JP2016079103A - Agent for alleviating feeling of stimulation - Google Patents
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本発明は、ＴＲＰＡ１活性抑制剤及び刺激感緩和剤に関する。 The present invention relates to a TRPA1 activity inhibitor and a stimulant sensation mitigator.
感覚は、外部から受けた刺激が電気信号に変換され、神経細胞を通じて脳に伝達されることで生じる。外部刺激を電気信号に変換するには、その外部刺激を感知する受容体の存在が必要である。
ＴＲＰＡ１は、一過性受容器電位（ＴＲＰ）イオンチャネルのスーパーファミリーに属する非選択性陽イオンチャネルであり、侵害受容ニューロンにおいて低温受容器（17℃）として見出された（非特許文献１）。その後、ＴＲＰＡ１は、マスタードオイルやそれに含まれるアリルイソチオシアネート（ＡＩＴＣ）、シナモン、ガーリック、メチルサリチレート、オイゲノール、アルコール類等に反応する化学受容体であること、更には低温と機械刺激、化学刺激に応答する痛み受容体であることが報告されている（非特許文献２、３、４及び５)。
Sensory sensation occurs when externally received stimuli are converted into electrical signals and transmitted to the brain through nerve cells. In order to convert an external stimulus into an electrical signal, the presence of a receptor that senses the external stimulus is necessary.
TRPA1 is a non-selective cation channel belonging to the superfamily of transient receptor potential (TRP) ion channels, and was found as a cold receptor (17 ° C.) in nociceptive neurons (Non-patent Document 1). . After that, TRPA1 is a chemical receptor that reacts with mustard oil and allyl isothiocyanate (AITC), cinnamon, garlic, methyl salicylate, eugenol, alcohols, etc. contained in it, as well as low temperature and mechanical stimulation, It has been reported to be a pain receptor that responds to stimuli (Non-Patent Documents 2, 3, 4, and 5).
また、最近では、パラベン類やアルカリ剤がＴＲＰＡ１に応答し、ＴＲＰＡ１で形質転換させた細胞を用いてパラベン類やアルカリ剤の刺激を抑制する物質をスクリーニングできること（特許文献１及び２）が報告されている。 Recently, it has been reported that parabens and alkaline agents respond to TRPA1 and that cells that are transformed with TRPA1 can be used to screen for substances that suppress the stimulation of parabens and alkaline agents (Patent Documents 1 and 2). ing.
斯様に、ＴＲＰＡ１は皮膚や粘膜の侵害受容器であり、様々な刺激によって活性化されることから、ＴＲＰＡ１の活性を抑制することは、刺激による痛みの軽減に有効であると考えられ、これまでに、被験物質とＡＩＴＣを、ＴＲＰＡ１を発現する細胞に接触させて、ＡＩＴＣによりＴＲＰＡ１を介して引き起こされる細胞内カルシウムイオン濃度の変化を測定することにより、刺激（痛み）抑制物質の探索・評価がなされ、刺激抑制物質が見出されている（非特許文献６）。本出願人においても、特定のフェニルペンタノール誘導体にＴＲＰＡ１活性抑制作用があることを見出している（特許文献４）。 Thus, since TRPA1 is a nociceptor of skin and mucous membranes and is activated by various stimuli, suppressing TRPA1 activity is considered to be effective in reducing pain caused by stimuli. Until then, the test substance and AITC are brought into contact with a cell expressing TRPA1, and the change in intracellular calcium ion concentration caused by TRPA1 by AITC is measured, so that a search (evaluation of a stimulus (pain) inhibitory substance is performed. Has been found, and a stimulus-suppressing substance has been found (Non-patent Document 6). The present applicant has also found that a specific phenylpentanol derivative has a TRPA1 activity inhibitory action (Patent Document 4).
本発明は、皮膚や粘膜に対する感覚刺激を緩和できるＴＲＰＡ１活性抑制剤、及び皮膚又は粘膜の刺激感緩和剤を提供することに関する。 The present invention relates to providing a TRPA1 activity inhibitor that can relieve sensory stimulation to skin and mucous membranes, and a skin or mucosal irritation mitigating agent.
本発明者らは、ＴＲＰＡ１の活性を抑制する素材について検討したところ、下記式（１）で表される化合物に、極めて優れたＴＲＰＡ１活性抑制作用があり、刺激感原因物質による皮膚や粘膜に対する刺激感の緩和に有効であること、さらに当該化合物はそれ自体には匂いが殆どなく、化粧品等の香粧品に配合しやすいことを見出した。 When the present inventors examined the material which suppresses the activity of TRPA1, the compound represented by the following formula (1) has an extremely excellent TRPA1 activity inhibitory effect, and irritation to the skin and mucous membrane by the substance causing irritation. It was found that the compound is effective in alleviating the feeling and that the compound itself has almost no odor and can be easily incorporated into cosmetics such as cosmetics.
すなわち本発明は、以下の１）〜３）に係るものである。
１）下記式（１）で表される化合物を有効成分とするＴＲＰＡ１活性抑制剤。
２）下記式（１）で表される化合物を有効成分とする皮膚又は粘膜の刺激感緩和剤。
３）下記式（１）で表される化合物を皮膚又は粘膜に適用する、皮膚又は粘膜の刺激感緩和方法。
That is, the present invention relates to the following 1) to 3).
1) A TRPA1 activity inhibitor comprising a compound represented by the following formula (1) as an active ingredient.
2) A skin or mucous membrane irritation reducing agent comprising a compound represented by the following formula (1) as an active ingredient.
3) A method for alleviating the irritation of skin or mucous membrane, wherein the compound represented by the following formula (1) is applied to the skin or mucous membrane.
〔式中、Ｒ１及びＲ４はそれぞれ独立して水素原子又は炭素数１〜３のアルキル基を示し、Ｒ２及びＲ３はそれぞれ独立して炭素数１〜３のアルキル基を示し、Ｘはハロゲン原子を示し、点線と実線の二重線は単結合又は二重結合を示す。〕 [Wherein, R 1 and R 4 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R 2 and R 3 each independently represent an alkyl group having 1 to 3 carbon atoms, and Represents a halogen atom, and a double line consisting of a dotted line and a solid line represents a single bond or a double bond. ]
本発明の式（１）で表される化合物は、ＴＲＰＡ１の活性化を効果的に抑制するという作用を有する。したがって、本発明のＴＲＰＡ１活性抑制剤、皮膚又は粘膜の刺激感緩和剤を、防腐剤、防腐助剤等の刺激感原因物質を含有する各種組成物と共に、或いは当該組成物の使用前後に使用することにより、当該刺激感原因物質による刺激感や痛みを緩和することができる。また、本発明の化合物はそれ自体には匂いが殆どないことから、化粧品等の香粧品にも容易に配合できる。 The compound represented by Formula (1) of this invention has the effect | action of suppressing the activation of TRPA1 effectively. Therefore, the TRPA1 activity inhibitor of the present invention, skin or mucous membrane irritation reducing agent is used together with various compositions containing irritation-causing substances such as preservatives and antiseptics, or before and after use of the composition. Thus, the irritation and pain caused by the irritation causing substance can be alleviated. Moreover, since the compound of the present invention itself has almost no odor, it can be easily blended into cosmetics such as cosmetics.
本発明の式（１）において、Ｒ１、Ｒ２、Ｒ３及びＲ４で示される炭素数１〜３のアルキル基としては、直鎖又は分岐の何れでもよく、具体的にはメチル基、エチル基、ｎ−プロピル基、イソプロピル基が挙げられるが、このうちメチル基が好ましい。
Ｒ１及びＲ４は、少なとも一方は水素原子であるのが好ましく、共に水素原子であるのがより好ましい。
Ｒ２及びＲ３は、少なとも一方はメチル基であるのが好ましく、共にメチル基であるのがより好ましい。
In the formula (1) of the present invention, the alkyl group having 1 to 3 carbon atoms represented by R 1 , R 2 , R 3 and R 4 may be either linear or branched, specifically a methyl group, Examples include an ethyl group, an n-propyl group, and an isopropyl group, and among them, a methyl group is preferable.
At least one of R 1 and R 4 is preferably a hydrogen atom, more preferably a hydrogen atom.
At least one of R 2 and R 3 is preferably a methyl group, more preferably a methyl group.
Ｘで示されるハロゲン原子としては、フッ素原子、塩素原子、臭素原子等が挙げられ、このうちフッ素原子、塩素原子が好ましく、フッ素原子がより好ましい。 Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, and a bromine atom. Among these, a fluorine atom and a chlorine atom are preferable, and a fluorine atom is more preferable.
本発明の式（１）で表される化合物において、点線と実線の二重線が二重結合である場合には、シス体（Ｚ体）及びトランス体（Ｅ体）が存在するが、トランス体であるのが好ましい。また、置換基の種類や組み合わせによって、ｄ体−、ｌ体−等の光学異性体及び回転異性体等の異性体が存在し得る。
本発明においては、当該各異性体の混合物や単離されたものの何れをも包含する。
In the compound represented by the formula (1) of the present invention, when the double line of the dotted line and the solid line is a double bond, a cis isomer (Z isomer) and a trans isomer (E isomer) exist. The body is preferred. Depending on the type and combination of substituents, there may exist optical isomers such as d-form and l-form and isomers such as rotational isomers.
In the present invention, any mixture of these isomers and isolated ones are included.
本発明の式（１)で表される化合物は、公知の方法（例えば、J. Org. Chem. 2005, 70, 1281-1290）に準じて化学合成することができる。例えば、下記反応式に示すように、塩基の存在下、Ａで示されるカルボニル化合物とホスホノカルボン酸トリエステル等を縮合させてα、β不飽和エステル体Ｂとし、これをＬｉＡｌＨ４等を用いた還元反応に付してアルコール体Ｃとすること、更にはこれを水素化して飽和のアルコール体Ｄとすること、更にはこれをＴＥＭＰＯとヨードベンゼンジアセテート等を用いた酸化反応に付してアルデヒド体Ｅとし、グリニャール試薬等のアルキル化剤を用いてアルキル基を導入して化合物Ｆとすることにより合成することができる。 The compound represented by the formula (1) of the present invention can be chemically synthesized according to a known method (for example, J. Org. Chem. 2005, 70, 1281-1290). For example, as shown in the following reaction formula, a carbonyl compound represented by A and a phosphonocarboxylic acid triester are condensed in the presence of a base to obtain an α, β unsaturated ester B, which is made of LiAlH 4 or the like. By subjecting it to a reduction reaction to give alcohol C, further hydrogenating it to saturated alcohol D, and further subjecting it to an oxidation reaction using TEMPO and iodobenzene diacetate or the like. It can be synthesized by converting the aldehyde body E into a compound F by introducing an alkyl group using an alkylating agent such as a Grignard reagent.
〔式中、Ｒ１〜Ｒ４及びＸは前記したものと同じ〕 [Wherein R 1 to R 4 and X are the same as those described above]
本発明の式（１）で表される化合物のうち好ましくは、Ｒ1及びＲ４が共に水素原子であり、Ｒ２及びＲ３が共にメチル基であり、Ｘがフッ素原子である化合物が挙げられ、より好適な化合物としては、後記表１に記載の、（Ｅ）−４−（ｐ−フルオロフェニル）−２，３−ジメチル−２−ブテン−１−オール(化合物１)、及び４−（ｐ−フルオロフェニル）−２，３−ジメチル−１−ブタノール（化合物２）を例示することができる。 Among the compounds represented by the formula (1) of the present invention, a compound in which R 1 and R 4 are both hydrogen atoms, R 2 and R 3 are both methyl groups, and X is a fluorine atom is preferable. More preferable compounds include (E) -4- (p-fluorophenyl) -2,3-dimethyl-2-buten-1-ol (compound 1) and 4- (P-Fluorophenyl) -2,3-dimethyl-1-butanol (compound 2) can be exemplified.
本発明の式（１)で表される化合物は、後記実施例に示すように、種々のＴＲＰＡ１刺激物質と共に、ＴＲＰＡ１を形質導入した細胞（ＴＲＰＡ１発現細胞）に接触させた場合に、刺激物質による細胞内の陽イオン量の流入を抑制するというＴＲＰＡ１活性抑制作用を有する（試験例１及び２）。
したがって、本発明の式（１)で表される化合物はＴＲＰＡ１活性抑制剤、及びＴＲＰＡ１を介して引き起こされる刺激や痛みの緩和に有効な刺激感緩和剤、例えば皮膚や粘膜に対する刺激感や痛みの緩和に有効な、皮膚又は粘膜の刺激感緩和剤となり得る。
The compound represented by the formula (1) of the present invention, as shown in Examples below, depends on a stimulating substance when it is brought into contact with various TRPA1-stimulating substances and cells (TRPA1-expressing cells) transduced with TRPA1. It has a TRPA1 activity inhibitory action of suppressing the inflow of cation amount in cells (Test Examples 1 and 2).
Therefore, the compound represented by the formula (1) of the present invention is a TRPA1 activity inhibitor, and a stimulant mitigating agent effective for alleviating irritation and pain caused by TRPA1, for example, irritation and pain of the skin and mucous membranes. It can be a skin or mucous membrane irritation relieving agent effective for relaxation.
ここで、「ＴＲＰＡ１の活性抑制」とは、受容体であるＴＲＰＡ１の活性を抑制すること、具体的にはＴＲＰＡ１刺激物質（アゴニスト）がＴＲＰＡ１に結合することによって発現する活性、例えばイオン流束の調節能（例えば、細胞外から細胞内へのカルシウムイオン、ナトリウムイオンなどの陽イオンの輸送能など）、膜電位の調節能（例えば、電流の発生能など）を抑制或いは阻害することを云う。
ここで、ＴＲＰＡ１刺激物質としては、例えば、アリルイソチオシアネート（ＡＩＴＣ）、アンモニア、ブラジキニン、シンナムアルデヒド、４−ヒドロキシノネナール、アリシン、アクロレイン、メントール、メチルサリチレート、オイゲノール、パラベン類、フェノキシエタノール、ブチルカルバミン酸ヨウ化プロピニル（ＩＰＢＣ）、トリクロサン、ベンジルアルコールなどが挙げられる。
Here, “inhibition of TRPA1 activity” means that the activity of TRPA1 which is a receptor is suppressed, specifically, the activity expressed by binding of TRPA1 stimulating substance (agonist) to TRPA1, for example, ion flux It refers to suppressing or inhibiting regulatory ability (eg, ability to transport cations such as calcium ions and sodium ions from the outside of the cell into the cell) and membrane potential regulation ability (eg, ability to generate current).
Here, as the TRPA1 stimulating substance, for example, allyl isothiocyanate (AITC), ammonia, bradykinin, cinnamaldehyde, 4-hydroxynonenal, allicin, acrolein, menthol, methyl salicylate, eugenol, parabens, phenoxyethanol, butylcarbamine Examples include propynyl oxyiodide (IPBC), triclosan, and benzyl alcohol.
尚、本発明の式（１)で表される化合物によるＴＲＰＡ１の活性の抑制効果は、例えば、ＴＲＰＡ１発現細胞を用い、式（１)で表される化合物の存在下にＴＲＰＡ１刺激物質（例えばＡＩＴＣ）と接触させたＴＲＰＡ１発現細胞内におけるカルシウムイオン濃度と、式（１)で表される化合物の非存在下でＴＲＰＡ１刺激物質と接触させたＴＲＰＡ１発現細胞内におけるカルシウムイオン濃度との差異を比較すること等によって評価することができる。 In addition, the inhibitory effect of the TRPA1 activity by the compound represented by the formula (1) of the present invention is, for example, using a TRPA1-expressing cell, and in the presence of the compound represented by the formula (1), a TRPA1 stimulating substance (for example, AITC) The difference between the calcium ion concentration in the TRPA1-expressing cell brought into contact with) and the calcium ion concentration in the TRPA1-expressing cell contacted with the TRPA1-stimulating substance in the absence of the compound represented by the formula (1) It can be evaluated by things.
また、「皮膚又は粘膜の刺激感緩和」とは、ＴＲＰＡ１を介して引き起こされる皮膚や粘膜に対する刺激感や痛みを抑制又は低減することを意味し、より具体的には、上述したＴＲＰＡ１刺激物質とされる化学物質によって引き起こされる、感覚刺激を抑制又は低減することが挙げられる。ここでいう好適なＴＲＰＡ１刺激物質としては、皮膚や粘膜に対して刺激感を与える可能性がある化学物質（「刺激感原因物質」という）、例えば、パラベン類、フェノキシエタノール、ブチルカルバミン酸ヨウ化プロピニル（ＩＰＢＣ）、トリクロサン等の防腐剤、ベンジルアルコール等の防腐助剤、アンモニア、アクロレイン、メントール、メチルサリチレート、オイゲノール、一価アルコール、多価アルコール等のアルコール類等が挙げられる。ここで、一価アルコールとしては、例えば、エチルアルコール、プロピルアルコール、ブチルアルコール、ペンチルアルコール、ヘキシルアルコール、ヘプチルアルコール、オクチルアルコール、ノニルアルコール、デシルアルコールなどの炭素数２〜１０の直鎖または分岐鎖の脂肪族一価アルコールなどが挙げられ、多価アルコールとしては、例えば、プロピレングリコール、ジプロピレングリコール、１，３−ブチレングリコール、ペンチレングリコール、ヘキシレングリコールなどの炭素数２〜６の脂肪族二価アルコールなどが挙げられる。 The term “skin or mucous membrane irritation mitigation” means to suppress or reduce the irritation or pain to the skin or mucous membrane caused by TRPA1, and more specifically, the above-mentioned TRPA1 stimulating substance and Inhibiting or reducing sensory stimulation caused by the chemicals to be applied. Suitable TRPA1-stimulating substances here are chemical substances that may give a feeling of irritation to the skin and mucous membranes (referred to as “irritant substances”), such as parabens, phenoxyethanol, propynyl iodide butylcarbamate. (IPBC), antiseptics such as triclosan, antiseptics such as benzyl alcohol, alcohols such as ammonia, acrolein, menthol, methyl salicylate, eugenol, monohydric alcohol, polyhydric alcohol, and the like. Here, as monohydric alcohol, for example, ethyl alcohol, propyl alcohol, butyl alcohol, pentyl alcohol, hexyl alcohol, heptyl alcohol, octyl alcohol, nonyl alcohol, decyl alcohol, etc., linear or branched chain having 2 to 10 carbon atoms Examples of polyhydric alcohols include aliphatic alcohols having 2 to 6 carbon atoms such as propylene glycol, dipropylene glycol, 1,3-butylene glycol, pentylene glycol, and hexylene glycol. Examples include dihydric alcohols.
尚、ここでいう、「粘膜」としては、口腔、咽喉、鼻腔、耳腔、結膜嚢等が挙げられる。
刺激感緩和効果は、後記実施例に示すような官能評価により測定してもよく、又は上記のＴＲＰＡ１発現細胞を用いた細胞内カルシウムイオン濃度の変化を以て評価することもできる。
As used herein, “mucosa” includes the oral cavity, throat, nasal cavity, ear cavity, conjunctival sac, and the like.
The stimulating sensation mitigating effect may be measured by sensory evaluation as shown in Examples below, or can be evaluated by a change in intracellular calcium ion concentration using the above-mentioned TRPA1-expressing cells.
ＴＲＰＡ１活性抑制剤及び皮膚又は粘膜の刺激感緩和剤は、本発明の式（１)で表される化合物を単独で用いたものであってもよく、あるいは油分、色素、香料、防腐剤、キレート剤、顔料、酸化防止剤、ビタミン、ミネラル、甘味料、調味料、保存料、結合剤、増量剤、崩壊剤、界面活性剤、滑沢剤、分散剤、緩衝剤、被膜剤、担体、希釈剤等の、医薬品、化粧品、香粧品、医薬部外品、生活用品等の各種製剤に用いられる添加剤や賦形剤等と組み合わせた組成物であってもよい。またそれらの形態も特に限定されず、例えば溶液、エマルジョン、サスペンジョン、ゲル、固形、粉体、粒体、エアゾールなど、任意の形態に調製できる。
当該組成物における式（１)で表される化合物の配合量は、製剤全質量の０．００１質量％以上、好ましくは０．０１質量％以上であり、そして、１０質量％以下、好ましくは１質量％以下である。例えば、０．００１〜１０質量％、好ましくは０．０１〜１質量％が挙げられる。
The TRPA1 activity inhibitor and the skin or mucosal irritation mitigating agent may be those using the compound represented by the formula (1) of the present invention alone, or oils, pigments, fragrances, preservatives, chelates. Agent, pigment, antioxidant, vitamin, mineral, sweetener, seasoning, preservative, binder, extender, disintegrant, surfactant, lubricant, dispersant, buffer, coating agent, carrier, dilution It may be a composition combined with additives and excipients used in various preparations such as pharmaceuticals, cosmetics, cosmetics, quasi-drugs, and daily necessities. Moreover, those forms are not particularly limited, and can be prepared in any form such as a solution, emulsion, suspension, gel, solid, powder, granule, aerosol, and the like.
The compounding amount of the compound represented by the formula (1) in the composition is 0.001% by mass or more, preferably 0.01% by mass or more, and 10% by mass or less, preferably 1% of the total mass of the preparation. It is below mass%. For example, 0.001-10 mass%, Preferably 0.01-1 mass% is mentioned.
本発明のＴＲＰＡ１活性抑制剤及び皮膚又は粘膜の刺激感緩和剤は、例えば、上述した刺激感原因物質を含有する組成物（皮膚洗浄剤、頭髪洗浄剤、メイクアップ剤、入浴剤、パーマネントウェーブ用剤、染毛剤、石鹸類、台所用洗剤、洗濯用洗剤、歯磨類等の化粧品、香粧品、医薬部外品、医薬品、生活用品等）に配合して使用すること、或いは刺激感原因物質を含有する組成物とは別個の組成物として調製し、前記組成物と同時或いは前記組成物の使用前後に使用することにより、当該刺激感原因物質により引き起こされる感覚刺激を緩和できる。 The TRPA1 activity inhibitor and the skin or mucous membrane irritation reducing agent of the present invention include, for example, a composition containing the above-mentioned irritation sensation causing substance (skin cleaning agent, hair cleaning agent, makeup agent, bath agent, permanent wave use). Cosmetics, hair dyes, soaps, kitchen detergents, laundry detergents, toothpaste cosmetics, cosmetics, quasi-drugs, pharmaceuticals, daily necessities, etc.) or substances that cause irritation The composition can be prepared as a composition separate from the composition containing, and can be used simultaneously with the composition or before and after use of the composition to relieve sensory stimulation caused by the substance causing the irritation.
本発明のＴＲＰＡ１活性抑制剤及び皮膚又は粘膜の刺激感緩和剤を、刺激感原因物質を含有する組成物と共に用いる場合、ＴＲＰＡ１活性抑制剤及び皮膚又は粘膜の刺激感緩和剤の使用量は、刺激感緩和効果を有する限り特に限定されないが、例えば、刺激感原因物質１質量部に対し、本発明の式（１)で表される化合物を好ましくは０．０１質量部以上、より好ましくは０．１質量部以上、そして好ましくは１０質量部以下、より好ましくは１質量部以下の割合とすることができる。例えば、刺激感原因物質１質量部に対し、好ましくは０．０１〜１０質量部、より好ましくは０．１〜１質量部の割合とすることができる。 When the TRPA1 activity inhibitor and the skin or mucosal irritation reducing agent of the present invention are used together with the composition containing the substance causing irritation, the amount of the TRPA1 activity inhibitor and the skin or mucosal irritation reducing agent used is irritation. Although it does not specifically limit as long as it has a sensation mitigating effect, For example, the compound represented by the formula (1) of the present invention is preferably 0.01 parts by mass or more, more preferably 0. The ratio can be 1 part by mass or more, preferably 10 parts by mass or less, more preferably 1 part by mass or less. For example, the ratio can be preferably 0.01 to 10 parts by mass, more preferably 0.1 to 1 part by mass with respect to 1 part by mass of the substance that causes irritation.
上述した実施形態に関し、本発明においてはさらに以下の態様が開示される。
＜１＞下記式（１）で表される化合物を有効成分とするＴＲＰＡ１活性抑制剤。
＜２＞下記式（１）で表される化合物を有効成分とする皮膚又は粘膜の刺激感緩和剤。
＜３＞ＴＲＰＡ１活性抑制剤を製造するための下記式（１）で表される化合物の使用。
＜４＞皮膚又は粘膜の刺激感緩和剤を製造するための下記式（１）で表される化合物の使用。
＜５＞ＴＲＰＡ１活性抑制に使用するための下記式（１）で表される化合物。
＜６＞皮膚又は粘膜の刺激感緩和に使用するための下記式（１）で表される化合物。
＜７＞下記式（１）で表される化合物を皮膚又は粘膜に適用する、ＴＲＰＡ１活性抑制方法。
＜８＞下記式（１）で表される化合物を皮膚又は粘膜に適用する、皮膚又は粘膜の刺激感緩和方法。
＜９＞上記＜２＞、＜４＞、＜６＞又は＜８＞において、感覚刺激の緩和は、例えば防腐剤、防腐助剤、アルコール類及びアンモニアから選ばれる刺激感原因物質による皮膚又は粘膜の感覚刺激の緩和である。
＜１０＞上記＜５＞、＜６＞、＜７＞又は＜８＞において、下記式（１）で表される化合物は、刺激感原因物質を含有する組成物に配合して使用するか、或いは当該組成物とは別個の組成物として調製し、前記組成物と同時又は前記組成物の使用前後に使用するものである。
＜１１＞上記＜１０＞において、下記式（１)で表される化合物を、刺激感原因物質１質量部に対し、好ましくは０．０１質量部以上、より好ましくは０．１質量部以上、そして好ましくは１０質量部以下、より好ましくは１質量部以下の割合で使用するものである。
Regarding the above-described embodiment, the following aspects are further disclosed in the present invention.
<1> A TRPA1 activity inhibitor comprising a compound represented by the following formula (1) as an active ingredient.
<2> A skin or mucous membrane irritation reducing agent comprising a compound represented by the following formula (1) as an active ingredient.
<3> Use of a compound represented by the following formula (1) for producing a TRPA1 activity inhibitor.
<4> Use of a compound represented by the following formula (1) for producing a skin or mucous membrane irritation reducing agent.
<5> A compound represented by the following formula (1) for use in inhibiting TRPA1 activity.
<6> A compound represented by the following formula (1) for use in reducing irritation of skin or mucous membranes.
<7> A method for inhibiting TRPA1 activity, which comprises applying a compound represented by the following formula (1) to the skin or mucous membrane.
<8> A method for reducing the irritation of skin or mucous membrane, wherein the compound represented by the following formula (1) is applied to the skin or mucous membrane.
<9> In the above <2>, <4>, <6> or <8>, the relaxation of sensory irritation is, for example, skin or mucous membrane caused by an irritation-causing substance selected from antiseptics, antiseptics, alcohols and ammonia The relaxation of sensory stimulation.
<10> In the above <5>, <6>, <7> or <8>, is the compound represented by the following formula (1) used in a composition containing a substance causing irritation? Alternatively, it is prepared as a composition separate from the composition and used at the same time as the composition or before and after use of the composition.
<11> In the above <10>, the compound represented by the following formula (1) is preferably 0.01 parts by mass or more, more preferably 0.1 parts by mass or more, with respect to 1 part by mass of the irritation sensation causing substance. And it is preferably used at a ratio of 10 parts by mass or less, more preferably 1 part by mass or less.
〔式中、Ｒ１及びＲ４はそれぞれ独立して水素原子又は炭素数１〜３のアルキル基を示し、Ｒ２及びＲ３はそれぞれ独立して炭素数１〜３のアルキル基を示し、Ｘはハロゲン原子を示し、点線と実線の二重線は単結合又は二重結合を示す。〕 [Wherein, R 1 and R 4 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R 2 and R 3 each independently represent an alkyl group having 1 to 3 carbon atoms, and Represents a halogen atom, and a double line consisting of a dotted line and a solid line represents a single bond or a double bond. ]
製造例１
以下に、下記表１に示す化合物（化合物１〜２）の製造例を示す。
Production Example 1
Below, the manufacture example of the compound (compounds 1-2) shown in following Table 1 is shown.
１Ｈ−ＮＭＲスペクトルは、ＣＨＣｌ３（７．２４）を内部標準物質として用いて、Ｂｒｕｋｅｒ社製Ａｖａｎｃｅ−６００により測定し、１３ＣＮＭＲスペクトルは、ＣＨＣｌ３（７７．０）を内部標準物質として用いて、Ｂｒｕｋｅｒ社製Ａｖａｎｃｅ−６００により測定した。 1 H-NMR spectrum was measured by Bruker Avance-600 using CHCl 3 (7.24) as an internal standard substance, and 13 CNMR spectrum was measured using CHCl 3 (77.0) as an internal standard substance. Then, it was measured by Bruker Avance-600.
（１）水素化ナトリウム（純度５５％、２４５ｍｇ）をテトラヒドロフラン（１０ｍＬ）に懸濁し、２−ホスホノプロピオン酸トリエチル（１．４６ｍＬ）を加え、室温・窒素雰囲気下、３０分撹拌した。反応液に、１−（４−フルオロフェニル）−２−プロパノン（３３５ｍｇ）をテトラヒドロフラン（５ｍＬ）に溶解したものを加え、さらに１７時間撹拌した。反応液に飽和塩化アンモニウム水溶液と酢酸エチルを加え、酢酸エチル層を減圧乾燥後、シリカゲルクロマトグラフィーによって精製し、(Z)-α,β不飽和エステル体（１１１ｍｇ）および(E)- α,β不飽和エステル体（１５１ｍｇ）を得た。 (1) Sodium hydride (purity 55%, 245 mg) was suspended in tetrahydrofuran (10 mL), triethyl 2-phosphonopropionate (1.46 mL) was added, and the mixture was stirred at room temperature / nitrogen atmosphere for 30 min. To the reaction solution was added 1- (4-fluorophenyl) -2-propanone (335 mg) dissolved in tetrahydrofuran (5 mL), and the mixture was further stirred for 17 hours. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction mixture, and the ethyl acetate layer was dried under reduced pressure and purified by silica gel chromatography to obtain (Z) -α, β unsaturated ester (111 mg) and (E) -α, β An unsaturated ester (151 mg) was obtained.
（２）ＬｉＡｌＨ４（６３．９ｍｇ）をテトラヒドロフラン（４ｍＬ）に懸濁し、（１）で得られた(E)-α,β不飽和エステル体（１３２．６ｍｇ）をテトラヒドロフラン（１ｍＬ）に溶解したものを加え、０℃で３０分撹拌した。反応液に水（１００μＬ）、１５％水酸化ナトリウム水溶液（１００μＬ）、水（３００μＬ）の順で加え、１日撹拌し、不溶物を濾過した。濾液を減圧乾燥後、シリカゲルクロマトグラフィーによって精製し、(E)-２，３ジメチル−４−（４−フルオロフェニル）−２−ブテン−１−オール（化合物１、９９．６ｍｇ）を得た。 (2) LiAlH 4 (63.9 mg) was suspended in tetrahydrofuran (4 mL), and the (E) -α, β unsaturated ester (132.6 mg) obtained in (1) was dissolved in tetrahydrofuran (1 mL). The mixture was added and stirred at 0 ° C. for 30 minutes. Water (100 μL), 15% aqueous sodium hydroxide solution (100 μL) and water (300 μL) were added to the reaction solution in this order, and the mixture was stirred for 1 day, and insoluble matters were filtered off. The filtrate was dried under reduced pressure and purified by silica gel chromatography to obtain (E) -2,3dimethyl-4- (4-fluorophenyl) -2-buten-1-ol (Compound 1, 99.6 mg).
化合物１のＮＭＲスペクトルを以下に示す。
1H NMR (600 MHz, CDCl3) d 7.10-7.05 (m, 2H), 6.96-6.91 (m, 2H), 4.18 (s, 2H), 3.36 (s, 2H), 1.87 (s, 3H), 1.64 (s, 3H); 13C NMR (150 MHz, CDCl3) d 162.1-160.5 (d), 135.5 (d), 131.4, 129.7 (d), 129.6, 115.1-115.0 (d), 63.9, 39.5, 17.7, 16.7.
The NMR spectrum of Compound 1 is shown below.
1 H NMR (600 MHz, CDCl 3 ) d 7.10-7.05 (m, 2H), 6.96-6.91 (m, 2H), 4.18 (s, 2H), 3.36 (s, 2H), 1.87 (s, 3H), 1.64 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) d 162.1-160.5 (d), 135.5 (d), 131.4, 129.7 (d), 129.6, 115.1-115.0 (d), 63.9, 39.5, 17.7, 16.7.
（３）（２）で得られた化合物１（７９．２ｍｇ）を酢酸エチル（５ｍＬ）に溶解し、窒素雰囲気下でＰｄ／Ｃ（１０％、７９ｍｇ）を加えた後、系内を水素ガスで置換して室温で１４時間撹拌した。反応液をセライト濾過し、濾液を減圧乾燥後、シリカゲルクロマトグラフィーによって精製し、２，３−ジメチル−４−（４−フルオロフェニル）−１−ブタノール（ｄｒ＝５７：４３、化合物２、１１．７ｍｇ）を得た。 (3) Compound 1 (79.2 mg) obtained in (2) was dissolved in ethyl acetate (5 mL), and Pd / C (10%, 79 mg) was added under a nitrogen atmosphere. And stirred at room temperature for 14 hours. The reaction solution was filtered through Celite, and the filtrate was dried under reduced pressure and purified by silica gel chromatography to obtain 2,3-dimethyl-4- (4-fluorophenyl) -1-butanol (dr = 57: 43, compounds 2, 11. 7 mg) was obtained.
化合物２のＮＭＲスペクトルを以下に示す。
1H NMR (600 MHz, CDCl3) d 7.10-7.06 (m, 2H-m,M), 6.96-6.91 (m, 2H-m,M), 3.66 (dd, J = 10.5, 5.8 Hz, 1H-m), 3.55-3.54 (m, 1H-m, 2H-M), 2.73 (dd, J= 13.5, 4.6 Hz, 1H-m), 2.60 (dd, J = 13.6, 6.6 Hz, 1H-M), 2.40 (dd, J = 13.6, 8.6 Hz, 1H-M), 2.22 (dd, J = 13.5, 9.9 Hz, 1H-m), 1.93 (m, 1H-M), 1.81 (m, 1H-m), 1.69-1.60 (m, 1H-m,M), 0.95 (d, J = 6.9 Hz, 3H-m), 0.85 (d, J = 7.1 Hz, 3H-M), 0.79 (d, J = 6.9 Hz, 3H-m), 0.75 (d, J = 7.0 Hz, 3H-M); 13C NMR (150 MHz, CDCl3) d 162.0-160.4 (d-m,M), 137.2 (d-m), 137.0 (d-M), 130.3 (d-m), 130.3-130.2 (d-M), 115.0-114.8 (d-M), 114.9-114.8 (d-m), 66.7 (M), 65.8 (m), 40.5 (M), 40.2 (m), 38.7 (M), 38.5 (m), 37.0 (m), 35.5 (M), 16.4 (m), 13.8 (M), 13.7 (m), 11.0 (M).
(m = minor diastereomer, M = Major diastereomer)
The NMR spectrum of Compound 2 is shown below.
1 H NMR (600 MHz, CDCl 3 ) d 7.10-7.06 (m, 2H-m, M), 6.96-6.91 (m, 2H-m, M), 3.66 (dd, J = 10.5, 5.8 Hz, 1H- m), 3.55-3.54 (m, 1H-m, 2H-M), 2.73 (dd, J = 13.5, 4.6 Hz, 1H-m), 2.60 (dd, J = 13.6, 6.6 Hz, 1H-M), 2.40 (dd, J = 13.6, 8.6 Hz, 1H-M), 2.22 (dd, J = 13.5, 9.9 Hz, 1H-m), 1.93 (m, 1H-M), 1.81 (m, 1H-m), 1.69-1.60 (m, 1H-m, M), 0.95 (d, J = 6.9 Hz, 3H-m), 0.85 (d, J = 7.1 Hz, 3H-M), 0.79 (d, J = 6.9 Hz, 3H-m), 0.75 (d, J = 7.0 Hz, 3H-M); 13 C NMR (150 MHz, CDCl 3 ) d 162.0-160.4 (dm, M), 137.2 (dm), 137.0 (dM), 130.3 (dm), 130.3-130.2 (dM), 115.0-114.8 (dM), 114.9-114.8 (dm), 66.7 (M), 65.8 (m), 40.5 (M), 40.2 (m), 38.7 (M), 38.5 (m), 37.0 (m), 35.5 (M), 16.4 (m), 13.8 (M), 13.7 (m), 11.0 (M).
(m = minor diastereomer, M = Major diastereomer)
試験例１ ＴＲＰＡ１活性抑制作用
（１）ヒトＴＲＰＡ１安定発現株の作製
ヒトＴＲＰＡ１遺伝子は、その全長をＯｐｅｎ ｂｉｏｓｙｓｔｅｍｓ社よりｐＥＮＴＲ２２３．１に挿入された状態で購入した。購入したエントリーベクターよりＴＲＰＡ１遺伝子を発現用ベクターｐｃＤＮＡ３．２−Ｖ５／ＤＥＳＴ（インビトロジェン社）へサブクローニングし、リポフェクトアミン２０００（インビトロジェン社）によりＨＥＫ２９３細胞へ形質導入した。形質導入された細胞をＧ−４１８（４５０μｇ／ｍＬ；プロメガ社）を含有するＤＭＥＭ培地中で増殖させることにより選抜した。なおＨＥＫ２９３細胞は内在性ＴＲＰＡ１を発現しないため、ＴＲＰＡ１形質導入株に対する対照（コントロール）として使用できる。
Test Example 1 TRPA1 activity inhibitory action (1) Production of stable expression strain of human TRPA1 The human TRPA1 gene was purchased from Open biosystems in a state where it was inserted into pENTR223.1. The TRPA1 gene was subcloned from the purchased entry vector into the expression vector pcDNA3.2-V5 / DEST (Invitrogen) and transduced into HEK293 cells with Lipofectamine 2000 (Invitrogen). Transduced cells were selected by growing in DMEM medium containing G-418 (450 μg / mL; Promega). Since HEK293 cells do not express endogenous TRPA1, they can be used as a control (control) for the TRPA1 transduced strain.
（２）カルシウムイメージング
蛍光カルシウムイメージング法を用いてＨＥＫ２９３細胞へ形質導入したＴＲＰＡ１活性の測定を行った。まず培養したＴＲＰＡ１発現細胞をポリ−Ｄ−リジンコートされた９６ウェルプレート（ＢＤファルコン社）に播種（３００００細胞／ウェル）し、３７℃で一晩、インキュベートした後、培養液を除去し、リンガー液に溶解させたＦｌｕｏ４−ＡＭ（２μｇ／ｍＬ；同仁化学社）を添加し、３７℃で６０分間インキュベートした。その後、Ｆｌｕｏ４−ＡＭ液を除去し、ウェルにリンガー液を添加して蛍光プレートリーダー（ＦＤＳＳ３０００；浜松ホトニクス社）にセットした。装置庫内温度２４℃にした状態で励起波長４８０ｎｍで励起させたときの蛍光イメージを検出波長５２０ｎｍにてＣＣＤカメラで検出した。測定は１秒毎に４分間行い、測定開始１５秒後にＦＤＳＳ３０００内蔵の分注器によりＴＲＰＡ１刺激物質であるアリルイソチオシアネート(ＡＩＴＣ)およびエタノールにて適当濃度に希釈した試験素材を添加し、その後の蛍光強度の変化によりＴＲＰＡ１活性を評価した。ＴＲＰＡ１活性は刺激物質添加後の蛍光強度のピーク（Ｆｐｅａｋ）を刺激物質添加前の蛍光強度（Ｆ０）で除算した蛍光強度比（Ｒａｔｉｏ；Ｆｐｅａｋ／Ｆ０）で表した。対照としてＴＲＰＡ１を形質導入していないＨＥＫ２９３細胞に同様の物質を添加し、その際の蛍光強度比（Ｒａｔｉｏ２９３）を算出し、刺激物質による活性がＴＲＰＡ１活性化に由来することを確認した。
(2) Calcium imaging TRPA1 activity transduced into HEK293 cells was measured using a fluorescent calcium imaging method. First, cultured TRPA1-expressing cells were seeded (30000 cells / well) in a 96-well plate (BD Falcon) coated with poly-D-lysine, incubated at 37 ° C. overnight, and then the culture solution was removed. Fluo4-AM (2 μg / mL; Dojin Chemical) dissolved in the solution was added and incubated at 37 ° C. for 60 minutes. Thereafter, the Fluo4-AM solution was removed, the Ringer solution was added to the wells, and the plate was set on a fluorescent plate reader (FDSS3000; Hamamatsu Photonics). A fluorescence image was detected with a CCD camera at a detection wavelength of 520 nm when excited at an excitation wavelength of 480 nm with the apparatus internal temperature set at 24 ° C. The measurement is performed every second for 4 minutes, and after 15 seconds from the start of the measurement, a test material diluted to an appropriate concentration with TRPA1 stimulating substance allyl isothiocyanate (AITC) and ethanol is added using a dispenser with a built-in FDSS 3000, and thereafter TRPA1 activity was evaluated by changes in fluorescence intensity. The TRPA1 activity was expressed as a fluorescence intensity ratio (Ratio; F peak / F 0 ) obtained by dividing the peak (F peak ) of fluorescence intensity after addition of the stimulating substance by the fluorescence intensity (F 0 ) before adding the stimulating substance. As a control, the same substance was added to HEK293 cells not transduced with TRPA1, and the fluorescence intensity ratio (Ratio 293 ) at that time was calculated, and it was confirmed that the activity by the stimulating substance was derived from TRPA1 activation.
（３）ＡＩＴＣに対するＴＲＰＡ１活性抑制評価（１）
ＡＩＴＣによるＴＲＰＡ１活性化に対する試験素材の効果を検証するため、ＡＩＴＣ（５．０μＭ）を添加した際のＴＲＰＡ１活性に対する試験素材の抑制作用（活性抑制率；％）を評価した。ＡＩＴＣ（刺激物質）と試験素材を混合し、添加することによるＴＲＰＡ１活性は下記の式により算出した。
〔数１〕
ＴＲＰＡ１活性（％）＝（（刺激物質＋試験素材添加によるＲａｔｉｏ）−（刺激物質＋試験素材添加によるＲａｔｉｏ２９３））／（（刺激物質＋エタノール添加によるＲａｔｉｏ）−（刺激物質＋エタノール添加によるＲａｔｉｏ２９３）））×１００
試験素材としては、上記化合物１及び２、並びに比較化合物１として国際特許公開ＷＯ２０１３／１０３１５５号（前記特許文献４）に記載された以下の２−メチル−４−フェニル−１−ペンタノールを用いた。
(3) TRPA1 activity inhibition evaluation against AITC (1)
In order to verify the effect of the test material on TRPA1 activation by AITC, the inhibitory action (activity inhibition rate;%) of the test material on TRPA1 activity when AITC (5.0 μM) was added was evaluated. The TRPA1 activity by mixing and adding AITC (stimulating substance) and the test material was calculated by the following equation.
[Equation 1]
TRPA1 activity (%) = ((stimulating substance + Ratio by adding test material) − (Stimulating substance + Ratio 293 by adding test material)) / ((stimulating substance + Ratio by adding ethanol) − (Ratio by adding stimulating substance + ethanol) 293 ))) x 100
As test materials, the following 2-methyl-4-phenyl-1-pentanol described in International Patent Publication No. WO2013 / 103155 (Patent Document 4) was used as the above-mentioned compounds 1 and 2 and comparative compound 1. .
その結果、化合物１及び２によるＴＲＰＡ１活性抑制効果に用量依存性が認められ、そのＩＣ５０値はそれぞれ、２．６、０．９μＭであった（図１）。そして、当該ＴＲＰＡ１活性抑制効は、比較化合物１に比べて優れていることが認められた。 As a result, dose-dependence was observed in the TRPA1 activity inhibitory effect of compounds 1 and 2, and the IC 50 values were 2.6 and 0.9 μM, respectively (FIG. 1). And it was recognized that the said TRPA1 activity inhibitory effect is excellent compared with the comparison compound 1.
試験例２ ＡＩＴＣに対するＴＲＰＡ１活性抑制評価（２）
試験例１と同様にして、ＡＩＴＣ１０μＭによるＴＲＰＡ１活性化に対する試験素材５０μＭの効果を測定した。
試験素材としては、上記化合物２、及び比較化合物２として国際特許公開第２０１３／１０３１５５号（前記特許文献４）に記載された以下の２，３−ジメチル−４−フェニル−１−ブタノールを同文献に記載の方法により合成し、使用した。
Test Example 2 TRPA1 activity inhibition evaluation against AITC (2)
In the same manner as in Test Example 1, the effect of 50 μM of the test material on TRPA1 activation by AITC 10 μM was measured.
As the test material, the following 2,3-dimethyl-4-phenyl-1-butanol described in International Patent Publication No. 2013/103155 (the above-mentioned Patent Document 4) as the above Compound 2 and Comparative Compound 2 was used. And synthesized by the method described in 1.
その結果、本発明の化合物２は、10μＭ ＡＩＴＣによるＴＲＰＡ１活性化を完全に抑制し、パラ位にハロゲン原子を有さない比較化合物２と比較して、遥かに優れたＴＲＰＡ１活性抑制効果が認められた（図２）。 As a result, Compound 2 of the present invention completely inhibits TRPA1 activation by 10 μM AITC, and far superior TRPA1 activity inhibitory effect was observed compared to Comparative Compound 2 having no halogen atom in the para position. (FIG. 2).
試験例３ 既存のＴＲＰＡ１活性抑制作用を有する化合物との匂い比較
ガラス瓶に綿球を入れ、プロピレングリコール、及びプロピレングリコールで希釈した下記表４に示す各化合物 (５．０％ｗ/ｗ) を綿球に３０μＬ滴下した。このガラス瓶を一晩室温で静置し、匂いをガラス瓶中に十分に揮発させた。官能評価は、パネラー４名で実施し、比較化合物１の匂いの強さを５．０とし、試験素材の匂いの強さを０−１０（０．５刻み）の２０段階で評価した。
その結果、比較化合物１と比して、化合物１及び２は匂いの強さが小さいことが認められた。(表４)
Test Example 3 Comparison of Odor with Existing TRPA1 Activity Inhibitory Compound A cotton ball was placed in a glass bottle and diluted with propylene glycol and propylene glycol. Each compound shown in Table 4 below (5.0% w / w) was treated with cotton. 30 μL was dropped onto the sphere. The glass bottle was allowed to stand overnight at room temperature, and the odor was sufficiently evaporated in the glass bottle. The sensory evaluation was performed by four panelists, and the odor intensity of the comparative compound 1 was set to 5.0, and the odor intensity of the test material was evaluated in 20 stages of 0-10 (in 0.5 increments).
As a result, it was confirmed that the compounds 1 and 2 were less odorous than the comparative compound 1. (Table 4)
Claims (5)
で表される化合物を有効成分とするＴＲＰＡ１活性抑制剤。 Following formula (1)
TRPA1 activity inhibitor which uses the compound represented by these as an active ingredient.
で表される化合物を有効成分とする皮膚又は粘膜の刺激感緩和剤。 Following formula (1)
A skin or mucous membrane irritation reducing agent comprising a compound represented by the formula:
で表される化合物を皮膚又は粘膜に適用する、皮膚又は粘膜の刺激感緩和方法。 Following formula (1)
A method of reducing irritation of skin or mucous membrane, wherein the compound represented by the formula is applied to the skin or mucous membrane.
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|---|---|---|---|---|
| US4610812A (en) * | 1984-12-14 | 1986-09-09 | International Flavors & Fragrances Inc. | Uses of methyl phenyl pentanol derivatives in augmenting or enhancing the aroma or taste of consumable materials |
| JP2008079528A (en) * | 2006-09-27 | 2008-04-10 | Mandom Corp | Method of screening substance for suppressing irritation due to parabens |
| JP2009082053A (en) * | 2007-09-28 | 2009-04-23 | Mandom Corp | Method of evaluation |
| JP2011205975A (en) * | 2010-03-30 | 2011-10-20 | Mandom Corp | Method for evaluating substance for inhibiting alcohol irritation |
| WO2013103155A1 (en) * | 2012-01-05 | 2013-07-11 | Kao Corporation | Agent for reduction of sensory irritation |
| JP2013256473A (en) * | 2012-06-13 | 2013-12-26 | Kao Corp | Trpa1 active inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4610812A (en) * | 1984-12-14 | 1986-09-09 | International Flavors & Fragrances Inc. | Uses of methyl phenyl pentanol derivatives in augmenting or enhancing the aroma or taste of consumable materials |
| JP2008079528A (en) * | 2006-09-27 | 2008-04-10 | Mandom Corp | Method of screening substance for suppressing irritation due to parabens |
| JP2009082053A (en) * | 2007-09-28 | 2009-04-23 | Mandom Corp | Method of evaluation |
| JP2011205975A (en) * | 2010-03-30 | 2011-10-20 | Mandom Corp | Method for evaluating substance for inhibiting alcohol irritation |
| WO2013103155A1 (en) * | 2012-01-05 | 2013-07-11 | Kao Corporation | Agent for reduction of sensory irritation |
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| JP2013256473A (en) * | 2012-06-13 | 2013-12-26 | Kao Corp | Trpa1 active inhibitor |
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