JP5590921B2 - Proton pump inhibitor - Google Patents
Proton pump inhibitor Download PDFInfo
- Publication number
- JP5590921B2 JP5590921B2 JP2010047219A JP2010047219A JP5590921B2 JP 5590921 B2 JP5590921 B2 JP 5590921B2 JP 2010047219 A JP2010047219 A JP 2010047219A JP 2010047219 A JP2010047219 A JP 2010047219A JP 5590921 B2 JP5590921 B2 JP 5590921B2
- Authority
- JP
- Japan
- Prior art keywords
- proton pump
- hydroxy
- compound
- gingerol
- general formula
- 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.)
- Active
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- 239000000612 proton pump inhibitor Substances 0.000 title claims description 55
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- -1 compound 1) Chemical compound 0.000 claims description 38
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- 125000000217 alkyl group Chemical group 0.000 claims description 26
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Description
本発明は、新規なプロトンポンプ阻害剤及び当該成分を含有する皮膚外用剤に関し、詳しくは、下記一般式（１）に表される化合物、その異性体及び／又はそれらの薬理学的に許容される塩からなるプロトンポンプ阻害剤及び当該成分を含有することを特徴とする皮膚外用剤に関する。 The present invention relates to a novel proton pump inhibitor and an external preparation for skin containing the component, and more specifically, a compound represented by the following general formula (1), its isomer and / or their pharmacologically acceptable. The present invention relates to a proton pump inhibitor comprising a salt and an external preparation for skin comprising the component.
[式中、Ｒ１及びＲ２は、それぞれ独立に、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表し、Ｒ３は、炭素数１〜１２の直鎖又は分岐のアルキル基を表す。]
[Wherein, R1 and R2 each independently represent a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and R3 represents a linear or branched alkyl group having 1 to 12 carbon atoms. . ]
細胞内外における必要な物質の取り込み、排出・分泌には、生体膜に存在するイオンチャネル（カルシウムチャネル、カリウムチャネル等）、トランスポ−タ−（モノアミントランスポ−タ−、プロトンポンプ等）、輸送体（糖輸送体、アミノ酸輸送体等）等による能動又は受動輸送が深く関与する。この様な生体膜に存在する生体機能分子を介し輸送される物質には、細胞内外における情報伝達、生体分子の機能維持又は調節に重要な役割を果たしている情報伝達物質も数多く存する。特に、水素イオン（プロトン）は、能動又は受動輸送により細胞及び細胞小器官内外等におけるプロトン濃度勾配形成に関与し、生命活動を維持するために必要なエネルギ−生産、生体分子の機能調節などの重要な役割を担っている。 For uptake, excretion and secretion of necessary substances inside and outside cells, ion channels (calcium channels, potassium channels, etc.) existing in biological membranes, transporters (monoamine transporters, proton pumps, etc.), transporters ( Active or passive transport by sugar transporters, amino acid transporters, etc.) is deeply involved. There are many information transmitting substances that play an important role in the transmission of information inside and outside the cell and the maintenance or regulation of the functions of the biomolecules among the substances transported through the biological function molecules present in such a biological membrane. In particular, hydrogen ions (protons) are involved in the formation of proton concentration gradients inside and outside cells and organelles by active or passive transport, and energy production necessary for maintaining life activity, function regulation of biomolecules, etc. It plays an important role.
細胞又は細胞小器官内外におけるプロトン濃度勾配の形成には、生体膜上に存在しプロトンを能動輸送する膜タンパク質である膜ATPase（膜H＋-ATPase）、更には、Na＋／K＋−ATPaseと共役的に働きプロトンを受動輸送するNa＋／Ｈ＋交換輸送蛋白質（NHE）などの関与が知られている。プロトンを能動輸送する膜H＋−ATPaseに付いては、ミトコンドリア内膜に存在するF型ATPase群、細胞内の液胞などの細胞膜に存在するV型ATPase群、形質膜に存在するP型ATPase群などが報告されている。一方、Na＋／K＋−ATPaseと共役的に働くことによりプロトンを受動輸送するNa＋／Ｈ＋交換輸送蛋白質は、あらゆる細胞に存在することが確認されており、細胞又は細胞小器官内のプロトンとナトリウムイオンをATP非依存的に交換輸送することにより、プロトン濃度を調整している（例えば、非特許文献１を参照）。細胞又は細胞小器官内におけるプロトン濃度変化は、生体機能を司る様々な生体分子の機能及び活性に大きく影響を与える（例えば、非特許文献２を参照）。このため、膜H＋−ATPase及びNa＋／H＋交換輸送蛋白質（NHE）などのプロトン濃度を調整する生体機能分子は、プロトン濃度により機能及び活性が大きく影響を受ける様々な生体機能分子が関与する疾患、例えば、本態性高血圧、不整脈、狭心症、心肥大、糖尿病、虚血若しくは虚血性再潅流による臓器障害、脳虚血障害等の予防又は治療薬に対する創薬標的分子として注目されている。 For the formation of a proton concentration gradient inside or outside a cell or organelle, membrane ATPase (membrane H + -ATPase), which is a membrane protein that exists on a biological membrane and actively transports protons, and Na + / K + -ATPase It is known that Na + / H + exchange transport protein (NHE) that acts in a conjugate manner and passively transports protons is involved. Membrane H + -ATPase that actively transports protons includes F-type ATPases present in the inner mitochondrial membrane, V-type ATPases present in cell membranes such as intracellular vacuoles, and P-type ATPases present in the plasma membrane Groups have been reported. On the other hand, Na + / H + exchange transport protein that passive transport protons by acting a conjugate manner Na + / K + -ATPase is is confirmed to be present in every cell, cells or organelles within the The proton concentration is adjusted by exchanging and transporting protons and sodium ions in an ATP-independent manner (see, for example, Non-Patent Document 1). Changes in proton concentration in cells or organelles greatly affect the functions and activities of various biomolecules that control biological functions (see, for example, Non-Patent Document 2). For this reason, biofunctional molecules that regulate proton concentration such as membrane H + -ATPase and Na + / H + exchange transport protein (NHE) involve various biofunctional molecules whose functions and activities are greatly affected by proton concentration. As a drug discovery target molecule for prophylactic or therapeutic drugs such as essential hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes, organ damage due to ischemia or ischemic reperfusion, cerebral ischemic damage, etc. Yes.
実際、細胞又は細胞小器官内外におけるプロトン濃度を調節するプロトンポンプ阻害作用を有する物質の内、膜H＋−ATPase阻害作用を有するプロトンポンプ阻害剤としては、胃潰瘍治療薬のオメプラゾ−ル、ランソプラゾ−ル等のベンズイミダゾ−ル誘導体がよく知られている。この様な、プロトンポンプ阻害剤は、胃潰瘍等の疾患治療に対する効果が期待されるが、稀にアナフィラキシ−等の副作用を発現する場合が存する。このため、前記プロトンポンプ阻害剤が示すアレルギ−性の副作用に対処する為、治療効果及び安全性の高い別構造の化合物開発が求められている。また、Na＋／H＋交換輸送系を選択的に阻害する物質としては、エチルイソプロピルアミロリド（ＥＩＰＡ）（例えば、非特許文献２を参照）、グアニジン誘導体（例えば、特許文献１を参照）、イソフラボン誘導体又はキサントン誘導体（例えば、特許文献２を参照）が、既に報告されている。しかしながら、この様なプロトンポンプ阻害剤の生物活性は十分に満足のいくものではなく、安全性又は安全性に課題がある化合物も存在するため、より高い活性及び選択性を有し、体内動態に優れ、副作用の少ない新しい骨格の阻害剤が望まれている。一方、プロトンポンプ阻害剤の皮膚への作用は全く知られていなかった。 In fact, among substances having a proton pump inhibitory action that regulates the proton concentration in and outside cells or organelles, proton pump inhibitors having a membrane H + -ATPase inhibitory action include omeprazole, lansoprazo- Benzimidazole derivatives such as R. are well known. Such a proton pump inhibitor is expected to have an effect on the treatment of diseases such as gastric ulcer, but rarely exhibits side effects such as anaphylaxis. For this reason, in order to cope with allergic side effects exhibited by the proton pump inhibitor, development of a compound having a different structure with high therapeutic effect and safety is required. Examples of substances that selectively inhibit the Na + / H + exchange transport system include ethyl isopropyl amiloride (EIPA) (for example, see Non-Patent Document 2), guanidine derivatives (for example, see Patent Document 1), Isoflavone derivatives or xanthone derivatives (see, for example, Patent Document 2) have already been reported. However, the biological activity of such a proton pump inhibitor is not fully satisfactory, and there are compounds with safety or safety issues, so it has higher activity and selectivity, and it is in pharmacokinetics. New skeletal inhibitors that are superior and have few side effects are desired. On the other hand, the action of proton pump inhibitors on the skin was not known at all.
本出願人は、細胞又は細胞小器官内等のプロトン濃度を調節する働きを担うプロトンポンプ阻害剤が、メラノサイト内の酸性化作用を有し、細胞内酸性化作用によりチロシナーゼ活性を低下させメラニン産生抑制効果を発揮することにより、美白をはじめとする皮膚色素異常関連疾患に有用であることを見出している。また、前記プロトンポンプ阻害剤は、細胞内における環境的な要因、即ち、細胞内酸性化作用によりチロシナーゼ活性を抑制することによりメラニン産生を抑制し美白効果を発揮する点において、従前のメラニン産生抑制剤に属するチロシナーゼの酵素活性を低下させるチロシナーゼ直接阻害剤、チロシナーゼファミリータンパク質を減少させるチロシナーゼファミリータンパク減少剤等とは全く異なる作用機序を有する美白剤であると言える。言い換えれば、従前のメラニン産生抑制剤とプロトンポンプ阻害剤は、メラニン産生抑制作用を有する物質としては共通するが、その作用機作により明確に区別されるものである。加えて、従前のメラニン産生抑制剤とは異なった作用機序によりメラニン産生抑制作用を発揮するので、プロトンポンプ阻害作用を有するメラニン産生抑制剤と、従前のメラニン産生抑制剤との併用は、少なくとも相加的効果を奏する。この様な背景からも、プロトンポンプ阻害剤は、高い効果が期待出来る新たな作用機作を有するメラニン産生抑制剤である。 The present applicant has found that a proton pump inhibitor responsible for regulating proton concentration in cells or organelles has an acidifying action in melanocytes, and reduces tyrosinase activity by intracellular acidifying action to produce melanin. It has been found to be useful for skin pigment abnormality-related diseases such as whitening by exerting an inhibitory effect. In addition, the proton pump inhibitor suppresses melanin production by suppressing the melanin production by suppressing tyrosinase activity by intracellular environmental factors, that is, intracellular acidification. It can be said that it is a whitening agent having a mechanism of action completely different from a tyrosinase direct inhibitor that reduces the enzyme activity of tyrosinase belonging to the agent, a tyrosinase family protein reducing agent that reduces tyrosinase family proteins, and the like. In other words, the conventional melanin production inhibitor and the proton pump inhibitor are common as substances having a melanin production inhibitory action, but are clearly distinguished by their action mechanism. In addition, since the melanin production inhibitory action is exhibited by a mechanism of action different from that of the conventional melanin production inhibitor, the combined use of the melanin production inhibitor having a proton pump inhibitory action and the conventional melanin production inhibitor is at least Has an additive effect. Against this background, the proton pump inhibitor is a melanin production inhibitor having a new mechanism of action that can be expected to be highly effective.
ショウガ科に属する植物には、ジンゲロール誘導体又はショウガオール誘導体が含有され、該誘導体が、角層修復促進作用（例えば、特許文献３を参照）、皮膚角質層水分量増加作用（例えば、特許文献４を参照）、血行促進作用（例えば、特許文献５を参照）を有することが知られている。また、前記誘導体とは別に、化学合成されたショウガオール及びジンゲロールと類似構造を有する化合物が、チロシナーゼ阻害作用（例えば、特許文献６を参照）を有することも既に知られている。しかしながら、ジンゲロール誘導体が、プロトンポンプ阻害作用を有することは全く知られていなかった。さらに、ジンゲロール誘導体のプロトンポンプ阻害作用に関する構造活性相関は全く明らかにされておらず、プロトンポンプ阻害作用の発現が、ジンゲロール誘導体の化学構造に制約を受けることも知られていなかった。加えて、前記のプロトンポンプ阻害作用を有するジンゲロール誘導体を含有する皮膚外用剤が、プロトンポンプ阻害作用を介し、美白をはじめとする色素異常疾患の予防又は治療に有効であることも全く知られていなかった。 Plants belonging to the family Ginger include a gingerol derivative or a gingerol derivative, and the derivative promotes horny layer repair promoting action (see, for example, Patent Document 3), skin stratum corneum moisture content increasing action (for example, Patent Document 4). ) And blood circulation promoting action (for example, see Patent Document 5). In addition to the above derivatives, it is already known that chemically synthesized compounds having a similar structure to gingerol and gingerol have a tyrosinase inhibitory action (see, for example, Patent Document 6). However, it has never been known that gingerol derivatives have a proton pump inhibitory action. Furthermore, the structure-activity relationship regarding the proton pump inhibitory action of the gingerol derivative has not been clarified at all, and it has not been known that the expression of the proton pump inhibitory action is restricted by the chemical structure of the gingerol derivative. In addition, it is also completely known that the above-mentioned skin external preparation containing a gingerol derivative having a proton pump inhibitory action is effective for the prevention or treatment of pigmented diseases such as whitening through the proton pump inhibitory action. There wasn't.
本発明は、この様な状況下において為されたものであり、色素沈着予防又は改善用の皮膚外用剤として好適な、新規なプロトンポンプ阻害剤を提供することを課題とする。 The present invention has been made under such circumstances, and an object of the present invention is to provide a novel proton pump inhibitor suitable as a skin external preparation for preventing or improving pigmentation.
この様な状況に鑑みて、本発明者等は、美白をはじめとする色素沈着の予防又は改善用の皮膚外用剤として好適な、プロトンポンプ阻害作用を有する新規の素材を求め鋭意研究を行った結果、前記一般式（１）に表される化合物、その異性体及び／又はそれらの薬理学的に許容される塩がプロトンポンプ阻害作用を有することを見出し、本発明を完成させるに至った。
＜１＞ 下記一般式（１）に表される化合物、その異性体及び／又はそれらの薬理学的に許容される塩からなるプロトンポンプ阻害剤。
In view of such circumstances, the present inventors conducted intensive research for a novel material having a proton pump inhibitory action suitable as a skin external preparation for preventing or improving pigmentation including whitening. As a result, it has been found that the compound represented by the general formula (1), its isomer and / or pharmacologically acceptable salt thereof has a proton pump inhibitory action, and has completed the present invention.
<1> A proton pump inhibitor comprising a compound represented by the following general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof.
[式中、Ｒ１及びＲ２は、それぞれ独立に、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表し、Ｒ３は、炭素数１〜１２の直鎖又は分岐のアルキル基を表す。]
[Wherein, R1 and R2 each independently represent a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and R3 represents a linear or branched alkyl group having 1 to 12 carbon atoms. . ]
＜２＞前記一般式（１）に表される化合物が、下記一般式（２）に表される化合物であることを特徴とする、＜１＞に記載のプロトンポンプ阻害剤。 <2> The compound represented by the general formula (1), characterized in that a compound represented by the following general formula (2), a proton pump inhibitor according to <1>.
[式中、Ｒ４及びＲ５は、それぞれ独立に、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表し、Ｒ６は、炭素数１〜１２の直鎖又は分岐のアルキル基を表す。]
[Wherein, R4 and R5 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R6 represents a linear or branched alkyl group having 1 to 12 carbon atoms. . ]
＜３＞前記一般式（２）に表される化合物が、下記一般式（３）に表される化合物であることを特徴とする、＜１＞又は＜２＞に記載のプロトンポンプ阻害剤。 <3> The compound represented by the general formula (2), characterized in that a compound represented by the following general formula (3), <1> or proton pump inhibitors described <2> .
[式中、Ｒ７は、炭素数１〜１２の直鎖又は分岐のアルキル基を表す。]
[Wherein R 7 represents a linear or branched alkyl group having 1 to 12 carbon atoms. ]
＜４＞前記一般式（２）に表される化合物が、下記一般式（４）に表される化合物であることを特徴とする、＜１＞又は＜２＞に記載のプロトンポンプ阻害剤。 <4> The compound represented by the general formula (2), characterized in that a compound represented by the following general formula (4), <1> or proton pump inhibitors described <2> .
[式中、R８及びＲ９は、それぞれ独立に、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表す。]
[Wherein, R8 and R9 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. ]
＜５＞前記一般式（１）〜（４）に表される化合物が、１０−ジンゲロール（１０−ｇｉｎｇｅｒｏｌ、化合物１）、８−ジンゲロール（８−ｇｉｎｇｅｒｏｌ、化合物２）、６−ジンゲロール（６−ｇｉｎｇｅｒｏｌ、化合物３）であることを特徴とする、＜１＞〜＜４＞の何れか１項に記載のプロトンポンプ阻害剤。 <5> The compounds represented by the general formulas (1) to (4) are 10-gingerol (10-gingerol, compound 1), 8-gingerol (8-gingerol, compound 2), 6-gingerol (6- The proton pump inhibitor according to any one of <1> to <4> , which is gingerol, compound 3 ) .
＜６＞ 前記プロトンポンプ阻害剤が、Ｎａ＋／Ｈ＋交換輸送系に作用するプロトンポンプ阻害剤であることを特徴とする、＜１＞〜＜５＞の何れか一項に記載のプロトンポンプ阻害剤。
＜７＞ ＜１＞〜＜６＞の何れか一項に記載のプロトンポンプ阻害剤を有効成分として含有する美白用の皮膚外用剤。
<6> The proton pump inhibitor according to any one of <1> to <5>, wherein the proton pump inhibitor is a proton pump inhibitor that acts on a Na + / H + exchange transport system. .
<7> A skin external preparation for whitening containing the proton pump inhibitor according to any one of <1> to <6> as an active ingredient .
＜本発明のプロトンポンプ阻害剤＞
本発明のプロトンポンプ阻害剤は、前記一般式（１）に表される化合物、その異性体及び／又はそれらの薬理学的に許容される塩からなることを特徴とする。本発明におけるプロトンポンプ阻害剤は、細胞又は細胞小器官内外のプロトン濃度を調節する生体機能分子に作用し、プロトン濃度を調節する（細胞又は細胞小器官内を酸性化する）作用を有する物質を意味し、具体的には、生体膜に存在し能動的なプロトン輸送を担う膜H＋−ATPaseに加え、Na＋／K＋−ATPase等のイオンポンプと共役的に働き受動的なプロトン輸送を担うNa＋／H＋交換輸送体等の生体機能分子に作用しプロトン濃度を調節する物質を意味する。本発明のプロトンポンプ阻害剤の内、好ましいものとしては、後述するメラノサイト内の酸性化を指標とする「メラサイト内酸性化（プロトンポンプ阻害作用）検討」において、メラノサイト内の酸性化作用を有するプロトンポンプ阻害剤が好適に例示出来る。尚、本発明のメラノサイト内の酸性化作用（プロトンポンプ阻害作用）を有する物質とは、後述するメラノサイト内の酸性化を指標とする「メラノソ−ム内酸性化（プロトンポンプ阻害作用）検討」において、蛍光顕微鏡による目視観察により、pH感受性蛍光色素の発色強度の増強が認められる物質を意味する。
<Proton pump inhibitor of the present invention>
The proton pump inhibitor of the present invention comprises the compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof. The proton pump inhibitor in the present invention acts on a biological function molecule that regulates the proton concentration inside and outside the cell or organelle, and a substance having an action of regulating the proton concentration (acidifying the inside of the cell or organelle). Specifically, in addition to membrane H + -ATPase, which is present in biological membranes and is responsible for active proton transport, it works in conjunction with ion pumps such as Na + / K + -ATPase to perform passive proton transport. It means a substance that acts on biological functional molecules such as Na + / H + exchange transporter and regulates proton concentration. Among the proton pump inhibitors of the present invention, preferred are those having an acidifying action in melanocytes in the “examination of acidification in melanocytes (proton pump inhibitory action) study” using the acidification in melanocytes described later as an index. A proton pump inhibitor can be preferably exemplified. In addition, the substance having an acidifying action (proton pump inhibitory action) in melanocytes of the present invention refers to the “acidification in melanosomes (proton pump inhibitory action) examination” that uses acidification in melanocytes described later as an index. It means a substance in which the enhancement of the color intensity of the pH-sensitive fluorescent dye is observed by visual observation with a fluorescence microscope.
ここで一般式（１）に表される化合物に付いて述べれば、式中、Ｒ１及びＲ２は、それぞれ独立に、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表し、Ｒ３は、炭素数１〜１２の直鎖又は分岐のアルキル基を表す。前記Ｒ１及びＲ２は、それぞれ独立に、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表し、具体例を挙げれば、水素原子、メチル基、エチル基、プロピル基、ブチル基を表す。さらに、Ｒ１及びＲ２の両置換基の置換位置に付いては、特段の限定はないが、芳香族環上におけるＲ３を有する置換基に対し、メタ位及びパラ位がより好ましい。前記Ｒ３は、炭素数１〜１２の直鎖又は分岐のアルキル基を表し、具体例を挙げれば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基、ドデシル基が好適に例示出来、より好ましくは、ペンチル基、ヘプチル基、ノニル基が好適に例示出来る。前記一般式（１）に表される化合物の内、好ましいものとしては、一般式（２）又は一般式（４）に表される化合物が好適に例示出来る。また、前記一般式（２）に表される化合物の内、より好ましいものとしては、一般式（３）に表される化合物が好適に例示出来る。前記一般式（１）〜（４）に表される化合物の内、好ましい化合物を具体的に挙げれば、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−デカノン（６−ジンゲロール、化合物３）、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−ドデカノン（８−ジンゲロール、化合物２）、（５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−テトラデカノン（１０−ジンゲロール、１０−ｇｉｎｇｅｒｏｌ、化合物１）が好適に例示出来る。また、前記一般式（１）〜（４）に表される化合物は、その化学構造中に不斉炭素原子を有するためラセミ化合物、光学活性体及び／又はその混合物等の様々な形態として存在し得るが、かかる化合物のプロトンポンプ阻害作用、生体内における安定性及び安全性等を考えた場合、（Ｓ）体であることが好ましい。かかる化合物は、優れたプロトンポンプ阻害作用、並びに、プロトンポンプ阻害作用に基づくメラニン産生抑制作用を有する。また、製剤化における溶剤等への溶解性に優れ、皮膚外用剤等への製剤化が容易であり、更に、製剤中の安定性、皮膚貯留性に優れ、色素沈着予防又は改善等の美白作用を発揮する。 Here, the compound represented by the general formula (1) will be described. In the formula, R1 and R2 each independently represent a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, and R3 Represents a linear or branched alkyl group having 1 to 12 carbon atoms. R1 and R2 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples include a hydrogen atom, a methyl group, an ethyl group, a propyl group, and a butyl group. Represent. Furthermore, there are no particular limitations on the substitution positions of both the substituents R1 and R2, but the meta and para positions are more preferred for the substituent having R3 on the aromatic ring. R3 represents a linear or branched alkyl group having 1 to 12 carbon atoms, and specific examples include methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, A nonyl group, a decyl group, an undecyl group, and a dodecyl group can be illustrated suitably, More preferably, a pentyl group, a heptyl group, and a nonyl group can be illustrated suitably. Of the compounds represented by the general formula (1), preferred examples include compounds represented by the general formula (2) or the general formula (4). Further, the inside of the general formula (2) in the compounds represented by, and more preferred are compounds represented by the general formula (3) is suitably be exemplified. Of the compounds represented by the general formulas (1) to (4), specific examples of preferred compounds include 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3-decanone (6- Zingerol, compound 3), 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3-dodecanone (8-gingerol, compound 2), (5-hydroxy-1- (4-hydroxy-3-methoxy) Phenyl) -3-tetradecanone (10-gingerol, 10-gingerol, compound 1 ) can be preferably exemplified, and the compounds represented by the general formulas (1) to (4) are asymmetric in the chemical structure. Since it has a carbon atom, it can exist in various forms such as a racemate, an optically active substance and / or a mixture thereof. In view of stability and safety, the (S) isomer is preferable, and such a compound has an excellent proton pump inhibitory action and a melanin production inhibitory action based on the proton pump inhibitory action. Excellent solubility in solvents, etc. in formulation, easy formulation into external preparations for skin, etc. In addition, excellent stability and skin retention in the formulation, whitening effect such as prevention or improvement of pigmentation To do.
ここで前記一般式（２）に表される化合物に付いて述べれば、式中、Ｒ４及びＲ５は、それぞれ独立に、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表し、Ｒ６は、炭素数１〜１２の直鎖又は分岐のアルキル基を表す。前記Ｒ４及びＲ５は、それぞれ独立に、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表し、具体例を挙げれば、水素原子、メチル基、エチル基、プロピル基、ブチル基などが好適に例示出来、これらの内、好ましいものとしては、水素原子又はメチル基が好適に例示出来る。前記Ｒ６は、炭素数１〜１２の直鎖又は分岐のアルキル基を表し、具体例を挙げれば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基、ドデシル基が好適に例示出来、より好ましくは、ペンチル基、ヘプチル基、ノニル基が好適に例示出来る。ここで、前記一般式（２）に表される化合物の内、前記一般式（３）に含まれない化合物を具体的に例示すれば、５−ヒドロキシ−１−（３−エトキシ−４−ヒドロキシフェニル）−３−デカノン、５−ヒドロキシ−１−（４−ヒドロキシ−３−プロピルオキシフェニル）−３−デカノン、５−ヒドロキシ−１−（３−ブチルオキシ−４−ヒドロキシフェニル）−３−デカノン、５−ヒドロキシ−１−（３−ヒドロキシ−４−メトキシフェニル）−３−デカノン、５−ヒドロキシ−１−（４−エトキシ−３−ヒドロキシフェニル）−３−デカノン、５−ヒドロキシ−１−（３−ヒドロキシ−４−プロピルオキシフェニル）−３−デカノン、５−ヒドロキシ−１−（４−ブチルオキシ−３−ヒドロキシフェニル）−３−デカノン、５−ヒドロキシ−１−（３，４−ジメトキシフェニル）−３−デカノン、５−ヒドロキシ−１−（３−エトキシ−４−ヒドロキシフェニル）−３−ドデカノン、５−ヒドロキシ−１−（４−ヒドロキシ−３−プロピルオキシフェニル）−３−ドデカノン、５−ヒドロキシ−１−（３−ブチルオキシ−４−ヒドロキシフェニル）−３−ドデカノン、５−ヒドロキシ−１−（３−ヒドロキシ−４−メトキシフェニル）−３−ドデカノン、５−ヒドロキシ−１−（４−エトキシ−３−ヒドロキシフェニル）−３−ドデカノン、５−ヒドロキシ−１−（３−ヒドロキシ−４−プロピルオキシフェニル）−３−ドデカノン、５−ヒドロキシ−１−（４−ブチルオキシ−３−ヒドロキシフェニル）−３−ドデカノン、５−ヒドロキシ−１−（３，４−ジメトキシフェニル）−３−ドデカノン、５−ヒドロキシ−１−（３−ヒドロキシ−４−メトキシフェニル）テトラデカ−３−オン、５−ヒドロキシ−１−（４−エトキシ−３−ヒドロキシフェニル）テトラデカ−３−オン、５−ヒドロキシ−１−（３−ヒドロキシ−４−プロピルオキシフェニル）テトラデカ−３−オン、５−ヒドロキシ−１−（４−ブチルオキシ−３−ヒドロキシフェニル）テトラデカ−３−オン、５−ヒドロキシ−１−（３，４−ジメトキシフェニル）テトラデカ−３−オンが好適に例示出来る。また、前記一般式（２）に表される化合物は、その化学構造中に不斉炭素原子を有するためラセミ化合物、光学活性体及び／又はそれらの混合物等の様々な形態として存在し得るが、かかる化合物のプロトンポンプ阻害作用、生体内における安定性及び安全性等を考えた場合、（Ｓ）体であることが好ましい。前記一般式（２）に表される化合物の内、より好ましいものを挙げれば、前記一般式（３）に表される化合物が好適に例示出来る。さらに好ましい化合物としては、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−デカノン（６−ジンゲロール、化合物３）、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−ドデカノン（８−ジンゲロール、化合物２）、（５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−テトラデカノン（１０−ジンゲロール、１０−ｇｉｎｇｅｒｏｌ、化合物１）が好適に例示出来る。かかる化合物は、優れたプロトンポンプ阻害作用、並びに、プロトンポンプ阻害作用に基づくメラニン産生抑制作用を有する。また、製剤化における溶剤等への溶解性に優れ、皮膚外用剤等への製剤化が容易であり、更に、製剤中の安定性、皮膚貯留性に優れ、色素沈着予防又は改善等の美白作用を発揮する。 Here, to describe the compound represented by the general formula (2), in the formula, R4 and R5 each independently represents a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, R6 represents a linear or branched alkyl group having 1 to 12 carbon atoms. R4 and R5 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples include a hydrogen atom, a methyl group, an ethyl group, a propyl group, and a butyl group. Can be preferably exemplified, and among these, a hydrogen atom or a methyl group can be suitably exemplified as a preferable one. R6 represents a linear or branched alkyl group having 1 to 12 carbon atoms, and specific examples include methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, A nonyl group, a decyl group, an undecyl group, and a dodecyl group can be illustrated suitably, More preferably, a pentyl group, a heptyl group, and a nonyl group can be illustrated suitably. Here, among the compounds represented by the general formula (2), a compound not included in the general formula (3) is specifically exemplified by 5-hydroxy-1- (3-ethoxy-4-hydroxy Phenyl) -3-decanone, 5-hydroxy-1- (4-hydroxy-3-propyloxyphenyl) -3-decanone, 5-hydroxy-1- (3-butyloxy-4-hydroxyphenyl) -3-decanone, 5-hydroxy-1- (3-hydroxy-4-methoxyphenyl) -3-decanone, 5-hydroxy-1- (4-ethoxy-3-hydroxyphenyl) -3-decanone, 5-hydroxy-1- (3 -Hydroxy-4-propyloxyphenyl) -3-decanone, 5-hydroxy-1- (4-butyloxy-3-hydroxyphenyl) -3-decanone, 5-hydroxy -1- (3,4-dimethoxyphenyl) -3-decanone, 5-hydroxy-1- (3-ethoxy-4-hydroxyphenyl) -3-dodecanone, 5-hydroxy-1- (4-hydroxy-3- Propyloxyphenyl) -3-dodecanone, 5-hydroxy-1- (3-butyloxy-4-hydroxyphenyl) -3-dodecanone, 5-hydroxy-1- (3-hydroxy-4-methoxyphenyl) -3-dodecanone 5-hydroxy-1- (4-ethoxy-3-hydroxyphenyl) -3-dodecanone, 5-hydroxy-1- (3-hydroxy-4-propyloxyphenyl) -3-dodecanone, 5-hydroxy-1- (4-Butyloxy-3-hydroxyphenyl) -3-dodecanone, 5-hydroxy-1- (3,4-dimethoxypheny ) -3-dodecanone, 5-hydroxy-1- (3-hydroxy-4-methoxyphenyl) tetradec-3-one, 5-hydroxy-1- (4-ethoxy-3-hydroxyphenyl) tetradec-3-one, 5-hydroxy-1- (3-hydroxy-4-propyloxyphenyl) tetradec-3-one, 5-hydroxy-1- (4-butyloxy-3-hydroxyphenyl) tetradec-3-one, 5-hydroxy-1 - (3,4-dimethoxyphenyl) tetradeca -3 on-be suitably be exemplified. Moreover, since the compound represented by the general formula (2) has an asymmetric carbon atom in its chemical structure, it can exist in various forms such as a racemate, an optically active substance, and / or a mixture thereof. In view of the proton pump inhibitory action, in vivo stability and safety of such compounds, the (S) isomer is preferred. Of the compounds represented by the general formula (2), the compounds represented by the general formula (3) can be suitably exemplified by more preferable ones. Further preferred compounds include 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3-decanone (6-gingerol, compound 3), 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) ) -3-dodecanone (8-gingerol, compound 2), (5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3-tetradecanone (10-gingerol, 10-gingerol, compound 1 ) are preferred. Such a compound has an excellent proton pump inhibitory action and a melanin production inhibitory action based on the proton pump inhibitory action, and is excellent in solubility in a solvent or the like in the formulation, and is a preparation for a skin external preparation or the like. It is easy to make, and also has excellent stability in the formulation and skin retention, and whitening for preventing or improving pigmentation. Demonstrate
ここで前記一般式（３）に表される化合物に付いて述べれば、式中、Ｒ７は、炭素数１〜１２の直鎖又は分岐のアルキル基を表す。前記Ｒ７は、炭素数１〜１２の直鎖又は分岐のアルキル基を表し、具体例を挙げれば、具体例を挙げれば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基、ウンデシル基、ドデシル基が好適に例示出来、より好ましくは、ペンチル基、ヘプチル基、ノニル基が好適に例示出来る。前記一般式（３）に表される化合物に関し、具体例を挙げれば、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−ヘキサノン、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−ヘプタノン、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−オクタノン、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−ノナノン、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−デカノン（６−ジンゲロール、化合物３）、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−ウンデカノン、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−ドデカノン（８−ジンゲロール、化合物２）、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−トリデカノン、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−テトラデカノン（１０ジンゲロール、化合物１）、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−ペンタデカノン）テトラデカ−３−オン、５−ヒドロキシ−１−（３−ブチルオキシ−４−ヒドロキシフェニル）テトラデカ−３−オンが好適に例示出来る。また、前記一般式（３）に表される化合物は、その化学構造中に不斉炭素原子を有するためラセミ化合物、光学活性体及び／又はその混合物等の様々な形態存在し得るが、かかる化合物のプロトンポンプ阻害作用、生体内における安定性及び安全性等を考えた場合、（Ｓ）体であることが好ましい。また、前記一般式（３）に表される化合物の内、より好ましい化合物としては、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−デカノン（６−ジンゲロール、化合物３）、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−ドデカノン（８−ジンゲロール、化合物２）、（５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−テトラデカノン（１０−ジンゲロール、１０−ｇｉｎｇｅｒｏｌ、化合物１）が好適に例示出来る。かかる化合物は、優れたプロトンポンプ阻害作用、並びに、プロトンポンプ阻害作用に基づくメラニン産生抑制作用を有する。また、製剤化における溶剤等への溶解性に優れ、皮膚外用剤等への製剤化が容易であり、更に、製剤中の安定性、皮膚貯留性に優れ、色素沈着予防又は改善等の美白作用を発揮する。 Here, the compound represented by the general formula (3) will be described. In the formula, R7 represents a linear or branched alkyl group having 1 to 12 carbon atoms. R7 represents a linear or branched alkyl group having 1 to 12 carbon atoms, and specific examples include, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, A heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, and a dodecyl group can be illustrated suitably, More preferably, a pentyl group, a heptyl group, and a nonyl group can be illustrated suitably. Specific examples of the compound represented by the general formula (3) include 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3-hexanone and 5-hydroxy-1- (4-hydroxy). -3-methoxyphenyl) -3-heptanone, 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3-octanone, 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3 -Nonanone, 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3-decanone (6-gingerol, compound 3), 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3 -Undecanone, 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3-dodecanone (8-gingerol, compound 2), 5- Droxy-1- (4-hydroxy-3-methoxyphenyl) -3-tridecanone, 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3-tetradecanone (10 gingerol, compound 1), 5-hydroxy -1- (4-hydroxy-3-methoxyphenyl) -3-pentadecanone) tetradeca-3-one, 5-hydroxy-1- (3-butyloxy-4-hydroxyphenyl) tetradeca -3 on-be suitably exemplified I can do it. Moreover, since the compound represented by the general formula (3) has an asymmetric carbon atom in its chemical structure, it can exist in various forms such as a racemic compound, an optically active substance and / or a mixture thereof. In view of the proton pump inhibitory action, in vivo stability and safety, etc., (S) is preferred. Of the compounds represented by the general formula (3), more preferred compounds are 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3-decanone (6-gingerol, compound 3). 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3-dodecanone (8-gingerol, compound 2), (5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3- Preferred examples include tetradecanone (10-gingerol, 10-gingerol, compound 1 ) , which has an excellent proton pump inhibitory action and a melanin production inhibitory action based on the proton pump inhibitory action. Excellent solubility in solvents, etc., easy to formulate into topical skin preparations, etc. It has excellent retention and exhibits whitening effects such as prevention or improvement of pigmentation.
ここで前記一般式（４）に表される化合物に付いて述べれば、式中、R８及びＲ９は、それぞれ独立に、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表す。前記Ｒ８及びＲ９は、それぞれ独立に、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表し、具体例を挙げれば、水素原子、メチル基、エチル基、プロピル基、ブチル基が好適に例示出来、より好ましくは、水素原子、メチル基が好適に例示出来る。前記一般式（４）に表される化合物に関し、具体例を挙げれば、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−テトラデカノン（１０−ジンゲロール、化合物１）、５−ヒドロキシ−１−（３−エトキシ−４−ヒドロキシフェニル）−３−テトラデカノン、５−ヒドロキシ−１−（４−ヒドロキシ−３−プロピルオキシフェニル）−３−テトラデカノン、５−ヒドロキシ−１−（３−ブチルオキシ−４−ヒドロキシフェニル）−３−テトラデカノン、５−ヒドロキシ−１−（３−ヒドロキシ−４−メトキシフェニル）−３−テトラデカノン、５−ヒドロキシ−１−（４−エトキシ−３−ヒドロキシフェニル）−３−テトラデカノン、５−ヒドロキシ−１−（３−ヒドロキシ−４−プロピルオキシフェニル）−３−テトラデカノン、５−ヒドロキシ−１−（４−ブチルオキシ−３−ヒドロキシフェニル）−３−テトラデカノン、５−ヒドロキシ−１−（３，４−ジメトキシフェニル）−３−テトラデカノンが好適に例示出来る。また、前記一般式（１）〜（４）に表される化合物は、その化学構造中に不斉炭素原子を有するためラセミ化合物、光学活性体及び／又はその混合物等の様々な形態として存在し得るが、かかる化合物のプロトンポンプ阻害作用、生体内における安定性及び安全性等を考えた場合、（Ｓ）体であることが好ましい。前記一般式（４）に表される化合物の内、より好ましいものとしては、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）テトラデカ−３−オン（１０−ジンゲロール、１０−ｇｉｎｇｅｒｏｌ、化合物１）が好適に例示出来る。かかる化合物は、優れたプロトンポンプ阻害作用、並びに、プロトンポンプ阻害作用に基づくメラニン産生抑制作用を有する。また、製剤化における溶剤等への溶解性に優れ、皮膚外用剤等への製剤化が容易であり、更に、製剤中の安定性、皮膚貯留性に優れ、色素沈着予防又は改善等の美白作用を発揮する。
Here, if it mentions about the compound represented by the said General formula (4), in formula, R8 and R9 represent a hydrogen atom and a C1-C4 linear or branched alkyl group each independently. R8 and R9 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples include a hydrogen atom, a methyl group, an ethyl group, a propyl group, and a butyl group. A hydrogen atom and a methyl group can be preferably exemplified. Specific examples of the compound represented by the general formula (4) include 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3-tetradecanone (10-gingerol, compound 1), 5- Hydroxy-1- (3-ethoxy-4-hydroxyphenyl) -3-tetradecanone, 5-hydroxy-1- (4-hydroxy-3-propyloxyphenyl) -3-tetradecanone, 5-hydroxy-1- (3- Butyloxy-4-hydroxyphenyl) -3-tetradecanone, 5-hydroxy-1- (3-hydroxy-4-methoxyphenyl) -3-tetradecanone, 5-hydroxy-1- (4-ethoxy-3-hydroxyphenyl)- 3-tetradecanone, 5-hydroxy-1- (3-hydroxy-4-propyloxyphenyl) -3-the Radekanon, 5-hydroxy-1- (4-butyloxy-3-hydroxyphenyl) -3-Tetoradekanon, 5-hydroxy-1- (3,4-dimethoxyphenyl) -3-Tetoradekano emissions is suitably be exemplified. Further, the compounds represented by the general formulas (1) to (4) have asymmetric carbon atoms in their chemical structures, and therefore exist in various forms such as racemates, optically active substances and / or mixtures thereof. However, in view of the proton pump inhibitory action, in vivo stability and safety of such compounds, the (S) form is preferred. Among the compounds represented by the general formula (4), more preferred are 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) tetradec-3-one (10-gingerol, 10-gingerol, Compound 1 ) can be preferably exemplified. Such a compound has an excellent proton pump inhibitory action and a melanin production inhibitory action based on the proton pump inhibitory action. In addition, it has excellent solubility in solvents, etc. in formulation, it is easy to formulate into external preparations for skin, etc. Furthermore, it is excellent in stability during formulation, skin retention, and whitening action such as prevention or improvement of pigmentation. Demonstrate.
斯くして得られた前記一般式（１）に表される化合物は、そのまま使用することも出来るし、アルカリと共に処理するなどして、塩の形態として使用することも出来る。前記一般式（１）に表される化合物の塩としては、薬理学的に許容される塩であれば特に限定されない。薬理学的に許容される塩としては、ナトリウム塩、カリウム塩等のアルカリ金属、カルシウム塩、マグネシウム塩等のアルカリ土類金属、トリエチルアミン塩、トリエタノ−ルアミン塩、アンモニウム塩、モノエタノ−ルアミン塩、ピペリジン塩等の有機アミン塩、リジン塩、アルギン酸塩等の塩基性アミノ酸塩などが好適に例示出来る。 The compound represented by the general formula (1) thus obtained can be used as it is, or can be used in the form of a salt by treating with an alkali. The salt of the compound represented by the general formula (1) is not particularly limited as long as it is a pharmacologically acceptable salt. Examples of pharmacologically acceptable salts include alkali metals such as sodium salt and potassium salt, alkaline earth metals such as calcium salt and magnesium salt, triethylamine salt, triethanolamine salt, ammonium salt, monoethanolamine salt, piperidine. Preferred examples include organic amine salts such as salts, basic amino acid salts such as lysine salts and alginates.
本出願人により出願された特願２００９−２１９２９２号公報によれば、プロトンポンプ阻害作用を有する成分が細胞又は細胞小器官内の酸性化作用（プロトンポンプ阻害作用）によりメラニン産生を抑制することが見出されている。さらに、前記一般式（１）に表される化合物、その異性体及び／又はそれらの薬理学的に許容される塩がプロトンポンプ阻害作用を有すること、更には、ジンゲロ−ル誘導体のプロトンポンプ阻害作用に関する構造活性相関は、これまで全く知られていなかった。 According to Japanese Patent Application No. 2009-219292 filed by the present applicant, a component having a proton pump inhibitory action suppresses melanin production by an acidifying action (proton pump inhibitory action) in cells or organelles. Has been found. Further, the compound represented by the general formula (1), its isomer and / or pharmacologically acceptable salt thereof has a proton pump inhibitory action, and further, the proton pump inhibition of the gingerol derivative. No structure-activity relationship for action has been known so far.
前記一般式（１）に表される化合物は、天然にも存在していることから、天然物より抽出し、精製を行い得ることも出来るし（例えば、薬学雑誌，１１３、３０７（１９９３））、文献記載の方法に従い合成する（例えば、Bioorg．Med．Chem．Lett．，１９，３９０９−３９１１（２００９）を参照）ことも出来るし、DALTON Pharma Services社より市販されている試薬として使用することも出来る。前記一般式（１）に表される化合物としては、例えば、前記の５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）テトラデカ−３−オン（１０−ジンゲロ−ル、１０−gingerol、化合物１）、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−ドデカノン（８−ジンゲロ−ル、化合物２）、５−ヒドロキシ−１−（４−ヒドロキシ−３−メトキシフェニル）−３−デカノン（６−ジンゲロ−ル、化合物３）が好適に例示出来、該化合物は、ショウガ科の植物、好ましくは、ショウガ科ショウガ属の植物、より好ましくは、ショウガ科ショウガ属ショウガの植物体より得られる植物抽出物に含有される。本発明のショウガ科ショウガ属ショウガの抽出物作製に用いる植物部位としては、特段の限定はないが、より好ましくは、根茎（ショウキョウ）が好適に例示出来る。ショウガ科ショウガ属ショウガは、熱帯アジア原産の世界中で栽培される多年草であり、日本においては、静岡、愛知、岡山等で食用又は生薬等として生産されており、生薬又は抽出物等の形態で市販されている。このため、前記一般式（１）に表される化合物を含有するショウガ科ショウガ属ショウガより得られる植物抽出物は、ショウガの根茎（ショウキョウ）を溶媒抽出により得ることも出来る。本発明の実施例においては、株式会社ウチダ和漢薬より日本国産のショウガの根茎（ショウキョウ）を購入し用い、後記製造例１に記載の方法に従い製造されたショウガ科ショウガ属ショウガより得られる植物抽出物を使用した。 Since the compound represented by the general formula (1) exists in nature, it can be extracted from a natural product and purified (for example, Pharmaceutical Journal, 113, 307 (1993)). Can be synthesized according to methods described in the literature (see, for example, Bioorg. Med. Chem. Lett., 19, 3909-3911 (2009)), or used as a reagent commercially available from DALTON Pharma Services. You can also. Examples of the compound represented by the general formula (1) include 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) tetradec-3-one (10-gingerol, 10-gingerol, Compound 1), 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) -3-dodecanone (8-gingerol, compound 2), 5-hydroxy-1- (4-hydroxy-3-methoxyphenyl) ) -3-decanone (6-gingerol, compound 3) can be suitably exemplified, and the compound is a ginger family plant, preferably a ginger family ginger plant, more preferably a ginger family ginger ginger. It is contained in a plant extract obtained from a plant body. Although there is no special limitation as a plant site | part used for the extract preparation of the ginger department ginger genus ginger of this invention, More preferably, a rhizome (ginger) can be illustrated suitably. Ginger Ginger is a perennial plant native to tropical Asia that is cultivated all over the world. In Japan, it is produced as food or herbal medicine in Shizuoka, Aichi, Okayama, etc., in the form of herbal medicine or extract etc. It is commercially available. For this reason, the plant extract obtained from the ginger department ginger genus ginger containing the compound represented by the general formula (1) can be obtained by solvent extraction of ginger rhizomes. In the Example of this invention, the plant obtained from the ginger department ginger genus ginger manufactured according to the method of postscript manufacture example 1 using the ginger rhizome (Ginger) produced in Japan from Uchida Wakayaku Co., Ltd. Extract was used.
本発明におけるショウガ科に属する植物より得られる植物抽出物は、日本においては、自生又は生育された植物、漢方生薬原料等として販売される日本産のものを用い抽出物を作製することも出来るし、丸善株式会社などの植物抽出物を取り扱う会社より販売されている市販の植物抽出物を購入し、使用することも出来る。前記植物より得られる抽出物の作製に用いる植物部位には、特段の限定がなされず、全草を用いることが出来るが、勿論、植物体、地上部、根茎部、木幹部、葉部、茎部、花穂、花蕾等の部位のみを使用することも出来、より好ましくは、根茎が好適に例示出来る。抽出に際し、植物体などの抽出に用いる部位は、予め、粉砕或いは細切して抽出効率を向上させるように加工することが好ましい。抽出物製造においては、植物体等の抽出に用いる部位乃至はその乾燥物１質量に対して、溶媒を１〜３０質量部加え、室温であれば数日間、沸点付近の温度であれば数時間浸漬する。浸漬後は、室温まで冷却し、所望により不溶物を除去した後、溶媒を減圧濃縮するなどにより除去することが出来る。しかる後、シリカゲルやイオン交換樹脂を充填したカラムクロマトグラフィ−などで分画精製し、所望の抽出物を得ることが出来る。ここで、本発明の植物より得られる抽出物とは、抽出物自体、抽出物の分画、精製した分画、抽出物乃至は分画、精製物の溶媒除去物の総称を意味する The plant extract obtained from a plant belonging to the family Gingeraceae in the present invention can be prepared by using an indigenous or grown plant, a Japanese product sold as a herbal medicine raw material or the like. It is also possible to purchase and use commercially available plant extracts sold by companies that handle plant extracts such as Maruzen Co., Ltd. The plant part used for producing the extract obtained from the plant is not particularly limited, and whole grass can be used. Of course, the plant body, the above-ground part, the rhizome part, the tree trunk part, the leaf part, the stem It is also possible to use only parts such as parts, flower spikes and flower buds, and more preferably, rhizomes can be suitably exemplified. At the time of extraction, it is preferable that a part used for extraction of a plant body or the like is processed in advance so as to improve extraction efficiency by crushing or chopping. In the production of extracts, 1 to 30 parts by mass of a solvent is added to 1 part by mass of a part used for extraction of a plant or the like, or a dry product thereof. Immerse. After the immersion, the solution can be cooled to room temperature, insoluble matter can be removed if desired, and then the solvent can be removed by concentration under reduced pressure. Thereafter, fractionation and purification can be performed by column chromatography packed with silica gel or an ion exchange resin to obtain a desired extract. Here, the extract obtained from the plant of the present invention means the generic name of the extract itself, the fraction of the extract, the purified fraction, the extract or the fraction, and the solvent-free product of the purified product.
前記抽出溶媒としては、ショウガ科に属する植物に含有される脂溶性成分を溶解することが出来る溶媒であれば、特段の限定なく適応することが出来、特に好ましくは、脂質可溶性溶媒である、メタノ−ル、エタノ−ル、イソプロピルアルコ−ル、ブタノ−ルなどのアルコ−ル類、１，３−ブタンジオ−ル、ポリプロピレングリコ−ルなどの多価アルコ−ル類、アセトン、メチルエチルケトンなどのケトン類、ジエチルエ−テル、テトラヒドロフランなどのエ−テル類、ヘキサン、ペンタン等の炭化水素類等のから選択される１種乃至は２種以上が好適に例示出来る。さらに、ジンゲロ−ル等の脂溶性成分の抽出効率の点からは、５〜４０％（溶量）エタノ−ルが好ましく例示出来る。 As the extraction solvent, any solvent that can dissolve fat-soluble components contained in plants belonging to the family Gingeraceae can be applied without particular limitation, and particularly preferably a lipid-soluble solvent, methanol. Alcohols such as alcohol, ethanol, isopropyl alcohol and butanol, polyhydric alcohols such as 1,3-butanediol and polypropylene glycol, and ketones such as acetone and methyl ethyl ketone One or more selected from ethers such as diethyl ether and tetrahydrofuran, hydrocarbons such as hexane and pentane, and the like can be preferably exemplified. Further, from the viewpoint of extraction efficiency of fat-soluble components such as gingerol, 5 to 40% (soluble amount) ethanol can be preferably exemplified.
本発明のプロトンポンプ阻害剤は、生体膜に存在しプロトンを能動輸送する膜H＋−ATPase、及び／又は、イオンポンプであるNａ＋／K＋−ATPaseと共役的に働きプロトンを受動輸送するNa＋／Ｈ＋交換輸送系等に作用し、細胞又は細胞小器官内におけるプロトン濃度を調節する生体機能分子に作用し、プロトン輸送を阻害することにより細胞又は細胞小器官内における酸性化を誘引するプロトンポンプ阻害作用に優れる。この様な作用は、pH依存的に働くイオンチャネル、酵素（例えば、チロシナ−ゼ等）などの生体機能分子の生物活性又は機能に大きな影響を与える。本発明のプロトンポンプ阻害剤は、細胞又は細胞小器官内を酸性化することによりチロシナ−ゼ酵素活性を低下させ、メラニン産生を抑制するため、美白をはじめとする色素沈着の予防又は改善用に有用である。 The proton pump inhibitor of the present invention acts in a conjugate manner with membrane H + -ATPase and / or ion pump Na + / K + -ATPase that are present in biological membranes and actively transport protons. Acts on Na + / H + exchange transport system, etc., acts on biological functional molecules that regulate proton concentration in cells or organelles, and induces acidification in cells or organelles by inhibiting proton transport Excellent proton pump inhibitory action. Such an action greatly affects the biological activity or function of biological functional molecules such as ion channels and enzymes (for example, tyrosinase etc.) that work in a pH-dependent manner. The proton pump inhibitor of the present invention reduces the activity of tyrosinase by acidifying cells or organelles and suppresses melanin production, and thus is used for prevention or improvement of pigmentation including whitening. Useful.
本発明のプロトンポンプ阻害剤は、プロトンポンプ阻害作用（細胞又は細胞小器官内における酸性化作用）、並びに、プロトンポンプ阻害作用によるメラニン産生抑制作用、標的部位への集積性及び選択性に優れ、高い安全性及び安定性を有するために、化粧料（但し、医薬部外品を含む）などへの使用が好ましい。この様な効果を奏するためには、本発明のプロトンポンプ阻害剤を皮膚外用剤に配合する場合の含有量としては、前記一般式（１）に表される化合物、その異性体及び／又はそれらの薬理学的に許容される塩から選択される１種乃至は２種以上を、総量として皮膚外用剤全量に対し、０．０００００１質量％〜１０質量％、より好ましくは、０．００００１質量％〜５質量％、さらに好ましくは、０．００１質量％〜３質量％含有されることが好ましい。これは、プロトンポンプ阻害作用を有する前記一般式（１）に表される化合物、その異性体及び／又はそれらの薬理学的に許容される塩、さらには、ショウガ科に属する植物より得られる抽出物の含有量が少なすぎると、細胞内又は細胞小器官内における酸性化作用（プロトンポンプ阻害作用）によるチロシナ−ゼ酵素の活性低下及びメラニン産生抑制作用を奏さない場合が存し、多すぎても、プロトンポンプ阻害作用が頭打ちになり、この系の自由度を損なう場合が存するためである。
The proton pump inhibitor of the present invention is excellent in proton pump inhibitory action (acidification action in cells or organelles), melanin production inhibitory action by proton pump inhibitory action, accumulation on target site and selectivity, In order to have high safety | security and stability, use to cosmetics (however, including a quasi-drug) etc. is preferable. In order to achieve such an effect, the content of the proton pump inhibitor of the present invention when blended with an external preparation for skin is the compound represented by the above general formula (1), its isomer and / or them. One or two or more selected from the pharmacologically acceptable salts of 0.000001% by mass to 10% by mass, more preferably 0.00001% by mass, based on the total amount of the external preparation for skin. -5% by mass, more preferably 0.001% by mass to 3% by mass. This is a compound represented by the above general formula (1) having a proton pump inhibitory activity, its isomers and / or their pharmacologically acceptable salts, and further an extract obtained from a plant belonging to the family Ginger. If the content of the product is too small, there may be cases where the activity of the tyrosinase enzyme due to acidification (proton pump inhibition) in cells or organelles is not reduced and the melanin production suppression effect is not achieved. This is because the proton pump inhibitory action reaches its peak, and the degree of freedom of this system may be impaired.
＜本発明のプロトンポンプ阻害剤を含有する皮膚外用剤＞
本発明の皮膚外用剤は、前記一般式（１）に表される化合物、その異性体及び／又はそれらの薬理学的に許容される塩からなるプロトンポンプ阻害剤を含有することを特徴とする。本発明のプロトンポンプ阻害剤としては、細胞又は細胞小器官内においてプロトン濃度を調節する生体機能分子に作用することによりプロトン濃度を調節する（細胞又は細胞小器官内を酸性化する）作用を有する物質であれば、特段の限定なく適応することが出来る。具体的には、生体膜に存在し能動的なプロトン輸送を担う膜H＋−ATPaseのみならず、Na＋／K＋−ATPase等のイオンポンプと共役的に働き受動的なプロトン輸送を担うNa＋／H＋交換輸送体等の生体機能分子に作用しプロトン濃度を調節する物質を包含する。本発明のプロトンポンプ阻害剤の内、特に好ましいものとしては、後述するメラノサイト内の酸性化度を指標とする「メラノサイト内酸性化（プロトンポンプ阻害作用）検討」において、メラノサイト内の酸性化作用を有するプロトンポンプ阻害剤が好適に例示出来る。尚、本発明のメラノサイト内における酸性化作用（プロトンポンプ阻害作用）を有する物質とは、後述するメラノサイト内の酸性化を指標とする「メラノサイト内酸性化（プロトンポンプ阻害作用）検討」において、蛍光顕微鏡による目視観察により、pH感受性蛍光色素の発色強度の増強が認められる物質を意味する。また、本発明のプロトンポンプ阻害剤は、単純な化学物質、生薬及び動植物からの抽出物とその分画精製物などの混合組成物のいずれでもよい。本発明の皮膚外用剤には、前記プロトンポンプ阻害剤を、唯１種を含有させることも出来るし、２種以上を組み合わせて含有させることも出来る。本発明の皮膚外用剤は、前記のプロトンポンプ阻害剤を配合することにより、美白、しみ、くすみをはじめとする色素関連異常疾患に関する予防又は治療効果を発揮する。
<External skin preparation containing the proton pump inhibitor of the present invention>
The topical skin preparation of the present invention contains a proton pump inhibitor comprising the compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof. . The proton pump inhibitor of the present invention has an action of regulating the proton concentration (acidifying the inside of the cell or organelle) by acting on a biological functional molecule that regulates the proton concentration in the cell or organelle. Any substance can be applied without any particular limitation. Specifically, not only the membrane H + -ATPase that exists in biological membranes and plays an active role in proton transport, but also Na ions that work in conjunction with ion pumps such as Na + / K + -ATPase and carry out passive proton transport. Includes substances that act on biologically functional molecules such as + / H + exchange transporters to regulate proton concentration. Among the proton pump inhibitors of the present invention, particularly preferable are the acidification actions in melanocytes in the “examination of acidification in melanocytes (proton pump inhibition action)” using the degree of acidification in melanocytes as described below as an index. The proton pump inhibitor which has can be illustrated suitably. In addition, the substance having an acidifying action (proton pump inhibitory action) in melanocytes of the present invention is a fluorescent substance in "examination of acidification in melanocytes (proton pump inhibitory action)" using the acidification in melanocytes described later as an index. It means a substance in which the enhancement of the color intensity of the pH-sensitive fluorescent dye is observed by visual observation with a microscope. In addition, the proton pump inhibitor of the present invention may be any of simple chemical substances, herbal medicines, mixed compositions such as extracts from animals and plants, and fractionated purified products thereof. The skin external preparation of the present invention can contain only one proton pump inhibitor or a combination of two or more thereof. The external preparation for skin of the present invention exhibits a preventive or therapeutic effect on pigment-related abnormal diseases such as whitening, blemishes and dullness by incorporating the proton pump inhibitor.
本発明の皮膚外用剤においては、前記必須成分以外に、通常化粧料で使用される任意成分を含有することが出来る。この様な任意成分としては、スクワラン、ワセリン、マイクロクリスタリンワックスなどの炭化水素類、ホホバ油、カルナウバワックス、オレイン酸オクチルドデシルなどのエステル類、オリ−ブ油、牛脂、椰子油などのトリグリセライド類、ステアリン酸、オレイン酸、レチノイン酸などの脂肪酸、オレイルアルコ−ル、ステアリルアルコ−ル、オクチルドデカノ−ル等の高級アルコ−ル、スルホコハク酸エステルやポリオキシエチレンアルキル硫酸ナトリウム等のアニオン界面活性剤類、アルキルベタイン塩等の両性界面活性剤類、ジアルキルアンモニウム塩等のカチオン界面活性剤類、ソルビタン脂肪酸エステル、脂肪酸モノグリセライド、これらのポリオキシエチレン付加物、ポリオキシエチレンアルキルエ−テル、ポリオキシエチレン脂肪酸エステル等の非イオン界面活性剤類、ポリエチレングリコ−ル、グリセリン、１，３−ブタンジオ−ル等の多価アルコ−ル類、増粘・ゲル化剤、酸化防止剤、紫外線吸収剤、色剤、防腐剤、粉体等を含有することができる。製造は、常法に従い、これらの成分を処理することにより、困難なく、為しうる。 In the skin external preparation of the present invention, in addition to the essential components, optional components usually used in cosmetics can be contained. Such optional ingredients include hydrocarbons such as squalane, petrolatum, microcrystalline wax, esters such as jojoba oil, carnauba wax, octyldodecyl oleate, triglycerides such as olive oil, beef tallow, coconut oil, etc. , Fatty acids such as stearic acid, oleic acid, retinoic acid, higher alcohols such as oleyl alcohol, stearyl alcohol, octyldodecanol, anionic surface activity such as sulfosuccinic acid ester and sodium polyoxyethylene alkyl sulfate Agents, amphoteric surfactants such as alkylbetaine salts, cationic surfactants such as dialkylammonium salts, sorbitan fatty acid esters, fatty acid monoglycerides, polyoxyethylene adducts thereof, polyoxyethylene alkyl ethers, polyoxyethylenes Nonionic surfactants such as fatty acid esters, polyhydric alcohols such as polyethylene glycol, glycerin, 1,3-butanediol, thickening / gelling agents, antioxidants, UV absorbers, Coloring agents, preservatives, powders and the like can be contained. Manufacture can be done without difficulty by treating these components according to conventional methods.
これらの必須成分、任意成分を常法に従って処理し、ロ−ション、乳液、エッセンス、クリ−ム、パック化粧料、洗浄料などに加工することにより、本発明の皮膚外用剤は製造できる。皮膚に適応させることの出来る剤型であれば、いずれの剤型でも可能であるが、有効成分が皮膚に浸透して効果を発揮することから、皮膚への馴染みの良い、ロ−ション、乳液、クリ−ム、エッセンスなどの剤型がより好ましい。 The skin external preparation of this invention can be manufactured by processing these essential components and arbitrary components according to a conventional method and processing them into lotions, emulsions, essences, creams, pack cosmetics, cleansing agents and the like. As long as the dosage form can be adapted to the skin, any dosage form is possible, but since the active ingredient penetrates the skin and exerts its effect, the lotion and emulsion that are well-familiar with the skin , Cream, essence and the like are more preferable.
以下に、実施例をあげて、本発明について更に詳細に説明を加えるが、本発明がかかる実施例にのみ、限定されないことは言うまでもない。 Hereinafter, the present invention will be described in more detail with reference to examples, but it is needless to say that the present invention is not limited to such examples.
＜製造例１： 本発明のショウガ科ショウガ属ショウガより得られる植物抽出物、及び、前記一般式（１）に表される化合物（化合物１、化合物２、化合物３）の単離精製方法＞
本発明のショウガ科ショウガ属ショウガ（ショウキョウ）より得られる植物抽出物の製造方法を示す。本抽出物は、ショウガZingiber officinale Roscoe( Zingiberaceae ) の根茎をエタノールに浸漬し製造した。具体的には、ショウガ科ショウガ属ショウガ（ショウキョウ）を粗粉末にしたもの２００ｇに、薄めたエタノール（３７〜５０％）約６００ｍLを加え、時々かき混ぜながら可溶性成分が充分に溶けるまで放置し、布ごしし、残留物を薄めたエタノール（３７〜５０％）少量で洗い、圧搾し、浸出液及び洗液をあわせ、２日間放置し、濾過し、さらに薄めたエタノール（３７〜５０％）を加え、本発明のショウガ科ショウガ属ショウガより得られる植物抽出物全量１０００ｍLを製造した。本発明のショウガ科ショウガ属ショウガより得られる植物抽出物は、上記の製造例に記載の方法に準じ製造することも出来るし、丸善株式会社、一丸ファルコス株式会社などにより市販されている抽出物を購入し、使用することも出来る。
前記一般式（１）に表される化合物の内、化合物１〜３に関し単離精製を行った。市販のショウキョウ（乾燥品、刻み、ウチダ和漢薬）１．８ｋｇを９リットルのメタノール中で２時間加熱還流抽出を２回行い、ろ過後２回分の濾液をあわせたものを減圧下濃縮、乾燥し、ショウキョウメタノールエキス１５９ｇを得た。ショウキョウメタノールエキス１５９ｇを１０％の水を含んだメタノール溶液に溶解させ、ｎ−ヘキサンで液液分配抽出を行い、得られたｎ−ヘキサン画分を減圧下濃縮・乾燥し、ｎ−ヘキサンエキス６１．８ｇを得た。ｎ−ヘキサンエキス６１．８ｇをシリカゲルカラムクロマトグラフィー（Fuji Silysia PSQ100B、６００ｇ）に付し、ｎ−ヘキサンと酢酸エチルの混合溶液の比率を変えながら溶出させ、２８のフラクションに分画した。このうち２０番目のフラクション４ｇをさらにTSK-gel ODS-80Ts（東ソー株式会社）カラムを装着した分取ＨＰＬＣにて分画、精製を行い、化合物１〜３を得た。さらに、前記化合物１〜３に関しては、試薬メーカーより購入した１０−ジンゲロール（化合物１、ChromaDex Inc.）、８−ジンゲロール（化合物２、ChromaDex Inc.）及び６−ジンゲロール（化合物３、和光純薬工業株式会社）を標準品として用い、例えば、Journal of Cromatography B，８５６，４１−４７（２００７）に記載の高速液体クロマトグラフィーにより保持時間を比較し、化合物１〜３であることを確認した。
<Production Example 1: Plant extract obtained from Ginger ginger genus ginger of the present invention and a method for isolating and purifying compounds represented by general formula (1) (compound 1, compound 2, compound 3)>
The manufacturing method of the plant extract obtained from the ginger department ginger genus ginger (ginger) of this invention is shown. This extract was produced by immersing the rhizome of ginger Zingiber officinale Roscoe (Zingiberaceae) in ethanol. Specifically, 200g those Zingiberaceae ginger genus ginger (ginger root) and the end of the coarse powder, diluted ethanol (37-50%) to about 600mL was added, the soluble component was allowed to dissolve sufficiently stirring occasionally Wash the cloth, wash the residue with a small amount of diluted ethanol (37-50%), squeeze, combine the leachate and washings, leave for 2 days, filter, and further dilute ethanol (37-50%) In addition, a total of 1000 mL of plant extract obtained from the ginger genus Ginger of the present invention was produced. The plant extract obtained from the ginger ginger genus ginger of the present invention can be produced in accordance with the method described in the above production example, and an extract marketed by Maruzen Co., Ltd., Ichimaru Falcos Co., Ltd., etc. It can be purchased and used.
Of the compounds represented by the general formula (1), the compounds 1 to 3 were isolated and purified. 1.8 kg of commercially available shokyo (dried product, chopped, Uchida Japanese medicine) was heated and refluxed twice in 9 liters of methanol for 2 hours, and after filtration, the combined filtrate was concentrated under reduced pressure and dried. As a result, 159 g of Tokyo methanol extract was obtained. 159 g of Tokyo methanol extract was dissolved in a methanol solution containing 10% water, liquid-liquid partition extraction was performed with n-hexane, and the resulting n-hexane fraction was concentrated and dried under reduced pressure to obtain n-hexane extract. 61.8 g was obtained. 61.8 g of n-hexane extract was subjected to silica gel column chromatography (Fuji Silysia PSQ100B, 600 g), eluted while changing the ratio of the mixed solution of n-hexane and ethyl acetate, and fractionated into 28 fractions. Of these, 4 g of the 20th fraction was further fractionated and purified by preparative HPLC equipped with a TSK-gel ODS-80Ts (Tosoh Corporation) column to obtain compounds 1-3. Further, with respect to the compounds 1 to 3, 10-gingerol (compound 1, ChromaDex Inc.), 8-gingerol (compound 2, ChromaDex Inc.) and 6-gingerol (compound 3, Wako Pure Chemical Industries, Ltd.) purchased from a reagent manufacturer. Was used as a standard product, and for example, retention times were compared by high performance liquid chromatography described in Journal of Cromatography B, 856, 41-47 (2007) to confirm that they were compounds 1 to 3.
＜試験例１： メラノサイト内酸性化検出（プロトンポンプ阻害作用）検討＞
前記の方法に従い得られた化合物１〜３、本発明のショウガ科ショウガ属ショウガより得られる植物抽出物に関し、以下に記載の手順に従い、メラノサイト内酸性化作用（プロトンポンプ阻害作用）検出を行った。ヒト正常メラノサイト（クラボウ株式会社）を４ウェルLab-Tek chamber slide（Thormo Fisher Scientific社）に１００００cells／cm２播種し、翌日、評価物質（最終濃度： 化合物１ １×１０−３（w/v％）、ショウガ科ショウガ属ショウガより得られる植物抽出物 ０．００１（v/v％））を含有する培地 ０．５ｍＬ／wellに交換し、３０分培養した。コントロ−ルとして評価物質を含まないサンプルを前記同様に調製した。その後、Lysosensor１８９（モレキュラ−プロ−ブ社：最終濃度１μM）を加え、１５分間培養した。培養終了後、PBSにて洗浄し、４％パラホルムアルデヒドで室温１５分固定を行った。その後、スライドガラスでサンプルを封入し、蛍光顕微鏡（カ−ルツァイツ社）にて観察した。結果を図1および図２に示す。評価物質無処理のコントロ−ルに比較し、評価物質処理によりLysosensor１８９の蛍光強度（緑色）が増強していれば、ヒト正常メラノサイト内の酸性化が亢進したと考えられる。
<Test Example 1: Detection of acidification in melanocytes (proton pump inhibitory action)>
The compounds 1 to 3 obtained according to the above method and the plant extract obtained from the ginger genus Ginger of the present invention were detected in the melanocyte acidification action (proton pump inhibition action) according to the procedure described below. . Normal human melanocytes (Kurabo Co., Ltd.) were seeded in a 4-well Lab-Tek chamber slide (Thormo Fisher Scientific) at 10,000 cells / cm 2 and the evaluation substance (final concentration: Compound 1 1 × 10 −3 (w / v%) the next day. ), And a medium containing 0.001 (v / v%) plant extract obtained from Ginger ginger genus ginger) was replaced with 0.5 mL / well and cultured for 30 minutes. A sample containing no evaluation substance as a control was prepared in the same manner as described above. Thereafter, Lysosensor 189 (Molecular Probes: final concentration 1 μM) was added and incubated for 15 minutes. After completion of the culture, the cells were washed with PBS and fixed with 4% paraformaldehyde for 15 minutes at room temperature. Thereafter, the sample was sealed with a slide glass and observed with a fluorescence microscope (Karlzeitz). The results are shown in FIG. 1 and FIG. If the fluorescence intensity (green) of Lysosensor 189 is enhanced by the evaluation substance treatment as compared with the control without the evaluation substance treatment, it is considered that the acidification in human normal melanocytes is enhanced.
図１及び図２の結果より、コントロ−ルでは、酸性化度を示す蛍光発色強度は弱く、一方、化合物１及び本発明のショウガ科ショウガ属ショウガより得られる植物抽出物は、いずれも蛍光強度は増強している。図１及び図２の結果より、化合物１、本発明のショウガ科ショウガ属ショウガより得られる抽出物は、顕著なメラノサイト内における酸性化作用（プロトンポンプ阻害作用）を示すことがわかった。
From the results shown in FIG. 1 and FIG. 2, the fluorescent intensity of the acidification indicating the degree of acidification is weak in the control, while the plant extract obtained from Compound 1 and the ginger genus Ginger of the present invention has a fluorescent intensity. Is strengthening. From the results of FIG. 1 and FIG. 2, it was found that the extract obtained from Compound 1 and the ginger genus Ginger of the present invention has a remarkable acidifying action (proton pump inhibitory action) in melanocytes.
＜試験例２： 本発明のプロトンポンプ阻害剤である植物抽出物、化合物１〜３のメラニン産生抑制作用の検討＞
前記の化合物１〜３、本発明のショウガ科ショウガ属ショウガより得られる植物抽出物に関し、以下に記載の方法に従い、メラニン産生抑制作用を評価した。同時に、陽性対象としてハイドロキノンを用い、メラニン産生抑制作用を評価した。２４穴プレ−トにヒト正常メラノサイト（クラボウ株式会社）を２２５００（cells/ｃｍ２）播種する。翌日、評価物質を含有する培地 ０．５（mL／well）に交換し、０．２５（μCi）２−[２−１４C]チオウラシル（GEヘルスケアバイオサイエンス社）を添加し培養を継続した。播種４日後、培地を除去しPBSで１回プレ−トを洗浄した後、細胞生存率を評価するため生細胞数測定試薬SF（ナカライテスク社）溶液を添加した培地に交換し、３７℃、３時間呈色反応を行った。反応後、４５０（nm）の吸光度をマイクロプレ−トリ−ダ−Benchmark Plus（Bio-Rad Laboratories）を用い測定した。コントロ−ルとして評価物質を含まないサンプルを前記同様に調製し、コントロ−ルに対する評価物質を含むサンプルの吸光度の百分率を求め細胞生存率とした。 メラニン量測定のため吸光度測定後、PBSで１回プレ−トを洗浄し、TCAを添加し、細胞を溶解した後、蒸留水 を加え溶液をバイアルに移した。氷上に放置後、１５０００ｒｐｍ、５分間遠心した後、上清を除去した。再度、各バイアルに１０％ＴＣＡ ５００（μＬ）を添加し、氷上１５分間放置した。１５０００ｒｐｍ、５分間遠心した後、上清を除去した。残渣にアクアゾ−ル−２（パ−キンエルマ−社） １（ｍＬ）を添加し、液体シンチレ−ションカウンタ− ＬＳＣ−６１００（アロカ社製）にて放射線量を測定した。コントロ−ルとして評価物質を含まないサンプルを前記同様に調製し、コントロ−ルに対する評価物質を含むサンプルの放射線量の百分率を求めメラニン量（％）とした。メラニン産生量の５０％阻害濃度（ＩＣ５０値）は、細胞毒性の認められない範囲でＳＡＳ software version 9.1.3（SAS Institute Inc.）を用い算出した。結果を表１及び表２に示す。
<Test Example 2: Examination of melanin production inhibitory action of plant extract and compounds 1 to 3 which are proton pump inhibitors of the present invention>
Regarding the plant extracts obtained from the aforementioned compounds 1 to 3 and the ginger family ginger of the present invention, the melanin production inhibitory action was evaluated according to the method described below. At the same time, hydroquinone was used as a positive target, and the melanin production inhibitory action was evaluated. 22500 (cells / cm 2 ) of normal human melanocytes (Kurabo Co., Ltd.) are seeded in a 24-well plate. The next day, the medium was replaced with a medium 0.5 containing evaluated substances (mL / well), was continued by adding cultured 0.25 (μCi) 2- [2- 14 C] thiouracil (GE Healthcare Bio-Sciences) . Four days after seeding, the medium was removed, and the plate was washed once with PBS. Then, in order to evaluate cell viability, the medium was replaced with a medium to which a viable cell count reagent SF (Nacalai Tesque) was added, The color reaction was carried out for 3 hours. After the reaction, the absorbance at 450 (nm) was measured using a microplate reader Benchmark Plus (Bio-Rad Laboratories). A sample containing no evaluation substance as a control was prepared in the same manner as described above, and the percentage of absorbance of the sample containing the evaluation substance relative to the control was determined to obtain the cell viability. After measuring the absorbance to measure the amount of melanin, the plate was washed once with PBS, TCA was added, the cells were lysed, distilled water was added, and the solution was transferred to a vial. After leaving it on ice, it was centrifuged at 15000 rpm for 5 minutes, and then the supernatant was removed. Again, 10% TCA 500 (μL) was added to each vial and left on ice for 15 minutes. After centrifugation at 15000 rpm for 5 minutes, the supernatant was removed. Aquazol-2 (Perkin Elmer) 1 (mL) was added to the residue, and the radiation dose was measured with a liquid scintillation counter LSC-6100 (Aloka). A sample containing no evaluation substance as a control was prepared in the same manner as described above, and the percentage of the radiation dose of the sample containing the evaluation substance relative to the control was determined and used as the melanin amount (%). The 50% inhibitory concentration (IC 50 value) of melanin production was calculated using SAS software version 9.1.3 (SAS Institute Inc.) within the range where cytotoxicity was not observed. The results are shown in Tables 1 and 2.
本発明の前記一般式（１）に表される化合物（化合物１〜３）及びショウガ科ショウガ属ショウガより得られる植物抽出物は、細胞毒性を示さない濃度において顕著なメラニン産生抑制作用を示した。前記化合物１〜３及びショウガ科ショウガ属ショウガより得られる植物抽出物のメラニン産生抑制作用は、プロトンポンプ阻害作用を介し発現するものであることが判った。また、本発明の前記一般式（１）に表される化合物（化合物１〜３）及びショウガ科ショウガ属ショウガより得られる植物抽出物が示すメラニン産生抑制作用は、前記のメラノサイト内酸性化検出（プロトンポンプ阻害作用）に特異的に作用することによるものであると考えられる。
The compounds represented by the general formula (1) of the present invention (compounds 1 to 3) and the plant extract obtained from Ginger ginger genus showed a remarkable melanin production inhibitory action at a concentration not showing cytotoxicity. . It was found that the melanin production inhibitory action of the plant extracts obtained from the compounds 1 to 3 and Ginger ginger genus ginger is expressed through a proton pump inhibitory action. Moreover, the melanin production inhibitory action which the plant extract obtained from the compound (compounds 1-3) represented by the said General formula (1) of this invention and the ginger department ginger genus ginger shows the said acidification detection in melanocytes ( This is considered to be due to the specific action on the proton pump inhibitory action.
＜製造例２： 本発明のプロトンポンプ阻害剤を含有する皮膚外用剤の製造＞
表３及び表４に示す処方に従って、本発明の皮膚外用剤である、エッセンス化粧料を作製した。即ち、イ、ロ及びハの成分をそれぞれ７５℃に加熱し、イにロを徐々に加え乳化し、更に、ハを加え中和、増粘させ、攪拌冷却してエッセンスエマルション（化粧料）を得た。また、表３の処方成分中、「本発明のプロトンポンプ阻害剤」を「アルブチン」に置換した比較例１、「本発明のプロトンポンプ阻害剤」を水に置換した比較例２を作製した。
<Production Example 2: Production of external preparation for skin containing proton pump inhibitor of the present invention>
In accordance with the formulations shown in Tables 3 and 4, essence cosmetics, which are external preparations for skin of the present invention, were prepared. That is, the ingredients of A, B and C are heated to 75 ° C., and B is gradually added to emulsify, and further, neutralized and thickened by adding C, stirred and cooled to obtain an essence emulsion (cosmetic). Obtained. In addition, Comparative Example 1 in which “Arbutin” was substituted for “Proton pump inhibitor of the present invention” and Comparative Example 2 in which “Proton pump inhibitor of the present invention” was replaced with water was prepared.
＜製造例３： 本発明の皮膚外用剤の製造例２＞
表５及び表６に示す処方に従って、本発明の皮膚外用剤であるエッセンス化粧料を作製した。即ち、イ、ロ及びハの成分をそれぞれ７５℃に加熱し、イにロを徐々に加え乳化し、更に、ハを加え中和、増粘させ、攪拌冷却してエッセンスエマルション（化粧料）を得た。
<Production Example 3: Production Example 2 of the skin external preparation of the present invention>
According to the formulations shown in Tables 5 and 6, essence cosmetics that are external preparations for skin of the present invention were prepared. That is, the ingredients of A, B and C are heated to 75 ° C., and B is gradually added to emulsify, and further, neutralized and thickened by adding C, stirred and cooled to obtain an essence emulsion (cosmetic). Obtained.
表７及び表８に示す処方に従って、本発明のプロトンポンプ阻害剤を含有する皮膚外用剤（ロ−ション化粧料）を作製した。即ち、処方成分を８０℃で攪拌し、可溶化し、しかる後に、攪拌下冷却して、ロ−ション化粧料を得た。 According to the formulations shown in Tables 7 and 8, a skin external preparation (lotion cosmetic) containing the proton pump inhibitor of the present invention was prepared. That is, the prescription ingredients were stirred at 80 ° C. to solubilize, and then cooled with stirring to obtain a lotion cosmetic.
＜試験例３： ヒトにおける紫外線による色素沈着抑制効果＞
前記実施例に従い製造された化粧料１〜４、比較例１及び比較例２の化粧料を用いて、色素沈着抑制効果を調べた。自由意思で参加したパネラ−の両上腕内側部に１．５ｃｍ×１．５ｃｍの部位を上下２段に分け、合計７ヶ所設け、最少紅斑量（１ＭＥＤ）の紫外線照射を１日１回、３日連続して３回照射した。照射終了後１日より、１日１回２８日連続してサンプル５０μLを塗布した。１部位は無処置部位とした。塗布終了２４時間後に色彩色差計（ＣＲ-３００、コニカミノルタ株式会社）にて各試験部位の皮膚明度（Ｌ＊値）を測定し、無処置部位のＬ値に対するΔＬ＊値を算出した。Ｌ＊値は、色素沈着の程度が強いほど低い値となる。従って、ΔＬ＊値が大きい程、色素沈着が抑制されたと判断することができる。結果を表９に示す。これにより、本発明の皮膚外用剤である化粧料１〜４及び比較例１は、色素沈着抑制効果を示すことが分かる。また、化粧料１〜４の色素沈着抑制効果は、アルブチンを配合した比較例１に比べ優れていた。これは、化粧料１〜４に含有される前記プロトンポンプ阻害剤のメラニン産生抑制作用によると考えられる。
<Test Example 3: Effect of inhibiting pigmentation by ultraviolet rays in humans>
Using the cosmetics 1 to 4 and Comparative Examples 1 and 2 manufactured according to the above Examples, the pigmentation inhibitory effect was examined. Part of the upper arm of the paneler who participated voluntarily, the 1.5cm x 1.5cm part was divided into two upper and lower tiers, a total of seven places were provided, and UV irradiation with a minimum amount of erythema (1 MED) was given once a day. Irradiated 3 times a day. From 1 day after the completion of irradiation, 50 μL of sample was applied once a day for 28 consecutive days. One site was an untreated site. 24 hours after the completion of application, the skin lightness (L * value) of each test site was measured with a color difference meter (CR-300, Konica Minolta Co., Ltd.), and the ΔL * value relative to the L value of the untreated site was calculated. The L * value decreases as the degree of pigmentation increases. Therefore, it can be determined that the greater the ΔL * value, the more pigmentation is suppressed. The results are shown in Table 9. Thereby, it turns out that the cosmetics 1-4 which are the skin external preparations of this invention, and the comparative example 1 show the pigmentation inhibitory effect. Moreover, the pigmentation inhibitory effect of the cosmetics 1-4 was excellent compared with the comparative example 1 which mix | blended arbutin. This is considered to be due to the melanin production inhibitory action of the proton pump inhibitor contained in cosmetics 1 to 4.
本発明は、美白用の化粧料などに応用出来る。 The present invention can be applied to cosmetics for whitening.
Claims (7)
［式中、Ｒ１及びＲ２は、それぞれ独立に、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表し、Ｒ３は、炭素数１〜１２の直鎖又は分岐のアルキル基を表す。］ A proton pump inhibitor comprising a compound represented by the following general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof.
[Wherein, R1 and R2 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R3 represents a linear or branched alkyl group having 1 to 12 carbon atoms. . ]
［式中、Ｒ４及びＲ５は、それぞれ独立に、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表し、Ｒ６は、炭素数１〜１２の直鎖又は分岐のアルキル基を表す。］ The proton pump inhibitor according to claim 1, wherein the compound represented by the general formula (1) is a compound represented by the following general formula (2).
[Wherein, R4 and R5 each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and R6 represents a linear or branched alkyl group having 1 to 12 carbon atoms. . ]
［式中、Ｒ７は、炭素数１〜１２の直鎖又は分岐のアルキル基を表す。］ The proton pump inhibitor according to claim 1 or 2, wherein the compound represented by the general formula (2) is a compound represented by the following general formula (3).
[Wherein R 7 represents a linear or branched alkyl group having 1 to 12 carbon atoms. ]
［式中、Ｒ８及びＲ９は、それぞれ独立に、水素原子、炭素数１〜４の直鎖又は分岐のアルキル基を表す。］ The proton pump inhibitor according to claim 1 or 2, wherein the compound represented by the general formula (2) is a compound represented by the following general formula (4).
[In formula, R8 and R9 represent a hydrogen atom and a C1-C4 linear or branched alkyl group each independently. ]
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