JP5588408B2 - Whitening agent - Google Patents
Whitening agent Download PDFInfo
- Publication number
- JP5588408B2 JP5588408B2 JP2011190517A JP2011190517A JP5588408B2 JP 5588408 B2 JP5588408 B2 JP 5588408B2 JP 2011190517 A JP2011190517 A JP 2011190517A JP 2011190517 A JP2011190517 A JP 2011190517A JP 5588408 B2 JP5588408 B2 JP 5588408B2
- Authority
- JP
- Japan
- Prior art keywords
- oxy
- carbon atoms
- group
- linear
- branched alkoxy
- 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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- 230000002087 whitening effect Effects 0.000 title claims description 27
- -1 methylenedioxy group Chemical group 0.000 claims description 85
- 150000001875 compounds Chemical class 0.000 claims description 55
- 230000000694 effects Effects 0.000 claims description 55
- 102000003425 Tyrosinase Human genes 0.000 claims description 43
- 108060008724 Tyrosinase Proteins 0.000 claims description 43
- 125000004432 carbon atom Chemical group C* 0.000 claims description 40
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 30
- 230000008099 melanin synthesis Effects 0.000 claims description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 239000004480 active ingredient Substances 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 239000003112 inhibitor Substances 0.000 claims description 17
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 15
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 235000002639 sodium chloride Nutrition 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000003814 drug Substances 0.000 description 23
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- 239000002537 cosmetic Substances 0.000 description 19
- 239000003960 organic solvent Substances 0.000 description 19
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical class O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 18
- 210000003491 skin Anatomy 0.000 description 18
- 230000002401 inhibitory effect Effects 0.000 description 17
- 238000000034 method Methods 0.000 description 16
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 102400000686 Endothelin-1 Human genes 0.000 description 3
- 101800004490 Endothelin-1 Proteins 0.000 description 3
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- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 3
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- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000003410 keratolytic agent Substances 0.000 description 1
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- WZNJWVWKTVETCG-UHFFFAOYSA-N kojic acid Natural products OC(=O)C(N)CN1C=CC(=O)C(O)=C1 WZNJWVWKTVETCG-UHFFFAOYSA-N 0.000 description 1
- BEJNERDRQOWKJM-UHFFFAOYSA-N kojic acid Chemical compound OCC1=CC(=O)C(O)=CO1 BEJNERDRQOWKJM-UHFFFAOYSA-N 0.000 description 1
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- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
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- 238000000874 microwave-assisted extraction Methods 0.000 description 1
- 235000020124 milk-based beverage Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 235000012149 noodles Nutrition 0.000 description 1
- 235000014593 oils and fats Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
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- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- BJRNKVDFDLYUGJ-UHFFFAOYSA-N p-hydroxyphenyl beta-D-alloside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000015927 pasta Nutrition 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 210000004694 pigment cell Anatomy 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 125000006225 propoxyethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 239000011814 protection agent Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 235000021067 refined food Nutrition 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- LUPBOBWJAIWMIH-UHFFFAOYSA-N retrohelioxanthine Natural products C1=C2OCOC2=CC(C=2C3=C4OCOC4=CC=C3C=C3COC(C=23)=O)=C1 LUPBOBWJAIWMIH-UHFFFAOYSA-N 0.000 description 1
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- 229920002545 silicone oil Polymers 0.000 description 1
- 235000011888 snacks Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
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- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- GBYROJNZMZOSDJ-UHFFFAOYSA-N taiwanin E methyl ether Natural products C12=CC=3OCOC=3C=C2C(OC)=C(OCC2=O)C2=C1C1=CC=C(OCO2)C2=C1 GBYROJNZMZOSDJ-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000002137 ultrasound extraction Methods 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
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- 229940088594 vitamin Drugs 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- WHNFPRLDDSXQCL-UAZQEYIDSA-N α-msh Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)[C@H](CO)NC(C)=O)C1=CC=C(O)C=C1 WHNFPRLDDSXQCL-UAZQEYIDSA-N 0.000 description 1
Landscapes
- Cosmetics (AREA)
Description
本発明は、美白剤、メラニン生成抑制剤又はドーパオキシダーゼ活性抑制剤に関する。 The present invention relates to a whitening agent, a melanin production inhibitor or a dopa oxidase activity inhibitor.
美容上、色素沈着や、シミ、ソバカスの少ない白い肌が好まれる傾向にあることから、長期間使用しても安全性の高い美白作用を有する物質が望まれている。
この色素沈着やシミ、ソバカス等は、一般に皮膚の紫外線暴露による刺激やホルモンの異常又は遺伝的要素等によって皮膚内に存在する色素細胞(メラノサイト)が活性化されメラニン生成が亢進した結果生じるものと考えられている。このメラニン生成亢進のメカニズムは複雑であるが、メラニンは酵素チロシナーゼの作用により生合成され、チロシナーゼのドーパオキシダーゼ活性はメラニン生成のメカニズムに深く関与していることが知られている(非特許文献1)。
From the viewpoint of beauty, white skin with less pigmentation, spots, and freckles tends to be preferred, and therefore a substance having a whitening action that is highly safe even after long-term use is desired.
This pigmentation, stains, buckwheat, etc. are generally caused as a result of activation of pigment cells (melanocytes) in the skin due to stimulation by ultraviolet exposure of the skin, hormonal abnormalities or genetic factors, etc., and increased melanin production. It is considered. The mechanism of this melanin enhancement is complex, but melanin is biosynthesized by the action of the enzyme tyrosinase, and it is known that the dopa oxidase activity of tyrosinase is deeply involved in the mechanism of melanin production (Non-patent Document 1). ).
このメラニン生成のメカニズムを標的とした美白剤が開発されている。例えば、酵素チロシナーゼの活性を抑制してメラニン産生を抑制する作用を有する皮膚美白剤として、アスコルビン酸、アルブチン、コウジ酸等が報告されている(非特許文献2)。
さらに、ドーパオキシダーゼ活性を抑制し、美白作用を有する植物エキスも報告されている。例えば、トウセンダン(Melia toosendan Sieb. et Zucc.)、ソウカ(Amomum tsao-ka Crevost et Lemaire)、セネシオ グラシリス(Senecio gracilis)及びコクリロ(Veratrum nigrum L.)(特許文献1)、セイヨウトウキ(Angelica archangelica)、ハナミズキ(Benthamidia florida)、カンスイ(Euphorbia kansui Liou)、ヌルデ(Rhus chinensis Mill.)、オカゼリ(Cnidium monnieri(L.)Cuss.)、キンミズヒキ(Agrimonia pilosa Ledeb.)、ロウロ(Diuranthera minor(C.H.Wright)Hemsl.)及びセイヨウメギ(Berberis aristata)(特許文献2)、イヌカラマツ、タイワンコマツナギ及びチョウセンアサガオ(特許文献3)、ならびにザクロ(Punica granatum)花(特許文献4)が知られている。
しかしながら、より効果の高い皮膚美白剤の開発が求められている。
Whitening agents that target this mechanism of melanin production have been developed. For example, ascorbic acid, arbutin, kojic acid, and the like have been reported as skin whitening agents that have the action of suppressing the activity of the enzyme tyrosinase to suppress melanin production (Non-patent Document 2).
Furthermore, plant extracts that suppress the dopa oxidase activity and have a whitening effect have also been reported. For example, Melia toosendan Sieb. Et Zucc., Soka (Amomum tsao-ka Crevost et Lemaire), Senecio gracilis and Veratrum nigrum L (Patent Document 1), Angelica archangelica , Dogwood (Benthamidia florida), Kansui (Euphorbia kansui Liou), Nurde (Rhus chinensis Mill.), Okazeri (Cnidium monnieri (L.) Cuss.), Kimizuki (Agrimonia pilosa Ledeb.), Lour (DiurantheraHems (CHWright) .) And Berberis aristata (patent document 2), dog larch, scallop and datura (patent document 3), and pomegranate (Punica granatum) flowers (patent document 4) are known.
However, there is a need for the development of a skin whitening agent that is more effective.
ハグロソウ(Peristrophe japonica)は、キツネノマゴ科ハグロソウ属の植物である。ハグロソウ属を含むキツネノマゴ科植物を含有し得るメタボリックシンドロームの予防又は改善用組成物が知られている(特許文献5)。しかし、この植物が美白作用、メラニン生成抑制作用又はドーパオキシダーゼ活性抑制作用を有していることは知られていない。 Osprey ( Peristrophe japonica ) is a plant belonging to the genus Vulgaridae. A composition for preventing or ameliorating metabolic syndrome that can contain a foxtail plant including the genus Hygropoda is known (Patent Document 5). However, it is not known that this plant has a whitening action, a melanin production inhibitory action, or a dopa oxidase activity inhibitory action.
アリールナフタレンリグナン類は、Haplophyllum patavinum、Cleistanthus collinus等の植物から単離できることが知られている(非特許文献3、4)。アリールナフタレンリグナン類の生理活性としては、justicidin A、justicidin B、diphyllin、tuberculatinが、骨吸収活性、抗ウイルス活性、又は抗腫瘍活性を有すること(非特許文献5、6)、ならびにjusticidin A及びcleistanthin Aが抗腫瘍活性を有すること(非特許文献7〜8、特許文献6)等が知られている。しかし、これら及び他のアリールナフタレンリグナン類が美白作用やメラニン生成抑制作用を有することはこれまで知られていなかった。 It is known that aryl naphthalene lignans can be isolated from plants such as Haplophyllum patavinum and Cleistanthus collinus (Non-patent Documents 3 and 4). As physiological activities of aryl naphthalene lignans, justicidin A, justicidin B, diphyllin, tuberculatin have bone resorption activity, antiviral activity, or antitumor activity (Non-patent Documents 5 and 6), and justicidin A and cleistanthin It is known that A has antitumor activity (Non-patent Documents 7 to 8, Patent Document 6) and the like. However, it has not been known so far that these and other arylnaphthalene lignans have a whitening action and a melanin production-inhibiting action.
本発明は、安全性が高く、ドーパオキシダーゼ活性を抑制することができ、化粧料や医薬等として有用な美白剤、メラニン生成抑制剤及びドーパオキシダーゼ活性抑制剤を提供することに関する。 The present invention relates to providing a whitening agent, a melanin production inhibitor, and a dopa oxidase activity inhibitor that are highly safe, can inhibit dopa oxidase activity, and are useful as cosmetics and medicines.
本発明者は、美白作用やメラニン生成抑制作用等を有する物質を探索したところ、ハグロソウにドーパオキシダーゼ活性抑制作用や美白作用があることを見出した。本発明者らはさらに、上記ハグロソウの美白作用の活性成分が特定の構造を有するアリールナフタレンリグナン類であること、ならびに当該アリールナフタレンリグナン類が、ドーパオキシダーゼ活性抑制作用を有し、メラニン過剰生成に伴う皮膚の褐色化やシミ・ソバカス等の予防、改善、治療等の効果を発揮する医薬、化粧料、皮膚外用剤及び美白用組成物等の素材として有用であることを見出した。 As a result of searching for a substance having a whitening action, a melanin production inhibitory action, and the like, the present inventor has found that the sunflower has a dopa oxidase activity inhibiting action and a whitening action. Further, the present inventors have further noted that the active ingredient for the whitening action of the sunflower is aryl naphthalene lignans having a specific structure, and that the aryl naphthalene lignans have a dopa oxidase activity inhibitory action, resulting in excessive production of melanin. The present inventors have found that it is useful as a material for pharmaceuticals, cosmetics, external preparations for skin, whitening compositions, etc. that exhibit effects such as prevention, improvement, treatment, etc. of browning of the skin and spots and freckles.
すなわち、本発明は以下を提供する。
(1)下記式(I)
That is, the present invention provides the following.
(1) The following formula (I)
R1及びR2は、同一又は異なって、ヒドロキシル基、又は炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表すか、あるいはR1及びR2は、一緒になってメチレンジオキシ基を形成し、
R3及びR4は、同一又は異なって、ヒドロキシル基、又は炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表すか、あるいはR3及びR4は、一緒になってメチレンジオキシ基を形成し、
R5は水素原子、ヒドロキシル基、炭素数1〜5の直鎖若しくは分岐のアルコキシ基、炭素数1〜4のアシル基、又は(D−アピオ−β−D−フラノシル)オキシ、(β-D−グルコピラノシル)オキシ、(3−O,4−O−ジメチル−D−キシロピラノシル)オキシ、(2−O,3−O,4−O−トリメチル−β−D−キシロピラノシル)オキシ、(3−O−メチル−β−D−グルコピラノシル)オキシから選択される糖残基を表し、
R6とR7は水素原子であり且つR8とR9は一緒になって酸素原子を表すか、又はR8とR9は水素原子であり、且つR6とR7は一緒になって酸素原子を表す。〕
で示される化合物又はその塩を有効成分とするドーパオキシダーゼ活性抑制剤。
(2)上記R1及びR2がいずれも炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表し、且つ上記R3及びR4が一緒になってメチレンジオキシ基を形成するか、あるいは該R1及びR2が一緒になってメチレンジオキシ基を形成し、且つ該R3及びR4がいずれも炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表す、(1)記載のドーパオキシダーゼ活性抑制剤。
(3)上記R1〜R4における炭素数1〜4の直鎖若しくは分岐のアルコキシ基がメトキシである、(2)記載のドーパオキシダーゼ活性抑制剤。
(4)上記R5が水素原子、ヒドロキシル基、メトキシ、エトキシ、アセチルオキシ、(D−アピオ−β−D−フラノシル)オキシである、(1)〜(3)のいずれか1に記載のドーパオキシダーゼ活性抑制剤。
(5)下記式(I)
R 1 and R 2 are the same or different and each represents a hydroxyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms, or R 1 and R 2 together represent a methylenedioxy group. Forming,
R 3 and R 4 are the same or different and each represents a hydroxyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms, or R 3 and R 4 together represent a methylenedioxy group. Forming,
R 5 represents a hydrogen atom, a hydroxyl group, a linear or branched alkoxy group having 1 to 5 carbon atoms, an acyl group having 1 to 4 carbon atoms, or (D-apio-β-D-furanosyl) oxy, (β-D -Glucopyranosyl) oxy, (3-O, 4-O-dimethyl-D-xylopyranosyl) oxy, (2-O, 3-O, 4-O-trimethyl-β-D-xylopyranosyl) oxy, (3-O- Represents a sugar residue selected from methyl-β-D-glucopyranosyl) oxy,
R 6 and R 7 are hydrogen atoms and R 8 and R 9 together represent an oxygen atom, or R 8 and R 9 are hydrogen atoms and R 6 and R 7 are together Represents an oxygen atom. ]
The dopa oxidase activity inhibitor which uses the compound shown by these, or its salt as an active ingredient.
(2) R 1 and R 2 both represent a linear or branched alkoxy group having 1 to 4 carbon atoms, and R 3 and R 4 together form a methylenedioxy group, or The R 1 and R 2 together form a methylenedioxy group, and the R 3 and R 4 both represent a linear or branched alkoxy group having 1 to 4 carbon atoms, Dopa oxidase activity inhibitor.
(3) The dopa oxidase activity inhibitor according to (2), wherein the linear or branched alkoxy group having 1 to 4 carbon atoms in R 1 to R 4 is methoxy.
(4) The dopa according to any one of (1) to (3), wherein R 5 is a hydrogen atom, a hydroxyl group, methoxy, ethoxy, acetyloxy, (D-apio-β-D-furanosyl) oxy. Oxidase activity inhibitor.
(5) The following formula (I)
R1及びR2は、同一又は異なって、ヒドロキシル基、又は炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表すか、あるいはR1及びR2は、一緒になってメチレンジオキシ基を形成し、
R3及びR4は、同一又は異なって、ヒドロキシル基、又は炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表すか、あるいはR3及びR4は、一緒になってメチレンジオキシ基を形成し、
R5は水素原子、ヒドロキシル基、炭素数1〜5の直鎖若しくは分岐のアルコキシ基、炭素数1〜4のアシル基、又は(D−アピオ−β−D−フラノシル)オキシ、(β-D−グルコピラノシル)オキシ、(3−O,4−O−ジメチル−D−キシロピラノシル)オキシ、(2−O,3−O,4−O−トリメチル−β−D−キシロピラノシル)オキシ、(3−O−メチル−β−D−グルコピラノシル)オキシから選択される糖残基を表し、
R6とR7は水素原子であり且つR8とR9は一緒になって酸素原子を表すか、又はR8とR9は水素原子であり、且つR6とR7は一緒になって酸素原子を表す。〕
で示される化合物又はその塩を有効成分とするメラニン生成抑制剤。
(6)下記式(I)
R 1 and R 2 are the same or different and each represents a hydroxyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms, or R 1 and R 2 together represent a methylenedioxy group. Forming,
R 3 and R 4 are the same or different and each represents a hydroxyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms, or R 3 and R 4 together represent a methylenedioxy group. Forming,
R 5 represents a hydrogen atom, a hydroxyl group, a linear or branched alkoxy group having 1 to 5 carbon atoms, an acyl group having 1 to 4 carbon atoms, or (D-apio-β-D-furanosyl) oxy, (β-D -Glucopyranosyl) oxy, (3-O, 4-O-dimethyl-D-xylopyranosyl) oxy, (2-O, 3-O, 4-O-trimethyl-β-D-xylopyranosyl) oxy, (3-O- Represents a sugar residue selected from methyl-β-D-glucopyranosyl) oxy,
R 6 and R 7 are hydrogen atoms and R 8 and R 9 together represent an oxygen atom, or R 8 and R 9 are hydrogen atoms and R 6 and R 7 are together Represents an oxygen atom. ]
The melanin production inhibitor which uses the compound or its salt shown by this as an active ingredient.
(6) The following formula (I)
R1及びR2は、同一又は異なって、ヒドロキシル基、又は炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表すか、あるいはR1及びR2は、一緒になってメチレンジオキシ基を形成し、
R3及びR4は、同一又は異なって、ヒドロキシル基、又は炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表すか、あるいはR3及びR4は、一緒になってメチレンジオキシ基を形成し、
R5は水素原子、ヒドロキシル基、炭素数1〜5の直鎖若しくは分岐のアルコキシ基、炭素数1〜4のアシル基、又は(D−アピオ−β−D−フラノシル)オキシ、(β-D−グルコピラノシル)オキシ、(3−O,4−O−ジメチル−D−キシロピラノシル)オキシ、(2−O,3−O,4−O−トリメチル−β−D−キシロピラノシル)オキシ、(3−O−メチル−β−D−グルコピラノシル)オキシから選択される糖残基を表し、
R6とR7は水素原子であり且つR8とR9は一緒になって酸素原子を表すか、又はR8とR9は水素原子であり、且つR6とR7は一緒になって酸素原子を表す。〕
で示される化合物又はその塩を有効成分とする美白剤。
R 1 and R 2 are the same or different and each represents a hydroxyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms, or R 1 and R 2 together represent a methylenedioxy group. Forming,
R 3 and R 4 are the same or different and each represents a hydroxyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms, or R 3 and R 4 together represent a methylenedioxy group. Forming,
R 5 represents a hydrogen atom, a hydroxyl group, a linear or branched alkoxy group having 1 to 5 carbon atoms, an acyl group having 1 to 4 carbon atoms, or (D-apio-β-D-furanosyl) oxy, (β-D -Glucopyranosyl) oxy, (3-O, 4-O-dimethyl-D-xylopyranosyl) oxy, (2-O, 3-O, 4-O-trimethyl-β-D-xylopyranosyl) oxy, (3-O- Represents a sugar residue selected from methyl-β-D-glucopyranosyl) oxy,
R 6 and R 7 are hydrogen atoms and R 8 and R 9 together represent an oxygen atom, or R 8 and R 9 are hydrogen atoms and R 6 and R 7 are together Represents an oxygen atom. ]
The whitening agent which uses the compound shown by these, or its salt as an active ingredient.
本発明のドーパオキシダーゼ活性抑制剤、メラニン生成抑制剤、又は美白剤を用いれば、皮膚におけるメラニンの過剰産生を抑制し、日焼け等の色素沈着、シミ、ソバカスの予防、改善又は治療が可能となる。 If the dopa oxidase activity inhibitor, melanin production inhibitor, or whitening agent of the present invention is used, the excessive production of melanin in the skin is suppressed, and it is possible to prevent, improve, or treat pigmentation such as sunburn, spots, and freckles. .
本明細書において、「非治療的」とは、医療行為、すなわち治療による人体への処置行為を含まない概念である。 In the present specification, “non-therapeutic” is a concept that does not include a medical act, that is, a treatment act on the human body by therapy.
本明細書において、「改善」とは、疾患、症状又は状態の好転、疾患、症状又は状態の悪化の防止又は遅延、あるいは疾患、症状又は状態の進行の逆転、防止又は遅延をいう。 In the present specification, “improvement” refers to improvement of a disease, symptom or condition, prevention or delay of deterioration of the disease, symptom or condition, or reversal, prevention or delay of progression of the disease, symptom or condition.
本明細書において、「予防」とは、個体における疾患若しくは症状の発症の防止又は遅延、あるいは個体の疾患若しくは症状の発症の危険性を低下させることをいう。 As used herein, “prevention” refers to preventing or delaying the onset of a disease or symptom in an individual, or reducing the risk of developing an individual's disease or symptom.
本発明のドーパオキシダーゼ活性抑制剤、メラニン生成抑制剤、及び美白剤は、下記式(I)で示されるアリールナフタレンリグナン類又はその塩を有効成分とする。 The dopa oxidase activity inhibitor, melanin production inhibitor, and whitening agent of the present invention contain an arylnaphthalene lignan represented by the following formula (I) or a salt thereof as an active ingredient.
式(I)中、R1及びR2は、同一又は異なって、ヒドロキシル基、又は炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表すか、あるいはR1及びR2は、一緒になってメチレンジオキシ基を形成する。R3及びR4は、同一又は異なって、ヒドロキシル基、又は炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表すか、あるいはR3及びR4は、一緒になってメチレンジオキシ基を形成する。ここで、R1及びR2と、R3及びR4とは、両方が同時にメチレンジオキシ基を形成してもよいが、好ましくは、R1及びR2と、R3及びR4とのいずれか一方のみがメチレンジオキシ基を形成する。 In formula (I), R 1 and R 2 are the same or different and each represents a hydroxyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms, or R 1 and R 2 are combined together. To form a methylenedioxy group. R 3 and R 4 are the same or different and each represents a hydroxyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms, or R 3 and R 4 together represent a methylenedioxy group. Form. Here, both R 1 and R 2 and R 3 and R 4 may simultaneously form a methylenedioxy group, but preferably R 1 and R 2 and R 3 and R 4 Only one of them forms a methylenedioxy group.
好ましくは、R1及びR2がともに炭素数1〜4の直鎖若しくは分岐のアルコキシ基であって、且つR3及びR4が一緒になってメチレンジオキシ基を形成するか、あるいはR1及びR2が一緒になってメチレンジオキシ基を形成し、且つ前記R3及びR4がともに炭素数1〜4の直鎖若しくは分岐のアルコキシ基である。より好ましくは、R1及びR2がともに炭素数1〜4の直鎖若しくは分岐のアルコキシ基であって、且つR3及びR4が一緒になってメチレンジオキシ基を形成する。 Preferably, R 1 and R 2 are both linear or branched alkoxy groups having 1 to 4 carbon atoms, and R 3 and R 4 together form a methylenedioxy group, or R 1 And R 2 together form a methylenedioxy group, and R 3 and R 4 are both linear or branched alkoxy groups having 1 to 4 carbon atoms. More preferably, R 1 and R 2 are both linear or branched alkoxy groups having 1 to 4 carbon atoms, and R 3 and R 4 together form a methylenedioxy group.
上記R1〜R4における炭素数1〜4の直鎖若しくは分岐のアルコキシ基としては、メトキシ、エトキシ、n−プロポキシ、iso−プロポキシ、n−ブトキシ、tert−ブトキシ、sec−ブトキシ及びiso−ブトキシが挙げられる。このうち、メトキシ及びエトキシが好ましく、メトキシがより好ましい。 Examples of the linear or branched alkoxy group having 1 to 4 carbon atoms in R 1 to R 4 include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy and iso-butoxy. Is mentioned. Of these, methoxy and ethoxy are preferable, and methoxy is more preferable.
式(I)中、R5は水素原子、ヒドロキシル基、炭素数1〜5の直鎖若しくは分岐のアルコキシ基、炭素数1〜4のアシル基、又は糖残基を表す。
炭素数1〜5の直鎖若しくは分岐のアルコキシ基としては、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、ペンチルオキシ、エトキシメチル、エトキシエチル、プロポキシメチル、プロポキシエチル、ブトキシメチルが挙げられ、このうち、メトキシ、エトキシ、プロポキシ、イソプロポキシ及びブトキシが好ましく、メトキシ及びエトキシがより好ましい。
炭素数1〜4のアシル基としては、ホルミルオキシ、アセチルオキシ、プロピオニルオキシ及びブチリルオキシが挙げられ、このうち、アセチルオキシ及びプロピオニルオキシが好ましく、アセチルオキシがより好ましい。
糖残基としては、(D−アピオ−β−D−フラノシル)オキシ、(β-D−グルコピラノシル)オキシ、(3−O,4−O−ジメチル−D−キシロピラノシル)オキシ、(2−O,3−O,4−O−トリメチル−β−D−キシロピラノシル)オキシ、(3−O−メチル−β−D−グルコピラノシル)オキシが挙げられ、このうち(D−アピオ−β−D−フラノシル)オキシが好ましい。
In formula (I), R 5 represents a hydrogen atom, a hydroxyl group, a linear or branched alkoxy group having 1 to 5 carbon atoms, an acyl group having 1 to 4 carbon atoms, or a sugar residue.
Examples of the linear or branched alkoxy group having 1 to 5 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, ethoxymethyl, ethoxyethyl, propoxymethyl, propoxyethyl, and butoxymethyl. , Methoxy, ethoxy, propoxy, isopropoxy and butoxy are preferred, and methoxy and ethoxy are more preferred.
Examples of the acyl group having 1 to 4 carbon atoms include formyloxy, acetyloxy, propionyloxy and butyryloxy. Among these, acetyloxy and propionyloxy are preferable, and acetyloxy is more preferable.
Examples of the sugar residue include (D-apio-β-D-furanosyl) oxy, (β-D-glucopyranosyl) oxy, (3-O, 4-O-dimethyl-D-xylopyranosyl) oxy, (2-O, 3-O, 4-O-trimethyl-β-D-xylopyranosyl) oxy, (3-O-methyl-β-D-glucopyranosyl) oxy, of which (D-apio-β-D-furanosyl) oxy Is preferred.
式(I)中、R6とR7はともに水素原子であり、且つR8とR9は一緒になって酸素原子を表す。あるいは、R6とR7は一緒になって酸素原子を表し、R8とR9はともに水素原子である。好ましくは、R6とR7がともに水素原子であって、R8とR9は一緒になって酸素原子を表す。 In formula (I), R 6 and R 7 are both hydrogen atoms, and R 8 and R 9 together represent an oxygen atom. Alternatively, R 6 and R 7 together represent an oxygen atom, and R 8 and R 9 are both hydrogen atoms. Preferably, R 6 and R 7 are both hydrogen atoms, and R 8 and R 9 together represent an oxygen atom.
本発明化合物の好ましい例としては、以下が挙げられる。
ジャスチシジンA(4,6,7−トリメトキシ−9−(1,3−ベンゾジオキソール−5−イル)ナフト[2,3−c]フラン−1(3H)−オン)
ジャスチシジンB(6,7−ジメトキシ−9−(1,3−ベンゾジオキソール−5−イル)ナフト[2,3−c]フラン−1(3H)−オン)
ジャスチシジンC(4−(1,3−ベンゾジオキソール−5−イル)−6,7,9−トリメトキシナフト[2,3−c]フラン−1(3H)−オン)
レトロジャスチシジンB(6,7−ジメトキシ−4−(1,3−ベンゾジオキソール−5−イル)ナフト[2,3−c]フラン−1(3H)−オン)
ジャスチシジンE(4−(1,3−ベンゾジオキソール−5−イル)−6,7−メチレンジオキシナフト[2,3−c]フラン−1(3H)−オン)
ツベルクラチン((−)−4−[(D−アピオ−β−D−フラノシル)オキシ]−9−(1,3−ベンゾジオキソール−5−イル)−6,7−ジメトキシ−1H−ナフト[2,3−c]フラン−3−オン)
ジフィリン(4−ヒドロキシ−6,7−ジメトキシ−9−(1,3−ベンゾジオキソール−5−イル)ナフト[2,3−c]フラン−1(3H)−オン)
ジフィリンアピオシド(9−(1,3−ベンゾジオキソール−5−イル)−4−(D−アピオ−β−D−フラノシルオキシ)−6,7−ジメトキシナフト[2,3−c]フラン−1(3H)−オン)
ハプロミルトシド(9−(1,3−ベンゾジオキソール−5−イル)−7−ヒドロキシ−6−メトキシ−4−(D−アピオ−β−D−フラノシルオキシ)ナフト[2,3−c]フラン−1(3H)−オン)
ハプロミルチン(9−(1,3−ベンゾジオキソール−5−イル)−4,7−ジヒドロキシ−6−メトキシナフト[2,3−c]フラン−1(3H)−オン)
クレイスタンチンA(9−(1,3−ベンゾジオキソール−5−イル)−4−[(3−O,4−O−ジメチル−D−キシロピラノシル)オキシ]−6,7−ジメトキシナフト[2,3−c]フラン−1(3H)−オン)
クレイスタンチンB(9−(1,3−ベンゾジオキソール−5−イル)−4−(β−D−グルコピラノシルオキシ)−6,7−ジメトキシナフト[2,3−c]フラン−1(3H)−オン)
クレイスタンチンD(4−(2−O,3−O,4−O−トリメチル−β−D−キシロピラノシルオキシ)−6,7−ジメトキシ−9−(1,3−ベンゾジオキソール−5−イル)−1,3−ジヒドロナフト[2,3−c]フラン−1−オン)
ダウリノール(9−(1,3−ベンゾジオキソール−5−イル)−6−ヒドロキシ−7−メトキシナフト[2,3−c]フラン−1(3H)−オン)
イソダウリノール(9−(1,3−ベンゾジオキソール−5−イル)−7−ヒドロキシ−6−メトキシナフト[2,3−c]フラン−1(3H)−オン)
コリヌシン((+)−9−(1,3−ベンゾジオキソール−5−イル)−3a,4−ジヒドロ−6,7−ジメトキシナフト[2,3−c]フラン−1(3H)−オン)
タイワニンC(5−(1,3−ベンゾジオキソール−5−イル)フロ[3',4':6,7]ナフト[2,3−d]−1,3−ジオキソール−6(8H)−オン)
タイワニンE(−(1,3−ベンゾジオキソール−5−イル)−9−ヒドロキシフロ[3',4':6,7]ナフト[2,3−d]−1,3−ジオキソール−6(8H)−オン)
フィランツスミンA(4,6−ジメトキシ−7−ヒドロキシ−9−(1,3−ベンゾジオキソール−5−イル)−1,3−ジヒドロナフト[2,3−c]フラン−1−オン)
ジャスチシジンF(5−(1,3−ベンゾジオキソール−5−イル)−9−メトキシフロ[3',4':6,7]ナフト[2,3−d]−1,3−ジオキソール−6(8H)−オン)
4−エトキシ−6,7−ジメトキシ−9−(1,3−ベンゾジオキソール−5−イル)ナフト[2,3−c]フラン−1(3H)−オン
4−アセトキシ−6,7−ジメトキシ−9−(1,3−ベンゾジオキソール−5−イル)ナフト[2,3−c]フラン−1(3H)−オン
(3aR)−3a,4−ジヒドロ−6,7−ジメトキシ−9−(1,3−ベンゾジオキソール−5−イル)ナフト[2,3−c]フラン−1(3H)−オン
(3aS)−3a,4−ジヒドロ−6,7−ジメトキシ−9−(1,3−ベンゾジオキソール−5−イル)ナフト[2,3−c]フラン−1(3H)−オン
4−(3−O−メチル−β−D−グルコピラノシルオキシ)−6,7−ジメトキシ−9−(1,3−ベンゾジオキソール−5−イル)ナフト[2,3−c]フラン−1(3H)−オン
Preferable examples of the compound of the present invention include the following.
Jasticidin A (4,6,7-trimethoxy-9- (1,3-benzodioxol-5-yl) naphtho [2,3-c] furan-1 (3H) -one)
Jasticidin B (6,7-dimethoxy-9- (1,3-benzodioxol-5-yl) naphtho [2,3-c] furan-1 (3H) -one)
Jasticidin C (4- (1,3-benzodioxol-5-yl) -6,7,9-trimethoxynaphtho [2,3-c] furan-1 (3H) -one)
Retrojasticidin B (6,7-dimethoxy-4- (1,3-benzodioxol-5-yl) naphtho [2,3-c] furan-1 (3H) -one)
Justicidin E (4- (1,3-benzodioxol-5-yl) -6,7-methylenedioxynaphtho [2,3-c] furan-1 (3H) -one)
Tuberculin ((−)-4-[(D-Apio-β-D-furanosyl) oxy] -9- (1,3-benzodioxol-5-yl) -6,7-dimethoxy-1H-naphtho [ 2,3-c] furan-3-one)
Diphyrin (4-hydroxy-6,7-dimethoxy-9- (1,3-benzodioxol-5-yl) naphtho [2,3-c] furan-1 (3H) -one)
Diphyrin apioside (9- (1,3-benzodioxol-5-yl) -4- (D-apio-β-D-furanosyloxy) -6,7-dimethoxynaphtho [2,3-c ] Fran-1 (3H) -on)
Hapromiltoside (9- (1,3-benzodioxol-5-yl) -7-hydroxy-6-methoxy-4- (D-apio-β-D-furanosyloxy) naphtho [2,3-c] Furan-1 (3H) -on)
Hapromiltin (9- (1,3-benzodioxol-5-yl) -4,7-dihydroxy-6-methoxynaphtho [2,3-c] furan-1 (3H) -one)
Claystantin A (9- (1,3-benzodioxol-5-yl) -4-[(3-O, 4-O-dimethyl-D-xylopyranosyl) oxy] -6,7-dimethoxynaphtho [ 2,3-c] furan-1 (3H) -one)
Claystantin B (9- (1,3-benzodioxol-5-yl) -4- (β-D-glucopyranosyloxy) -6,7-dimethoxynaphtho [2,3-c] furan -1 (3H) -on)
Claystantin D (4- (2-O, 3-O, 4-O-trimethyl-β-D-xylopyranosyloxy) -6,7-dimethoxy-9- (1,3-benzodioxole) -5-yl) -1,3-dihydronaphtho [2,3-c] furan-1-one)
Daurinol (9- (1,3-benzodioxol-5-yl) -6-hydroxy-7-methoxynaphtho [2,3-c] furan-1 (3H) -one)
Isodaurinol (9- (1,3-benzodioxol-5-yl) -7-hydroxy-6-methoxynaphtho [2,3-c] furan-1 (3H) -one)
Corinosine ((+)-9- (1,3-benzodioxol-5-yl) -3a, 4-dihydro-6,7-dimethoxynaphtho [2,3-c] furan-1 (3H) -one )
Taiwanin C (5- (1,3-benzodioxol-5-yl) furo [3 ′, 4 ′: 6,7] naphtho [2,3-d] -1,3-dioxole-6 (8H) -ON)
Thaiwanin E (-(1,3-benzodioxol-5-yl) -9-hydroxyfuro [3 ′, 4 ′: 6,7] naphtho [2,3-d] -1,3-dioxole-6 (8H)-ON)
Filanthsumin A (4,6-dimethoxy-7-hydroxy-9- (1,3-benzodioxol-5-yl) -1,3-dihydronaphtho [2,3-c] furan-1-one)
Jasticidin F (5- (1,3-benzodioxol-5-yl) -9-methoxyfuro [3 ′, 4 ′: 6,7] naphtho [2,3-d] -1,3-dioxole-6 (8H)-ON)
4-Ethoxy-6,7-dimethoxy-9- (1,3-benzodioxol-5-yl) naphtho [2,3-c] furan-1 (3H) -one 4-acetoxy-6,7- Dimethoxy-9- (1,3-benzodioxol-5-yl) naphtho [2,3-c] furan-1 (3H) -one (3aR) -3a, 4-dihydro-6,7-dimethoxy- 9- (1,3-Benzodioxol-5-yl) naphtho [2,3-c] furan-1 (3H) -one (3aS) -3a, 4-dihydro-6,7-dimethoxy-9- (1,3-Benzodioxol-5-yl) naphtho [2,3-c] furan-1 (3H) -one 4- (3-O-methyl-β-D-glucopyranosyloxy)- 6,7-dimethoxy-9- (1,3-benzodioxol-5-yl) naphtho [2,3-c Fran -1 (3H) - ON
上記に挙げた化合物のうち、さらに好ましいものとしては、ジャスチシジンA、ジャスチシジンB、ツベルクラチン、ジフィリン、4−エトキシ−6,7−ジメトキシ−9−(1,3−ベンゾジオキソール−5−イル)ナフト[2,3−c]フラン−1(3H)−オン、4−アセトキシ−6,7−ジメトキシ−9−(1,3−ベンゾジオキソール−5−イル)ナフト[2,3−c]フラン−1(3H)−オン、ジャスチシジンFが挙げられる。
また、上記に挙げたジャスチシジン類の配糖体も本発明化合物の好ましい例として挙げられる。
Of the compounds listed above, more preferred are jasticidin A, jasticidin B, tuberculin, diphylline, 4-ethoxy-6,7-dimethoxy-9- (1,3-benzodioxol-5-yl). Naphtho [2,3-c] furan-1 (3H) -one, 4-acetoxy-6,7-dimethoxy-9- (1,3-benzodioxol-5-yl) naphtho [2,3-c ] Furan-1 (3H) -one and jasticidin F are mentioned.
Moreover, the glycoside of the jasticidins mentioned above is also mentioned as a preferable example of this invention compound.
上記式(I)化合物は、公知の方法に従って合成してもよく、又は市販品を購入することもできる。合成方法としては、例えば、J.Org.Chem.,1996,61:3452−3457に記載の方法に準じて合成することができる。合成方法の一部の例を以下に示す。 The compound of the above formula (I) may be synthesized according to a known method, or a commercially available product can be purchased. Examples of the synthesis method include J.P. Org. Chem. , 1996, 61: 3452-3457. Some examples of synthesis methods are shown below.
ジフィリンの合成
2-bromo-5,6-dimethoxybenzaldehydeとエチレングリコールとの反応から得られたアセタール化合物を、塩基性条件下で3,4-(methylenedioxy)benzaldehydeと反応させ、さらにDEADCと加温条件下で反応を行ない、最後にNaBH4による還元を行なうことで目的化合物を得ることができる。
ジャスチシジンBの合成
2-bromo-5,6-dimethoxybenzaldehydeとエチレングリコールの反応から得られたアセタール化合物を、塩基性条件下で3,4-(methylenedioxy)benzaldehydeと反応させ、無水マレイン酸と酸性条件下加熱し、最後にNaBH4による還元を行なうことで目的化合物を得ることができる。
ジャスチシジンAの合成
ジフィリンに対して塩基性条件下、ヨウ化メチルを作用させることで目的化合物得ることが出来る。
Synthesis of diphylline
The acetal compound obtained from the reaction of 2-bromo-5,6-dimethoxybenzaldehyde and ethylene glycol is reacted with 3,4- (methylenedioxy) benzaldehyde under basic conditions, and further reacted with DEADC under heating conditions. The final compound can be obtained by performing reduction and NaBH 4 reduction.
Synthesis of jasticidin B
The acetal compound obtained from the reaction of 2-bromo-5,6-dimethoxybenzaldehyde and ethylene glycol is reacted with 3,4- (methylenedioxy) benzaldehyde under basic conditions, heated under maleic anhydride and acidic conditions, and finally The target compound can be obtained by performing reduction with NaBH 4 .
Synthesis of Jasticidin A The target compound can be obtained by reacting diphylline with methyl iodide under basic conditions.
または、Med.Chem.Res.,2010,19:71−76に記載の方法に従って、塩基性条件下でジフィリンにブロモアルカンを添加することによって、4−エトキシ−6,7−ジメトキシ−9−(1,3−ベンゾジオキソール−5−イル)ナフト[2,3−c]フラン−1(3H)−オンを得ることができる。
または、第5版実験化学講座16第42頁に記載されているように、ジフィリンを出発物質として、ジフィリンの水酸基を一般的なアシル化方法によりアシル化することで4−アセトキシ−6,7−ジメトキシ−9−(1,3−ベンゾジオキソール−5−イル)ナフト[2,3−c]フラン−1(3H)−オンを得ることができる。
Or, Med. Chem. Res. 4-ethoxy-6,7-dimethoxy-9- (1,3-benzodioxole) by adding a bromoalkane to diphylline under basic conditions according to the method described in US Pat. -5-yl) naphtho [2,3-c] furan-1 (3H) -one can be obtained.
Alternatively, as described in the 5th edition, Experimental Chemistry Course 16, page 42, 4-acetoxy-6,7- can be obtained by acylating the hydroxyl group of diphyrin by a general acylation method using diphylline as a starting material. Dimethoxy-9- (1,3-benzodioxol-5-yl) naphtho [2,3-c] furan-1 (3H) -one can be obtained.
市販品としては、TimTec Inc.のカタログNo.ST077116、Pharmeks LTD.のカタログNo.P2000N−07371、P2000N−22338、P2000N−10719、ChromaDex Inc.のカタログNo.ABS−00020012−001、等が挙げられる。 Commercially available products include TimTec Inc. Catalog No. ST0771116, Pharmeks LTD. Catalog No. P2000N-07371, P2000N-22338, P2000N-10719, ChromaDex Inc. Catalog No. ABS-00020012-001, etc.
あるいは、上記式(I)化合物は、ハグロソウ(Peristrophe japonica)、キツネノマゴ(Justicia procumbens)、Haplophyllum patavinum、Cleistanthus Collinus等の植物から単離することもできる。
Haplophyllum patavinum、及びCleistanthus Collinusからの単離は、Chem.Pharm.Bull.,2002,50:844−846、及びTetrahedron,1969,25:2815−2821に記載の方法に従って行えばよく、これらの植物から単離される化合物としてジャスチシジンB、ジフィリン、クレイスタンチンAが挙げられる。
Alternatively, the compound of the above formula (I) can also be isolated from plants such as Hakuso ( Peristrophe japonica ), Foxtail ( Justicia procumbens ), Haplophyllum patavinum , Cleistanthus Collinus and the like.
Haplophyllum patavinum, and is isolated from the Cleistanthus Collinus, Chem. Pharm. Bull. 2002, 50: 844-846, and Tetrahedron, 1969, 25: 2815-2821, and compounds isolated from these plants include jasticidin B, diphylline, and craistatin A.
ハグロソウ及びキツネノマゴから単離する場合は、これらの植物の抽出物をカラムクロマトグラフィー等により精製することで、式(I)化合物を得ることができる。これらの植物から単離される化合物としてジャスチシジンA、ジャスチシジンB、ツベルクラチンが挙げられる。
より具体的には、ハグロソウ又はキツネノマゴの任意の部位、好ましくはハグロソウの場合は全草、キツネノマゴの場合は全草を必要に応じて乾燥、粉砕したものを抽出にかけ、得られた抽出物を、必要に応じて濃縮及び夾雑物を除去し、カラムクロマトグラフィー精製する。
In the case of isolation from the sunflower and foxtail, compounds of formula (I) can be obtained by purifying extracts of these plants by column chromatography or the like. Examples of compounds isolated from these plants include justicidin A, justicidin B, and tuberculin.
More specifically, an arbitrary portion of the sunflower or foxtail, preferably whole grass in the case of brown grass, dried and pulverized as necessary in the case of foxtail is subjected to extraction, and the resulting extract is extracted, Concentrate and remove impurities as necessary, and purify by column chromatography.
上記抽出に使用する溶媒としては、極性有機溶媒、非極性有機溶媒等の有機溶媒が好ましい。当該有機溶剤としては、1価、2価又は多価のアルコール類;アセトン、メチルエチルケトン等のケトン類;酢酸メチル、酢酸エチル等のエステル類;テトラヒドロフラン、ジエチルエーテル等の鎖状又は環状のエーテル類;ポリエチレングリコール等のポリエーテル類;飽和又は不飽和の炭化水素類;ベンゼン、トルエン等の芳香族炭化水素類;ジクロロメタン、クロロホルム、ジクロロエタン、四塩化炭素等のハロゲン化炭化水素類;ピリジン類;ジメチルスルホキシド;アセトニトリル;二酸化炭素、超臨界二酸化炭素;油脂、ワックス、その他のオイル類等が挙げられる。これらの有機溶媒は、単独で又は2種以上混合して使用することができる。 As a solvent used for the said extraction, organic solvents, such as a polar organic solvent and a nonpolar organic solvent, are preferable. Examples of the organic solvent include monovalent, divalent or polyhydric alcohols; ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate and ethyl acetate; chain or cyclic ethers such as tetrahydrofuran and diethyl ether; Polyethers such as polyethylene glycol; saturated or unsaturated hydrocarbons; aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride; pyridines; dimethyl sulfoxide Acetonitrile; carbon dioxide, supercritical carbon dioxide; fats and oils, waxes, and other oils. These organic solvents can be used alone or in admixture of two or more.
上記アルコール類としては、特に限定されないが、好ましい例としては、メタノール、エタノール、1,3−ブチレングリコール、n−プロパノール、イソプロパノール、n−ブタノール、イソブタノール、sec−ブタノール、t−ブタノール等が挙げられ、取り扱いが容易な点から、エタノール及び1,3−ブチレングリコールがより好ましい。 The alcohols are not particularly limited, but preferred examples include methanol, ethanol, 1,3-butylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, t-butanol and the like. In view of easy handling, ethanol and 1,3-butylene glycol are more preferable.
上記飽和炭化水素類としては、直鎖、分岐鎖又は環状の飽和炭化水素が挙げられ、好ましい例としては、n−ペンタン、n−ヘキサン、n−ヘプタン、n−オクタン、2−メチルブタン、2,2−ジメチルプロパン、2−メチルペンタン、3−メチルペンタン、2,2−ジメチルブタン、2,3−ジメチルブタン、2−メチルヘキサン、3−メチルヘキサン、シクロヘキサン等が挙げられ、取り扱いが容易な点から、n−ヘキサンが好ましい。 Examples of the saturated hydrocarbons include linear, branched or cyclic saturated hydrocarbons. Preferred examples include n-pentane, n-hexane, n-heptane, n-octane, 2-methylbutane, 2, Examples include 2-dimethylpropane, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, 2-methylhexane, 3-methylhexane, cyclohexane and the like. Therefore, n-hexane is preferable.
上記抽出に使用する有機溶媒は含水のものでもよい。該含水有機溶媒に使用される有機溶媒としては、特に限定されないが、好ましい例としては上記アルコール類が挙げられ、エタノール及び1,3−ブチレングリコールがより好ましい。該含水有機溶媒中の有機溶媒の濃度は、少なくとも30容量%以上、より好ましくは50〜100容量%、さらに好ましくは75〜100容量%、なお好ましくは75〜99.9容量%である。 The organic solvent used for the extraction may be one containing water. Although it does not specifically limit as an organic solvent used for this water-containing organic solvent, As a preferable example, the said alcohol is mentioned, Ethanol and 1, 3- butylene glycol are more preferable. The concentration of the organic solvent in the water-containing organic solvent is at least 30% by volume or more, more preferably 50 to 100% by volume, still more preferably 75 to 100% by volume, still more preferably 75 to 99.9% by volume.
上記抽出の手段としては、特に限定されないが、例えば、液液抽出、固液抽出、浸漬、浸出、煎出、還流抽出、超音波抽出、マイクロ波抽出、遠心抽出等が挙げられ、単独で又は2種以上を組み合わせて用いることができる。このとき、バッチ式抽出器やソックスレー抽出器等を用いてもよい。また、抽出は、煮沸脱気や窒素ガス等の不活性ガスを通気して溶存酸素を除去しつつ、非酸化的雰囲気下で行ってもよい。 The extraction means is not particularly limited, and examples thereof include liquid-liquid extraction, solid-liquid extraction, immersion, leaching, decoction, reflux extraction, ultrasonic extraction, microwave extraction, centrifugal extraction, and the like. Two or more kinds can be used in combination. At this time, a batch type extractor or a Soxhlet extractor may be used. The extraction may be performed in a non-oxidative atmosphere while removing dissolved oxygen by bubbling degassing or inert gas such as nitrogen gas.
抽出条件の一例として、植物1質量部(乾燥物換算)に対して、抽出溶媒として溶媒濃度50〜95容量%含有の1価若しくは2価のアルコール水溶液1〜50質量部を用いて、10〜40℃、好ましくは20〜40℃で、1時間〜30日間、好ましくは5〜20日間抽出する条件が挙げられる。 As an example of extraction conditions, 1 to 50 parts by mass of a monovalent or divalent aqueous alcohol solution containing a solvent concentration of 50 to 95% by volume is used as an extraction solvent with respect to 1 part by mass of the plant (in terms of dry matter). The conditions include extraction at 40 ° C., preferably 20 to 40 ° C., for 1 hour to 30 days, preferably 5 to 20 days.
上述のようにして得られたハグロソウ又はキツネノマゴ抽出物は、好ましくは、カラムクロマトグラフィーにかける前に、必要に応じて濃縮乾固された後、水洗や液液分配、固液抽出等にかけられる。これらの手段を用いると、抽出物から水溶性の夾雑物等を除去できるため有利である。
具体的には、ハグロソウ又はキツネノマゴの抽出物、好ましくは親水性有機溶剤抽出物に、水及び/又は疎水性有機溶媒等の溶媒を添加し、混合、撹拌、振とう、遠心分離等の物理的手段を行ったのち、活性成分が主として含まれる疎水性画分(層)の回収を行う。適宜この操作を1〜3回繰り返し行ってもよい。集めた疎水性画分は、次いでカラムクロマトグラフィーに供される。
The ginseng or foxtail extract obtained as described above is preferably concentrated and dried as necessary before being subjected to column chromatography, followed by washing with water, liquid-liquid distribution, solid-liquid extraction and the like. Use of these means is advantageous because water-soluble impurities and the like can be removed from the extract.
Specifically, a solvent such as water and / or a hydrophobic organic solvent is added to an extract of sunflower or foxtail, preferably a hydrophilic organic solvent extract, and physical, such as mixing, stirring, shaking, centrifugation, etc. After performing the means, the hydrophobic fraction (layer) mainly containing the active ingredient is recovered. You may repeat this operation 1-3 times suitably. The collected hydrophobic fraction is then subjected to column chromatography.
上記抽出物に添加する溶媒(以下、「添加溶媒」とする。)としては、水、疎水性有機溶媒又は水−疎水性有機溶媒混合液を用いればよいが、水−疎水性有機溶媒混合液を用いるのが、水洗と疎水性有機溶剤抽出とが同時に行え、作業効率がよいため有利である。疎水性有機溶媒としては、特に限定されないが、例えば、上述した、飽和又は不飽和の炭化水素類;芳香族炭化水素類;ハロゲン化炭化水素類;鎖状若しくは環状のエーテル類又はポリエーテル類;酢酸エチル等のエステル類;オイル等が挙げられ、このうち、n−ヘキサン、酢酸エチル等が好ましい。尚、これら各疎水性有機溶剤を単独で又は2種以上混合して使用することができる。
上記水−疎水性有機溶媒混合液中の水と疎水性有機溶媒との混合割合は、特に限定されないが、水(v):疎水性有機溶媒(v)=1:0.1〜1:10、より1:0.1〜1:5とするのが好ましい。
上記添加溶媒の使用量は、特に限定されないが、抽出液の乾固物1gに対して、10〜100mLであるのが好ましい。また、温度は、4〜80℃であるのが好ましく、10〜40℃、さらに10〜30℃であるのがより好ましい。
As a solvent to be added to the extract (hereinafter referred to as “addition solvent”), water, a hydrophobic organic solvent, or a water-hydrophobic organic solvent mixed solution may be used, but a water-hydrophobic organic solvent mixed solution may be used. It is advantageous to use water since washing with water and extraction with a hydrophobic organic solvent can be performed simultaneously and the working efficiency is good. Although it does not specifically limit as a hydrophobic organic solvent, For example, the above-mentioned saturated or unsaturated hydrocarbons; Aromatic hydrocarbons; Halogenated hydrocarbons; Linear or cyclic ethers or polyethers; Examples include esters such as ethyl acetate; oils, etc. Among these, n-hexane, ethyl acetate and the like are preferable. Each of these hydrophobic organic solvents can be used alone or in admixture of two or more.
The mixing ratio of water and the hydrophobic organic solvent in the water-hydrophobic organic solvent mixture is not particularly limited, but water (v): hydrophobic organic solvent (v) = 1: 0.1 to 1:10. More preferably, the ratio is 1: 0.1 to 1: 5.
Although the usage-amount of the said addition solvent is not specifically limited, It is preferable that it is 10-100 mL with respect to 1g of the dried solids of an extract. The temperature is preferably 4 to 80 ° C, more preferably 10 to 40 ° C, and further preferably 10 to 30 ° C.
添加溶媒による液液分配の一例として、濃縮して溶媒を除去した抽出物の水−酢酸エチル(1:1)溶媒による液液分配が挙げられる。得られた酢酸エチル層を以下に記載するカラムクロマトグラフィーに供すればよい。 As an example of liquid-liquid distribution by an added solvent, liquid-liquid distribution by a water-ethyl acetate (1: 1) solvent of an extract that has been concentrated to remove the solvent can be mentioned. The obtained ethyl acetate layer may be subjected to column chromatography described below.
上記手順で得られたハグロソウ又はキツネノマゴ抽出物、又は必要に応じて上記添加溶媒によるさらなる抽出若しくは液液分配にかけられた抽出物は、シリカゲルカラム等によるカラムクロマトグラフィーにかけられる。
カラムクロマトグラフィーでは、例えば、ヘキサン−酢酸エチルで酢酸エチル比率0%から100%まで60分間でグラジエントをかけ、その後酢酸エチル−メタノールでメタノール比率0%から10%まで30分間でグラジエントかけた後、100%メタノールで30分間溶出を行ない、この際ヘキサン/酢酸エチル=1/9比率付近から100%MeOHで溶出されてくる画分を取得すればよい。それらの画分はMeOHに不溶であるものと可溶であるものに分離することができ、MeOHに不溶であるものは0.1%ギ酸水溶液‐アセトニトリルの2層系で逆相HPLCにかけられ、20分間の50%アセトニトリルによる溶出でおよそ10分から15分付近に溶出されてくる画分を取得すればよい。一方MeOH可溶であるものは、0.1%ギ酸水溶液‐アセトニトリルの2層系で逆相HPLCにかけられ、16分間の35%アセトニトリルによる溶出でおよそ12分から15分付近に溶出されてくる画分を取得すればよい。
必要に応じて、得られた画分のドーパオキシダーゼ活性を測定することによって、目的の式(I)化合物を含む画分であることを確認することができる。ドーパオキシダーゼ活性の測定方法は、例えば後述の実施例に記載されるような方法に準じて行えばよい。
The extract of Amaranthus or Vulpes obtained by the above procedure, or an extract subjected to further extraction or liquid-liquid distribution with the above-described additional solvent as necessary, is subjected to column chromatography using a silica gel column or the like.
In column chromatography, for example, a gradient from 60% to 100% ethyl acetate in hexane-ethyl acetate is applied for 60 minutes, and then a gradient from 0% to 10% in methanol in ethyl acetate-methanol is applied for 30 minutes. Elution is performed with 100% methanol for 30 minutes, and at this time, a fraction eluted with 100% MeOH from around hexane / ethyl acetate = 1/9 ratio may be obtained. Those fractions can be separated into those that are insoluble in MeOH and those that are soluble, and those that are insoluble in MeOH are subjected to reverse phase HPLC in a two-layer system of 0.1% aqueous formic acid-acetonitrile, What is necessary is just to acquire the fraction eluted in about 10 to 15 minutes by elution with 50% acetonitrile for 20 minutes. On the other hand, MeOH-soluble fractions were subjected to reversed-phase HPLC in a 0.1% formic acid aqueous solution-acetonitrile two-layer system and eluted at about 12 to 15 minutes by elution with 35% acetonitrile for 16 minutes. Just get it.
If necessary, by measuring the dopa oxidase activity of the obtained fraction, it can be confirmed that the fraction contains the target compound of formula (I). What is necessary is just to perform the measuring method of dopa oxidase activity according to a method as described in the below-mentioned Example, for example.
斯くして得られた式(I)化合物は、後記実施例に示すように、ドーパオキシダーゼ活性を強く抑制すると云う優れたドーパ−オキシダーゼ活性抑制作用を有し、且つ細胞毒性も低いことから、長期間使用しても安全性の高い美白作用を有している。ドーパオキシダーゼ活性はメラニン生成のメカニズムに深く関与する(非特許文献1)。後記実施例に示すように、式(I)化合物により、皮膚組織中のメラニン生成量を抑えることができる。
従って、式(I)化合物又はその塩により、ドーパオキシダーゼ活性を抑制する効果が得られるとともに、メラニン生成抑制効果、及び美白作用や紫外線被爆等による皮膚の色素沈着、シミ、ソバカス等の症状を予防、改善又は治療する効果を得ることができる。
すなわち、式(I)化合物又はその塩は、ドーパ−オキシダーゼ活性抑制のため、メラニン生成抑制のため、美白のため、又は皮膚の色素沈着、シミ、ソバカス等の症状を予防、改善、若しくは治療するために使用することができる。
これらの使用は、ヒト若しくは非ヒト動物、又はそれらに由来する組織、器官、細胞における使用であり得、また治療的使用であっても非治療的使用であってもよい。
The compound of formula (I) thus obtained has an excellent dopa-oxidase activity inhibitory action of strongly suppressing dopa oxidase activity and has low cytotoxicity, as shown in Examples below. Even if used for a long period of time, it has a highly safe whitening effect. The dopa oxidase activity is deeply involved in the mechanism of melanin production (Non-patent Document 1). As shown in Examples below, the amount of melanin produced in the skin tissue can be suppressed by the compound of formula (I).
Therefore, the compound of formula (I) or a salt thereof has an effect of suppressing dopa oxidase activity, and also has an effect of suppressing melanin production, and prevention of symptoms such as skin pigmentation, spots and freckles due to whitening and UV exposure. The effect of improving or treating can be obtained.
That is, the compound of formula (I) or a salt thereof prevents, ameliorates or treats symptoms such as skin pigmentation, stains, freckles, etc., for inhibiting dopa-oxidase activity, for inhibiting melanin production, for whitening, or for skin pigmentation. Can be used for.
These uses can be in humans or non-human animals, or tissues, organs, cells derived therefrom, and can be either therapeutic or non-therapeutic.
従って、本発明は、式(I)化合物又はその塩を有効成分とするドーパオキシダーゼ活性抑制剤を提供する。
また本発明は、式(I)化合物又はその塩を有効成分とするメラニン生成抑制剤を提供する。
また本発明は、式(I)化合物又はその塩を有効成分とする美白剤を提供する。
上記剤は、式(I)化合物又はその塩から本質的に構成されていてもよい。
Accordingly, the present invention provides a dopa oxidase activity inhibitor comprising the compound of formula (I) or a salt thereof as an active ingredient.
Moreover, this invention provides the melanin production inhibitor which uses a formula (I) compound or its salt as an active ingredient.
The present invention also provides a whitening agent comprising a compound of formula (I) or a salt thereof as an active ingredient.
The agent may consist essentially of the compound of formula (I) or a salt thereof.
式(I)化合物又はその塩は、ドーパオキシダーゼ活性抑制のため、メラニン生成抑制のため、美白のため、皮膚の色素沈着、シミ、ソバカス等の症状を予防、改善、若しくは治療するための組成物、医薬、医薬部外品、外用剤、化粧料、飲食品、飼料、又は飲食品若しくは飼料の原料等に素材として配合することができ、あるいはそれらの製造のために使用することができる。当該組成物、医薬、医薬部外品、外用剤、化粧料、飲食品、飼料、又は飲食品若しくは飼料の原料等もまた、本発明の範囲内である。 The compound of formula (I) or a salt thereof is a composition for preventing, ameliorating or treating symptoms such as skin pigmentation, spots, freckles, etc., for inhibiting dopa oxidase activity, for inhibiting melanin production, for whitening It can be blended as a raw material in medicines, quasi-drugs, external preparations, cosmetics, foods and drinks, feeds, raw materials for foods and drinks or feeds, or can be used for their production. The composition, medicine, quasi drug, external preparation, cosmetics, food and drink, feed, food and drink or feed raw material are also within the scope of the present invention.
上記組成物、医薬、医薬部外品、外用剤、化粧料、飲食品、飼料、又は飲食品若しくは飼料の原料等は、ヒト又は非ヒト動物用として製造され、又は使用され得る。式(I)化合物又はその塩は、当該組成物、医薬、医薬部外品、外用剤、化粧料、飲食品、飼料、又は飲食品若しくは飼料の原料等に配合され、ドーパオキシダーゼ活性抑制のため、メラニン生成抑制のため、美白のため、あるいは皮膚の色素沈着、シミ、ソバカス等の症状を予防、改善、若しくは治療するための有効成分であり得る。 The composition, medicine, quasi-drug, external preparation, cosmetic, food and drink, feed, food or drink or feed raw material, etc. can be produced or used for human or non-human animals. The compound of formula (I) or a salt thereof is blended in the composition, medicine, quasi-drug, external preparation, cosmetic, food / beverage product, feed, food / beverage product or feed raw material, etc. for suppressing dopa oxidase activity In addition, it may be an active ingredient for inhibiting melanin production, for whitening, or for preventing, ameliorating, or treating symptoms such as skin pigmentation, spots, and freckles.
上記医薬又は医薬部外品は、式(I)化合物又はその塩を有効成分として含有する。当該医薬又は医薬部外品は、任意の投与形態で投与され得る。投与は経口でも非経口でもよい。経口投与のための剤型としては、例えば、錠剤、被覆錠剤、顆粒剤、散剤、カプセル剤のような固形投薬形態、ならびにエリキシロール、シロップおよび懸濁液のような液体投薬形態が挙げられ、非経口投与のための剤型としては、注射、輸液、局所、外用剤、経皮、経粘膜、経鼻、経腸、吸入、坐剤、ボーラス、貼布剤等が挙げられる。
好ましくは、当該医薬又は医薬部外品は、皮膚外用剤の形態であり得る。
The said pharmaceutical or quasi-drug contains the compound of formula (I) or a salt thereof as an active ingredient. The pharmaceutical or quasi drug can be administered in any dosage form. Administration may be oral or parenteral. Dosage forms for oral administration include, for example, solid dosage forms such as tablets, coated tablets, granules, powders, capsules, and liquid dosage forms such as elixirol, syrups and suspensions, Examples of the dosage form for parenteral administration include injection, infusion, topical, external preparation, transdermal, transmucosal, nasal, enteral, inhalation, suppository, bolus, patch and the like.
Preferably, the medicine or quasi drug may be in the form of a skin external preparation.
上記医薬又は医薬部外品は、式(I)化合物又はその塩を単独で含有していてもよく、又は薬学的に許容される担体と組み合わせて含有していてもよい。斯かる担体としては、例えば、賦形剤、被膜剤、結合剤、増量剤、崩壊剤、滑沢剤、希釈剤、浸透圧調整剤、pH調整剤、分散剤、乳化剤、防腐剤、安定剤、酸化防止剤、着色剤、紫外線吸収剤、保湿剤、増粘剤、活性増強剤、抗炎症剤、殺菌剤、香料、矯味剤、矯臭剤等が挙げられる。また、当該医薬や医薬部外品は、式(I)化合物又はその塩のドーパオキシダーゼ活性抑制作用が失われない限り、他の有効成分や薬理成分を含有していてもよい。 The medicament or quasi-drug may contain the compound of formula (I) or a salt thereof alone or in combination with a pharmaceutically acceptable carrier. Examples of such carriers include excipients, coating agents, binders, extenders, disintegrating agents, lubricants, diluents, osmotic pressure adjusting agents, pH adjusting agents, dispersing agents, emulsifiers, preservatives, and stabilizers. , Antioxidants, colorants, ultraviolet absorbers, humectants, thickeners, activity enhancers, anti-inflammatory agents, bactericides, flavoring agents, flavoring agents, flavoring agents and the like. Moreover, the said pharmaceutical and quasi-drug may contain another active ingredient and a pharmacological component, as long as the dopa oxidase activity inhibitory effect of a compound of formula (I) or its salt is not lost.
上記化粧料は、式(I)化合物又はその塩を有効成分として含有する。当該化粧料は、式(I)化合物又はその塩を単独で含有していてもよく、又は化粧料として許容される担体と組み合わせて含有していてもよい。斯かる担体としては、例えば、賦形剤、被膜剤、結合剤、増量剤、崩壊剤、滑沢剤、希釈剤、浸透圧調整剤、pH調整剤、分散剤、乳化剤、防腐剤、安定剤、酸化防止剤、着色剤、紫外線吸収剤、保湿剤、増粘剤、活性増強剤、抗炎症剤、殺菌剤、香料、矯味剤、矯臭剤等が挙げられる。
また、当該化粧料は、式(I)化合物又はその塩のドーパオキシダーゼ活性抑制作用作用が失われない限り、他の有効成分や化粧成分、例えば、保湿剤、美白剤、紫外線保護剤、細胞賦活剤、洗浄剤、角質溶解剤、メークアップ成分(例えば、化粧下地、ファンデーション、おしろい、パウダー、チーク、口紅、アイメーク、アイブロウ、マスカラ、その他)等を含有していてもよい。
化粧料とする場合の形態としては、クリーム、乳液、ローション、懸濁液、ジェル、パウダー、パック、シート、パッチ、スティック、ケーキ等、化粧料に使用され得る任意の形態が挙げられる。好ましくは、上記化粧料は美白用化粧料である。
The cosmetic contains the compound of formula (I) or a salt thereof as an active ingredient. The cosmetic may contain the compound of formula (I) or a salt thereof alone or in combination with a carrier acceptable as a cosmetic. Examples of such carriers include excipients, coating agents, binders, extenders, disintegrating agents, lubricants, diluents, osmotic pressure adjusting agents, pH adjusting agents, dispersing agents, emulsifiers, preservatives, and stabilizers. , Antioxidants, colorants, ultraviolet absorbers, humectants, thickeners, activity enhancers, anti-inflammatory agents, bactericides, flavoring agents, flavoring agents, flavoring agents and the like.
In addition, as long as the dopa oxidase activity inhibitory action of the compound of formula (I) or a salt thereof is not lost, the cosmetics may contain other active ingredients and cosmetic ingredients such as humectants, whitening agents, UV protection agents, cell activation agents. An agent, a detergent, a keratolytic agent, a make-up component (for example, makeup base, foundation, funny, powder, teak, lipstick, eye makeup, eyebrow, mascara, etc.) may be contained.
Examples of the form of the cosmetic include creams, emulsions, lotions, suspensions, gels, powders, packs, sheets, patches, sticks, cakes, and the like, which can be used for cosmetics. Preferably, the cosmetic is a whitening cosmetic.
上記医薬、医薬部外品又は化粧料は、式(I)化合物又はその塩から、あるいは必要に応じて上記担体及び/又は他の有効成分や、化粧成分、薬理成分を組みあわせて、常法により製造することができる。
例えば、上述した皮膚外用剤である医薬若しくは医薬部外品又は皮膚外用化粧料は、式(I)化合物又はその塩を、単独で、又は外用剤、外用医薬品、医薬部外品若しくは皮膚化粧料に通常配合される添加剤と組み合わせることにより調製することができる。当該添加剤としては、油又は油状物質(油脂類、ロウ類、高級脂肪酸類、精油類、シリコーン油類等)、保湿剤(グリセロール、ソルビトール、ゼラチン、ポリエチレングリコール等)、粉体(チョーク、タルク、フラー土、カオリン、デンプン、ゴム等)、色素、乳化剤、可溶化剤、洗浄剤、紫外線吸収剤、増粘剤、薬効成分、香料、樹脂、防菌防黴剤、他の植物抽出物(生薬、漢方薬、ハーブ類)、アルコール類、多価アルコール類、無機酸(重炭酸塩、炭酸塩、塩化ナトリウム、塩化カリウム、硫酸ナトリウム等)、有機酸(コハク酸、グルタル酸、フマル酸、グルタミン酸、リンゴ酸、クエン酸、アスコルビン酸等)、ビタミン類(ビタミンA類、ビタミンE類、ビタミンB類、ビタミンC、葉酸等)、水溶性高分子、アニオン性界面活性剤(アルキルベンゼンスルホン酸塩、アルキル硫酸塩等)、カチオン性界面活性剤(アルキル四級アンモニウム塩、アルキルジメチルベンジルアンモニウム塩等)、非イオン性界面活性剤(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アルキルフェニルエーテル等)、両性界面活性剤(アルキル基を有するイミダゾリン系、カルボベタイン系等)等が挙げられる。
The above-mentioned medicine, quasi-drug or cosmetic can be prepared from the compound of formula (I) or a salt thereof, or in combination with the above carrier and / or other active ingredients, cosmetic ingredients and pharmacological ingredients as necessary. Can be manufactured.
For example, the above-mentioned pharmaceutical preparation for external use for skin or quasi-drug or cosmetic preparation for skin is a compound of formula (I) or a salt thereof alone, or an external preparation, a pharmaceutical preparation for external use, a quasi-drug or skin cosmetic. It can be prepared by combining with additives usually blended in Such additives include oils or oily substances (oils and fats, waxes, higher fatty acids, essential oils, silicone oils, etc.), humectants (glycerol, sorbitol, gelatin, polyethylene glycol, etc.), powders (chalk, talc, etc.) , Fuller earth, kaolin, starch, rubber, etc.), pigments, emulsifiers, solubilizers, detergents, UV absorbers, thickeners, medicinal ingredients, fragrances, resins, antibacterial and antifungal agents, other plant extracts ( Herbal medicine, herbal medicine, herbs), alcohols, polyhydric alcohols, inorganic acids (bicarbonate, carbonate, sodium chloride, potassium chloride, sodium sulfate, etc.), organic acids (succinic acid, glutaric acid, fumaric acid, glutamic acid) , Malic acid, citric acid, ascorbic acid, etc.), vitamins (vitamin A, vitamin E, vitamin B, vitamin C, folic acid, etc.), water-soluble polymer, anionic field Activators (alkyl benzene sulfonates, alkyl sulfates, etc.), cationic surfactants (alkyl quaternary ammonium salts, alkyl dimethyl benzyl ammonium salts, etc.), nonionic surfactants (polyoxyethylene alkyl ether, polyoxyethylene) Alkylphenyl ethers, etc.), amphoteric surfactants (imidazoline type having an alkyl group, carbobetaine type, etc.).
当該医薬、医薬部外品又は化粧料における式(I)化合物又はその塩の含有量は、式(I)化合物として、1.0×10-10〜0.01質量%が好ましく、1.0×10-8〜0.005質量%がより好ましい。 The content of the compound of formula (I) or a salt thereof in the medicine, quasi-drug or cosmetic is preferably 1.0 × 10 −10 to 0.01% by mass as the compound of formula (I). × 10 −8 to 0.005 mass% is more preferable.
上記飲食品や飼料は、ドーパオキシダーゼ活性抑制、メラニン生成抑制、美白、又は皮膚の色素沈着、シミ、ソバカス等の症状の予防、改善若しくは治療等の機能を得ることを企図し、当該機能を必要に応じて表示した食品、機能性食品、病者用食品、特定保健用食品、ペットフード等であり得る。 The above-mentioned food and drink and feed are intended to obtain functions such as suppression of dopa oxidase activity, suppression of melanin production, whitening, or prevention, improvement or treatment of symptoms such as skin pigmentation, spots and freckles. Food, functional food, food for the sick, food for specified health use, pet food and the like.
上記飲食品の種類は特に限定されない。飲料としては、例えば、果汁飲料、炭酸飲料、茶系飲料、コーヒー飲料、乳飲料、アルコール飲料、清涼飲料等、あらゆる飲料が挙げられる。食品の形態は、固形、半固形、液状等の任意の形態であってもよく、また錠剤形態、丸剤形態、タブレット、カプセル形態、液剤形態、シロップ形態、粉末形態、顆粒形態等であってもよい。例えば、食品としては、パン類、麺類、パスタ、ゼリー状食品、各種スナック類、ケーキ類、菓子類、アイスクリーム類、スープ類、乳製品、冷凍食品、インスタント食品、その他加工食品、調味料、サプリメント等が挙げられる。上記飼料の種類も特に限定されず、任意の動物のための飼料であってよく、その形態も上記食品の場合と同様に任意の形態であり得る。 The kind of said food / beverage products is not specifically limited. Examples of the beverage include all beverages such as fruit juice beverages, carbonated beverages, tea beverages, coffee beverages, milk beverages, alcoholic beverages, and soft drinks. The form of the food may be any form such as solid, semi-solid, liquid, etc., and may be tablet form, pill form, tablet, capsule form, liquid form, syrup form, powder form, granule form, etc. Also good. For example, as food, breads, noodles, pasta, jelly-like foods, various snacks, cakes, confectionery, ice creams, soups, dairy products, frozen foods, instant foods, other processed foods, seasonings, And supplements. The kind of the feed is not particularly limited and may be a feed for any animal, and the form thereof may be any form as in the case of the food.
上記飲食品、飼料、又はそれらの原料は、式(I)化合物又はその塩を単独で含有していてもよく、又は他の食材や、溶剤、軟化剤、油、乳化剤、防腐剤、香科、安定剤、着色剤、酸化防止剤、保湿剤、増粘剤等の添加剤を組み合わせて含有していてもよい。当該飲食品若しくは飼料中の式(I)化合物又はその塩の含有量は、式(I)化合物として、1.0×10-10〜0.01質量%が好ましく、1.0×10-9〜0.001質量%がより好ましく、1.0×10-8〜1.0×10-4質量%がさらに好ましい。 The above food and drink, feed, or raw materials thereof may contain the compound of formula (I) or a salt thereof alone, or other foods, solvents, softeners, oils, emulsifiers, preservatives, fragrances , Stabilizers, colorants, antioxidants, humectants, thickeners, and other additives may be included in combination. The content of the compound of formula (I) or a salt thereof in the food or drink or feed is preferably 1.0 × 10 −10 to 0.01% by mass as the compound of formula (I), and 1.0 × 10 −9. -0.001 mass% is more preferable, 1.0 * 10 < -8 > -1.0 * 10 < -4 > mass% is further more preferable.
また本発明は、細胞のドーパオキシダーゼ活性を抑制する方法を提供する。当該方法は、チロシナーゼ発現能を有し且つドーパオキシダーゼ活性を抑制したい細胞に、式(I)化合物又はその塩を添加する工程を含む。
また本発明は、細胞のメラニン生成を抑制する方法を提供する。当該方法は、メラニン生成能を有し且つメラニン生成を抑制したい細胞に、式(I)化合物又はその塩を添加する工程を含む。
The present invention also provides a method for suppressing cellular dopa oxidase activity. The method includes a step of adding a compound of formula (I) or a salt thereof to a cell having the ability to express tyrosinase and suppressing dopa oxidase activity.
The present invention also provides a method for suppressing cellular melanin production. The method includes a step of adding a compound of formula (I) or a salt thereof to a cell having melanin production ability and suppressing melanin production.
また本発明において、式(I)化合物又はその塩は、ドーパオキシダーゼ活性抑制のため、メラニン生成抑制のため、美白のため、あるいは皮膚の色素沈着、シミ、ソバカス等の症状を予防、改善、若しくは治療するために、それらを必要とする対象に有効量で投与又は摂取され得る。当該投与又は摂取は、健康増進又は美容目的により非治療的に行われてもよい。
投与又は摂取の対象としては、ドーパオキシダーゼ活性の抑制を必要とする動物が挙げられる。あるいは、投与又は摂取の対象としては、メラニン生成抑制や美白を所望する動物、又は皮膚の色素沈着、シミ、ソバカス等の症状の予防、改善、若しくは治療することを所望する動物が挙げられる。動物は、好ましくはヒト又は非ヒト哺乳動物であり、より好ましくはヒトである。
In the present invention, the compound of formula (I) or a salt thereof is used for preventing or improving symptoms such as skin pigmentation, spots, freckles, etc. for inhibiting dopa oxidase activity, for inhibiting melanin production, for whitening, or for skin pigmentation, To treat, they can be administered or ingested in an effective amount to a subject in need thereof. Such administration or ingestion may be performed non-therapeutically for health promotion or cosmetic purposes.
Subjects for administration or ingestion include animals that require inhibition of dopa oxidase activity. Alternatively, the subject of administration or ingestion includes animals that desire suppression of melanin production and whitening, or animals that desire prevention, amelioration, or treatment of symptoms such as skin pigmentation, spots, and freckles. The animal is preferably a human or non-human mammal, more preferably a human.
好ましい投与又は摂取量は、対象の種、体重、性別、年齢、状態又はその他の要因に従って変動し得る。投与又は摂取の用量、経路、間隔、及び摂取の量や間隔は、当業者によって適宜決定され得る。例えば、ヒトの皮膚に局所投与する場合、式(I)化合物又はその塩の投与量は、成人(60kg)1人当たり、式(I)化合物として1.0×10-7〜0.1mg/日とすることが好ましく、1.0×10-6〜0.001mg/日がより好ましい。 The preferred dosage or intake may vary according to the subject's species, weight, sex, age, condition or other factors. The dose or route of administration or ingestion, the interval, and the amount or interval of ingestion can be appropriately determined by those skilled in the art. For example, when topically administered to human skin, the dose of the compound of formula (I) or a salt thereof is 1.0 × 10 −7 to 0.1 mg / day as a compound of formula (I) per adult (60 kg). It is preferable to be 1.0 × 10 −6 to 0.001 mg / day.
以下、本発明を実施例に基づきさらに詳細に説明するが、本発明はこれに限定されるものではない。 EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to this.
製造例1 式(I)化合物の調製
ハグロソウ500gを50%エタノール(5L)で抽出し、溶媒を濃縮して、抽出固形分44gを得た。得られた抽出固形分を、水と酢酸エチルを用いて液液分配を行い、酢酸エチル層4.7g(収率11%)を得た。後述する実施例1と同様の手順で水層及び酢酸エチル層のドーパオキシダーゼ活性を測定し、活性が酢酸エチル層に集約されていることを確認した。
酢酸エチル層をさらにシリカゲルカラムにより分画した。シリカゲルカラムとしてHi−Flushカラム(4L、山善製)を用いた。まずヘキサン100%で10分間流した後、ヘキサン−酢酸エチルで酢酸エチル比率0%から100%まで60分間グラジエントをかけ、その後酢酸エチル−メタノールでメタノール比率0%から10%まで30分間でグラジエントをかけた後、最後に100%メタノールで30分間溶出した。流速30mL/minで流して2分ごとに分画を行なった後、各フラクションのTLC分析より、Rf値の近いものをそれぞれまとめることで7画分を得た。上記の手順で各画分のドーパオキシダーゼ活性を測定し、画分(4)(0.8g、収率1.8%)と画分(7)(1.91g、収率4.3%)の2画分に活性が集約していることを確認した。画分(4)に関しては、さらにMeOH添加による沈殿物にドーパオキシダーゼ活性が集約していることを確認した。
Production Example 1 Preparation of Compound of Formula (I) 500 g of sunflower was extracted with 50% ethanol (5 L), and the solvent was concentrated to obtain 44 g of an extracted solid content. The extracted solid was subjected to liquid-liquid partition using water and ethyl acetate to obtain 4.7 g (yield 11%) of an ethyl acetate layer. The dopa oxidase activity of the aqueous layer and the ethyl acetate layer was measured in the same procedure as in Example 1 described later, and it was confirmed that the activity was concentrated in the ethyl acetate layer.
The ethyl acetate layer was further fractionated by a silica gel column. A Hi-Flush column (4 L, manufactured by Yamazen) was used as the silica gel column. First, after flowing for 10 minutes with 100% hexane, a gradient was applied from hexane-ethyl acetate to an ethyl acetate ratio of 0% to 100% for 60 minutes, and then with an ethyl acetate-methanol gradient from 0% to 10% for 30 minutes. After applying, 100% methanol was finally eluted for 30 minutes. After flowing at a flow rate of 30 mL / min and performing fractionation every 2 minutes, 7 fractions were obtained by collecting those having similar Rf values by TLC analysis of each fraction. The dopa oxidase activity of each fraction was measured by the above procedure, and fraction (4) (0.8 g, yield 1.8%) and fraction (7) (1.91 g, yield 4.3%) were measured. It was confirmed that the activity was concentrated in the two fractions. Regarding the fraction (4), it was further confirmed that the dopa oxidase activity was concentrated in the precipitate resulting from the addition of MeOH.
この沈殿物をHPLCで分画した。カラムはInertsil ODS−3(14×250mm、ジーエルサイエンス社製)を用い、流速15mL/min、検出波長254nm、0.1%ギ酸水溶液−アセトニトリルで、アセトニトリル比率50%で20分間溶出したところ、主な2つのピークが得られた。各ピークを分取し画分(8)、画分(9)とした。画分(8)(48mg、収率0.38%)および画分(9)(58mg、収率0.46%)の両方にドーパオキシダーゼ活性があることを確認した。
一方、画分(7)に関しては、この内470mgを用いてさらにHPLCによる分画を行なった。カラムはInertsil ODS−3(10×250mm、ジーエルサイエンス社製)を用い、流速7.5mL/min、検出波長254nm、0.1%ギ酸水溶液−アセトニトリルで、アセトニトリル比率35%で20分間溶出した。ピークに応じて分画し、画分(10)、画分(11)、画分(12)を得たが、画分(11)(14.1mg、収率0.13%)にドーパオキシダーゼ活性があることを確認した。
This precipitate was fractionated by HPLC. The column was Inertsil ODS-3 (14 × 250 mm, manufactured by GL Sciences Inc.) and eluted at a flow rate of 15 mL / min, a detection wavelength of 254 nm, a 0.1% formic acid aqueous solution-acetonitrile at an acetonitrile ratio of 50% for 20 minutes. Two peaks were obtained. Each peak was collected and used as fraction (8) and fraction (9). It was confirmed that both fraction (8) (48 mg, yield 0.38%) and fraction (9) (58 mg, yield 0.46%) had dopa oxidase activity.
On the other hand, fraction (7) was further fractionated by HPLC using 470 mg of this. The column was Inertsil ODS-3 (10 × 250 mm, manufactured by GL Sciences Inc.) and eluted at a flow rate of 7.5 mL / min, a detection wavelength of 254 nm, 0.1% formic acid aqueous solution-acetonitrile at an acetonitrile ratio of 35% for 20 minutes. Fractionation was performed according to the peak to obtain fraction (10), fraction (11), and fraction (12). Dopoxidase was added to fraction (11) (14.1 mg, yield 0.13%). It was confirmed that there was activity.
上記画分(8)、画分(9)、画分(11)についてそれぞれNMR構造解析を行ったところ、下記表1〜3に示すとおり、画分(8)はジャスチシジンB、画分(9)はジャスチシジンA、画分(11)はツベルクラチンであると同定された。 NMR structural analysis was performed on the fraction (8), the fraction (9), and the fraction (11). As shown in Tables 1 to 3 below, the fraction (8) was found to contain jasticidin B and the fraction (9 ) Was identified as jasticidin A, and fraction (11) was identified as tuberculin.
実施例1 式(I)化合物によるドーパオキシダーゼ活性抑制
正常ヒト新生児表皮由来メラノサイト(NHEMs;クラボウ社)を96ウェルプレートに1×104細胞/ウェル(100μL/ウェル)の細胞密度で播種し、37℃、5%CO2下にて培養した。培地には、PMA(−)の増殖用添加剤(HMGS)を含むMedium 254を用いた。
3日間培養した後、それぞれ培地中終濃度で1nMになるように調整したEndothelin−1(ET−1)、SCF、α−MSH、Histamine、PGE2とともに、表4に記載の各化合物を同表に記載の終濃度となるように培地に添加し、37℃、5%CO2の条件下で3日間培養を行った。コントロールとしては、同量のDMSO溶液を添加した。
培養終了後、アラマーブルー(インビトロジェン社)試薬を20μL/ウェルで添加し、2〜3時間インキュベートした後、培地の蛍光強度を測定して細胞呼吸活性を測定した。その後、細胞をPBSで洗浄し、抽出バッファー(0.1M Tris−HCL(pH7.2)、1% NP−40、0.01%SDS、100μM PMSF、1μg/mアプロチニン)を20μL/ウェル、Assay Buffer(4%ジメチルホルムアミド、100mM Sodium phosphate−buffered(pH7.1))を20μL/ウェル添加し、4℃、3時間で細胞を可溶化し、ドーパオキシダーゼ活性の測定を行った。ドーパオキシダーゼ活性測定は、MBTH法(Winder A. et al., Eur.J. Biochem., 1991, 198:317-326)を参考に、以下の方法で行った。
可溶化した細胞溶液の各ウェルに、上記Assay Bufferを80μL、20.7mM MBTH(3−メチル−2−ベンゾチアゾリノンヒドラゾン)溶液を60μL、基質として5mM L−ドーパ(L−ジヒドロキシフェニルアラニン)溶液を40μL、それぞれ加え、37℃で30〜60分反応させた後、その呈色反応を490nmの吸光度で測定した(N=3)。測定値をコントロールの結果に対する相対値として表した。
Example 1 Inhibition of Dopa Oxidase Activity by Formula (I) Compound Normal human neonatal epidermis-derived melanocytes (NHEMs; Kurabo Industries) were seeded in a 96-well plate at a cell density of 1 × 10 4 cells / well (100 μL / well), 37 The cells were cultured at 5 ° C. and 5% CO 2 . Medium 254 containing PMA (-) growth additive (HMGS) was used as the medium.
After culturing for 3 days, each compound shown in Table 4 was added together with Endothelin-1 (ET-1), SCF, α-MSH, Histamine, PGE 2 adjusted to a final concentration of 1 nM in the medium. Was added to the medium so as to achieve the final concentration described in 1. and cultured at 37 ° C. under 5% CO 2 for 3 days. As a control, the same amount of DMSO solution was added.
After completion of the culture, Alamar Blue (Invitrogen) reagent was added at 20 μL / well, incubated for 2 to 3 hours, and then the fluorescence intensity of the medium was measured to measure cell respiration activity. Thereafter, the cells were washed with PBS, and extraction buffer (0.1 M Tris-HCL (pH 7.2), 1% NP-40, 0.01% SDS, 100 μM PMSF, 1 μg / m aprotinin) was added at 20 μL / well, Assay. Buffer (4% dimethylformamide, 100 mM sodium phosphate-buffered (pH 7.1)) was added at 20 μL / well, the cells were solubilized at 4 ° C. for 3 hours, and the dopa oxidase activity was measured. The dopa oxidase activity was measured by the following method with reference to the MBTH method (Winder A. et al., Eur. J. Biochem., 1991, 198: 317-326).
In each well of the solubilized cell solution, 80 μL of the above Assay Buffer, 60 μL of 20.7 mM MBTH (3-methyl-2-benzothiazolinone hydrazone) solution, and 5 mM L-dopa (L-dihydroxyphenylalanine) solution as a substrate 40 μL of each was added and reacted at 37 ° C. for 30 to 60 minutes, and then the color reaction was measured by absorbance at 490 nm (N = 3). The measured value was expressed as a relative value to the control result.
結果を表4に示す。式(I)化合物によってドーパオキシダーゼ活性がエキス添加濃度依存的に抑制された。また、アラマーブルー法による細胞呼吸活性の測定から、表4に示す濃度の化合物添加が細胞増殖に影響を及ぼさないことを確認した。 The results are shown in Table 4. The dopa oxidase activity was inhibited depending on the extract addition concentration by the compound of formula (I). Moreover, it was confirmed from the measurement of the cell respiration activity by the Alamar Blue method that the addition of the compound at the concentration shown in Table 4 does not affect the cell growth.
実施例2 式(I)化合物によるメラニン産生抑制
ET−1とSCFを終濃度10nMで添加したEPI−100−NMM113培地を用いて、三次元培養皮膚モデル(MEL300A)を37℃、5%CO2条件下にて培養した。培養初日より、各化合物の100%DMSO溶液を、終濃度が0.5μMになるように添加した。コントロールとしては、同量のDMSO溶液を添加した。培地交換は3日に一度行った。14日後に、アラマーブルー試薬を用いて細胞呼吸活性を測定した。続いて三次元培養皮膚を培養支持体であるカップごとPBSで洗浄し、ピンセットで皮膚シートを剥離してチューブに移し、さらにPBSで3回洗浄した。50%エタノールで3回、100%エタノールで2回洗浄した後、室温で一晩放置して完全に乾燥させた。最終的に2M NaOHを200μL加えた後で100℃にて溶解させ、遠心分離によって得られた上清について405nmの測定波長で吸光度を測定し、メラニン量を算出した。測定値をコントロールの結果に対する相対値として表した。
Example 2 Suppression of Melanin Production by Formula (I) Compound Using a EPI-100-NMM113 medium supplemented with ET-1 and SCF at a final concentration of 10 nM, a three-dimensional cultured skin model (MEL300A) was cultured at 37 ° C., 5% CO 2. Cultured under conditions. From the first day of culture, a 100% DMSO solution of each compound was added so that the final concentration was 0.5 μM. As a control, the same amount of DMSO solution was added. The medium was changed once every 3 days. After 14 days, cell respiratory activity was measured using Alamar Blue reagent. Subsequently, the three-dimensional cultured skin was washed with PBS as a culture support with PBS, the skin sheet was peeled off with tweezers, transferred to a tube, and further washed with PBS three times. After washing 3 times with 50% ethanol and 2 times with 100% ethanol, it was left at room temperature overnight to dry completely. Finally, 200 μL of 2M NaOH was added and then dissolved at 100 ° C., and the supernatant obtained by centrifugation was measured for absorbance at a measurement wavelength of 405 nm to calculate the amount of melanin. The measured value was expressed as a relative value to the control result.
14日培養後の三次元培養皮膚モデルの写真及びメラニン量測定結果を図1に示す。式(I)化合物添加により、細胞の黒化抑制効果が視覚的に認められ(図1A)、細胞のメラニン量が60%以上減少した(図1B)。また、アラマーブルー法による細胞呼吸活性測定の結果、この濃度の抽出物が細胞毒性を示さないことが確認された。 A photograph of a three-dimensional cultured skin model after 14 days of culture and the results of melanin measurement are shown in FIG. By adding the compound of formula (I), the effect of inhibiting cell darkening was visually recognized (FIG. 1A), and the amount of melanin in the cells decreased by 60% or more (FIG. 1B). Moreover, as a result of measuring the cellular respiration activity by the Alamar Blue method, it was confirmed that the extract at this concentration did not show cytotoxicity.
Claims (6)
R1及びR2は、同一又は異なって、ヒドロキシル基、又は炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表すか、あるいはR1及びR2は、一緒になってメチレンジオキシ基を形成し、
R3及びR4は、同一又は異なって、ヒドロキシル基、又は炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表すか、あるいはR3及びR4は、一緒になってメチレンジオキシ基を形成し、
R5は水素原子、ヒドロキシル基、炭素数1〜5の直鎖若しくは分岐のアルコキシ基、炭素数1〜4のアシル基、又は(D−アピオ−β−D−フラノシル)オキシ、(β-D−グルコピラノシル)オキシ、(3−O,4−O−ジメチル−D−キシロピラノシル)オキシ、(2−O,3−O,4−O−トリメチル−β−D−キシロピラノシル)オキシ、(3−O−メチル−β−D−グルコピラノシル)オキシから選択される糖残基を表し、
R6とR7は水素原子であり且つR8とR9は一緒になって酸素原子を表すか、又はR8とR9は水素原子であり、且つR6とR7は一緒になって酸素原子を表す。〕
で示される化合物又はその塩を有効成分とするドーパオキシダーゼ活性抑制剤。 Formula (I)
R 1 and R 2 are the same or different and each represents a hydroxyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms, or R 1 and R 2 together represent a methylenedioxy group. Forming,
R 3 and R 4 are the same or different and each represents a hydroxyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms, or R 3 and R 4 together represent a methylenedioxy group. Forming,
R 5 represents a hydrogen atom, a hydroxyl group, a linear or branched alkoxy group having 1 to 5 carbon atoms, an acyl group having 1 to 4 carbon atoms, or (D-apio-β-D-furanosyl) oxy, (β-D -Glucopyranosyl) oxy, (3-O, 4-O-dimethyl-D-xylopyranosyl) oxy, (2-O, 3-O, 4-O-trimethyl-β-D-xylopyranosyl) oxy, (3-O- Represents a sugar residue selected from methyl-β-D-glucopyranosyl) oxy,
R 6 and R 7 are hydrogen atoms and R 8 and R 9 together represent an oxygen atom, or R 8 and R 9 are hydrogen atoms and R 6 and R 7 are together Represents an oxygen atom. ]
The dopa oxidase activity inhibitor which uses the compound shown by these, or its salt as an active ingredient.
R1及びR2は、同一又は異なって、ヒドロキシル基、又は炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表すか、あるいはR1及びR2は、一緒になってメチレンジオキシ基を形成し、
R3及びR4は、同一又は異なって、ヒドロキシル基、又は炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表すか、あるいはR3及びR4は、一緒になってメチレンジオキシ基を形成し、
R5は水素原子、ヒドロキシル基、炭素数1〜5の直鎖若しくは分岐のアルコキシ基、炭素数1〜4のアシル基、又は(D−アピオ−β−D−フラノシル)オキシ、(β-D−グルコピラノシル)オキシ、(3−O,4−O−ジメチル−D−キシロピラノシル)オキシ、(2−O,3−O,4−O−トリメチル−β−D−キシロピラノシル)オキシ、(3−O−メチル−β−D−グルコピラノシル)オキシから選択される糖残基を表し、
R6とR7は水素原子であり且つR8とR9は一緒になって酸素原子を表すか、又はR8とR9は水素原子であり、且つR6とR7は一緒になって酸素原子を表す。〕
で示される化合物又はその塩を有効成分とするメラニン生成抑制剤。 Formula (I)
R 1 and R 2 are the same or different and each represents a hydroxyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms, or R 1 and R 2 together represent a methylenedioxy group. Forming,
R 3 and R 4 are the same or different and each represents a hydroxyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms, or R 3 and R 4 together represent a methylenedioxy group. Forming,
R 5 represents a hydrogen atom, a hydroxyl group, a linear or branched alkoxy group having 1 to 5 carbon atoms, an acyl group having 1 to 4 carbon atoms, or (D-apio-β-D-furanosyl) oxy, (β-D -Glucopyranosyl) oxy, (3-O, 4-O-dimethyl-D-xylopyranosyl) oxy, (2-O, 3-O, 4-O-trimethyl-β-D-xylopyranosyl) oxy, (3-O- Represents a sugar residue selected from methyl-β-D-glucopyranosyl) oxy,
R 6 and R 7 are hydrogen atoms and R 8 and R 9 together represent an oxygen atom, or R 8 and R 9 are hydrogen atoms and R 6 and R 7 are together Represents an oxygen atom. ]
The melanin production inhibitor which uses the compound or its salt shown by this as an active ingredient.
R1及びR2は、同一又は異なって、ヒドロキシル基、又は炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表すか、あるいはR1及びR2は、一緒になってメチレンジオキシ基を形成し、
R3及びR4は、同一又は異なって、ヒドロキシル基、又は炭素数1〜4の直鎖若しくは分岐のアルコキシ基を表すか、あるいはR3及びR4は、一緒になってメチレンジオキシ基を形成し、
R5は水素原子、ヒドロキシル基、炭素数1〜5の直鎖若しくは分岐のアルコキシ基、炭素数1〜4のアシル基、又は(D−アピオ−β−D−フラノシル)オキシ、(β-D−グルコピラノシル)オキシ、(3−O,4−O−ジメチル−D−キシロピラノシル)オキシ、(2−O,3−O,4−O−トリメチル−β−D−キシロピラノシル)オキシ、(3−O−メチル−β−D−グルコピラノシル)オキシから選択される糖残基を表し、
R6とR7は水素原子であり且つR8とR9は一緒になって酸素原子を表すか、又はR8とR9は水素原子であり、且つR6とR7は一緒になって酸素原子を表す。〕
で示される化合物又はその塩を有効成分とする美白剤。 Formula (I)
R 1 and R 2 are the same or different and each represents a hydroxyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms, or R 1 and R 2 together represent a methylenedioxy group. Forming,
R 3 and R 4 are the same or different and each represents a hydroxyl group or a linear or branched alkoxy group having 1 to 4 carbon atoms, or R 3 and R 4 together represent a methylenedioxy group. Forming,
R 5 represents a hydrogen atom, a hydroxyl group, a linear or branched alkoxy group having 1 to 5 carbon atoms, an acyl group having 1 to 4 carbon atoms, or (D-apio-β-D-furanosyl) oxy, (β-D -Glucopyranosyl) oxy, (3-O, 4-O-dimethyl-D-xylopyranosyl) oxy, (2-O, 3-O, 4-O-trimethyl-β-D-xylopyranosyl) oxy, (3-O- Represents a sugar residue selected from methyl-β-D-glucopyranosyl) oxy,
R 6 and R 7 are hydrogen atoms and R 8 and R 9 together represent an oxygen atom, or R 8 and R 9 are hydrogen atoms and R 6 and R 7 are together Represents an oxygen atom. ]
The whitening agent which uses the compound shown by these, or its salt as an active ingredient.
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