JP2004224762A - Naphthol glycoside and bleaching external preparation composition containing the same - Google Patents
Naphthol glycoside and bleaching external preparation composition containing the same Download PDFInfo
- Publication number
- JP2004224762A JP2004224762A JP2003017067A JP2003017067A JP2004224762A JP 2004224762 A JP2004224762 A JP 2004224762A JP 2003017067 A JP2003017067 A JP 2003017067A JP 2003017067 A JP2003017067 A JP 2003017067A JP 2004224762 A JP2004224762 A JP 2004224762A
- Authority
- JP
- Japan
- Prior art keywords
- naphthol
- naphthol glycoside
- external preparation
- whitening
- hydroxy
- 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.)
- Pending
Links
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- -1 Naphthol glycoside Chemical class 0.000 title claims abstract description 25
- 229930182470 glycoside Natural products 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000004061 bleaching Methods 0.000 title abstract 3
- 230000002087 whitening effect Effects 0.000 claims abstract description 18
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- 239000008103 glucose Substances 0.000 claims abstract description 8
- 150000002772 monosaccharides Chemical class 0.000 claims abstract description 7
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Abstract
Description
【０００１】
【発明の属する技術分野】
本発明はナフトールの配糖体および該化合物を含有する美白外用剤組成物に関する。
【０００２】
【従来の技術】
皮膚の黒色化はメラニンの沈着による皮膚のくすみ、黒ずみが主な原因と言われている。メラニンは、Ｌ−チロシンを基質として紫外線により惹起されたチロシナーゼの酸化触媒作用によってＬ−ドーパ、ドーパキノン等を経て生合成される黒色色素である。
【０００３】
メラニン生合成は、チロシナーゼの酸化触媒作用によってＬ−チロシンが酸化されることから始まる。基質Ｌ−チロシンはチロシナーゼのモノフェノール・モノオキシゲナーゼ活性によって酸素分子のうち１原子が取り込まれてＬ−ドーパに置換され、もう一段階チロシナーゼのジフェノールオキシダーゼ活性により酸化されてドーパキノンになる。
【０００４】
ドーパキノンは自動酸化により自発的にロイコドーパクロムとなる。また、ロイコドーパクロムはドーパキノンと反応し、ドーパクロム（赤色）が生合成される。さらに、ドーパクロム以降の生成物質とドーパクロムが異なる比率で重合してメラニンが生合成される。（非特許文献１）
【０００５】
チロシナーゼはこの一連の反応に関与し、その活性部位において基質の一価フェノール部位を分子状酸素によって相当するｏ−二価フェノール、さらに相当するｏ−キノンへ酸化触媒する酵素である。
チロシナーゼはメラニン生合成の過程で４箇所に関与しているが、メラニン生合成の律速段階はＬ−チロシンからドーパクロムに至る過程なので、チロシナーゼの主な介在部位は基質Ｌ−チロシンからＬ−ドーパを経てドーパキノンまで２箇所となる。（非特許文献２）
【０００６】
一般に、美白剤はこの２箇所に介在しているチロシナーゼの活性を抑制することによって効果を発現すると言われている。
美白作用を目的とした医薬部外品、化粧品の場合、Ｌ−アスコルビン酸及びその誘導体をはじめとしてコウジ酸、アルブチン等がすでに美白剤として使用されている。（例えば特許文献１、非特許文献３、非特許文献４）
【０００７】
一方、日焼けによる色素沈着や肝斑、雀卵班、老人性色素班等の表皮性色素沈着性は、メラニン生合成と排泄のバランスが崩れ、表皮内でメラニンが異常増加することが原因である。（非特許文献５）
【０００８】
これらの疾患の治療にはチロシナーゼ活性抑制作用を目的としたヒドロキノン、レゾルシン等フェノール誘導体のメラニン生合成抑制剤を配合した医薬品が以前より使用されていることが記載されている。（例えば、非特許文献６）
しかしながら、ヒドロキノンはメラニン細胞に対して刺激性を有している。そのため日本においては化粧品、医薬部外品への配合が禁止されている。
【０００９】
また、ヒドロキシ−もしくはジヒドロキシナフタレン類も美白作用を有すること（特許文献２）が開示されているが皮膚への刺激性等未解決な問題が存在している。
今後は効力の高いメラニン生合成抑制作用を有しかつ皮膚に対する刺激性のない美白剤が望まれている。
【００１０】
【特許文献１】
特公昭５６−１８５６９号公報
【特許文献２】
特開平７−３０９７３７号公報
【非特許文献１】
赤堀四郎編、酵素研究法、１１版、２巻、株式会社朝倉書店、１９７１年、ｐ．３５６−３６８
【非特許文献２】
高木啓二、他４名、生薬学雑誌、日本生薬学会、平成１１年、５３巻、１号、ｐ．１５−２１
【非特許文献３】
高島弘道、他３名、ビタミン、ビタミン学会、１９７０年、４１号、ｐ．３８７−３９８
【非特許文献４】
Ｍａｅｄａ，Ｋａｚｕｈｉｓａ、Ｆｕｋｕｄａ，Ｍｉｎｏｒｕ、Ｊｏｕｒｎａｌ ｏｆ Ｐｈａｒｍａｃｏｌｏｇｙ ａｎｄ Ｅｘｐｅｒｉｍｅｎｔａｌ Ｔｈｅｒａｐｅｕｔｉｃｓ、（ＵＳＡ）、１９９６年、２７６号、ｐ．７６５−７６９
【非特許文献５】
清寺真、他３名編、色素増加症 肝班 現代皮膚科学大系、１版、１５巻、中山書店株式会社、１９８３年 ｐ．１０４−１０７
【非特許文献６】
Ｇｉｕｓｅｐｐｅ Ｐｒｏｔａ 他７名、Ｂｉｏｃｈｉｍｉｃａ ｅｔ Ｂｉｏｐｈｙｓｉｃａ Ａｃｔａ、（ＮＬＤ）、１９９１年、１１１５号、ｐ．８５−９０
【００１１】
【発明が解決しようとする課題】
本発明はナフトールの上述した有用な作用を維持しつつその皮膚への刺激性が解消した化合物を提供することを目的とするものである。
【００１２】
【課題を解決するための手段】
前記課題を解決するために、本発明者らは鋭意検討した結果、ナフトール類を配糖体とすることによって高いメラニン生成抑制作用を維持しつつ皮膚刺激が解消することを見出し、本発明を完成した。すなわち、本発明は、式（Ｉ）
【化３】
【００１３】
特に式（ＩＩ）
【化４】
【００１４】
また本発明は、前記ナフトール配糖体を含有する美白外用剤組成物であり、さらに、Ｌ−アスコルビン酸及びその誘導体、コウジ酸、エラグ酸、アルブチン、ヒドロキノン、オキシレスベラトール及びその誘導体、プラセンタエキス、ヒノキチオール、レゾルシノールからなる群から選ばれる美白剤の一種又は二種以上と前記ナフトール配糖体とを含有することを特徴とする美白外用剤組成物である。
【００１５】
【発明の実施の形態】
本発明の化合物（Ｉ）は、ルイス酸存在下に２，３−ジヒドロキシナフタレンと、水酸基が保護された糖とを反応させ、次いで加溶媒分解することによりジヒドロキシナフタレンモノ配糖体が容易に、かつ、収率よく合成できる
【００１６】
本発明で用いられるルイス酸は、ルイス酸であれば特に限定されることはなく、例えば五塩化アンチモン、塩化アルミニウム、臭化アルミニウム、四塩化チタン、四塩化スズ、三弗化硼素、塩化亜鉛、塩化銅、塩化鉄などが例示され、三弗化硼素エーテル錯体が取り扱いに優れており特に好ましく用いられる。
【００１７】
本発明で用いられる保護された糖は、糖であれば特に限定されることはなく、例えばグルコース、フルクトース、マンノース、ガラクトース、キシロースおよびＮ−アセチルグルコサミンなどの単糖類、マルトース、セロビオース、ゲンチオビオース、プリメベロース、ルチノース、ストロファントビオース、ラフィノース、ゲンチアノース、メレチトース、マルトトリオース、セロトリオースおよびマンニノトリオースなどの少糖類が例示され、好ましくは単糖類が用いられ、グルコースが最も好ましく用いられる。保護されるのは糖における全ての水酸基であり、保護基は特に限定されることはないが、酢酸エステルが好ましく用いることができる。したがって、本発明で特に好ましい保護された糖は、ペンタアセチルグルコースである。
【００１８】
本発明のナフトール配糖体を含有する美白外用剤組成物は、主として、化粧水、クリーム、乳液、パックなどの皮膚化粧料、または軟膏剤、パック剤などの医薬品及び医薬部外品として使用されるものであり、各外用剤に使用される基剤に助剤などとともに、ナフトール配糖体を配合して製造される。
【００１９】
本発明のナフトール配糖体の配合量は使用する系によって様々で、一概には言えないが、以下の実施例からも明らかなように既存のこの種の物質と同等もしくはかなり低濃度でよく、外用組成物全体の０．０１〜１５．０％、好ましくは０．１〜１０％を用いることができる。
【００２０】
本発明のナフトール配糖体を含有する美白外用剤組成物には、必要に応じて、通常、化粧品、医薬品、医薬部外品等の皮膚外用剤に配合される油脂類、保湿剤類、色素類、界面活性剤類、香料類、抗酸化剤類、紫外線吸収剤類、防腐剤類、水溶性高分子類、樹脂類等を適宜配合することができる。
【００２１】
また、軟膏類、ローション類、乳液類、クリーム類、パック類、顆粒類等の任意の剤型とすることができる。
【００２２】
【実施例】
次に実施例を示して本発明を更に具体的に説明する。
【００２３】
実施例１
２，３−ジヒドロキシナフタレン ３．２ｇ、ペンタアセチル−β−Ｄ−グルコース １０．１５ｇをアセトニトリル２０ｍＬ、エーテル６０ｍＬに溶解し、ボロントリフルオリドエチルエーテルコンプレックス（ＢＦ３・Ｅｔ２Ｏ）７．５ｍＬを滴下して加えて、室温で７８時間撹拌した。この間３６時間後にＢＦ３ １ｍＬ、５７時間後にＢＦ３ １ｍＬ追加した。反応液を半量になるまで減圧留去し、クロロホルム４５ｍＬを加え、飽和ＮａＨＣＯ３ａｑで中和、蒸留水で洗浄，有機層をＮａ２ＳＯ４で乾燥した後溶媒を留去し、得られた油状物質をシリカゲルクロマトグラフィーで分離精製し、３−ヒドロキシ−２−ナフタレニル−２’，３’，４’，６’−テトラ−Ｏ−アセチル−β−Ｄ−グルコピラノサイド（ＩＩＩ）を５．０５ｇ得た（収率５１．５％）。
【００２４】
（ＩＩＩ ）ｍｐ １５８〜１６０℃、ＦＡＢ−ＭＳ ｍ／ｚ ５１３［Ｍ＋Ｎａ］＋、４９０（Ｍ＋）
１Ｈ−ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ３） δＨ：７．６８（１Ｈ， ｄ， Ｊ ＝８．２４， Ｈ−５）， ７．６５（１Ｈ， ｄ， Ｊ ＝８．２４， Ｈ−８）， ７．３８（１Ｈ， ｄｔ， Ｊ ＝８．２， １．５， Ｈ−７）， ７．３０−７．３４（１Ｈ， ｍ， Ｈ−６ ）， ７．３２（１Ｈ， ｓ， Ｈ−４）， ７．３０（１Ｈ， ｓ， Ｈ−１）， ６．０４（１Ｈ， ｓ， ＯＨ−３）， ５．１７−５．４１（３Ｈ， ｍ， Ｈ−２’，３’，４’）， ５．１５（１Ｈ， ｄ， Ｊ ＝７．６， Ｈ−１’）， ４．３４（１Ｈ， ｄｄ， Ｊ ＝１２．４， ２．４， Ｈ−６’）， ４．２３（１Ｈ， ｄｄ， Ｊ ＝１２．４， ５．５， Ｈ−６’）， ３．９６（１Ｈ， ｄｄｄ， Ｊ ＝１０．１， ５．５，
２．４， Ｈ−５’）， ２．１３（６Ｈ， ｓ， ＯＡｃ ）， ２．０７（６Ｈ， ｓ， ＯＡｃ）
【００２５】
式（ＩＩＩ）：
【化５】
３−ヒドロキシ−２−ナフタレニル−２’，３’，４’，６’−テトラ−Ｏ−アセチル−β−Ｄ−グルコピラノサイド（ＩＩＩ）４．８５ｇを５％ＫＯＨａｑ（ＭｅＯＨ／精製水＝３／１）１２０ｍＬ、ＭｅＯＨ６０ｍＬに溶かし、室温で１２時間撹拌した。酢酸で中和し、溶媒を留去した後、残渣をイオン交換樹脂（Ｄｉａｉｏｎ Ｈｐ−２０カラムクロマトグラフィー）に付し、蒸留水、次いで精製水／ＭｅＯＨ（６０／４０）溶液で溶出させた。溶媒を留去し、３−ヒドロキシ−２−ナフタレニル−β−Ｄ−グルコピラノサイド（ＩＩ）を１．９３ｇ得た（収率６０．６％）。
【００２７】
（ＩＩ）ｍｐ １８８〜１９１℃、ＦＡＢ−ＭＳ ｍ／ｚ ３４５［Ｍ＋Ｎａ］＋、３２２（Ｍ＋）
１Ｈ−ＮＭＲ（５００ＭＨｚ、ＤＭＳＯ−ｄ６） δＨ：７．６５（１Ｈ ， ｄ， Ｊ ＝７．８Ｈｚ， Ｈ−５）， ７．６３（１Ｈ，ｄ，Ｊ ＝７．８Ｈｚ， Ｈ−８）， ７．５０（１Ｈ， ｓ， Ｈ−４）， ７．２８（１Ｈ，ｄｔ， Ｊ ＝１．５， ７．８Ｈｚ， Ｈ−６） ，７．２４（１Ｈ、ｄｔ， Ｊ ＝１．５， ７．８Ｈｚ， Ｈ−７）， ７．１９（１Ｈ， ｓ， Ｈ−１）， ５．５（１Ｈ， ｓ， ＯＨ−３）， ４．９３（１Ｈ， ｄ， Ｊ ＝７．６３Ｈｚ， Ｈ−１’）， ４．６９（１Ｈ， ｔ， Ｊ ＝５．６５Ｈｚ， ＯＨ−６’）， ３．７７（１Ｈ， ｍ， Ｈ−６’）， ３．５２（１Ｈ， ｍ， Ｈ−６’）， ３．４４（１Ｈ， ｍ， Ｈ−３’）， ３．３７（１Ｈ， ｍ， Ｈ−２’）， ３．３３（１Ｈ， ｍ， Ｈ−５’）， ３．２３（１Ｈ， ｍ， Ｈ−４’）、１３Ｃ−ＮＭＲ、（ＤＭＳＯ−ｄ６） δ：６０．８（Ｃ−６’）， ６９．９（Ｃ−４’）， ７３．３（Ｃ−２’）， ７６．０（Ｃ−５’）， ７７．３（Ｃ−３’）， １０１．６（Ｃ−１’）， １１０．０， １１１．４， １２３．３， １２４．４， １２５．７， １２６．８， １２８．２， １３０．１， １４６．５， １４６．９ （Ａｒ−Ｃ）、［α］２０ ｄ−９３°（ｃ ０．０１， ＭｅＯＨ）
【００２８】
式（ＩＩ）：
【化６】
次に、３−ヒドロキシ−２−ナフタレニル−β−Ｄ−グルコピラノサイドのメラニン生成抑制効果を明らかにする。
【００３０】
３−ヒドロキシ−２−ナフタレニル−β−Ｄ−グルコピラノサイドのメラニン生成抑制効果は、チロシナーゼ活性抑制作用の測定を行うことで評価した。チロシナーゼ活性抑制作用によるメラニン生成抑制効果の評価は、美白剤のスクリーニングに繁用されている常法である。この方法はＪ． Ｐｈａｒｍａｃｏｌ． Ｅｘｐ． Ｔｈｅｒ．誌、１９９６年２７６号、７６５−７６９頁、アメリカ生物医薬研究会、韓国薬学会発行、Ａｒｃｈ． Ｐｈａｒｍ． Ｒｅｓ．誌、１９９９年２２巻第４号、３３５−３３９頁をはじめとして多くの論文に掲載されている方法である。
【００３１】
試験例１：
この試験はＬ−チロシンからメラニン生成の反応鎖の間に生成されたドーパクロム色素の量を４７５ｎｍの可視スペクトルにより検出する方法である。
Ｌ−チロシンからＬ−ドーパへのヒドロキシル化反応、次いでＬ−ドーパからドーパキノン、さらにドーパクロム色素への酸化はマッシュルーム由来のチロシナーゼによりイン−ビトロで触媒されメラニン生成過程における中間生成物ドーパクロムを生成する。
このチロシナーゼ活性抑制作用は美白剤なしで得られたドーパクロム色素の可視スペクトルの吸光度を抑制率０％としたときの抑制率増加によって表わす。美白剤の効力は、抑制率５０％に到達したときの抑制剤のモル濃度（ｍＭ）で比較した。
【００３２】
Ｌ−チロシン溶液（０．５ｍｇ／ｍＬ）０．５ｍＬ、１／１５Ｍゼーレンゼンリン酸緩衝液（ｐＨ６．８）１．０ｍＬ、チロシナーゼ溶液（０．０４ｍｇ／ｍＬに１／１５Ｍゼーレンゼンリン酸緩衝液で稀釈）０．５ｍＬ、及び試料溶液（所定濃度にリン酸緩衝液で稀釈）１．０ｍＬを加え、３７±０．１℃の恒温水槽において、５分間反応後、４７５ｎｍ吸光度（Ｓ）を測定した。
また、試料非存在下における酵素活性を得る目的で、試料溶液の代わりに１／１５Ｍゼーレンゼンリン酸緩衝液を１ｍＬ加え反応後４７５ｎｍにおける吸光度を測定した。（Ｂ）。
【００３３】
次に、試料溶液の着色による影響を考慮し、チロシナーゼ溶液の代わりに１／１５Ｍゼーレンゼンリン酸緩衝液を０．５ｍＬ加え反応後４７５ｎｍにおける吸光度を測定した。（Ｃ）。
測定した吸光度Ｓ、Ｂ、Ｃを次式に代入し、抑制率を算出した。
抑制率（％）＝［Ｂ−（Ｓ−Ｃ）］／Ｂ×１００
試料濃度を変化させた試料溶液を調製し、求めた各抑制率から５０％抑制時の濃度（ｍＭ）を算出した。
【００３４】
測定結果を表１に示す。
表１の結果から、本発明のナフトール配糖体は、医薬品、化粧品等に汎用されているアルブチン、コウジ酸に比しては劣るが、Ｌ−アスコルビン酸とほぼ同等である優れたメラニン生成抑制効果を持つ事が判った。
【００３６】
次に、２，３−ジヒドロキシナフタレンの持つ皮膚への刺激性が３−ヒドロキシ−２−ナフタレニル−β−Ｄ−グルコピラノサイドでは解消されたことを明らかにする。
【００３７】
皮膚に対する刺激試験は、モルモットの背部皮膚に対する刺激試験を行うことで評価した。モルモットの背部皮膚に対する刺激試験の評価は、刺激物質のスクリーニングに繁用されている常法である。この方法は日本薬学会発行、薬学雑誌、１９８３年１０３巻第４号、４５５−４６５頁、同誌、１９８２年１２巻第１号、８９−９８頁に論文が掲載されている方法である。
【００３８】
試験例２：
この試験はモルモットを一群１０匹とし、その背部抜毛部の皮膚に２，３−ジヒドロキシナフタレン及び３−ヒドロキシ−２−ナフタレニル−β−Ｄ−グルコピラノサイドの１％親水軟膏を１日１回８日間塗布し、この間毎日刺激の有無強弱を観察した。
【００３９】
抜毛した皮膚における刺激試験の結果、１％３−ヒドロキシ−２−ナフタレニル−β−Ｄ−グルコピラノサイドが添加された試料及び試験物質を含まない親水軟膏には発赤等が観察されなかった。しかし、１％２，３−ジヒドロキシナフタレンが添加された試料では１０例中５例に軽い発赤が見られた。
【００４０】
評価結果を表２に示す。
表２の結果から、本発明のナフトール配糖体は２，３−ジヒドロキシナフタレンの持つ皮膚への刺激性が解消されたことが判った。
【００４２】
次に、本発明の３−ヒドロキシ−２−ナフタレニル−β−Ｄ−グルコピラノサイドを配合した具体的な美白（メラニン生成抑制）外用組成物について説明する。
【００４３】
実施例２（化粧水）
処方例１に示すように、精製水に１，３−ブチレングリコール、グリセリンなどの保湿剤、オレイルアルコールなどの皮膚栄養剤と防腐剤、香料などを溶解したエチルアルコールとを室温にて混合した化粧料基剤に、前記３−ヒドロキシ−２−ナフタレニル−β−Ｄ−グルコピラノサイドを０．３％配合する。
【００４４】
実施例３（クリーム）
処方例２に示すように水相部として、精製水に、１，３−ブチレングリコール、ＰＥＧ１５００などの保湿剤を配合したものを用意し、これに前記３−ヒドロキシ−２−ナフタレニル−β−Ｄ−グルコピラノサイドを０．３％配合する。
【００４６】
油相部として、ステアリン酸、ステアリルアルコール、水添ラノリンなどの固形油分、スクワラン、オクチルドデカノールなどの液体油分、防腐剤、界面活性剤などの油性成分を配合したものを用意する。
【００４７】
次に、水相部を徐々に加熱し、約８０℃になったところで、これに、ほぼ同じ温度に加熱された油相部を少しずつ添加し、乳化してクリームとする。
【００４８】
実施例４（乳液）
処方例３に示すように水相部として、精製水に、１，３−ブチレングリコール、グリセリンなどの保湿剤を配合したものを用意し、これに前記３−ヒドロキシ−２−ナフタレニル−β−Ｄ−グルコピラノサイドを０．３％配合する。
【００５０】
油相部として、ミツロウ、セチルアルコール、ワセリンなどの固形油分、スクワランなどの液体油分、防腐剤、界面活性剤などの油性成分を配合し、約７０℃に加熱したものを用意する。
この油相部を、７０℃に加熱した水相部にクインスシードなどの増粘剤を加え、ホモミキサーで攪拌しながら徐々に加え乳化し、乳液とする。
【００５１】
実施例５（パック）
処方例４に示すように精製水に、１，３−ブチレングリコール、グリセリンなどの保湿剤を配合し、それに前記３−ヒドロキシ−２−ナフタレニル−β−Ｄ−グルコピラノサイドを０．３％配合する。
【００５３】
これを７０〜８０℃に加熱し、カルボキシメチルセルロースなどの増粘剤、ポリビニルアルコールなどの皮膜剤を添加し攪拌溶解する。
さらにエチルアルコールに防腐剤、界面活性剤などを溶解したものを添加して可溶化し、パックとする。
【００５４】
実施例６（軟膏剤）
処方例５に示すように水相部は、精製水に１，３−ブチレングリコールなどの保湿剤を配合し、それに前記３−ヒドロキシ−２−ナフタレニル−β−Ｄ−グルコピラノサイドを０．３％配合する。
【００５６】
油相部は、ミツロウ、パラフィン、マイクロクリスタリンワックス、高級脂肪酸などの固形油分、ワセリンなどの半固形分、流動パラフィン、ソルビタン脂肪酸エステルなどの液状油分に防腐剤、界面活性剤と馬油を混合し、８０℃に加熱溶解する。
【００５７】
次に、水相部を８０℃に加熱溶解し、攪拌しながら同程度に加熱された油相部を徐々に加えて乳化し、軟膏剤とする。
【００５８】
このように、本発明における３−ヒドロキシ−２−ナフタレニル−β−Ｄ−グルコピラノサイドは、任意に外用組成物基剤に配合されるものであるが、外用組成物が水相と油相からなるものである場合は、必ず、水相部に配合されることが必要である。
【００５９】
【発明の効果】
本発明によれば、前記ナフトール配糖体（Ｉ）を外用剤に配合することにより、美白外用剤組成物を得ることができる。本発明の美白外用剤組成物は美白効果が優れており、皮膚への刺激性が少ないという特徴を有している。[0001]
TECHNICAL FIELD OF THE INVENTION
TECHNICAL FIELD The present invention relates to a naphthol glycoside and an external whitening composition containing the compound.
[0002]
[Prior art]
It is said that the main cause of darkening of the skin is dullness and darkening of the skin due to deposition of melanin. Melanin is a black pigment that is biosynthesized via L-dopa, dopaquinone, and the like by the oxidation catalysis of tyrosinase induced by ultraviolet light using L-tyrosine as a substrate.
[0003]
Melanin biosynthesis begins with the oxidation of L-tyrosine by the oxidative catalysis of tyrosinase. The substrate L-tyrosine is replaced with L-dopa by taking in one atom of the oxygen molecule by the monophenol / monooxygenase activity of tyrosinase, and oxidized to dopaquinone by the diphenol oxidase activity of another step tyrosinase.
[0004]
Dopaquinone spontaneously becomes leucodopachrome by autoxidation. Leukodopachrome reacts with dopaquinone, and dopachrome (red) is biosynthesized. Further, the product after dopachrome and dopachrome are polymerized at different ratios, and melanin is biosynthesized. (Non-Patent Document 1)
[0005]
Tyrosinase is an enzyme that participates in this series of reactions and catalyzes the oxidation of the monohydric phenolic site of the substrate at its active site to the corresponding o-dihydric phenol and the corresponding o-quinone by molecular oxygen.
Tyrosinase is involved in four places in the process of melanin biosynthesis, but since the rate-limiting step of melanin biosynthesis is from L-tyrosine to dopachrome, the main intervening site of tyrosinase is to transfer L-dopa from substrate L-tyrosine. After that, there will be two places to dopaquinone. (Non-Patent Document 2)
[0006]
Generally, it is said that a whitening agent exerts its effect by suppressing the activity of tyrosinase which is present at these two sites.
In the case of quasi-drugs and cosmetics for the purpose of whitening, kojic acid, arbutin, etc., as well as L-ascorbic acid and its derivatives, have already been used as whitening agents. (For example, Patent Document 1, Non-Patent Document 3, Non-Patent Document 4)
[0007]
On the other hand, pigmentation due to sunburn and epidermal pigmentation such as melasma, sparrow egg spots, senile pigment spots, etc., are caused by an imbalance in melanin biosynthesis and excretion, and abnormal increase in melanin in the epidermis. . (Non-Patent Document 5)
[0008]
It is described that a medicinal product containing a melanin biosynthesis inhibitor of a phenol derivative such as hydroquinone or resorcin for the purpose of suppressing tyrosinase activity has been used for the treatment of these diseases. (For example, Non-Patent Document 6)
However, hydroquinone is irritating to melanocytes. For this reason, blending into cosmetics and quasi-drugs is prohibited in Japan.
[0009]
Further, it is disclosed that hydroxy- or dihydroxynaphthalenes also have a whitening effect (Patent Document 2), but there are unsolved problems such as irritation to the skin.
In the future, a whitening agent which has a highly effective melanin biosynthesis inhibitory action and has no irritating effect on the skin is desired.
[0010]
[Patent Document 1]
JP-B-56-18569 [Patent Document 2]
JP-A-7-309737 [Non-Patent Document 1]
Edited by Shiro Akahori, Enzyme Research, 11th Edition, Volume 2, Asakura Shoten Co., Ltd., 1971, p. 356-368
[Non-patent document 2]
Keiji Takagi and 4 others, Pharmaceutical Science Journal, Japanese Society of Pharmaceutical Sciences, 1999, Vol. 53, No. 1, p. 15-21
[Non-Patent Document 3]
Hiromichi Takashima, 3 others, Vitamin, Vitamin Society of Japan, 1970, No. 41, p. 387-398
[Non-patent document 4]
Maeda, Kazuhisa, Fukuda, Minoru, Journal of Pharmacology and Experimental Therapeutics, (USA), 1996, 276, p. 765-769
[Non-Patent Document 5]
Makoto Kiyoji, 3 others, hyperpigmentation liver group, modern dermatology, 1st edition, volume 15, Nakayama Shoten Co., Ltd., 1983 p. 104-107
[Non-Patent Document 6]
Giuseppe Prota and 7 others, Biochimica et Biophysica Acta, (NLD), 1991, 1115, p. 85-90
[0011]
[Problems to be solved by the invention]
An object of the present invention is to provide a compound in which irritability to the skin has been eliminated while maintaining the above-mentioned useful effects of naphthol.
[0012]
[Means for Solving the Problems]
In order to solve the above-mentioned problems, the present inventors have conducted intensive studies and found that skin irritation is eliminated while maintaining a high melanin production inhibitory effect by using naphthols as glycosides, and completed the present invention. did. That is, the present invention provides a compound of the formula (I)
Embedded image
[0013]
In particular, formula (II)
Embedded image
[0014]
The present invention is also a whitening external preparation composition containing the naphthol glycoside, further comprising L-ascorbic acid and its derivatives, kojic acid, ellagic acid, arbutin, hydroquinone, oxyresveratrol and its derivatives, placenta extract, An external whitening composition comprising one or more whitening agents selected from the group consisting of hinokitiol and resorcinol, and the naphthol glycoside.
[0015]
BEST MODE FOR CARRYING OUT THE INVENTION
The compound (I) of the present invention is prepared by reacting 2,3-dihydroxynaphthalene with a sugar having a protected hydroxyl group in the presence of a Lewis acid, followed by solvolysis to easily produce a dihydroxynaphthalene monoglycoside. And can be synthesized with good yield.
The Lewis acid used in the present invention is not particularly limited as long as it is a Lewis acid.For example, antimony pentachloride, aluminum chloride, aluminum bromide, titanium tetrachloride, tin tetrachloride, boron trifluoride, zinc chloride, Examples thereof include copper chloride and iron chloride, and boron trifluoride etherate is excellent in handling and is particularly preferably used.
[0017]
The protected sugar used in the present invention is not particularly limited as long as it is a sugar, for example, monosaccharides such as glucose, fructose, mannose, galactose, xylose and N-acetylglucosamine, maltose, cellobiose, gentiobiose, primeverose. , Rutinose, strophantobiose, raffinose, gentianose, meletitose, maltotriose, cellotriose, manninotriose and the like, and monosaccharides are preferably used, and glucose is most preferably used. All the hydroxyl groups in the sugar are protected, and the protecting group is not particularly limited, but acetic ester can be preferably used. Thus, a particularly preferred protected sugar in the present invention is pentaacetylglucose.
[0018]
The whitening composition for external use containing the naphthol glycoside of the present invention is mainly used as skin cosmetics such as lotions, creams, emulsions and packs, or ointments and pharmaceuticals such as packs and quasi-drugs. It is manufactured by blending a naphthol glycoside together with an auxiliary and the like in a base used for each external preparation.
[0019]
The blending amount of the naphthol glycoside of the present invention varies depending on the system used, and cannot be specified unconditionally, but as is clear from the following examples, the concentration may be equal to or considerably lower than that of existing substances of this kind, 0.01 to 15.0%, preferably 0.1 to 10%, of the whole external composition can be used.
[0020]
The whitening composition for external use containing the naphthol glycoside of the present invention may, if necessary, be used as an oil, fat, humectant, or pigment, which is usually added to an external preparation for skin such as cosmetics, pharmaceuticals, and quasi-drugs. , Surfactants, fragrances, antioxidants, ultraviolet absorbers, preservatives, water-soluble polymers, resins and the like can be appropriately blended.
[0021]
Further, it can be in any dosage form such as ointments, lotions, emulsions, creams, packs, granules and the like.
[0022]
【Example】
Next, the present invention will be described more specifically with reference to examples.
[0023]
Example 1
3.2 g of 2,3-dihydroxynaphthalene and 10.15 g of pentaacetyl-β-D-glucose are dissolved in 20 mL of acetonitrile and 60 mL of ether, and 7.5 mL of boron trifluoride ethyl ether complex (BF 3 .Et 2 O) is added dropwise. And stirred at room temperature for 78 hours. BF 3 1 mL, 57 hours later BF 3 during which 36 hours later 1 mL was added. The reaction solution was distilled off under reduced pressure to a half volume, chloroform (45 mL) was added, neutralized with saturated NaHCO 3 aq, washed with distilled water, the organic layer was dried over Na 2 SO 4 and then the solvent was distilled off. The oily substance was separated and purified by silica gel chromatography, and 3-hydroxy-2-naphthalenyl-2 ′, 3 ′, 4 ′, 6′-tetra-O-acetyl-β-D-glucopyranoside (III) was added to 5 0.05 g was obtained (yield: 51.5%).
[0024]
(III) mp 158-160 ° C, FAB-MS m / z 513 [M + Na] + , 490 (M + ).
1 H-NMR (500 MHz, CDCl 3 ) δ H : 7.68 (1H, d, J = 8.24, H-5), 7.65 (1H, d, J = 8.24, H-8) , 7.38 (1H, dt, J = 8.2, 1.5, H-7), 7.30-7.34 (1H, m, H-6), 7.32 (1H, s, H -4), 7.30 (1H, s, H-1), 6.04 (1H, s, OH-3), 5.17-5.41 (3H, m, H-2 ', 3', 4 '), 5.15 (1H, d, J = 7.6, H-1'), 4.34 (1H, dd, J = 12.4, 2.4, H-6 '), 4. 23 (1H, dd, J = 12.4, 5.5, H-6 '), 3.96 (1H, ddd, J = 10.1, 5.5,
2.4, H-5 '), 2.13 (6H, s, OAc), 2.07 (6H, s, OAc)
[0025]
Formula (III):
Embedded image
3.85 g of 3-hydroxy-2-naphthalenyl-2 ′, 3 ′, 4 ′, 6′-tetra-O-acetyl-β-D-glucopyranoside (III) was added to 5% KOHaq (MeOH / purified water = 3/1) Dissolved in 120 mL and MeOH 60 mL, and stirred at room temperature for 12 hours. After neutralizing with acetic acid and distilling off the solvent, the residue was applied to an ion exchange resin (Diaion Hp-20 column chromatography) and eluted with distilled water and then purified water / MeOH (60/40) solution. The solvent was distilled off to obtain 1.93 g of 3-hydroxy-2-naphthalenyl-β-D-glucopyranoside (II) (yield: 60.6%).
[0027]
(II) mp 188-191 ° C, FAB-MS m / z 345 [M + Na] + , 322 (M + ).
1 H-NMR (500MHz, DMSO -d 6) δ H: 7.65 (1H, d, J = 7.8Hz, H-5), 7.63 (1H, d, J = 7.8Hz, H- 8), 7.50 (1H, s, H-4), 7.28 (1H, dt, J = 1.5, 7.8 Hz, H-6), 7.24 (1H, dt, J = 1) .5, 7.8 Hz, H-7), 7.19 (1H, s, H-1), 5.5 (1H, s, OH-3), 4.93 (1H, d, J = 7. 63 Hz, H-1 '), 4.69 (1H, t, J = 5.65 Hz, OH-6'), 3.77 (1H, m, H-6 '), 3.52 (1H, m, H-6 '), 3.44 (1H, m, H-3'), 3.37 (1H, m, H-2 '), 3.33 (1H, m, H-5'), 3. 23 (1H, m, H-4 ') 13 C-NMR, (DMSO- d 6) δ: 60.8 (C-6 '), 69.9 (C-4'), 73.3 (C-2 '), 76.0 (C-5 '), 77.3 (C-3'), 101.6 (C-1 '), 110.0, 111.4, 123.3, 124.4, 125.7, 126.8, 128.2. , 130.1, 146.5, 146.9 (Ar-C), [α] 20 d -93 ° (c 0.01, MeOH).
[0028]
Formula (II):
Embedded image
Next, the melanin production inhibitory effect of 3-hydroxy-2-naphthalenyl-β-D-glucopyranoside will be clarified.
[0030]
The melanin production inhibitory effect of 3-hydroxy-2-naphthalenyl-β-D-glucopyranoside was evaluated by measuring the tyrosinase activity inhibitory effect. The evaluation of the melanin production inhibitory effect by the tyrosinase activity inhibitory action is a common method that is frequently used for screening for whitening agents. This method is described in J. Pharmacol. Exp. Ther. 276, 1996, pp. 765-769, American Society for Biomedical Research, Korean Pharmaceutical Association, Arch. Pharm. Res. Journal, 1999 Vol. 22, No. 4, pp. 335-339, and many other papers.
[0031]
Test example 1:
This test is a method of detecting the amount of dopachrome dye formed during the reaction chain of melanin production from L-tyrosine by a visible spectrum at 475 nm.
The hydroxylation reaction of L-tyrosine to L-dopa, followed by oxidation of L-dopa to dopaquinone and further to dopachrome dye, is catalyzed in vitro by tyrosinase from mushrooms to produce the intermediate product dopachrome in the melanin production process.
This tyrosinase activity inhibitory action is represented by an increase in the inhibition rate when the absorbance in the visible spectrum of the dopachrome dye obtained without a whitening agent is 0%. The efficacy of the whitening agent was compared by the molar concentration (mM) of the inhibitor when the inhibition rate reached 50%.
[0032]
0.5 mL of L-tyrosine solution (0.5 mg / mL), 1.0 mL of 1/15 M Zelenzen phosphate buffer (pH 6.8), Tyrosinase solution (0.015 mg / mL in 1/15 M Zelenzen phosphate buffer) After adding 0.5 mL of a dilution (dilution) and 1.0 mL of a sample solution (diluted to a predetermined concentration with a phosphate buffer) and reacting in a constant temperature water bath at 37 ± 0.1 ° C. for 5 minutes, the absorbance (S) at 475 nm was measured. .
Further, in order to obtain the enzyme activity in the absence of the sample, 1 mL of 1/15 M zelensen phosphate buffer was added instead of the sample solution, and the absorbance at 475 nm was measured after the reaction. (B).
[0033]
Next, in consideration of the influence of the coloring of the sample solution, 0.5 mL of 1 / 15M zelenzen phosphate buffer was added instead of the tyrosinase solution, and the absorbance at 475 nm was measured after the reaction. (C).
The measured absorbances S, B, and C were substituted into the following equation to calculate the suppression rate.
Suppression rate (%) = [B− (S−C)] / B × 100
A sample solution with a changed sample concentration was prepared, and the concentration (mM) at the time of 50% inhibition was calculated from each of the obtained inhibition rates.
[0034]
Table 1 shows the measurement results.
From the results shown in Table 1, the naphthol glycoside of the present invention is inferior to arbutin and kojic acid, which are widely used in pharmaceuticals and cosmetics, but excellent in suppressing melanin production, which is almost equivalent to L-ascorbic acid. It turned out to be effective.
[0036]
Next, it will be clarified that the irritation to the skin of 2,3-dihydroxynaphthalene was eliminated by 3-hydroxy-2-naphthalenyl-β-D-glucopyranoside.
[0037]
The irritation test on the skin was evaluated by performing an irritation test on the back skin of the guinea pig. Evaluation of irritation tests on guinea pig back skin is a common practice used for screening irritants. This method is a method published in the Pharmaceutical Journal of the Pharmaceutical Society of Japan, 1983, Vol. 103, No. 4, pp. 455-465, and the same journal, 1982, Vol. 12, No. 1, pp. 89-98.
[0038]
Test Example 2:
In this test, a group of 10 guinea pigs was treated with a 1% hydrophilic ointment of 2,3-dihydroxynaphthalene and 3-hydroxy-2-naphthalenyl-β-D-glucopyranoside once a day on the skin at the back of the hair removal part. It was applied for 8 days, during which time the presence or absence of irritation was observed daily.
[0039]
As a result of an irritation test on the depilated skin, no redness or the like was observed in the sample to which 1% 3-hydroxy-2-naphthalenyl-β-D-glucopyranoside was added and in the hydrophilic ointment containing no test substance. However, in the sample to which 1% 2,3-dihydroxynaphthalene was added, slight redness was observed in 5 out of 10 cases.
[0040]
Table 2 shows the evaluation results.
From the results in Table 2, it was found that the naphthol glycoside of the present invention eliminated the skin irritancy of 2,3-dihydroxynaphthalene.
[0042]
Next, a specific whitening (melanin generation suppressing) external composition containing 3-hydroxy-2-naphthalenyl-β-D-glucopyranoside of the present invention will be described.
[0043]
Example 2 (Lotion)
As shown in Formulation Example 1, a makeup obtained by mixing a humectant such as 1,3-butylene glycol and glycerin, a skin nutrient such as oleyl alcohol, and an ethyl alcohol in which a preservative and a fragrance are dissolved in purified water at room temperature. 0.3% of the above-mentioned 3-hydroxy-2-naphthalenyl-β-D-glucopyranoside is blended with the base material.
[0044]
Example 3 (cream)
As shown in Formulation Example 2, as the aqueous phase portion, a mixture of purified water and a humectant such as 1,3-butylene glycol or PEG 1500 was prepared, and the 3-hydroxy-2-naphthalenyl-β-D was added thereto. -Incorporate 0.3% glucopyranoside.
[0046]
The oil phase is prepared by blending a solid oil such as stearic acid, stearyl alcohol and hydrogenated lanolin, a liquid oil such as squalane and octyldodecanol, and an oil component such as a preservative and a surfactant.
[0047]
Next, the aqueous phase is gradually heated, and when the temperature reaches about 80 ° C., the oil phase heated to substantially the same temperature is added little by little, and emulsified into a cream.
[0048]
Example 4 (Emulsion)
As shown in Formulation Example 3, as the aqueous phase portion, a mixture of purified water and a humectant such as 1,3-butylene glycol and glycerin was prepared, and to this was added 3-hydroxy-2-naphthalenyl-β-D. -Incorporate 0.3% glucopyranoside.
[0050]
As the oil phase portion, a solid oil component such as beeswax, cetyl alcohol, and petrolatum, a liquid oil component such as squalane, and an oil component such as a preservative and a surfactant are blended and heated to about 70 ° C.
This oil phase is added to a water phase heated to 70 ° C. with a thickener such as quince seed and gradually added with stirring with a homomixer to emulsify to obtain an emulsion.
[0051]
Example 5 (pack)
As shown in Formulation Example 4, humectants such as 1,3-butylene glycol and glycerin were mixed with purified water, and the above-mentioned 3-hydroxy-2-naphthalenyl-β-D-glucopyranoside was added in an amount of 0.3%. Mix.
[0053]
This is heated to 70 to 80 ° C., and a thickener such as carboxymethyl cellulose and a film agent such as polyvinyl alcohol are added and dissolved by stirring.
Further, a solution obtained by dissolving a preservative, a surfactant, and the like in ethyl alcohol is added to solubilize the mixture to form a pack.
[0054]
Example 6 (ointment)
As shown in Formulation Example 5, the aqueous phase was prepared by adding a humectant such as 1,3-butylene glycol to purified water, and adding the 3-hydroxy-2-naphthalenyl-β-D-glucopyranoside to the purified water. Mix 3%.
[0056]
The oil phase consists of a preservative, surfactant and horse oil mixed with solid oils such as beeswax, paraffin, microcrystalline wax, higher fatty acids, semi-solids such as petrolatum, liquid oils such as liquid paraffin and sorbitan fatty acid esters. And heat to 80 ° C.
[0057]
Next, the aqueous phase is heated and dissolved at 80 ° C., and the oil phase, which has been heated to the same degree while stirring, is gradually added and emulsified to obtain an ointment.
[0058]
As described above, the 3-hydroxy-2-naphthalenyl-β-D-glucopyranoside in the present invention is arbitrarily compounded in an external composition base, and the external composition is composed of an aqueous phase and an oil phase. When it consists of, it is necessary to be always blended in the aqueous phase part.
[0059]
【The invention's effect】
According to the present invention, a whitening external preparation composition can be obtained by adding the naphthol glycoside (I) to an external preparation. The whitening composition for external use of the present invention is characterized by having an excellent whitening effect and being less irritating to the skin.
Claims (6)
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| JP2003017067A JP2004224762A (en) | 2003-01-27 | 2003-01-27 | Naphthol glycoside and bleaching external preparation composition containing the same |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100395242C (en) * | 2006-06-08 | 2008-06-18 | 华东理工大学 | Alkoxynaphthalene and naphthoquinone carbopyranoside compounds and preparation method thereof |
| US7605056B2 (en) | 2005-05-31 | 2009-10-20 | Semiconductor Energy Laboratory Co., Ltd. | Method of manufacturing a semiconductor device including separation by physical force |
| WO2013140153A3 (en) * | 2012-03-23 | 2015-01-08 | Curapel (Scotland) Limited | Cosmetic and pharmaceutical uses of saccharides |
| WO2015067927A1 (en) * | 2013-11-08 | 2015-05-14 | Glycosynth Limited | Naphthalene derived chromogenic enzyme substrates |
| CN109223634A (en) * | 2018-09-27 | 2019-01-18 | 广州航美化妆品有限公司 | Clear and rich moisturizing whitening mask |
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2003
- 2003-01-27 JP JP2003017067A patent/JP2004224762A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7605056B2 (en) | 2005-05-31 | 2009-10-20 | Semiconductor Energy Laboratory Co., Ltd. | Method of manufacturing a semiconductor device including separation by physical force |
| US8508027B2 (en) | 2005-05-31 | 2013-08-13 | Semiconductor Energy Laboratory Co., Ltd. | Semiconductor device and manufacturing method thereof |
| US8928131B2 (en) | 2005-05-31 | 2015-01-06 | Semiconductor Energy Laboratory Co., Ltd. | Semiconductor device and manufacturing method thereof |
| CN100395242C (en) * | 2006-06-08 | 2008-06-18 | 华东理工大学 | Alkoxynaphthalene and naphthoquinone carbopyranoside compounds and preparation method thereof |
| WO2013140153A3 (en) * | 2012-03-23 | 2015-01-08 | Curapel (Scotland) Limited | Cosmetic and pharmaceutical uses of saccharides |
| WO2015067927A1 (en) * | 2013-11-08 | 2015-05-14 | Glycosynth Limited | Naphthalene derived chromogenic enzyme substrates |
| US9938562B2 (en) | 2013-11-08 | 2018-04-10 | Glycosynth Limited | Naphthalene derived chromogenic enzyme substrates |
| US10443084B2 (en) | 2013-11-08 | 2019-10-15 | Glycosynth Limited | Naphthalene derived chromogenic enzyme substrates |
| CN109223634A (en) * | 2018-09-27 | 2019-01-18 | 广州航美化妆品有限公司 | Clear and rich moisturizing whitening mask |
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