JP2004175778A - New cinnamic acid - Google Patents
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- JP2004175778A JP2004175778A JP2003008994A JP2003008994A JP2004175778A JP 2004175778 A JP2004175778 A JP 2004175778A JP 2003008994 A JP2003008994 A JP 2003008994A JP 2003008994 A JP2003008994 A JP 2003008994A JP 2004175778 A JP2004175778 A JP 2004175778A
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Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は優れた紫外線吸収作用、チロシナーゼ活性阻害作用及び抗酸化活性を有する桂皮酸類、これを有効成分とする紫外線吸収剤、美白剤、抗酸化剤及び皮膚外用剤に関する。
【０００２】
【従来の技術】
紫外線は、急性の紅斑形成等の他、シミ、ソバカス等の色素沈着、さらにはしわの形成等にも深く関与することが知られており、紫外線吸収剤の開発が重要視されている。
【０００３】
紫外線吸収剤としては、ジベンゾイルメタン誘導体（特許文献１）、５−アリール−２，４−ペンタジエン酸誘導体（特許文献２〜４）、シンナミリデンマロン酸誘導体（特許文献５）、５−アリール−２，４−ペンタジエノン類（特許文献６）などが報告されている。
【０００４】
【特許文献１】
特公昭６１−１６２５８号公報
【特許文献２】
特開平６−３３６４１７号公報
【特許文献３】
特開平７−２３８２７５号公報
【特許文献４】
米国特許第５，３２０，８３３号明細書
【特許文献５】
特開平７−１７９１２号公報
【特許文献６】
特開平７−１７８９２号公報
【０００５】
【発明が解決しようとする課題】
しかしながら、上記の紫外線吸収剤は、紫外線吸収能が十分でなかったり、基剤に対する溶解性が低いなどの欠点があり、必ずしも化粧料等の皮膚外用剤として有用であるとはいえなかった。
従って、皮膚外用剤に配合できる優れた紫外線吸収剤が望まれていた。
【０００６】
【課題を解決するための手段】
そこで本発明者は、多くの化合物を合成し、その紫外線吸収作用と溶剤などへの溶解性を検討してきた結果、特定の構造を有する桂皮酸エステル及び桂皮酸アミド類が優れた紫外線吸収作用と基剤への溶解性を有し、皮膚外用剤成分として有用であることを見出した。また当該化合物の薬理作用を検討したところ、優れたチロシナーゼ活性阻害作用及び不飽和脂肪酸の抗酸化能を有することから、当該化合物は美白化剤、抗酸化剤としても有用であることを見出し、本発明を完成するに至った。
【０００７】
すなわち、本発明は次の一般式（１）
【０００８】
【化３】
（式中、Ｒ1は水素原子又は低級アルキル基を示し；Ｒ2及びＲ3は同一又は異なって水素原子、ヒドロキシ基又は低級アルコキシ基を示し；Ａは次式（２）又は（３）
【００１０】
【化４】
（式中、Ｒ4は低級アルコキシ基もしくはヒドロキシ基が置換していてもよいベンゾイル基、又は低級アルコキシ基を示し；Ｒ5は水素原子、低級アルキル基、ベンジル基又はヒドロキシベンジル基を示し；Ｒ6は水素原子又は低級アルキル基を示す）
で表される基を示す）
で表される桂皮酸類を提供するものである。
【００１２】
また本発明は、当該桂皮酸類（１）を有効成分とする紫外線吸収剤、美白剤及び抗酸化剤、並びにこれを含有する皮膚外用剤を提供するものである。
【００１３】
【発明の実施の形態】
一般式（１）中、Ｒ1、Ｒ5及びＲ6で示される低級アルキル基としては、炭素数１〜６の直鎖又は分岐鎖のアルキル基が好ましい。具体例としては、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｔｅｒｔ−ブチル基、ｎ−ペンチル基、ｎ−ヘキシル基等が挙げられる。このうち、メチル基、エチル基、ｎ−プロピル基、イソプロピル基等の炭素数１〜４の直鎖又は分岐鎖のアルキル基が特に好ましい。
【００１４】
Ｒ2、Ｒ3及びＲ4で示される低級アルコキシ基としては、炭素数１〜６の直鎖又は分岐鎖のアルコキシ基、特に炭素数１〜４のアルコキシ基が好ましい。具体例としてはメトキシ基、エトキシ基、ｎ−プロポキシ基、イソプロポキシ基、ｎ−ブトキシ基等が挙げられる。
【００１５】
本発明桂皮酸類（１）のうち、Ａが式（２）の基である場合は桂皮酸フェニルエステル類であり、Ａが式（３）である場合は桂皮酸アミド類である。
【００１６】
本発明化合物（１）は、例えば次の反応式に従って製造することができる。
【００１７】
【化５】
（式中、Ｒ1、Ｒ2、Ｒ3及びＡは前記と同じ）
【００１９】
すなわち、桂皮酸（４）又はその反応性誘導体にフェノール類又はアミノ酸類（５）を反応させることにより本発明化合物（１）が得られる。
【００２０】
桂皮酸（４）の反応性誘導体としては、酸ハライド、混合酸無水物等が挙げられる。桂皮酸（４）を直接反応させる場合にはＮ，Ｎ−ジシクロカルボジイミド等の縮合剤を用いるのが好ましい。反応は、４−ジメチルアミノピリジン、トリエチルアミン等の塩基の存在下、０〜１００℃で行うのが好ましい。
【００２１】
かくして得られた本発明化合物（１）は、後記実施例に示すように、優れたＵＶ−Ａ又はＵＶ−Ｂ領域の紫外線吸収能を有し、かつ有機溶媒、基剤等に対する溶解性も良好である。従って、本発明化合物（１）は、単独で、又は二種以上を組み合せて紫外線吸収剤として使用することができる。また、本発明化合物（１）は優れたチロシナーゼ活性阻害作用及び不飽和脂肪酸の抗酸化能も有することから、これらを紫外線吸収剤、美白剤及び／又は抗酸化剤として配合し、化粧料等の皮膚外用剤とすることができる。
【００２２】
本発明における皮膚外用剤としては、皮膚化粧料、薬用化粧料が挙げられ、その剤型としてはクリーム、化粧水、乳液、軟膏、ゲル、スプレー、スティック、ファンデーション等が挙げられる。皮膚外用剤中に本発明化合物（１）は、例えば０．００１〜２０重量％、特に０．１〜１０重量％含有させるのが好ましい。
【００２３】
皮膚外用剤には、他に水、エタノール、セチルアルコール、ステアリルアルコール等のアルコール類；グリセリン、プロピレングリコール等の多価アルコール；パルミチン酸、ステアリン酸、オレイン酸等の脂肪酸類；ミリスチン酸イソプロピル、モノステアリン酸プロピレングリコール、グリセリントリカプラート、グリセリントリミリスタート等のエステル類；ヒマシ油、オリーブ油、ヤシ油、ラノリン、スクワラン、鯨ろう等の植物性又は動物性油脂類；パラフィン、流動パラフィン、シリコーン油等の鉱物油類；エアゾール噴射剤として用いられる低沸点炭化水素又はハロゲン化炭化水素類；澱粉、タルク等を配合することができる。
【００２４】
【実施例】
次に実施例を挙げて本発明をさらに詳細に説明するが、本発明はこれらの実施例に限定されるものではない。
【００２５】
実施例１ ２−（４−メトキシベンゾイル）フェニル ４−メトキシシンナメート
４−メトキシ桂皮酸(16.03g, 90.0mmol)、２−ヒドロキシ−４′−メトキシベンゾフェノン(11.4g, 50.0mmol)、４−ジメチルアミノピリジン(4.9g, 40.1mmol)をジクロロメタン(80mL)に分散させ、０℃まで冷却後、Ｎ，Ｎ−ジシクロヘキシルカルボジイミド(11.4g, 50.0mmol)をジクロロメタン(20mL)に溶解し、約０℃を保ちながら５分間で滴下した。０〜３℃で５分間撹拌した後、室温で一晩撹拌し、反応液を濾過、残渣をジクロロメタン(100mL)で洗浄した。濾液を０．５Ｍ ＨＣｌ(25mL×2)、２０％Na2CO3(25mL×2)で洗浄し、有機層にNa2SO4(20g)を加え、乾燥した。２時間後にNa2SO4を濾過し、濾液をロータリーエバポレーターで減圧濃縮、得られた濃縮残にエチル アセテート(100mL)を加え、６０℃で加熱溶解、ごみ濾過した後、冷却した。析出した結晶を濾過し、１４．１ｇの粗結晶を得た。このうち４．１ｇをメタノール(250mL)に６５℃で溶解、再結晶を行い、２−（４−メトキシベンゾイル）フェニル ４−メトキシシンナメート(3.0g, 7.72mmol)を得た。
【００２６】
収率53.1％, m.p. 131.0-131.9℃
1H-NMR(400MHz,CDCl3)δ：3.77(3H,s), 3.82(3H,s), 6.20(1H,d,J=15.87Hz), 6.88(2H,d,J=8.79Hz), 6.90(2H,d,J=8.79Hz), 7.28(1H,d,J=8.06Hz), 7.33(1H,t,J=7.57Hz), 7.37(2H,d,J=9.03Hz), 7.47(1H,d,J=15.62Hz), 7.51(1H,d,J=9.28Hz), 7.55(1H,t,J=7.81Hz), 7.79(2H,d,J=8.79Hz)
【００２７】
実施例２ ４′−ベンゾイルフェニル ４−メトキシシンナメート
４−ヒドロキシベンゾフェノン(9.9g, 50.0mmol)、４−メトキシ桂皮酸(8.9g,50.0mmol)、４−ジメチルアミノピリジン(4.9g, 40.0mmol)を用い、実施例１と同様の手順で反応、抽出を行い、１３．５ｇの粗結晶を得た。このうち４．８ｇを用いて同様の手順で再結晶を行い、４′−ベンゾイルフェニル ４−メトキシシンナメート(4.2g, 11.7mmol)を得た。
【００２８】
収率65.9％, m.p. 130.7-131.5℃
1H-NMR(400MHz,CDCl3)δ：3.88(3H,s), 6.49(1H,d,J=15.87Hz), 6.94(2H,d,J=8.79Hz), 7.29(2H,d,J=8.54Hz), 7.5(2H,t,J=7.32Hz), 7.55(2H,d,J=8.79Hz), 7.60(1H,t,J=7.57Hz), 7.805(1H,d,J=15.87Hz), 7.809(2H,d,J=7.81Hz), 7.87(2H,d,J=8.54Hz)
【００２９】
実施例３ ２′−ベンゾイルフェニル ４−メトキシシンナメート
２−ヒドロキシベンゾフェノン(9.9g, 50.0mmol)、４−メトキシ桂皮酸(8.9g,50.0mmol)、４−ジメチルアミノピリジン(4.9g, 40.0mmol)を用いて実施例１と同様の手順で反応、抽出を行い、１３．１ｇの粗結晶を得た。このうち３．５ｇを用いて同様の手順で再結晶を行い、２′−ベンゾイルフェニル ４−メトキシシンナメート(2.7g, 7.5mmol)を得た。
【００３０】
収率56.4％, m.p. 128.0-129.7℃
1H-NMR(400MHz,CDCl3)δ：3.83(3H,s), 6.13(1H,d,J=15.87Hz), 6.86(2H,d,J=8.79Hz), 7.29(1H,d,J=8.05Hz), 7.34(1H,t,J=7.81Hz), 7.36(2H,d,J=8.78Hz), 7.40(2H,t,J=7.82Hz), 7.45(1H,d,J=15.87Hz), 7.50(1H,t,J=7.57Hz), 7.55(1H,d,J=7.81Hz), 7.56(1H,t,J=7.57Hz), 7.80(2H,d,J=7.08Hz)
【００３１】
実施例４ ４′−エトキシフェニル ４−メトキシシンナメート
４−エトキシフェノール(11.0g, 163.6mmol)、４−メトキシ桂皮酸(16.03g, 163.6mmol)、４−ジメチルアミノピリジン(8.8g, 71.8mmol)を用いて実施例１と同様の手順で反応、抽出を行い、２６．９ｇの粗結晶を得た。このうち７．０ｇをメタノール(300mL)に６４℃で溶解、再結晶を行い、４′−エトキシフェニル４−メトキシシンナメート(5.9g, 19.8mmol)を得た。
【００３２】
収率76.6％, m.p. 130.1-131.8℃
1H-NMR(400MHz,CDCl3)δ：1.41(3H,t,J=6.83Hz), 3.85(3H,s), 3.99(2H,q,J=6.84Hz), 6.46(1H,d,J=15.87Hz), 6.87(2H,d,J=7.32Hz), 6.92(2H,d,J=8.54Hz), 7.05(2H,d,J=8.3Hz), 7.52(2H,d,J=8.79Hz), 7.78(1H,d,J=15.87Hz)
【００３３】
実施例５ ４′−ブトキシフェニル ３，４，５−トリメトキシシンナメート
４−ブトキシフェノール(24.5g, 163.6mmol)、３，４，５−トリメトキシ桂皮酸(38.9g, 163.6mmol)、４−ジメチルアミノピリジン(8.8g, 71.8mmol)を用いて実施例１と同様の手順で反応、抽出を行い、２５．０ｇの粗結晶を得た。このうち１０．０ｇをメタノール(150mL)に６４℃で溶解、再結晶を行い、４′−ブトキシフェニル ３，４，５−トリメトキシシンナメート(6.4g, 16.6mmol)を得た。
【００３４】
収率50.0％, m.p. 80.1-82.7℃
1H-NMR(400MHz,CDCl3)δ：0.98(3H,t,J=7.32Hz), 1.47(2H,six,J=7.57Hz), 1.77(2H,qui,J=7.08Hz), 3.90(3H,s), 3.91(6H,s), 3.96(2H,t,J=6.35Hz), 6.50(1H,d,J=15.87Hz), 6.81(2H,s), 6.92(2H,d,J=9.03Hz), 7.04(2H,d,J=8.79Hz), 7.75(1H,d,J=15.87Hz)
【００３５】
実施例６ ４′−ブトキシフェニル ４−メトキシシンナメート
４−ブトキシフェノール(24.5g, 163.6mmol)、４−メトキシ桂皮酸(16.03g, 163.6mmol)、４−ジメチルアミノピリジン(8.8g, 71.8mmol)を用いて実施例１と同様の手順で反応、抽出を行い、２６．５ｇの粗結晶を得た。このうち１０．０ｇを用いて実施例４と同様の手順で再結晶を行い、４′−ブトキシフェニル ４−メトキシシンナメート(8.4g, 25.7mmol)を得た。
【００３６】
収率68.2％, m.p. 93.3-100.4℃
1H-NMR(400MHz,CDCl3)δ：0.97(3H,t,J=7.32Hz), 1.48(2H,six,J=7.56Hz), 1.76(2H,qui,J=7.32Hz), 3.85(3H,s), 3.95(2H,t,J=6.59Hz), 6.46(1H,d,J=15.87Hz), 6.88(2H,d,J=9.03Hz), 6.91(2H,d,J=8.79Hz), 7.04(2H,d,J=8.79Hz), 7.51(2H,d,J=9.03Hz),7.78(1H,d,J=15.87Hz)
【００３７】
実施例７ ４′−エトキシフェニル ３，４，５−トリメトキシシンナメート
４−エトキシフェノール(11.0g, 163.6mmol)、３，４，５−トリメトキシ桂皮酸(38.9g, 163.6mmol)、４−ジメチルアミノピリジン(8.8g, 71.8mmol)を用いて実施例１と同様の手順で反応、抽出を行い、２８．８ｇの粗結晶を得た。このうち１０．０ｇを用いて実施例４と同様の手順で再結晶を行い、４′−エトキシフェニル ３，４，５−トリメトキシシンナメート(8.8g, 24.5mmol)を得た。
【００３８】
収率70.4％, m.p. 131.75-132.4℃
1H-NMR(400MHz,CDCl3)δ：1.42(3H,t,J=6.83Hz), 3.90(3H,s), 3.91(6H,s), 4.02(2H,q,J=7.08Hz), 6.51(1H,d,J=15.87Hz), 6.81(2H,s), 6.88(2H,d,J=9.4Hz), 7.06(2H,d,J=8.79Hz), 7.75(1H,d,J=15.87Hz)
【００３９】
実施例８ エチル ３，４，５−トリメトキシシンナミル−Ｌ−チロシン
Ｌ−チロシンエチルエステル塩酸塩(12.3g, 50.0mmol)、３，４，５−トリメトキシ桂皮酸(11.9g, 50.0mmol)をジクロロメタン(80mL)に溶解し、約０℃に保ちながらトリエチルアミン(5.1g, 50.0mmol)を滴下した。Ｎ，Ｎ−ジシクロヘキシルカルボジイミド(11.4g, 50.0mmol)をジクロロメタン(20mL)に溶解し、約０℃を保ちながら滴下した。室温で一晩撹拌した後、ロータリーエバポレーターで減圧濃縮し、エチル アセテート(200mL)に溶解し、１０％クエン酸水溶液(300mL)、水(300mL)、１％Na2CO3(300mL)、水(300mL)、飽和食塩水(300mL)の順に洗浄し、Na2SO4(80g)を加えて乾燥させ、Na2SO4を濾過、濾液をロータリーエバポレーターで減圧濃縮し、１８．１ｇの粗結晶を得た。このうち１０．０ｇをカラムクロマトグラフィー(エチル アセテート)で精製し、エチル ３，４，５−トリメトキシシンナミル−Ｌ−チロシン(8.0g, 18.6mmol)を分取した。
【００４０】
収率67.4％, m.p. 70.1-77.9℃
1H-NMR(400MHz,CDCl3)δ：1.28(3H,t,J=7.08Hz), 3.12(2H,d,J=7.32Hz), 3.87(3H,s), 3.88(6H,s), 4.20(2H,q,J=7.32Hz), 4.96(1H,q,J=7.81Hz), 6.11(1H,d,J=7.81Hz), 6.29(1H,d,J=15.38Hz), 6.71(2H,s), 6.73(2H,d,J=8.30Hz), 6.97(2H,d,J=8.30Hz), 7.51(1H,d,J=15.63Hz)
【００４１】
実施例９ エチル フェルロイル−Ｌ−チロシン
フェルラ酸(9.7g, 50.0mmol)、Ｌ−チロシンエチルエステル塩酸塩(12.3g, 50.0mmol)、１−ヒドロキシ−１Ｈ−ベンゾトリアゾール(8.9g, 50.0mmol)をピリジン(100g)に溶解し、約０℃に保ちながらトリエチルアミン(5.1g, 50.0mmol)を滴下した。Ｎ，Ｎ−ジシクロヘキシルカルボジイミド(11.4g, 50.0mmol)をピリジン(45g)に溶解し、約０℃を保ちながら滴下した。室温で一晩撹拌した後、ロータリーエバポレーターで減圧濃縮し、エチル アセテート(200mL)に溶解し、実施例８と同様の手順で抽出、Na2SO4(80g)を加えて乾燥させ、Na2SO4を濾過、濾液をロータリーエバポレーターで減圧濃縮し、１６．６ｇの粗結晶を得た。このうち７．２ｇをエチル アセテート(300mL)に溶解、濾過して不溶物を取り除き、ロータリーエバポレーターで減圧濃縮した後、残渣をイソプロピルアルコール(50mL)に７２℃で溶解、再結晶を行い、エチル フェルロイル−Ｌ−チロシン(5.9g, 15.3mmol)を得た。
【００４２】
収率70.5％, m.p. 176.6-180.4℃
1H-NMR(400MHz,DMSO-d6)δ：1.12(3H,t,J=7.32Hz), 2.82(2H,d,J=5.86Hz), 3.35(3H,s), 4.04(2H,q,J=7.08Hz), 4.48(1H,q,J=6.11Hz), 6.49(1H,d,J=15.62Hz), 6.64(2H,d,J=8.06Hz), 6.77(1H,d,J=8.06Hz), 6.97(1H,d,J=8.3Hz), 7.00(2H,d,J=8.3Hz), 7.11(1H,s), 7.27(1H,d,J=15.87Hz), 8.28(1H,d,J=7.82Hz), 9.21(1H,s), 9.44(1H,s),
【００４３】
実施例１０ エチル ４′−メトキシシンナミル−Ｌ−チロシン
４−メトキシ桂皮酸(8.9g, 50.0mmol)、Ｌ−チロシンエチルエステル塩酸塩(12.3g, 50.0mmol)、１−ヒドロキシ−１Ｈ−ベンゾトリアゾール(8.9g, 50.0mmol)を用いて実施例９と同様の手順で反応、抽出を行い、粗結晶(9.0g)を得た。そのうち６．９ｇをイソプロピルアルコール(40mL)に６２℃で溶解、再結晶を行い、エチル ４′−メトキシシンナミル−Ｌ−チロシン(3.7g, 10.0mmol)を得た。
【００４４】
収率39.2％, m.p. 143.3-144.3℃
1H-NMR(400MHz,CDCl3)δ：1.27(3H,t,J=7.08Hz), 3.09(2H,d,J=5.86Hz), 3.82(3H,s), 4.18(2H,q,J=7.08Hz), 4.96(1H,q,J=7.81Hz), 5.84(1H,s), 6.08(1H,d,J=7.81Hz), 6.24(1H,d,J=15.63Hz), 6.72(2H,d,J=8.54Hz), 6.86(2H,d,J=8.79Hz), 6.96(2H,d,J=8.30Hz), 7.41(2H,d,J=8.79Hz), 7.55(1H,d,J=15.63Hz)
【００４５】
実施例１１ エチル ４−メトキシシンナミル−Ｌ−バリン
Ｌ−バリンエチルエステル塩酸塩(9.1g, 50.0mmol)、４−メトキシ桂皮酸(8.9g, 50.0mmol)、トリエチルアミン(5.1g, 50.0mmol)を用いて実施例８と同様の手順で反応、抽出を行い、１３．３ｇの粗結晶を得た。このうち１０．７ｇをカラムクロマトグラフィー(エチル アセテート)で精製し、エチル ４−メトキシシンナミル−Ｌ−バリン(9.0g, 29.5mmol)を分取した。
【００４６】
収率76.0％, m.p. 61.5-69.7℃
1H-NMR(400MHz,CDCl3)δ：0.94(3H,d,J=6.83Hz), 0.96(3H,d,J=7.08Hz), 0.98(3H,t,J=7.08Hz), 2.22(1H,oct,J=6.84Hz), 3.85(3H,s), 4.21(2H,q,J=7.32Hz),4.69(1H,d,J=8.78Hz), 6.11(1H,d,J=8.78Hz), 6.33(1H,d,J=15.63Hz), 6.88(2H,d,J=8.78Hz), 7.45(2H,d,J=8.78Hz), 7.57(1H,d,J=15.63Hz)
【００４７】
実施例１２ エチル ４−メトキシシンナミルグリシン
グリシンエチルエステル塩酸塩(7.0g, 50.0mmol)、４−メトキシ桂皮酸(8.9g,50.0mmol)、トリエチルアミン(5.1g, 50.0mmol)を用いて実施例８と同様の手順で反応、抽出を行い、９．２ｇの粗結晶を得た。このうち８．３ｇをイソプロピルアルコール(40mL)に７９℃で溶解、再結晶を行い、エチル ４−メトキシシンナミルグリシン(5.8g, 22.0mmol)を得た。
【００４８】
収率74.4％, m.p. 124.5-126.1℃
1H-NMR(400MHz,CDCl3)δ：1.30(3H,t,J=7.32Hz),3.83(3H,s), 4.16(2H,d,J=4.88Hz), 4.23(2H,q,J=7.08Hz), 6.14(1H,s), 6.32(1H,d,J=15.63Hz), 6.88(2H,d,J=8.78Hz), 7.44(2H,d,J=8.78Hz), 7.58(1H,d,J=15.38Hz)
【００４９】
実施例１３ ４−メトキシシンナミルグリシン
実施例１２で得られたエチル ４−メトキシシンナミルグリシン(3.0g, 11.4mmol)を１Ｎ NaOH(14mL)に溶解し、室温で一晩撹拌した。反応液を５％ＨＣｌで中和し、エチル アセテート(200mL)で洗浄、水層を５％ＨＣｌで酸性(pH4)にした後、エチル アセテート(200mL)で抽出、有機層を、水(200mL)、飽和食塩水(200mL)で洗浄、Na2SO4で一晩乾燥させた。Na2SO4を濾過、濾液をロータリーエバポレーターで減圧濃縮し、４−メトキシシンナミルグリシン(1.5g, 6.4mmol)を得た。
【００５０】
収率56.2％, m.p. 162.3-164.4℃
1H-NMR(400MHz,DMSO-d6)δ：3.78(3H,s), 3.87(2H,d,J=5.86Hz), 6.55(1H,d,J=15.6Hz), 6.96(2H,d,J=8.54Hz), 7.37(1H,d,J=15.9Hz), 7.51(2H,d,J=8.78Hz),8.29(1H,d,J=5.85Hz)
【００５１】
実施例１４ エチル カフェオイル−Ｌ−チロシン
３，４−ジヒドロキシ桂皮酸(9.0g, 50.0mmol)、Ｌ−チロシンエチルエステル塩酸塩(12.3g, 50.0mmol)、１−ヒドロキシ−１Ｈ−ベンゾトリアゾール(8.9g, 50.0mmol)を用いて実施例１と同様の手順で反応を行い、粗結晶(12.0g)を得た。そのうち２．０ｇをイソプロピルアルコール(10mL)に溶解し、水(30mL)を徐々に加え、一晩冷却、析出した結晶を濾過で取り除き、母液をロータリーエバポレーターで減圧濃縮し、エチル カフェオイル−Ｌ−チロシン(1.5g, 4.0mmol)を得た。
【００５２】
収率44.4％, m.p. 75.2-77.0℃
1H-NMR(400MHz,CD3OD)δ：1.21(3H,t,J=7.32Hz), 2.94(1H,d,J=8.3Hz), 3.03(1H,d,J=6.34Hz), 4.14(2H,d,J=7.08Hz), 4.67(1H,d,J=8.06Hz), 6.38(1H,d,J=15.8Hz), 6.68(2H,d,J=8.79Hz), 6.74(1H,d,J=8.3Hz), 6.89(1H,d,J=8.3Hz), 7.02(2H,d,J=8.55Hz), 7.34(1H,d,J=15.6Hz)
【００５３】
実施例１５ フェルロイル−Ｌ−チロシン
実施例９で得られたエチル フェルロイル−Ｌ−チロシン(5.0g, 13.0mmol)を２Ｎ NaOH(100mL)に溶解、室温で一晩撹拌し、実施例１３と同様の手順で粗結晶(3.8g)を得た。結晶を少量のエチル アセテートに溶解し、カラムクロマトグラフィー(エチル アセテート)でフェルロイル−Ｌ−チロシン(1.3g, 3.6mmol)を分取した。
【００５４】
収率28.1％, m.p. 108.3-111.0℃
1H-NMR(400MHz,DMSO-d6)δ：3.56(2H,d,J=7.08Hz), 4.6(1H,s), 4.83(1H,q,J=8.3Hz), 5.27(1H,d,J=15.62Hz), 7.30(2H,d,J=8.06Hz), 7.43(1H,d,J=8.3Hz), 7.57(1H,d,J=8.05Hz), 7.76(2H,d,J=8.3Hz), 7.81(1H,s), 8.05(1H,d,J=15.86Hz), 8.92(1H,d,J=7.81Hz), 9.99(1H,s), 10.23(1H,s)
【００５５】
実施例１６ カフェオイル−Ｌ−チロシン
実施例１４で得られたエチル カフェオイル−Ｌ−チロシン(9.0g, 26.2mmol)を２Ｎ NaOH(100mL)に溶解、室温で一晩撹拌し、実施例１３と同様の手順で粗結晶(7.1g)を得た。結晶を少量のエチル アセテートに溶解し、カラムクロマトグラフィー(エチル アセテート)でカフェオイル−Ｌ−チロシン(1.5g, 4.36mmol)を分取した。
【００５６】
収率16.7％, m.p. 67.3-72.4℃
1H-NMR(400MHz,DMSO-d6)δ：2.79(2H,d,J=9.03Hz), 4.20(1H,q,J=7.32Hz), 6.38(1H,d,J=15.38Hz), 6.63(2H,d,J=7.81Hz), 6.72(1H,d,J=8.06Hz), 6.81(1H,d,J=7.33Hz), 6.93(1H,s), 7.01(2H,d,J=7.82Hz), 7.16(1H,d,J=15.87Hz), 8.17(1H,d,J=7.32Hz),9.09(1H,s), 9.17(1H,s), 9.33(1H,s)
【００５７】
試験例１
前記実施例で得た化合物の紫外線に対するモル吸光係数を測定した。すなわち、被験化合物をエタノールに溶解し、分光光度計（島津自記分光光度計：UV−2100S）で１９０〜４５０nmにおける吸光度（Ａ）を測定し、下記式（６）よりモル吸光係数（ε）を算出した。化合物濃度は吸光度が１．０以下になるようにそれぞれ調節した。結果を表１に示す。
【００５８】
Ａ＝εＣ×１ （６）
【００５９】
Ａ：吸光度
ε：モル吸光係数（mol-1cm-1Ｌ）
Ｃ：化合物濃度（mol／Ｌ）
【００６０】
試験例２
実施例で得た化合物の各種溶剤に対する溶解性を評価した。
被験化合物０．１ｇを量り取り、溶媒（水、エタノール、酢酸エチル）１０mLに室温で溶解させた。溶解性は、完全に溶解したもの（＞１％：○）、溶け残りが認められたもの（＜１％：△）、全く溶解しなかったもの（insol.：×）の３つに分類し、評価した。結果を表１に示す。
【００６１】
【表１】
試験例３
実施例で得た化合物のチロシナーゼ活性阻害作用を検討した。
０．０６６Ｍリン酸緩衝液(pH6.8)１．０mL、Ｌ−チロシン(1.66μM)１．０mL、各試料溶液〔各試験化合物を0.066Mリン酸緩衝液(pH6.8)に溶解し、１mM、0.5mM、0.1mMとしたもの〕０．９mLを混合し、３７℃で５分間インキュベートした。次いで、酵素溶液〔シグマ社製、3620unit/mgのチロシナーゼを0.066Mリン酸緩衝液(pH6.8)に溶解し、2000unit/mLに希釈したもの〕０．１mLを加え、混合し、温度を３７℃に保ちながら、４７５nmにおける吸光度(ODS)を分光光度計(島津自記分光光度計：UV-2100S)で１０分間測定した。
同様に、加熱失活させた前記酵素を用いて反応させたときの吸光度(ODHE)及び試料無添加時の吸光度(ODB)を測定し、次式（７）よりチロシナーゼ活性の阻害率を算出した。得られた阻害率から５０％阻害濃度(IC50)を求めた。結果を表２に示す。
【００６３】
【数１】
ＯＤS：試料添加時の吸光度
ＯＤB：試料無添加時の吸光度
ＯＤHE：酵素不活性時の吸光度
【００６５】
【表２】
試験例４
実施例で得た化合物の抗酸化活性を測定した。
リノール酸を終濃度が５％W/Vになるようにエタノールに溶解した。このエタノール溶液１０mLに終濃度が５．０mMになるように各試験化合物を溶解し、リン酸緩衝液（pH7.0）１５mLを加えて各試料溶液とした。このとき化合物を加えずに調製したものをブランクとした。各試料溶液をサンプル瓶に入れ密栓し、振とうしながら５０℃で１４４時間加温した。加温後、反応液（０．３mL）に０．０５N ＨＣｌ（３．０mL）、0.67％チオバルビツール酸水溶液（１．０mL）、5.0mM塩化第一鉄水溶液（１．０mL）を加え密栓し、９５℃の沸騰水浴中で正確に３０分間加熱した。氷浴で冷却後、85％ブタノール溶液（BuOH:MeOH=85:15、４．０mL）を加え抽出し、2500rpmで１０分間遠心分離した。上澄みのブタノール層の５３５nmにおける吸光度(ODB)を分光光度計（島津自記分光光度計：UV-2100S）で測定し、（式８）より、リノール酸の酸化に対する各化合物の抗酸化活性（％）を算出した。結果を表３に示す。
【００６７】
【数２】
ＯＤS：試料添加時の吸光度
ＯＤB：試料無添加時の吸光度
【００６９】
【表３】
表１、表２及び表３から明らかなように、本発明化合物（１）は優れた紫外線吸収能、チロシナーゼ活性阻害作用及び抗酸化活性を有し、有機溶媒にも溶解するので、紫外線吸収剤、美白剤及び／又は抗酸化剤として皮膚外用剤、特に化粧料に使用できることがわかる。
【００７１】
【発明の効果】
本発明化合物（１）は、優れた紫外線吸収能、チロシナーゼ活性阻害作用及び抗酸化活性を有し、また基剤への溶解性も良好であり、紫外線吸収剤、美白剤及び／又は抗酸化剤として皮膚外用剤に利用できる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to cinnamic acids having excellent ultraviolet absorbing action, tyrosinase activity inhibiting action and antioxidant activity, and ultraviolet absorbents, whitening agents, antioxidants and skin external preparations containing these as active ingredients.
[0002]
[Prior art]
Ultraviolet rays are known to be deeply involved in pigmentation of spots, freckles and the like, as well as in the formation of wrinkles, in addition to acute erythema formation and the like, and development of ultraviolet absorbers is regarded as important.
[0003]
Examples of the ultraviolet absorber include dibenzoylmethane derivatives (Patent Document 1), 5-aryl-2,4-pentadienoic acid derivatives (Patent Documents 2 to 4), cinnamylidenemalonic acid derivatives (Patent Document 5), and 5-aryl -2,4-pentadienones (Patent Document 6) and the like have been reported.
[0004]
[Patent Document 1]
JP-B-61-16258 [Patent Document 2]
JP-A-6-336417 [Patent Document 3]
JP-A-7-238275 [Patent Document 4]
US Pat. No. 5,320,833 [Patent Document 5]
JP-A-7-17912 [Patent Document 6]
JP-A-7-17892 [0005]
[Problems to be solved by the invention]
However, the above-mentioned ultraviolet absorber has drawbacks such as insufficient ultraviolet absorption ability and low solubility in a base, and thus cannot always be said to be useful as an external preparation for skin such as cosmetics.
Therefore, there has been a demand for an excellent ultraviolet absorber which can be added to a skin external preparation.
[0006]
[Means for Solving the Problems]
Therefore, the present inventors have synthesized a number of compounds, and have studied the ultraviolet absorbing action and solubility in solvents and the like.As a result, cinnamic acid esters and cinnamic amides having a specific structure have excellent ultraviolet absorbing action. It has solubility in a base and was found to be useful as a skin external preparation component. In addition, when the pharmacological action of the compound was examined, it was found that the compound is also useful as a whitening agent and an antioxidant because it has an excellent tyrosinase activity inhibitory action and an antioxidant ability of unsaturated fatty acids. The invention has been completed.
[0007]
That is, the present invention provides the following general formula (1)
[0008]
Embedded image
(Wherein, R 1 represents a hydrogen atom or a lower alkyl group; R 2 and R 3 are the same or different and represent a hydrogen atom, a hydroxy group or a lower alkoxy group; A represents the following formula (2) or (3)
[0010]
Embedded image
(Wherein, R 4 represents a benzoyl group which may be substituted with a lower alkoxy group or a hydroxy group, or a lower alkoxy group; R 5 represents a hydrogen atom, a lower alkyl group, a benzyl group or a hydroxybenzyl group; 6 represents a hydrogen atom or a lower alkyl group)
Represents a group represented by)
And a cinnamic acid represented by the formula:
[0012]
The present invention also provides an ultraviolet absorber, a whitening agent and an antioxidant containing the cinnamic acid (1) as an active ingredient, and an external preparation for skin containing the same.
[0013]
BEST MODE FOR CARRYING OUT THE INVENTION
In the general formula (1), the lower alkyl group represented by R 1 , R 5 and R 6 is preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, an n-pentyl group, and an n-hexyl group. Among them, a linear or branched alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, an n-propyl group and an isopropyl group is particularly preferred.
[0014]
As the lower alkoxy group represented by R 2 , R 3 and R 4 , a linear or branched alkoxy group having 1 to 6 carbon atoms, particularly an alkoxy group having 1 to 4 carbon atoms is preferable. Specific examples include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, and an n-butoxy group.
[0015]
Among the cinnamic acids (1) of the present invention, when A is a group of the formula (2), they are cinnamate phenyl esters, and when A is the formula (3), they are cinnamic amides.
[0016]
The compound (1) of the present invention can be produced, for example, according to the following reaction formula.
[0017]
Embedded image
(Wherein R 1 , R 2 , R 3 and A are the same as described above)
[0019]
That is, the compound (1) of the present invention can be obtained by reacting a phenol or an amino acid (5) with cinnamic acid (4) or a reactive derivative thereof.
[0020]
Examples of the reactive derivative of cinnamic acid (4) include an acid halide and a mixed acid anhydride. When cinnamic acid (4) is directly reacted, it is preferable to use a condensing agent such as N, N-dicyclocarbodiimide. The reaction is preferably performed at 0 to 100 ° C. in the presence of a base such as 4-dimethylaminopyridine and triethylamine.
[0021]
The thus-obtained compound (1) of the present invention has excellent UV-A or UV-B absorption capacity in the UV-A region and good solubility in organic solvents, bases, and the like, as described in Examples below. It is. Therefore, the compound (1) of the present invention can be used alone or in combination of two or more as an ultraviolet absorber. Further, since the compound (1) of the present invention also has an excellent tyrosinase activity inhibitory activity and an antioxidant ability of unsaturated fatty acids, these compounds are blended as an ultraviolet absorber, a whitening agent and / or an antioxidant, and are used for cosmetics and the like. It can be a skin external preparation.
[0022]
Examples of the external preparation for skin in the present invention include skin cosmetics and medicinal cosmetics, and examples of the dosage form include creams, lotions, emulsions, ointments, gels, sprays, sticks, foundations and the like. The compound (1) of the present invention is preferably contained in the external preparation for skin, for example, in an amount of 0.001 to 20% by weight, particularly preferably 0.1 to 10% by weight.
[0023]
Other skin external preparations include alcohols such as water, ethanol, cetyl alcohol, and stearyl alcohol; polyhydric alcohols such as glycerin and propylene glycol; fatty acids such as palmitic acid, stearic acid, and oleic acid; isopropyl myristate; Esters such as propylene glycol stearate, glycerin tricaprate, and glycerin trimyristate; vegetable or animal fats and oils such as castor oil, olive oil, coconut oil, lanolin, squalane, and spermaceti; paraffin, liquid paraffin, and silicone oil Mineral oils; low-boiling hydrocarbons or halogenated hydrocarbons used as aerosol propellants; starch, talc and the like.
[0024]
【Example】
Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
[0025]
Example 1 2- (4-methoxybenzoyl) phenyl 4-methoxycinnamate 4-methoxycinnamic acid (16.03 g, 90.0 mmol), 2-hydroxy-4'-methoxybenzophenone (11.4 g, 50.0 mmol), 4-dimethyl Aminopyridine (4.9 g, 40.1 mmol) was dispersed in dichloromethane (80 mL), cooled to 0 ° C., and N, N-dicyclohexylcarbodiimide (11.4 g, 50.0 mmol) was dissolved in dichloromethane (20 mL). The solution was dropped for 5 minutes while keeping the temperature. After stirring at 0 to 3 ° C for 5 minutes, the mixture was stirred at room temperature overnight, the reaction solution was filtered, and the residue was washed with dichloromethane (100 mL). The filtrate was washed with 0.5 M HCl (25 mL × 2), 20% Na 2 CO 3 (25 mL × 2), Na 2 SO 4 (20 g) was added to the organic layer, and the organic layer was dried. Two hours later, Na 2 SO 4 was filtered, the filtrate was concentrated under reduced pressure by a rotary evaporator, ethyl acetate (100 mL) was added to the obtained concentrated residue, and the mixture was heated and dissolved at 60 ° C., refuse-filtered, and then cooled. The precipitated crystals were filtered to obtain 14.1 g of crude crystals. Of these, 4.1 g was dissolved in methanol (250 mL) at 65 ° C. and recrystallized to obtain 2- (4-methoxybenzoyl) phenyl 4-methoxycinnamate (3.0 g, 7.72 mmol).
[0026]
Yield 53.1%, mp 131.0-131.9 ° C
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.77 (3H, s), 3.82 (3H, s), 6.20 (1 H, d, J = 15.87 Hz), 6.88 (2H, d, J = 8.79 Hz), 6.90 (2H, d, J = 8.79Hz), 7.28 (1H, d, J = 8.06Hz), 7.33 (1H, t, J = 7.57Hz), 7.37 (2H, d, J = 9.03Hz), 7.47 ( 1H, d, J = 15.62Hz), 7.51 (1H, d, J = 9.28Hz), 7.55 (1H, t, J = 7.81Hz), 7.79 (2H, d, J = 8.79Hz)
[0027]
Example 2 4'-benzoylphenyl 4-methoxycinnamate 4-hydroxybenzophenone (9.9 g, 50.0 mmol), 4-methoxycinnamic acid (8.9 g, 50.0 mmol), 4-dimethylaminopyridine (4.9 g, 40.0 mmol) The reaction and extraction were carried out in the same manner as in Example 1 to obtain 13.5 g of crude crystals. Using 4.8 g of these, recrystallization was performed in the same procedure to obtain 4'-benzoylphenyl 4-methoxycinnamate (4.2 g, 11.7 mmol).
[0028]
65.9% yield, mp 130.7-131.5 ° C
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.88 (3H, s), 6.49 (1H, d, J = 15.87 Hz), 6.94 (2H, d, J = 8.79 Hz), 7.29 (2H, d, J = 8.54Hz), 7.5 (2H, t, J = 7.32Hz), 7.55 (2H, d, J = 8.79Hz), 7.60 (1H, t, J = 7.57Hz), 7.805 (1H, d, J = 15.87 Hz), 7.809 (2H, d, J = 7.81Hz), 7.87 (2H, d, J = 8.54Hz)
[0029]
Example 3 2'-benzoylphenyl 4-methoxycinnamate 2-hydroxybenzophenone (9.9 g, 50.0 mmol), 4-methoxycinnamic acid (8.9 g, 50.0 mmol), 4-dimethylaminopyridine (4.9 g, 40.0 mmol) Was used to carry out a reaction and extraction in the same manner as in Example 1 to obtain 13.1 g of crude crystals. Using 3.5 g of these, recrystallization was performed in the same procedure to obtain 2'-benzoylphenyl 4-methoxycinnamate (2.7 g, 7.5 mmol).
[0030]
Yield 56.4%, mp 128.0-129.7 ° C
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.83 (3H, s), 6.13 (1H, d, J = 15.87 Hz), 6.86 (2H, d, J = 8.79 Hz), 7.29 (1H, d, J = 8.05Hz), 7.34 (1H, t, J = 7.81Hz), 7.36 (2H, d, J = 8.78Hz), 7.40 (2H, t, J = 7.82Hz), 7.45 (1H, d, J = 15.87) Hz), 7.50 (1H, t, J = 7.57Hz), 7.55 (1H, d, J = 7.81Hz), 7.56 (1H, t, J = 7.57Hz), 7.80 (2H, d, J = 7.08Hz)
[0031]
Example 4 4'-ethoxyphenyl 4-methoxycinnamate 4-ethoxyphenol (11.0 g, 163.6 mmol), 4-methoxycinnamic acid (16.03 g, 163.6 mmol), 4-dimethylaminopyridine (8.8 g, 71.8 mmol) The reaction and extraction were carried out in the same manner as in Example 1 using, to obtain 26.9 g of crude crystals. Of these, 7.0 g was dissolved in methanol (300 mL) at 64 ° C. and recrystallized to obtain 4′-ethoxyphenyl 4-methoxycinnamate (5.9 g, 19.8 mmol).
[0032]
76.6% yield, mp 130.1-131.8 ° C
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.41 (3H, t, J = 6.83 Hz), 3.85 (3H, s), 3.99 (2H, q, J = 6.84 Hz), 6.46 (1H, d, J = 15.87Hz), 6.87 (2H, d, J = 7.32Hz), 6.92 (2H, d, J = 8.54Hz), 7.05 (2H, d, J = 8.3Hz), 7.52 (2H, d, J = 8.79 Hz), 7.78 (1H, d, J = 15.87Hz)
[0033]
Example 5 4'-butoxyphenyl 3,4,5-trimethoxycinnamate 4-butoxyphenol (24.5 g, 163.6 mmol), 3,4,5-trimethoxycinnamic acid (38.9 g, 163.6 mmol), 4-dimethyl Reaction and extraction were carried out in the same manner as in Example 1 using aminopyridine (8.8 g, 71.8 mmol) to obtain 25.0 g of crude crystals. Of these, 10.0 g was dissolved in methanol (150 mL) at 64 ° C. and recrystallized to obtain 4′-butoxyphenyl 3,4,5-trimethoxycinnamate (6.4 g, 16.6 mmol).
[0034]
Yield 50.0%, mp 80.1-82.7 ° C
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.98 (3H, t, J = 7.32 Hz), 1.47 (2H, six, J = 7.57 Hz), 1.77 (2H, qui, J = 7.08 Hz), 3.90 ( 3H, s), 3.91 (6H, s), 3.96 (2H, t, J = 6.35Hz), 6.50 (1H, d, J = 15.87Hz), 6.81 (2H, s), 6.92 (2H, d, J = 9.03Hz), 7.04 (2H, d, J = 8.79Hz), 7.75 (1H, d, J = 15.87Hz)
[0035]
Example 6 4'-butoxyphenyl 4-methoxycinnamate 4-butoxyphenol (24.5 g, 163.6 mmol), 4-methoxycinnamic acid (16.03 g, 163.6 mmol), 4-dimethylaminopyridine (8.8 g, 71.8 mmol) The reaction and extraction were carried out in the same manner as in Example 1 by using, to obtain 26.5 g of crude crystals. Of these, 10.0 g was recrystallized in the same manner as in Example 4 to obtain 4'-butoxyphenyl 4-methoxycinnamate (8.4 g, 25.7 mmol).
[0036]
68.2% yield, mp 93.3-100.4 ° C
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.97 (3H, t, J = 7.32 Hz), 1.48 (2H, six, J = 7.56 Hz), 1.76 (2H, qui, J = 7.32 Hz), 3.85 ( 3H, s), 3.95 (2H, t, J = 6.59Hz), 6.46 (1H, d, J = 15.87Hz), 6.88 (2H, d, J = 9.03Hz), 6.91 (2H, d, J = 8.79 Hz), 7.04 (2H, d, J = 8.79Hz), 7.51 (2H, d, J = 9.03Hz), 7.78 (1H, d, J = 15.87Hz)
[0037]
Example 7 4'-ethoxyphenyl 3,4,5-trimethoxycinnamate 4-ethoxyphenol (11.0 g, 163.6 mmol), 3,4,5-trimethoxycinnamic acid (38.9 g, 163.6 mmol), 4-dimethyl The reaction and extraction were carried out in the same manner as in Example 1 using aminopyridine (8.8 g, 71.8 mmol) to obtain 28.8 g of crude crystals. Of these, 10.0 g was recrystallized in the same procedure as in Example 4 to obtain 4'-ethoxyphenyl 3,4,5-trimethoxycinnamate (8.8 g, 24.5 mmol).
[0038]
70.4% yield, mp 131.75-132.4 ° C
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.42 (3H, t, J = 6.83 Hz), 3.90 (3H, s), 3.91 (6H, s), 4.02 (2H, q, J = 7.08 Hz), 6.51 (1H, d, J = 15.87Hz), 6.81 (2H, s), 6.88 (2H, d, J = 9.4Hz), 7.06 (2H, d, J = 8.79Hz), 7.75 (1H, d, J = 15.87Hz)
[0039]
Example 8 Ethyl 3,4,5-trimethoxycinnamyl-L-tyrosine L-tyrosine ethyl ester hydrochloride (12.3 g, 50.0 mmol) and 3,4,5-trimethoxycinnamic acid (11.9 g, 50.0 mmol) It was dissolved in dichloromethane (80 mL), and triethylamine (5.1 g, 50.0 mmol) was added dropwise while maintaining the temperature at about 0 ° C. N, N-dicyclohexylcarbodiimide (11.4 g, 50.0 mmol) was dissolved in dichloromethane (20 mL) and added dropwise while maintaining the temperature at about 0 ° C. After stirring at room temperature overnight, the mixture was concentrated under reduced pressure using a rotary evaporator, dissolved in ethyl acetate (200 mL), and a 10% aqueous citric acid solution (300 mL), water (300 mL), 1% Na 2 CO 3 (300 mL), water ( (300 mL) and saturated saline (300 mL) in that order, Na 2 SO 4 (80 g) was added and dried, Na 2 SO 4 was filtered, and the filtrate was concentrated under reduced pressure with a rotary evaporator to obtain 18.1 g of crude crystals. Obtained. Of these, 10.0 g was purified by column chromatography (ethyl acetate) to separate ethyl 3,4,5-trimethoxycinnamyl-L-tyrosine (8.0 g, 18.6 mmol).
[0040]
67.4% yield, mp 70.1-77.9 ° C
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.28 (3H, t, J = 7.08 Hz), 3.12 (2H, d, J = 7.32 Hz), 3.87 (3H, s), 3.88 (6H, s), 4.20 (2H, q, J = 7.32Hz), 4.96 (1H, q, J = 7.81Hz), 6.11 (1H, d, J = 7.81Hz), 6.29 (1H, d, J = 15.38Hz), 6.71 ( 2H, s), 6.73 (2H, d, J = 8.30Hz), 6.97 (2H, d, J = 8.30Hz), 7.51 (1H, d, J = 15.63Hz)
[0041]
Example 9 Ethyl feruloyl-L-tyrosine ferulic acid (9.7 g, 50.0 mmol), L-tyrosine ethyl ester hydrochloride (12.3 g, 50.0 mmol), 1-hydroxy-1H-benzotriazole (8.9 g, 50.0 mmol) It was dissolved in pyridine (100 g), and triethylamine (5.1 g, 50.0 mmol) was added dropwise while maintaining the temperature at about 0 ° C. N, N-dicyclohexylcarbodiimide (11.4 g, 50.0 mmol) was dissolved in pyridine (45 g) and added dropwise while maintaining the temperature at about 0 ° C. After stirring at room temperature overnight, the mixture was concentrated under reduced pressure using a rotary evaporator, dissolved in ethyl acetate (200 mL), extracted in the same manner as in Example 8, dried by adding Na 2 SO 4 (80 g), and dried with Na 2 SO 4. 4 was filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain 16.6 g of crude crystals. Of these, 7.2 g was dissolved in ethyl acetate (300 mL), filtered to remove insolubles, concentrated under reduced pressure by a rotary evaporator, and the residue was dissolved in isopropyl alcohol (50 mL) at 72 ° C and recrystallized. -L-tyrosine (5.9 g, 15.3 mmol) was obtained.
[0042]
70.5% yield, mp 176.6-180.4 ° C
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.12 (3H, t, J = 7.32 Hz), 2.82 (2H, d, J = 5.86 Hz), 3.35 (3H, s), 4.04 (2H, q , J = 7.08Hz), 4.48 (1H, q, J = 6.11Hz), 6.49 (1H, d, J = 15.62Hz), 6.64 (2H, d, J = 8.06Hz), 6.77 (1H, d, J = 8.06Hz), 6.97 (1H, d, J = 8.3Hz), 7.00 (2H, d, J = 8.3Hz), 7.11 (1H, s), 7.27 (1H, d, J = 15.87Hz), 8.28 ( 1H, d, J = 7.82Hz), 9.21 (1H, s), 9.44 (1H, s),
[0043]
Example 10 Ethyl 4'-methoxycinnamyl-L-tyrosine 4-methoxycinnamic acid (8.9 g, 50.0 mmol), L-tyrosine ethyl ester hydrochloride (12.3 g, 50.0 mmol), 1-hydroxy-1H-benzotriazole Using 8.9 g (50.0 mmol), the reaction and extraction were carried out in the same manner as in Example 9 to obtain crude crystals (9.0 g). 6.9 g thereof was dissolved in isopropyl alcohol (40 mL) at 62 ° C. and recrystallized to obtain ethyl 4′-methoxycinnamyl-L-tyrosine (3.7 g, 10.0 mmol).
[0044]
39.2% yield, mp 143.3-144.3 ° C
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.27 (3H, t, J = 7.08 Hz), 3.09 (2H, d, J = 5.86 Hz), 3.82 (3H, s), 4.18 (2H, q, J = 7.08Hz), 4.96 (1H, q, J = 7.81Hz), 5.84 (1H, s), 6.08 (1H, d, J = 7.81Hz), 6.24 (1H, d, J = 15.63Hz), 6.72 ( 2H, d, J = 8.54Hz), 6.86 (2H, d, J = 8.79Hz), 6.96 (2H, d, J = 8.30Hz), 7.41 (2H, d, J = 8.79Hz), 7.55 (1H, d, J = 15.63Hz)
[0045]
Example 11 Ethyl 4-methoxycinnamyl-L-valine L-valine ethyl ester hydrochloride (9.1 g, 50.0 mmol), 4-methoxycinnamic acid (8.9 g, 50.0 mmol), and triethylamine (5.1 g, 50.0 mmol) The reaction and extraction were carried out in the same manner as in Example 8 to obtain 13.3 g of crude crystals. Of these, 10.7 g was purified by column chromatography (ethyl acetate), and ethyl 4-methoxycinnamyl-L-valine (9.0 g, 29.5 mmol) was separated.
[0046]
76.0% yield, mp 61.5-69.7 ℃
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.94 (3H, d, J = 6.83 Hz), 0.96 (3H, d, J = 7.08 Hz), 0.98 (3H, t, J = 7.08 Hz), 2.22 ( 1H, oct, J = 6.84Hz), 3.85 (3H, s), 4.21 (2H, q, J = 7.32Hz), 4.69 (1H, d, J = 8.78Hz), 6.11 (1H, d, J = 8.78 Hz), 6.33 (1H, d, J = 15.63Hz), 6.88 (2H, d, J = 8.78Hz), 7.45 (2H, d, J = 8.78Hz), 7.57 (1H, d, J = 15.63Hz)
[0047]
Example 12 Example 8 using ethyl 4-methoxycinnamylglycine lysine ethyl ester hydrochloride (7.0 g, 50.0 mmol), 4-methoxycinnamic acid (8.9 g, 50.0 mmol), and triethylamine (5.1 g, 50.0 mmol). Reaction and extraction were carried out in the same manner as in the above to obtain 9.2 g of crude crystals. Of these, 8.3 g was dissolved in isopropyl alcohol (40 mL) at 79 ° C. and recrystallized to obtain ethyl 4-methoxycinnamylglycine (5.8 g, 22.0 mmol).
[0048]
74.4% yield, mp 124.5-126.1 ° C
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.30 (3H, t, J = 7.32 Hz), 3.83 (3H, s), 4.16 (2H, d, J = 4.88 Hz), 4.23 (2H, q, J = 7.08Hz), 6.14 (1H, s), 6.32 (1H, d, J = 15.63Hz), 6.88 (2H, d, J = 8.78Hz), 7.44 (2H, d, J = 8.78Hz), 7.58 ( (1H, d, J = 15.38Hz)
[0049]
Example 13 4-Methoxycinnamylglycine Ethyl 4-methoxycinnamylglycine (3.0 g, 11.4 mmol) obtained in Example 12 was dissolved in 1N NaOH (14 mL) and stirred at room temperature overnight. The reaction solution was neutralized with 5% HCl, washed with ethyl acetate (200 mL), the aqueous layer was made acidic (pH 4) with 5% HCl, and extracted with ethyl acetate (200 mL), and the organic layer was washed with water (200 mL). , Washed with saturated saline (200 mL) and dried over Na 2 SO 4 overnight. Na 2 SO 4 was filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain 4-methoxycinnamylglycine (1.5 g, 6.4 mmol).
[0050]
Yield 56.2%, mp 162.3-164.4 ° C
1 H-NMR (400MHz, DMSO -d 6) δ: 3.78 (3H, s), 3.87 (2H, d, J = 5.86Hz), 6.55 (1H, d, J = 15.6Hz), 6.96 (2H, d , J = 8.54Hz), 7.37 (1H, d, J = 15.9Hz), 7.51 (2H, d, J = 8.78Hz), 8.29 (1H, d, J = 5.85Hz)
[0051]
Example 14 Ethyl caffeoyl-L-tyrosine 3,4-dihydroxycinnamic acid (9.0 g, 50.0 mmol), L-tyrosine ethyl ester hydrochloride (12.3 g, 50.0 mmol), 1-hydroxy-1H-benzotriazole (8.9 g, 50.0 mmol) to carry out a reaction in the same manner as in Example 1 to obtain crude crystals (12.0 g). 2.0 g thereof was dissolved in isopropyl alcohol (10 mL), water (30 mL) was gradually added, the mixture was cooled overnight, the precipitated crystals were removed by filtration, and the mother liquor was concentrated under reduced pressure with a rotary evaporator to give ethylcaffeoyl-L-. Tyrosine (1.5 g, 4.0 mmol) was obtained.
[0052]
Yield 44.4%, mp 75.2-77.0 ° C
1 H-NMR (400 MHz, CD 3 OD) δ: 1.21 (3 H, t, J = 7.32 Hz), 2.94 (1 H, d, J = 8.3 Hz), 3.03 (1 H, d, J = 6.34 Hz), 4.14 (2H, d, J = 7.08Hz), 4.67 (1H, d, J = 8.06Hz), 6.38 (1H, d, J = 15.8Hz), 6.68 (2H, d, J = 8.79Hz), 6.74 (1H , d, J = 8.3Hz), 6.89 (1H, d, J = 8.3Hz), 7.02 (2H, d, J = 8.55Hz), 7.34 (1H, d, J = 15.6Hz)
[0053]
Example 15 Feruloyl-L-tyrosine Ethyl feruloyl-L-tyrosine (5.0 g, 13.0 mmol) obtained in Example 9 was dissolved in 2N NaOH (100 mL), stirred at room temperature overnight, and treated in the same manner as in Example 13. The procedure yielded crude crystals (3.8 g). The crystals were dissolved in a small amount of ethyl acetate, and feruloyl-L-tyrosine (1.3 g, 3.6 mmol) was separated by column chromatography (ethyl acetate).
[0054]
Yield 28.1%, mp 108.3-111.0 ° C
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 3.56 (2 H, d, J = 7.08 Hz), 4.6 (1 H, s), 4.83 (1 H, q, J = 8.3 Hz), 5.27 (1 H, d , J = 15.62Hz), 7.30 (2H, d, J = 8.06Hz), 7.43 (1H, d, J = 8.3Hz), 7.57 (1H, d, J = 8.05Hz), 7.76 (2H, d, J = 8.3Hz), 7.81 (1H, s), 8.05 (1H, d, J = 15.86Hz), 8.92 (1H, d, J = 7.81Hz), 9.99 (1H, s), 10.23 (1H, s)
[0055]
Example 16 Caffeoyl-L-tyrosine Ethyl caffeoyl-L-tyrosine (9.0 g, 26.2 mmol) obtained in Example 14 was dissolved in 2N NaOH (100 mL), and the mixture was stirred at room temperature overnight. Crude crystals (7.1 g) were obtained by the same procedure. The crystals were dissolved in a small amount of ethyl acetate, and caffeoyl-L-tyrosine (1.5 g, 4.36 mmol) was separated by column chromatography (ethyl acetate).
[0056]
Yield 16.7%, mp 67.3-72.4 ° C
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 2.79 (2 H, d, J = 9.03 Hz), 4.20 (1 H, q, J = 7.32 Hz), 6.38 (1 H, d, J = 15.38 Hz), 6.63 (2H, d, J = 7.81Hz), 6.72 (1H, d, J = 8.06Hz), 6.81 (1H, d, J = 7.33Hz), 6.93 (1H, s), 7.01 (2H, d, J = 7.82Hz), 7.16 (1H, d, J = 15.87Hz), 8.17 (1H, d, J = 7.32Hz), 9.09 (1H, s), 9.17 (1H, s), 9.33 (1H, s)
[0057]
Test example 1
The molar extinction coefficient of the compound obtained in the above example with respect to ultraviolet light was measured. That is, the test compound is dissolved in ethanol, and the absorbance (A) at 190 to 450 nm is measured with a spectrophotometer (Shimadzu self-recording spectrophotometer: UV-2100S). Calculated. The compound concentrations were adjusted so that the absorbance was 1.0 or less. Table 1 shows the results.
[0058]
A = εC × 1 (6)
[0059]
A: absorbance ε: molar extinction coefficient (mol -1 cm -1 L)
C: Compound concentration (mol / L)
[0060]
Test example 2
The solubility of the compounds obtained in the examples in various solvents was evaluated.
0.1 g of the test compound was weighed out and dissolved in 10 mL of a solvent (water, ethanol, ethyl acetate) at room temperature. Solubility was classified into three types: completely dissolved (> 1%: ○), undissolved (<1%: Δ), and completely undissolved (insol .: ×). ,evaluated. Table 1 shows the results.
[0061]
[Table 1]
Test example 3
The tyrosinase activity inhibitory effect of the compounds obtained in the examples was examined.
1.0 mL of 0.066 M phosphate buffer (pH 6.8), 1.0 mL of L-tyrosine (1.66 μM), each sample solution (each test compound was dissolved in 0.066 M phosphate buffer (pH 6.8), 0.9 mM], and the mixture was incubated at 37 ° C for 5 minutes. Then, 0.1 mL of an enzyme solution (manufactured by Sigma, 3620 unit / mg tyrosinase dissolved in 0.066 M phosphate buffer (pH 6.8) and diluted to 2000 unit / mL) was added, mixed, and the temperature was adjusted to 37. While maintaining the temperature at ° C., the absorbance (OD S ) at 475 nm was measured with a spectrophotometer (Shimadzu self-recording spectrophotometer: UV-2100S) for 10 minutes.
Similarly, the absorbance (OD HE ) and the absorbance (OD B ) when the reaction was carried out using the enzyme inactivated by heating and when no sample was added were measured, and the inhibition rate of tyrosinase activity was determined from the following equation (7). Calculated. A 50% inhibitory concentration (IC 50 ) was determined from the obtained inhibition rate. Table 2 shows the results.
[0063]
(Equation 1)
OD S : Absorbance when sample is added OD B : Absorbance when sample is not added OD HE : Absorbance when enzyme is inactive
[Table 2]
Test example 4
The antioxidant activity of the compounds obtained in the examples was measured.
Linoleic acid was dissolved in ethanol to a final concentration of 5% W / V. Each test compound was dissolved in 10 mL of this ethanol solution to a final concentration of 5.0 mM, and 15 mL of a phosphate buffer (pH 7.0) was added to prepare each sample solution. At this time, one prepared without adding the compound was used as a blank. Each sample solution was placed in a sample bottle, sealed, and heated at 50 ° C. for 144 hours with shaking. After warming, add 0.05N HCl (3.0 mL), 0.67% thiobarbituric acid aqueous solution (1.0 mL) and 5.0 mM ferrous chloride aqueous solution (1.0 mL) to the reaction solution (0.3 mL), and seal the mixture. And heated in a boiling water bath at 95 ° C. for exactly 30 minutes. After cooling in an ice bath, an 85% butanol solution (BuOH: MeOH = 85: 15, 4.0 mL) was added for extraction, followed by centrifugation at 2500 rpm for 10 minutes. The absorbance (OD B ) of the supernatant butanol layer at 535 nm was measured with a spectrophotometer (Shimadzu self-recording spectrophotometer: UV-2100S). ) Was calculated. Table 3 shows the results.
[0067]
(Equation 2)
OD S : Absorbance when sample is added OD B : Absorbance when sample is not added
[Table 3]
As is clear from Tables 1, 2 and 3, the compound (1) of the present invention has excellent ultraviolet absorbing ability, tyrosinase activity inhibiting action and antioxidant activity, and is soluble in an organic solvent. It can be seen that it can be used as a skin lightening agent and / or antioxidant in skin external preparations, especially cosmetics.
[0071]
【The invention's effect】
The compound (1) of the present invention has excellent ultraviolet absorbing ability, tyrosinase activity inhibitory action and antioxidant activity, and has good solubility in a base, and has an ultraviolet absorber, a whitening agent and / or an antioxidant. It can be used as an external preparation for skin.
Claims (5)
で表される基を示す）
で表される桂皮酸類。General formula (1)
Represents a group represented by)
Cinnamic acids represented by
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006232685A (en) * | 2005-02-23 | 2006-09-07 | Toagosei Co Ltd | Maillard reaction inhibitor |
| JP2006232686A (en) * | 2005-02-23 | 2006-09-07 | Toagosei Co Ltd | New carnosine ester compound |
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| JP2006232686A (en) * | 2005-02-23 | 2006-09-07 | Toagosei Co Ltd | New carnosine ester compound |
| JP2006232685A (en) * | 2005-02-23 | 2006-09-07 | Toagosei Co Ltd | Maillard reaction inhibitor |
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| CN104610054A (en) * | 2015-02-04 | 2015-05-13 | 中国科学院华南植物园 | Caffeoyl hydroquinone ester and preparation method and application of caffeoyl hydroquinone ester in preparation of tyrosinase inhibitor |
| KR101754826B1 (en) * | 2015-07-20 | 2017-07-06 | 주식회사 앤코스메슈 | Whitening functional ingredients made from cinnamic acid |
| WO2018080166A3 (en) * | 2016-10-26 | 2018-08-09 | (주)아모레퍼시픽 | 3,4,5-trimethoxycinnamic acid ester derivative, method for preparing same, and skin whitening composition comprising same |
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| CN110121491B (en) * | 2016-10-26 | 2022-02-01 | 株式会社爱茉莉太平洋 | 3,4,5-trimethoxycinnamate derivative, method for preparing the same, and skin whitening composition containing the same |
| CN113234047A (en) * | 2021-04-30 | 2021-08-10 | 深圳海创生物科技有限公司 | Polyphenol compound and composition and application thereof in preparation of anti-aging product |
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