧料のｐＨは、特に限定されるものではないが、化粧料の一般的な保存状態において安定性を高めるために、ｐＨ４．０〜９．０とすることが好ましく、その他のｐＨ領域ではエステルの加水分解が起こりやすく安定な製剤が得られないことがある。 The pH of the whitening cosmetic composition of the present invention is not particularly limited, but is preferably set to pH 4.0 to 9.0 in order to enhance stability in a general storage state of the cosmetic composition. In the pH range, ester hydrolysis is likely to occur, and a stable preparation may not be obtained.
この発明の皮膚外用剤は上記必須成分の他に、通常の化粧料、医薬部外品、医薬品等に用いられる各種成分、例えば油性成分、乳化剤、保湿剤、増粘剤、薬効成分、防腐剤、顔料、粉体、ｐＨ調整剤、紫外線吸収剤、抗酸化剤、香料等を適宜配合することができる。 In addition to the above essential components, the external preparation for skin of the present invention includes various components used in normal cosmetics, quasi-drugs, pharmaceuticals, etc., such as oily components, emulsifiers, moisturizers, thickeners, medicinal components, preservatives Pigments, powders, pH adjusters, ultraviolet absorbers, antioxidants, fragrances, and the like can be appropriately blended.
前記した油性成分の具体例としては、流動パラフィン、ワセリン、マイクロクリスタリンワックス、スクワラン、ホホバ油、ミツロウ、カルナウバロウ、ラノリン、オリーブ油、ヤシ油、高級アルコール、脂肪酸、高級アルコールと脂肪酸のエステル、シリコーン油等が挙げられる。乳化剤としては、例えばポリオキシエチレンアルキルエーテル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ソルビタン脂肪酸エステル、グリセリン脂肪酸エステル、ポリグリセリン脂肪酸エステル、ポリオキシエチレン硬化ヒマシ油等の非イオン界面活性剤、ステアロイル乳酸ナトリウム等のアニオン界面活性剤、大豆リン脂質等の両性界面活性剤、塩化アルキルトリメチルアンモニウム等のカチオン界面活性剤が挙げられる。保湿剤としては、例えばグリセリン、ソルビトール、キシリトール、マルチトール、プロピレングリコール、ポリエチレングリコール、１，３−ブチレングリコール、１，２−ペンタンジオールなどが挙げられる。増粘剤としては、例えばカルボキシビニルポリマー、キサンタンガム、メチルセルロース、ポリビニルピロリドン、ゼラチン、ベントナイト等の粘土鉱物等が挙げられる。薬効成分としては、例えば各種ビタミンおよびその誘導体、アラントイン、グリチルリチン酸およびその誘導体、各種動植物抽出物等の老化防止剤、保湿剤、育毛剤、発毛剤、経皮吸収促進剤、紫外線吸収剤、細胞賦活剤、抗炎症剤、美白剤、防腐防カビ剤が挙げられる。 Specific examples of the oil component described above include liquid paraffin, petrolatum, microcrystalline wax, squalane, jojoba oil, beeswax, carnauba wax, lanolin, olive oil, coconut oil, higher alcohol, fatty acid, ester of higher alcohol and fatty acid, silicone oil, etc. Is mentioned. Examples of the emulsifier include nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, and polyoxyethylene hydrogenated castor oil. And anionic surfactants such as sodium stearoyl lactate, amphoteric surfactants such as soybean phospholipid, and cationic surfactants such as alkyltrimethylammonium chloride. Examples of the humectant include glycerin, sorbitol, xylitol, maltitol, propylene glycol, polyethylene glycol, 1,3-butylene glycol, and 1,2-pentanediol. Examples of the thickening agent include clay minerals such as carboxyvinyl polymer, xanthan gum, methyl cellulose, polyvinyl pyrrolidone, gelatin, and bentonite. Examples of medicinal components include various vitamins and derivatives thereof, allantoin, glycyrrhizic acid and derivatives thereof, anti-aging agents such as various animal and plant extracts, moisturizers, hair restorers, hair growth agents, transdermal absorption promoters, ultraviolet absorbers, Examples include cell activators, anti-inflammatory agents, whitening agents, and antiseptic and antifungal agents.
この発明の抗しわ剤である皮膚外用剤は、前記した所定のアスコルビン酸誘導体を有効成分として配合することの他に、特に限定されるものではなく、これを周知の化粧料の製造方法により製造することができ、また一般的な皮膚化粧料に限定されることなく、医薬部外品、外用医薬品等にも適用できる。また、それらの剤型は、目的に応じて選択的にクリーム状、乳液状、液状、ゲル状、軟膏状、パック状、スティック状、パウダー状等の形態を採用することができる。 The external preparation for skin which is an anti-wrinkle agent of the present invention is not particularly limited in addition to blending the above-mentioned predetermined ascorbic acid derivative as an active ingredient, and is produced by a well-known cosmetic production method. In addition, the present invention is not limited to general skin cosmetics, and can also be applied to quasi-drugs, external medicines, and the like. Moreover, those dosage forms can employ | adopt selectively forms, such as cream form, emulsion, liquid form, gel form, ointment form, pack form, stick form, powder form, according to the objective.
[アスコルビン酸誘導体の製造例１]
レチノイル類では３,７−ジメチル−９−（２,６,６−トリメチルシクロヘキセ−１−イル）ノナ−２,４,６,８−テトラエン−１−オールとオキシ塩化リンを反応させ、モノレチノイルジクロロフォスフェートである［３,７−ジメチル−９−（２,６,６−トリメチルシクロヘキセ−１−イル）ノナ−２,４,６,８−テトラエン］ジクロロフォスフェートを合成した。
これを別途、Ｌ−アスコルビン酸をアセチルクロライドもしくは発煙硫酸などの脱水剤の存在下で、−３０℃〜２０℃においてアセトンを反応させて得た５，６−Ｏ−イソプロピリデン−Ｌ−アスコルビン酸と反応させ、生成したレチノイル−２−Ｏ−イソプロピリデンアスコルビルホスフェートを塩酸にて加水分解し、洗浄し単離精製して２−[９,１３−ジメチル−１５−（１７,１７,２１−トリメチルシクロヘキセ−７−イル）ノナ−８,１０,１２,１４−テトラエン]−Ｌ−アスコルビルフォスフェート（その化学構造は、化６に後述する13Ｃ−ＮＭＲにおけるピークの帰属番号を併記した。）を製造した。以下、合成工程毎に詳細に説明する。
[Production Example 1 of Ascorbic Acid Derivative]
In retinoyls, 3,7-dimethyl-9- (2,6,6-trimethylcyclohex-1-yl) nona-2,4,6,8-tetraen-1-ol and phosphorus oxychloride are reacted. [3,7-dimethyl-9- (2,6,6-trimethylcyclohex-1-yl) nona-2,4,6,8-tetraene] dichlorophosphate, which is a retinoyl dichlorophosphate, was synthesized.
Separately, 5,6-O-isopropylidene-L-ascorbic acid obtained by reacting L-ascorbic acid with acetone at −30 ° C. to 20 ° C. in the presence of a dehydrating agent such as acetyl chloride or fuming sulfuric acid. The resulting retinoyl-2-O-isopropylidene ascorbyl phosphate was hydrolyzed with hydrochloric acid, washed, isolated and purified to give 2- [9,13-dimethyl-15- (17,17,21-trimethyl). Cyclohex-7-yl) nona-8,10,12,14-tetraene] -L-ascorbyl phosphate (the chemical structure is shown in chemical formula 6 with the peak assignment number in 13C-NMR described later). Manufactured. Hereinafter, each synthesis step will be described in detail.
(1) ５，６−Ｏ−イソプロピリデン−Ｌ−アスコルビン酸の合成
窒素置換下、アセトン５５７．８ｇ（９．６モル）を−５℃に冷却し、２８％発煙硫酸５４．３ｇ（０．２モル）を滴下し、Ｌ−アスコルビン酸１７６．１ｇ（１．０モル）を仕込む。同温度で１７時間反応させ、濾過、冷アセトンにより洗浄し、２４９．５ｇの５，６−Ｏ−イソプロピリデン−Ｌ−アスコルビン酸（純度８６．７％）をｗｅｔケーキとして得た。
(1) Synthesis of 5,6-O-isopropylidene-L-ascorbic acid Under nitrogen substitution, 557.8 g (9.6 mol) of acetone was cooled to −5 ° C., and 54.3 g (0. 2 mol) is added dropwise, and 176.1 g (1.0 mol) of L-ascorbic acid is charged. The mixture was reacted at the same temperature for 17 hours, filtered and washed with cold acetone to obtain 249.5 g of 5,6-O-isopropylidene-L-ascorbic acid (purity: 86.7%) as a wet cake.
(2) ［３,７−ジメチル−９−（２,６,６−トリメチルシクロヘキセ−１−イル）ノナ−２,４,６,８−テトラエン］ジクロロフォスフェートの合成
窒素置換下、トルエン５４０ｍＬ及びオキシ塩化リン１３８．０ｇ（０．９モル）を仕込み、−１０℃に冷却する。そこに、３,７−ジメチル−９−（２,６,６−トリメチルシクロヘキセ−１−イル）ノナ−２,４,６,８−テトラエン−１−オール２５７．８ｇ（０．９モル、１．０モル比）とトリエチルアミン９１．１ｇ（０．９モル）の溶液を滴下し、０℃で１２時間反応した。２５℃に昇温した後、濾過によりトリエチルアミンの塩酸塩を除去し、１００７．２ｇの［３,７−ジメチル−９−（２,６,６−トリメチルシクロヘキセ−１−イル）ノナ−２,４,６,８−テトラエン］ジクロロフォスフェートのトルエン溶液（濃度３１．１％）を得た。
(2) Synthesis of [3,7-dimethyl-9- (2,6,6-trimethylcyclohex-1-yl) nona-2,4,6,8-tetraene] dichlorophosphate 540 mL of toluene under nitrogen substitution And 138.0 g (0.9 mol) of phosphorus oxychloride are charged and cooled to -10 ° C. There was 257.8 g (0.9 mol, 3,7-dimethyl-9- (2,6,6-trimethylcyclohex-1-yl) nona-2,4,6,8-tetraen-1-ol). 1.0 mol ratio) and a solution of 91.1 g (0.9 mol) of triethylamine were dropped and reacted at 0 ° C. for 12 hours. After raising the temperature to 25 ° C, triethylamine hydrochloride was removed by filtration, and 1007.2 g of [3,7-dimethyl-9- (2,6,6-trimethylcyclohex-1-yl) nona-2, A toluene solution (concentration 31.1%) of 4,6,8-tetraene] dichlorophosphate was obtained.
(3) ２−［３,７−ジメチル−９−（２,６,６−トリメチルシクロヘキセ−１−イル）ノナ−２,４,６,８−テトラエン］−Ｌ−アスコルビルホスフェートの合成
窒素置換下、トルエン２０００ｍＬに上記の５，６−Ｏ−イソプロピリデン−Ｌ−アスコルビン酸２４９．５ｇ（１．０モル）を仕込み、室温でトリエチルアミン２０２．４ｇを滴下し、１時間攪拌する。その後、−１０℃に冷却し、上記の［３,７−ジメチル−９−（２,６,６−トリメチルシクロヘキセ−１−イル）ノナ−２,４,６,８−テトラエン］ジクロロフォスフェートのトルエン溶液１００６．４ｇ（０．９モル）を１時間かけて滴下し、同温度で１４時間攪拌する。得られた反応マスに６．７％の塩酸水溶液１２３１２ｇを加え、３５℃で４時間加水分解を行い、トルエン層を１０％塩酸／７．１％塩化ナトリウム水溶液１０００ｇで２回洗浄した後、更に２０％塩化ナトリウム水溶液で１回洗浄した。そして、トルエン層についてカラムクロマトを行い、分取したフラクションを減圧濃縮（３５℃、２Ｔｏｒｒ）によりトルエンを留去し、３３８．９ｇの２−［３,７−ジメチル−９−（２,６,６−トリメチルシクロヘキセ−１−イル）ノナ−２,４,６,８−テトラエン］−Ｌ−アスコルビルホスフェート（純度９０．４％）を得た。収率は６２．１％（対Ｌ−アスコルビン酸）であった。
(3) Synthesis of 2- [3,7-dimethyl-9- (2,6,6-trimethylcyclohex-1-yl) nona-2,4,6,8-tetraene] -L-ascorbyl phosphate Nitrogen substitution Then, 249.5 g (1.0 mol) of the above 5,6-O-isopropylidene-L-ascorbic acid is charged into 2000 mL of toluene, and 202.4 g of triethylamine is added dropwise at room temperature, followed by stirring for 1 hour. Thereafter, the mixture was cooled to −10 ° C. and the above-mentioned [3,7-dimethyl-9- (2,6,6-trimethylcyclohex-1-yl) nona-2,4,6,8-tetraene] dichlorophosphate. 1006.4 g (0.9 mol) of toluene solution is added dropwise over 1 hour and stirred at the same temperature for 14 hours. To the obtained reaction mass, 12312 g of a 6.7% hydrochloric acid aqueous solution was added, hydrolyzed at 35 ° C. for 4 hours, and the toluene layer was washed twice with 1000 g of 10% hydrochloric acid / 7.1% aqueous sodium chloride solution. Washed once with 20% aqueous sodium chloride solution. The toluene layer was subjected to column chromatography, and the fraction collected was concentrated under reduced pressure (35 ° C., 2 Torr) to distill off the toluene, and 338.9 g of 2- [3,7-dimethyl-9- (2,6, 6-Trimethylcyclohex-1-yl) nona-2,4,6,8-tetraene] -L-ascorbyl phosphate (purity 90.4%) was obtained. The yield was 62.1% (vs L-ascorbic acid).
得られた２−［３,７−ジメチル−９−（２,６,６−トリメチルシクロヘキセ−１−イル）ノナ−２,４,６,８−テトラエン］−Ｌ−アスコルビルホスフェートの分子構造を質量分析マス(ＭＳ)スペクトル、赤外線吸収（ＩＲ）スペクトルおよび核磁気構造(1Ｈ−ＮＭＲ)スペクトルによって同定し、ＭＳスペクトルにより５２５．５４２０ ([Ｍ+], Ｃ２６Ｈ３７Ｏ９Ｐ)となり、またそれ以外の結果(ピークの位置と対応する基または炭素原子)を表１、２にそれぞれまとめて示した。これにより得られた化合物が、所期した分子構造のアスコルビン酸誘導体である２−［３,７−ジメチル−９−（２,６,６−トリメチルシクロヘキセ−１−イル）ノナ−２,４,６,８−テトラエン］−Ｌ−アスコルビルホスフェートであることが確認できた。 The molecular structure of the obtained 2- [3,7-dimethyl-9- (2,6,6-trimethylcyclohex-1-yl) nona-2,4,6,8-tetraene] -L-ascorbyl phosphate Identified by mass spectrometry mass (MS) spectrum, infrared absorption (IR) spectrum and nuclear magnetic structure (1H-NMR) spectrum, MS spectrum gave 525.5420 ([M +], C26H37O9P), and other results ( Tables 1 and 2 collectively show the positions of the peaks and the corresponding groups or carbon atoms). The compound thus obtained is 2- [3,7-dimethyl-9- (2,6,6-trimethylcyclohex-1-yl) nona-2,4 which is an ascorbic acid derivative having the expected molecular structure. , 6,8-tetraene] -L-ascorbyl phosphate.
[アスコルビン酸誘導体の製造例２]
製造例１において、３,７−ジメチル−９−（２,６,６−トリメチルシクロヘキセ−１−イル）ノナ−２,４,６,８−テトラエンの代わりにユビキノール類である２,３−ジメトキシ−５−メチル−６−デカプレニル−１,４−ジヒドロキシベンゼンを用いたこと以外は実施例１と全く同様の方法で化合物を得た。なお、得られた化合物の分子構造を下記の化７の式に示し、その分子構造を赤外線吸収スペクトル（ＩＲ）および核磁気構造スペクトル(1Ｈ−ＮＭＲ、13Ｃ−ＮＭＲ)によって同定し、所期した分子構造のアスコルビン酸誘導体である２−（８,９−ジメトキシ−１０−メチル−１１−デカプレニル−ヒドロキシベンゼン）−Ｌ−アスコルビルフォスフェートであることを確認した。なお、ピークの位置と対応する基または炭素原子の結果による同定については、実施例１を代表例とし、その記載を省略した。
[Production Example 2 of Ascorbic Acid Derivative]
In Production Example 1, 2,3-dimethyl-9- (2,6,6-trimethylcyclohex-1-yl) nona-2,4,6,8-tetraene is replaced by ubiquinols 2,3- A compound was obtained in the same manner as in Example 1 except that dimethoxy-5-methyl-6-decaprenyl-1,4-dihydroxybenzene was used. In addition, the molecular structure of the obtained compound is shown in the following chemical formula 7, and the molecular structure was identified by an infrared absorption spectrum (IR) and a nuclear magnetic structure spectrum (1H-NMR, 13C-NMR). It was confirmed that it was 2- (8,9-dimethoxy-10-methyl-11-decaprenyl-hydroxybenzene) -L-ascorbyl phosphate which is an ascorbic acid derivative having a molecular structure. In addition, about the identification by the result of the group or carbon atom corresponding to the position of a peak, Example 1 was made into the representative example and the description was abbreviate | omitted.
これにより得られた化合物が、所期した分子構造のアスコルビン酸誘導体である２−（８,９−ジメトキシ−１０−メチル−１１−デカプレニル−ヒドロキシベンゼン）−Ｌ−アスコルビルフォスフェート（純度８９．５％）であることが確認できた。その収率は５５．７％（対Ｌ−アスコルビン酸）であった。 The compound thus obtained was 2- (8,9-dimethoxy-10-methyl-11-decaprenyl-hydroxybenzene) -L-ascorbyl phosphate (purity 89.5) which is an ascorbic acid derivative having the expected molecular structure. %). The yield was 55.7% (vs L-ascorbic acid).
[アスコルビン酸誘導体の製造例３]
２−（１２−メトキシ−９−メチル−１０−デカプレニル−８,１１−ベンゾキノン）−Ｌ−アスコルビルフォスフェートのナトリウム塩を以下の方法で製造した。
３,７−ジメチル−９−（２,６,６−トリメチルシクロヘキセ−１−イル）ノナ−２,４,６,８−テトラエンの代わりにユビキノン類である２−ヒドロキシ−３−メトキシ−５−メチル−６−デカプレニル−１,４−ベンゾキノンを用いたこと以外は製造例１と全く同様の方法で、２−（１２−メトキシ−９−メチル−１０−デカプレニル−８,１１−ベンゾキノン）−Ｌ−アスコルビルフォスフェートの反応マスを得て、その反応マスに６．７％の塩酸水溶液１２３１２ｇを加え、３５℃で４時間加水分解を行い、トルエン層を１０％塩酸／７．１％塩化ナトリウム水溶液１０００ｇで２回洗浄した後、更に２０％塩化ナトリウム水溶液で１回洗浄した。
[Production Example 3 of Ascorbic Acid Derivative]
The sodium salt of 2- (12-methoxy-9-methyl-10-decaprenyl-8,11-benzoquinone) -L-ascorbyl phosphate was prepared by the following method.
2-Hydroxy-3-methoxy-5 which is a ubiquinone instead of 3,7-dimethyl-9- (2,6,6-trimethylcyclohex-1-yl) nona-2,4,6,8-tetraene 2- (12-methoxy-9-methyl-10-decaprenyl-8,11-benzoquinone)-in the same manner as in Production Example 1 except that methyl-6-decaprenyl-1,4-benzoquinone was used A reaction mass of L-ascorbyl phosphate was obtained, and 12312 g of a 6.7% hydrochloric acid aqueous solution was added to the reaction mass, followed by hydrolysis at 35 ° C. for 4 hours, and the toluene layer was treated with 10% hydrochloric acid / 7.1% sodium chloride. After washing twice with 1000 g of an aqueous solution, it was further washed once with a 20% aqueous sodium chloride solution.
そして、トルエン層に３０％ＮａＯＨ水溶液を加え、ｐＨを７に調整する。分液後の水層にエタノールを加え、減圧濃縮により水及びエタノールを留去し、析出した結晶を濾過、乾燥し、２−（１２−メトキシ−９−メチル−１０−デカプレニル−８,１１−ベンゾキノン）−Ｌ−アスコルビルフォスフェートナトリウム塩（純度９６．１％）を得た。その収率は７５．７％（対Ｌ−アスコルビン酸）であった。 And 30% NaOH aqueous solution is added to a toluene layer, and pH is adjusted to seven. Ethanol was added to the aqueous layer after separation, and water and ethanol were removed by concentration under reduced pressure. The precipitated crystals were filtered and dried, and 2- (12-methoxy-9-methyl-10-decaprenyl-8,11- Benzoquinone) -L-ascorbyl phosphate sodium salt (purity 96.1%) was obtained. The yield was 75.7% (vs L-ascorbic acid).
なお、得られた化合物の分子構造を下記の化８の式に示し、その分子構造を赤外線吸収スペクトル（ＩＲ）および核磁気構造スペクトル(1Ｈ−ＮＭＲ、13Ｃ−ＮＭＲ)によって同定し、所期した分子構造のヒドロキシフェノール誘導体である２−（１２−メトキシ−９−メチル−１０−デカプレニル−８,１１−ベンゾキノン）−Ｌ−アスコルビルフォスフェートナトリウム塩であることを確認した。なお、ピークの位置と対応する基または炭素原子の結果による同定については、実施例１を代表例とし、その記載を省略した。 The molecular structure of the obtained compound is shown in the following chemical formula (8), and the molecular structure was identified by an infrared absorption spectrum (IR) and a nuclear magnetic structure spectrum (1H-NMR, 13C-NMR). It was confirmed to be 2- (12-methoxy-9-methyl-10-decaprenyl-8,11-benzoquinone) -L-ascorbyl phosphate sodium salt, which is a hydroxyphenol derivative having a molecular structure. In addition, about the identification by the result of the group or carbon atom corresponding to the position of a peak, Example 1 was made into the representative example and the description was abbreviate | omitted.
［ヒト正常線維芽細胞によるコラーゲン合成能の評価］
ヒト正常線維芽細胞を５％子牛血清（ＦＢＳ）含有ＤＭＥＭを用いて９６穴マイクロプレートにほぼコンフルエントになるように播種し、播種２４時間後に１００μｇの濃度の試料（表３参照）を含有した０．５％ＦＢＳ含有ＤＭＥＭと交換した。陽性コントロールとして１００μｇアスコルビン酸リン酸マグネシウムを用いた。７２時間、試料含有培地で培養したのち、培地を回収してＥＬＩＳＡに供した。細胞は０．１％ Triton Ｘ−１００溶液にて溶解したのち、Ｌｏｗｒｙ法を用いてタンパク量を定量した。コラーゲンのＥＬＩＳＡは、Procollagen type Ｉ C-peptide（ＰＩＰ） Ｋｉｔ (タカラバイオ株式会社)を用いて測定した。
[Evaluation of collagen synthesis ability by human normal fibroblasts]
Human normal fibroblasts were seeded almost confluently in a 96-well microplate using DMEM containing 5% calf serum (FBS), and contained a sample (see Table 3) at a concentration of 100 μg 24 hours after seeding. Replaced with DMEM containing 0.5% FBS. 100 μg magnesium ascorbate phosphate was used as a positive control. After culturing in a sample-containing medium for 72 hours, the medium was collected and subjected to ELISA. The cells were lysed with 0.1% Triton X-100 solution, and then the protein amount was quantified using the Lowry method. Collagen ELISA was measured using Procollagen type I C-peptide (PIP) Kit (Takara Bio Inc.).
培地中のコラーゲン含有量は、同じプレートで測定した検量線から算出した。Lowry法によって測定した全細胞のタンパク量で、ＥＬＩＳＡを用いて測定した培地中のコラーゲン含有量を除することによって、細胞の単位タンパク量あたりのコラーゲン産生量を算出した。 Collagen content in the medium was calculated from a calibration curve measured on the same plate. The amount of collagen produced per unit protein amount of cells was calculated by dividing the collagen content in the medium measured using ELISA by the protein amount of all cells measured by the Lowry method.
コラーゲン産生量（ｎｇ／ｍｇ protein）＝培地中のコラーゲン含有量（ｎｇ／ｗｅｌｌ）÷全タンパク量（ｍｇ／ｗｅｌｌ） Collagen production (ng / mg protein) = collagen content in the medium (ng / well) ÷ total protein (mg / well)
コラーゲン合成能は、試料を添加せずに培養した細胞（コントロール）のコラーゲン産生量を１００として、各濃度の試料で培養した時のコラーゲン産生量の割合（％）で表した。 Collagen synthesis ability was expressed as a ratio (%) of the amount of collagen produced when the cells were cultured in each concentration sample, where the amount of collagen produced by the cells cultured without adding the sample (control) was 100.
（試験結果）
試験結果のコラーゲン産生率を表３に示した。表３の結果からも明らかなように、アスコルビン酸誘導体の製造例１〜３は、未添加の場合と比べて明らかにコラーゲン量が増大した。
(Test results)
The collagen production rates of the test results are shown in Table 3. As is clear from the results of Table 3, the production amounts 1 to 3 of ascorbic acid derivatives clearly increased the amount of collagen as compared with the case of no addition.
［実施例１〜５、比較例１〜３：ヒトによるしわ改善効果の評価］
以下の表４に示す配合割合でアスコルビン酸誘導体の化粧料組成物(化粧水)を調製し、しわの悩みを持つ被験者を一群２０名とし、各化粧料を毎日、朝と夜、３ヶ月間塗布使用させ、３ヶ月後に累積塗布効果を以下の判定基準により自己判定させ、さらに判定結果を以下の基準で評価し、表４中に併記した。
[Examples 1-5, Comparative Examples 1-3: Evaluation of wrinkle improvement effect by human]
A cosmetic composition (skin lotion) of an ascorbic acid derivative was prepared at the blending ratio shown in Table 4 below, and a group of 20 subjects with wrinkle problems was prepared. Each cosmetic was applied daily, morning and night for 3 months. After 3 months, the cumulative application effect was self-determined according to the following criteria, and the determination results were evaluated according to the following criteria, and are also shown in Table 4.
著効：しわがほとんど目立たなくなった。
有効：しわが少し目立たなくなった。
やや有効：しわがやや目立たなくなった。
無効：変化なし。
Remarkable: Wrinkles are almost inconspicuous.
Effective: Wrinkles are a little less noticeable.
Slightly effective: Wrinkles are slightly less noticeable.
Invalid: No change.
[評価]
◎：被験者のうち著効、有効の示す割合（有効率）が80％以上。
○：被験者のうち著効、有効の示す割合（有効率）が60％以上80％未満。
△：被験者のうち著効、有効の示す割合（有効率）が40％以上60％未満。
×：被験者のうち著効、有効の示す割合（有効率）が40％未満。
[Evaluation]
(Double-circle): The ratio (effective rate) which shows remarkable effect and effectiveness among test subjects is 80% or more.
○: The ratio (effective rate) showing the effectiveness and effectiveness among the subjects is 60% or more and less than 80%.
(Triangle | delta): The ratio (effective rate) which shows remarkable and effective among test subjects is 40% or more and less than 60%.
X: The ratio (effective rate) which shows remarkable and effective among test subjects is less than 40%.
このことから、アスコルビン酸誘導体は抗老化剤として有用であり、有効成分として含有され抗老化剤として応用される他、皮膚外用剤に配合して、皮膚の線維芽細胞において細胞賦活作用、コラーゲンおよびヒアルロン酸合成促進作用を発揮して、細胞賦活作用、コラーゲンおよびヒアルロン酸合成促進作用によるしわの改善効果等の抗老化作用の機能を持つ、抗老化用皮膚外用剤として有用であることが分かる。 As a result, ascorbic acid derivatives are useful as anti-aging agents, and are contained as active ingredients and applied as anti-aging agents. In addition, they are incorporated into topical skin preparations to activate cells in skin fibroblasts, collagen and It can be seen that it is useful as an anti-aging skin external preparation that exhibits hyaluronic acid synthesis promoting action and has anti-aging functions such as cell activation, wrinkle improvement by collagen and hyaluronic acid synthesis promoting action.
以下に、所定のアスコルビン酸誘導体を有効成分とする実施例として、化粧料の代表的な処方例を示す。各行右端の数値は配合割合(質量％)である。 In the following, typical examples of cosmetic preparations are shown as examples using a predetermined ascorbic acid derivative as an active ingredient. The numerical value at the right end of each row is the blending ratio (mass%).
［処方例１］（化粧水）
２−（２−ヘキシルデシル）−Ｌ−アスコルビルフォスフェート 5.0
グリセリン 5.0
１，３−ブチレングリコール 5.0
ジプロピレングリコール ５．０％ 5.0
ヒアルロン酸ナトリウム１％水溶液 5.0
ＰＯＥ（４０）硬化ヒマシ油 1.5
防腐剤 適量
精製水 残余
[Prescription Example 1] (Lotion)
2- (2-Hexyldecyl) -L-ascorbyl phosphate 5.0
Glycerin 5.0
1,3-butylene glycol 5.0
Dipropylene glycol 5.0% 5.0
Sodium hyaluronate 1% aqueous solution 5.0
POE (40) hydrogenated castor oil 1.5
Preservative Appropriate amount of purified water Residual
［処方例２］（ゲル状クリーム）
２−（２−ヘキシルデシル）−Ｌ−アスコルビルフォスフェート 5.0
グリセリン 5.0
エタノール 5.0
水酸化ナトリウム 0.5
カルボキシビニルポリマー 0.8
香料 適量
防腐剤 適量
精製水 残余
[Prescription Example 2] (Gel Cream)
2- (2-Hexyldecyl) -L-ascorbyl phosphate 5.0
Glycerin 5.0
Ethanol 5.0
Sodium hydroxide 0.5
Carboxyvinyl polymer 0.8
Perfume Appropriate amount Preservative Appropriate amount of purified water Residue
［処方例３］（乳液）
２−（２−ヘプチルウンデシル）−Ｌ−アスコルビルフォスフェート 10.0
１，３−ブチレングリコール 10.0
カルボキシビニルポリマー 0.3
スクワラン 5.0
セタノール 0.6
Ｌ−アルギニン 0.3
香料 適量
防腐剤 適量
精製水 残余
[Prescription Example 3] (Emulsion)
2- (2-Heptylundecyl) -L-ascorbyl phosphate 10.0
1,3-butylene glycol 10.0
Carboxyvinyl polymer 0.3
Squalane 5.0
Cetanol 0.6
L-Arginine 0.3
Perfume Appropriate amount Preservative Appropriate amount of purified water Residue
［処方例４］（クリーム）
２−ビス（２−オクチルドデシル）−Ｌ−アスコルビルフォスフェート 10.0
１，３−ブチレングリコール 10.0
カルボキシビニルポリマー 0.4
スクワラン 5.0
セタノール 3.0
ミツロウ 3.0
Ｌ−アルギニン 0.3
香料 適量
防腐剤 適量
精製水 残余
[Prescription Example 4] (Cream)
2-Bis (2-octyldodecyl) -L-ascorbyl phosphate 10.0
1,3-butylene glycol 10.0
Carboxyvinyl polymer 0.4
Squalane 5.0
Cetanol 3.0
Beeslow 3.0
L-Arginine 0.3
Perfume Appropriate amount Preservative Appropriate amount of purified water Residue
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| WO2021215440A1 (en) * | 2020-04-22 | 2021-10-28 | 株式会社 資生堂 | Hyaluronic acid production promoter |
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| JPS61152613A (en) * | 1984-12-26 | 1986-07-11 | Kanebo Ltd | Skin cosmetic |
| JPH05152613A (en) * | 1991-11-26 | 1993-06-18 | Isuzu Motors Ltd | Thermoelectric conversion material |
| EP1262168A1 (en) * | 2001-03-23 | 2002-12-04 | L'oreal | Composition containing fibres to combat the skin aging process |
| JP4190539B2 (en) * | 2004-03-25 | 2008-12-03 | 東洋ビューティ株式会社 | Ascorbic acid derivatives and whitening cosmetics |
| JP5111822B2 (en) * | 2006-10-11 | 2013-01-09 | 東洋ビューティ株式会社 | Collagen production promoter and anti-aging cosmetic |
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