JP2014227395A - Antiinflammatory agent, hyaluronidase inhibitor, and antiallergic agent - Google Patents
Antiinflammatory agent, hyaluronidase inhibitor, and antiallergic agent Download PDFInfo
- Publication number
- JP2014227395A JP2014227395A JP2013109641A JP2013109641A JP2014227395A JP 2014227395 A JP2014227395 A JP 2014227395A JP 2013109641 A JP2013109641 A JP 2013109641A JP 2013109641 A JP2013109641 A JP 2013109641A JP 2014227395 A JP2014227395 A JP 2014227395A
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- Prior art keywords
- agent
- hyaluronidase
- chemical formula
- compound
- hyaluronidase inhibitor
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Abstract
Description
本発明は、高いヒアルロニダーゼ阻害作用を有する抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤に関する。 The present invention relates to an anti-inflammatory agent, a hyaluronidase inhibitor, and an antiallergic agent having a high hyaluronidase inhibitory action.
ヒアルロン酸は、皮膚・関節液などの組織に多く存在するムコ多糖の一種であり、例えば、皮膚においては、細胞の保護・栄養の運搬・組織水分の保持・柔軟性の維持等に、また、関節液としては、組織構造・機能の維持および潤滑性の保持等に重要な役割を果たしている。 Hyaluronic acid is a kind of mucopolysaccharide that is abundant in tissues such as skin and joint fluid.For example, in the skin, cell protection, nutrient transport, tissue moisture retention, flexibility maintenance, etc. As synovial fluid, it plays an important role in maintaining the tissue structure / function and maintaining lubricity.
皮膚や関節等の生体中のヒアルロン酸量は、老化又は病的状態により減少し、それが皮膚の乾燥、弾力性の低下、シワの増加、肌荒れ、あるいは関節の湿潤性悪化による関節痛等を惹き起こす。これ対し、ヒアルロン酸を加水分解する酵素であるヒアルロニダーゼを阻害することにより、ヒアルロン酸の分解を抑制し、生体ヒアルロン酸量の維持に寄与することができる。 The amount of hyaluronic acid in living bodies such as skin and joints decreases due to aging or pathological conditions, which may cause dry skin, decreased elasticity, increased wrinkles, rough skin, joint pain due to deterioration of joint wettability, etc. Raise. On the other hand, by inhibiting hyaluronidase, which is an enzyme that hydrolyzes hyaluronic acid, it is possible to suppress the degradation of hyaluronic acid and contribute to the maintenance of the amount of biological hyaluronic acid.
ヒアルロニダーゼが炎症時に活性化されることにより、結合組織のマトッリクスを破壊し、炎症系の組織への浸潤・血管の透過性を亢進することが知られている。また、ヒアルロニダーゼがI型アレルギーにおける肥満細胞からのヒスタミンの遊離の過程に介在していることが知られている。そのためヒアルロニダーゼ阻害剤は、ヒアルロニダーゼに起因する抗炎症・抗アレルギー剤としても利用することができる。 It is known that hyaluronidase is activated at the time of inflammation, thereby destroying the matrix of connective tissue and enhancing the infiltration of inflammatory tissues and the permeability of blood vessels. It is also known that hyaluronidase mediates the process of histamine release from mast cells in type I allergy. Therefore, the hyaluronidase inhibitor can be used as an anti-inflammatory / anti-allergic agent caused by hyaluronidase.
従って、ヒアルロニダーゼ阻害剤は、近年患者数が増加しつつあり、社会問題化しているアトピー性皮膚炎、花粉症、気管支喘息、食物アレルギー等のアレルギー性疾患の予防や改善効果が期待されている。例えば、抗アレルギー剤であるクロモグリク酸ナトリウムやトラニラスト、抗炎症薬であるアスピリンやインドメタシンにはヒアルロニダーゼ活性阻害能が認められ、該阻害能が治療効果の発揮に一定の役割を果たすことが示唆されている(非特許文献1及び2)。 Therefore, hyaluronidase inhibitors are increasing in number of patients in recent years, and are expected to prevent or improve allergic diseases such as atopic dermatitis, hay fever, bronchial asthma and food allergies, which are becoming social problems. For example, anti-allergic sodium cromoglycate and tranilast, and anti-inflammatory drugs aspirin and indomethacin have hyaluronidase activity inhibitory activity, suggesting that this inhibitory role plays a role in exerting therapeutic effects. (Non-patent Documents 1 and 2).
これまでヒアルロニダーゼ阻害剤として、カラギーナン、アルギン酸、アルギン酸の加水分解物(特許文献1参照)、マンリョウ抽出物(特許文献2参照)、低分子化サイリウムシードガム(特許文献3参照)等が知られていたが、その効果は十分なものではなかった。 Conventionally, as a hyaluronidase inhibitor, carrageenan, alginic acid, hydrolyzate of alginic acid (see Patent Document 1), manly extract (see Patent Document 2), low molecular weight psyllium seed gum (see Patent Document 3), and the like are known. However, the effect was not sufficient.
クロロゲン酸の誘導体としては、クロロゲン酸のエチルエステルが抗インフルエンザウィルス効果を発揮することが知られている(特許文献4参照)。 As a derivative of chlorogenic acid, it is known that ethyl ester of chlorogenic acid exerts an anti-influenza virus effect (see Patent Document 4).
本発明は高いヒアルロニダーゼ阻害作用を有する抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤を提供する。 The present invention provides an anti-inflammatory agent, a hyaluronidase inhibitor, and an antiallergic agent having a high hyaluronidase inhibitory action.
本発明は、下記化学式(1)で示される化合物 The present invention relates to a compound represented by the following chemical formula (1)
(式1中R1は、H若しくは炭素数1〜12の直鎖若しくは分岐鎖を有する、飽和若しくは不飽和のアルキル基を示し、R2〜R6は同一若しくは異なってもよくH若しくは炭素数2〜8の直鎖若しくは分岐鎖を有する、飽和若しくは不飽和のアシル基を示し、R1〜R6が全てHであることはない)を有効成分とする抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤である。 (In formula 1, R 1 represents H or a saturated or unsaturated alkyl group having a linear or branched chain having 1 to 12 carbon atoms, and R 2 to R 6 may be the same or different, and H or carbon number. An anti-inflammatory agent, a hyaluronidase inhibitor, an anti-inflammatory agent containing 2 to 8 straight-chain or branched-chain, saturated or unsaturated acyl groups, and R 1 to R 6 are not all H) It is an allergic agent.
本願第2の発明は、化学式(1)において、R1がエチル基、2−エチルヘキシル基から選択される1種又は2種であり、R2〜R6がHである化合物を有効成分とする抗炎症剤である。 In the second invention of the present application, in the chemical formula (1), R 1 is one or two selected from an ethyl group and a 2-ethylhexyl group, and a compound in which R 2 to R 6 are H is an active ingredient. It is an anti-inflammatory agent.
本願第3の発明は、化学式(1)において、R1がH、R2〜R6の1以上がアセチル基であり、アセチル基以外のR2〜R6がHである化合物を有効成分とする請求項1に記載の抗炎症剤である。 The third aspect of the invention, in the chemical formula (1), R 1 is H, is 1 or more acetyl groups R 2 to R 6, the active ingredient a compound R 2 to R 6 other than acetyl group is H The anti-inflammatory agent according to claim 1.
本願第4の発明は、化学式(1)において、R1がH、R2〜R6のすべてがアセチル基である化合物を有効成分とする請求項1に記載の抗炎症剤である。 Fourth aspect of the invention, in the chemical formula (1), R 1 is an anti-inflammatory agent according to claim 1 H, all R 2 to R 6 is the compound as an active ingredient is an acetyl group.
本願第5の発明は、請求項1〜4の1項に記載の化合物を有効成分とする、ヒアルロニダーゼ阻害剤剤である。 5th invention of this application is a hyaluronidase inhibitor which uses the compound of 1 of Claims 1-4 as an active ingredient.
本願第6の発明は、請求項1〜4の1項に記載の化合物を有効成分とする、抗アレルギー剤である。 6th invention of this application is an antiallergic agent which uses the compound of Claim 1-4 as an active ingredient.
本願発明の化学式(1)に記載した化合物は、高いヒアルロニダーゼ阻害効果を有するため、抗アレルギー効果、抗炎症効果を発揮する。 Since the compound described in the chemical formula (1) of the present invention has a high hyaluronidase inhibitory effect, it exhibits an antiallergic effect and an antiinflammatory effect.
以下本発明を実施するための形態を説明する。 Hereinafter, modes for carrying out the present invention will be described.
本発明は、下記化学式(1)で示される化合物 The present invention relates to a compound represented by the following chemical formula (1)
(式1中R1は、H若しくは炭素数1〜12の直鎖若しくは分岐鎖を有する、飽和若しくは不飽和のアルキル基を示し、R2〜R6は同一若しくは異なってもよくH若しくは炭素数2〜8の直鎖若しくは分岐鎖を有する、飽和若しくは不飽和のアシル基を示し、R1〜R6が全てHであることはない)を有効成分とする抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤である。 (In formula 1, R 1 represents H or a saturated or unsaturated alkyl group having a linear or branched chain having 1 to 12 carbon atoms, and R 2 to R 6 may be the same or different, and H or carbon number. An anti-inflammatory agent, a hyaluronidase inhibitor, an anti-inflammatory agent containing 2 to 8 straight-chain or branched-chain, saturated or unsaturated acyl groups, and R 1 to R 6 are not all H) It is an allergic agent.
本願発明の効果の点から、化学式(1)において、R1がエチル基、2−エチルヘキシル基から選択される1種又は2種であり、R2〜R6がHである化合物が好ましく用いられる。 From the viewpoint of the effect of the present invention, in the chemical formula (1), a compound in which R 1 is one or two selected from an ethyl group and a 2-ethylhexyl group, and R 2 to R 6 are H is preferably used. .
本願発明の効果の点から、化学式(1)において、R1がH、R2〜R6の1以上がアセチル基であり、アセチル基以外のR2〜R6がHである化合物が好ましく用いられる。 From the viewpoint of the effect of the present invention, in the chemical formula (1), R 1 is H, is 1 or more acetyl groups R 2 to R 6, the compound R 2 to R 6 other than acetyl groups are H are preferably used It is done.
本願発明の効果の点から、化学式(1)において、R1がH、R2〜R6のすべてがアセチル基である化合物が好ましく用いられる。 From the viewpoint of the effect of the present invention, a compound in which R 1 is H and all of R 2 to R 6 are acetyl groups in the chemical formula (1) is preferably used.
本願発明の化合物は、下記化学式(2)で示される化合物であるクロロゲン酸を出発物質として合成することができる。 The compound of the present invention can be synthesized using chlorogenic acid, which is a compound represented by the following chemical formula (2), as a starting material.
R1にアルキル基をエステル結合させる際には、化学式(2)の化合物と炭素数1から12のアルコールを希酸水溶液中で混合し、常温若しくは60℃以下の温度条件下で適時反応させることにより合成することができる。 When an alkyl group is bonded to R 1 by ester bonding, the compound of formula (2) and an alcohol having 1 to 12 carbon atoms are mixed in a dilute aqueous acid solution and reacted at room temperature or under a temperature condition of 60 ° C. or less. Can be synthesized.
R2〜R6にアシル基を結合させる際には、化学式(2)の化合物と無水カルボン酸−ピリミジン混液を混合し、常温若しくは60℃以下の温度条件下で適時反応させることにより合成することができる。この際、アシル基を結合させない水酸基については、予め他の化合物でマスキングを行ってから、反応後マスキングを取り外すこともできる。 When an acyl group is bonded to R 2 to R 6 , synthesis is performed by mixing the compound of the chemical formula (2) and a carboxylic anhydride-pyrimidine mixed solution and reacting them at room temperature or at a temperature of 60 ° C. or less in a timely manner. Can do. At this time, for the hydroxyl group to which no acyl group is bonded, the masking can be removed after the reaction after masking with another compound in advance.
化学式(1)で示された化合物は高いヒアルロニダーゼ阻害効果有し、抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤として有用である。 The compound represented by the chemical formula (1) has a high hyaluronidase inhibitory effect and is useful as an anti-inflammatory agent, a hyaluronidase inhibitor, and an antiallergic agent.
本発明の抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤は、化学式(1)に示した化合物のみからなるものでもよいし、製剤化したものでもよい。対象となるアレルギーの種類は限定されず、例えば、アトピー性皮膚炎、花粉症、気管支喘息、食物アレルギー等を挙げることができる。 The anti-inflammatory agent, hyaluronidase inhibitor, and antiallergic agent of the present invention may be composed only of the compound represented by the chemical formula (1) or may be formulated. The type of allergy to be targeted is not limited, and examples include atopic dermatitis, hay fever, bronchial asthma, food allergy, and the like.
本発明の抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤は、医薬品(医薬品および医薬部外品を含む。)として用いることができる。上記医薬品は、ヒトに用いることもできるし、ヒト以外の動物に用いることも可能である。 The anti-inflammatory agent, hyaluronidase inhibitor, and antiallergic agent of the present invention can be used as pharmaceuticals (including pharmaceuticals and quasi drugs). The above pharmaceutical products can be used for humans or for animals other than humans.
本発明の抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤は、剤形に応じて適宜選択することができる。適宜配合して製造することができる。本発明の抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤に配合しうる添加剤としては、例えば、賦形剤(ブドウ糖、乳糖、白糖、塩化ナトリウム、デンプン、炭酸カルシウム、カオリン、結晶セルロース、カカオ脂、硬化植物油、カオリン、タルク等)、結合剤(蒸留水、生理食塩水、エタノール水、単シロップ、ブドウ糖液、デンプン液、ゼラチン溶液、カルボキシメチルセルロース、リン酸カリウム、ポリビニルピロリドン等)、崩壊剤(カンテン、炭酸水素ナトリウム、炭酸カルシウム、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、デンプン、乳糖、ゼラチン、エタノール等)、崩壊抑制剤(白糖、ステアリン、カカオ脂、水素添加油等)、吸収促進剤(第四級アンモニウム塩基、ラウリル硫酸ナトリウム等)、吸着剤(グリセリン、デンプン、乳糖、カオリン、ベントナイト、硅酸等)、滑沢剤(精製タルク、ステアリン酸塩、ポリエチレングリコール等)などが挙げられる。 The anti-inflammatory agent, hyaluronidase inhibitor, and antiallergic agent of the present invention can be appropriately selected depending on the dosage form. It can be produced by appropriately blending. Examples of additives that can be incorporated into the anti-inflammatory agent, hyaluronidase inhibitor, and antiallergic agent of the present invention include excipients (glucose, lactose, sucrose, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, cocoa butter, etc. , Hydrogenated vegetable oil, kaolin, talc, etc.), binder (distilled water, physiological saline, ethanol water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrant ( Kantene, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, gelatin, ethanol, etc.), disintegration inhibitors (sucrose, stearin, cocoa butter, hydrogenated oil, etc.), absorption enhancers (fourth) Secondary ammonium base, sodium lauryl sulfate, etc.) Agents (glycerin, starch, lactose, kaolin, bentonite, silicic acid, etc.), lubricants (purified talc, stearates, polyethylene glycol, and the like) and the like.
本発明による抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤の投与方法は、一般的には、錠剤、丸剤、軟・硬カプセル剤、細粒剤、散剤、顆粒剤等の形態で経口投与することができる。また、水溶性製剤は、液剤として経口的に投与することができる。さらに非経口投与であってもよい。非経口剤として投与する場合は、本発明の抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤をエタノールや水など適当な可溶化剤に分散させた後、パップ剤、ローション剤、軟膏剤、チンキ剤、クリーム剤などの剤形で適用することができる。また本抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤の水溶性製剤は、そのままで、あるいは分散剤、懸濁剤、安定剤などを添加した状態で、パップ剤、ローション剤、軟膏剤、チンキ剤、クリーム剤などの剤形で適用することができる。 The administration method of the anti-inflammatory agent, hyaluronidase inhibitor and antiallergic agent according to the present invention is generally administered orally in the form of tablets, pills, soft / hard capsules, fine granules, powders, granules, etc. be able to. The water-soluble preparation can be administered orally as a liquid. Furthermore, parenteral administration may be used. When administered as a parenteral agent, the anti-inflammatory agent, hyaluronidase inhibitor and antiallergic agent of the present invention are dispersed in a suitable solubilizing agent such as ethanol or water, and then a poultice, lotion, ointment, tincture It can be applied in a dosage form such as a cream. The water-soluble preparations of this anti-inflammatory agent, hyaluronidase inhibitor, and antiallergic agent are used as they are or with the addition of a dispersing agent, suspending agent, stabilizer, etc., poultices, lotions, ointments, tinctures It can be applied in a dosage form such as a cream.
本発明の抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤を薬品として使用する際の配合比は、剤型によって適宜変更することが可能であるが、通常、経口または粘膜吸収により投与される場合は約0.01〜10wt%、非経口投与による場合は、0.01〜20wt%程度にするとよい。なお、投与量は種々の条件で異なるので、前記投与量より少ない量で十分な場合もあるし、また、範囲を超えて投与する必要のある場合もある。医薬組成物は、前記抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤以外に、医薬分野において常用される既知の他の化合物、および経口投与に適した形態に成型するのに必要な化合物を包含していてもよい。そのような化合物としては、例えば、乳糖、デンプン、ヒドロキシプロピルセルロース、カオリン、タルク、炭酸カルシウムなどが挙げられる。 The compounding ratio when using the anti-inflammatory agent, hyaluronidase inhibitor and antiallergic agent of the present invention as a drug can be appropriately changed depending on the dosage form, but is usually administered orally or by mucosal absorption. In the case of parenteral administration, about 0.01 to 10 wt% is recommended. In addition, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or it may be necessary to administer beyond the range. The pharmaceutical composition includes, in addition to the anti-inflammatory agent, hyaluronidase inhibitor, and antiallergic agent, other known compounds commonly used in the pharmaceutical field, and compounds necessary for molding into a form suitable for oral administration. It may be. Examples of such compounds include lactose, starch, hydroxypropyl cellulose, kaolin, talc, calcium carbonate and the like.
本発明の抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤は、皮膚外用剤(化粧品、医薬品および医薬部外品を含む。)として用いても、抗炎症作用、ヒアルロニダーゼ阻害作用、抗アレルギー作用を期待することができる。尚、上記皮膚外用剤は人間に用いても良いし、人間以外の哺乳類動物に用いても良い。本発明のヒアルロニダーゼ阻害剤、抗アレルギー剤、抗炎症剤を配合しうる皮膚外用剤の形態としては、例えば、乳液、石鹸、洗顔料、入浴剤、クリーム、乳液、化粧水、オーデコロン、ひげ剃り用クリーム、ひげ剃り用ローション、化粧油、日焼け・日焼け止めローション、おしろいパウダー、ファンデーション、香水、パック、爪クリーム、エナメル、エナメル除去液、眉墨、ほお紅、アイクリーム、アイシャドー、マスカラ、アイライナー、口紅、リップクリーム、シャンプー、リンス、染毛料、分散液、洗浄料等が挙げられる。また、本発明の抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤を配合しうる医薬品または医薬部外品の形態としては、軟膏剤、クリーム剤、外用液剤等が挙げられる。 The anti-inflammatory agent, hyaluronidase inhibitor and anti-allergic agent of the present invention are expected to have anti-inflammatory action, hyaluronidase inhibitory action and anti-allergic action even when used as an external preparation for skin (including cosmetics, pharmaceuticals and quasi drugs). can do. In addition, the said skin external preparation may be used for a human and may be used for mammals other than a human. Examples of the external preparation for skin to which the hyaluronidase inhibitor, antiallergic agent and anti-inflammatory agent of the present invention can be incorporated include, for example, emulsion, soap, facial cleanser, bath preparation, cream, emulsion, lotion, eau de cologne, shaving Cream, shave lotion, cosmetic oil, suntan / sunscreen lotion, funny powder, foundation, perfume, pack, nail cream, enamel, enamel remover, eyebrow, blusher, eye cream, eye shadow, mascara, eyeliner, lipstick Lip balm, shampoo, rinse, hair dye, dispersion, detergent and the like. Examples of the form of pharmaceuticals or quasi drugs that can contain the anti-inflammatory agent, hyaluronidase inhibitor, and antiallergic agent of the present invention include ointments, creams, and liquids for external use.
上記形態の皮膚外用剤には、本発明による抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤の他に、その抗炎症作用、ヒアルロニダーゼ阻害作用、抗アレルギー作用を損なわない範囲で化粧品、医薬部外品などの皮膚外用剤に配合される成分、油分、高級アルコール、脂肪酸、紫外線吸収剤、粉体、顔料、界面活性剤、多価アルコール・糖、高分子、生理活性成分、溶媒、酸化防止剤、香料、防腐剤等を配合することができる。 In addition to the anti-inflammatory agent, hyaluronidase inhibitor, and antiallergic agent according to the present invention, the external preparation for skin of the above form includes cosmetics and quasi-drugs as long as the anti-inflammatory action, hyaluronidase inhibitory action, and antiallergic action are not impaired. Ingredients blended in skin external preparations such as oils, higher alcohols, fatty acids, UV absorbers, powders, pigments, surfactants, polyhydric alcohols / sugars, polymers, bioactive ingredients, solvents, antioxidants, A fragrance | flavor, antiseptic | preservative, etc. can be mix | blended.
本発明の化学式(1)に示した化合物は経口摂取することができるため、飲食品として利用することもできる。この場合は、本発明の組成物をそのまま食するか腸溶カプセルに包含して投与することができる。あるいは液体(例えば水)に適切な濃度になるように溶解し、混合、浸漬、塗布、噴霧等の方法で食品等に添加することができる。 Since the compound represented by the chemical formula (1) of the present invention can be taken orally, it can also be used as a food or drink. In this case, the composition of the present invention can be eaten as it is or contained in an enteric capsule for administration. Or it can melt | dissolve in liquid (for example, water) so that it may become a suitable density | concentration, and it can add to foodstuff etc. by methods, such as mixing, immersion, application | coating, and spraying.
本発明の飲食品において、化学式(1)に示した化合物の含有割合は限定されず、各種用途に応じて、適宜設定することができる。また、本発明の飲食品を得る際にも、各種用途に応じた公知の製造方法において、任意の手法又はタイミングで化学式(1)に示した化合物を含有させることができる。当該含有させる際の化学式(1)に示した化合物の形態は限定されるものではなく、スラリー状であっても粉状であってもよく、各種用途に応じて適宜選択すればよい。 In the food and drink of the present invention, the content ratio of the compound represented by the chemical formula (1) is not limited, and can be set as appropriate according to various uses. Moreover, also when obtaining the food / beverage products of this invention, in the well-known manufacturing method according to various uses, the compound shown to Chemical formula (1) can be contained by arbitrary methods or timing. The form of the compound represented by the chemical formula (1) at the time of inclusion is not limited, and may be a slurry or a powder, and may be appropriately selected according to various uses.
本発明の飲食品としては、特に限定されるものではなく、ヒトが食することが可能なあらゆる食品類をあげることができる。例えば、食用油(サラダ油)、菓子類(ガム、キャンディー、キャラメル、チョコレート、クッキー、スナック、ゼリー、グミ、錠菓等)、麺類(そば、うどん、ラーメン等)、乳製品(ミルク、アイスクリーム、ヨーグルト等)、調味料(味噌、醤油等)、スープ類、飲料(ジュース、コーヒー、紅茶、茶、炭酸飲料、スポーツ飲料等)をはじめとする一般食品や、健康食品(錠剤、カプセル等)、栄養補助食品(栄養ドリンク等)が挙げられる。これらの飲食品に本発明の化学式(1)に示した化合物を適宜配合するとよい。 The food / beverage products of the present invention are not particularly limited, and can include all foods that humans can eat. For example, edible oil (salad oil), confectionery (gum, candy, caramel, chocolate, cookies, snacks, jelly, gummy, tablet confectionery, etc.), noodles (soba, udon, ramen, etc.), dairy products (milk, ice cream, Yogurt, etc.), seasonings (miso, soy sauce, etc.), soups, beverages (juice, coffee, tea, tea, carbonated beverages, sports drinks, etc.) and general foods, health foods (tablets, capsules, etc.), Nutritional supplements (such as energy drinks) are listed. A compound represented by the chemical formula (1) of the present invention may be appropriately blended with these foods and drinks.
これらの飲食品への本発明の組成物の添加量は、添加の対象となる飲食品の種類に応じて選択することができる。但し、当該添加量が少なすぎると、期待される抗炎症効果、ヒアルロニダーゼ阻害効果、抗アレルギー効果を十分に発揮できない。また、逆に添加量が多すぎると添加の対象となる食品が本来有する風味を損なう場合がある。そこで、これらの事情を考慮して添加量を決定することが好ましい。かかる観点より、上記組成物の添加量は、添加の対象となる飲食品の質量の概ね0.01%〜20%程度、好ましくは0.01%〜5%程度である。 The addition amount of the composition of this invention to these food / beverage products can be selected according to the kind of food / beverage products used as the object of addition. However, if the amount added is too small, the expected anti-inflammatory effect, hyaluronidase inhibitory effect, and anti-allergic effect cannot be exhibited sufficiently. On the other hand, if the amount added is too large, the flavor inherent to the food to be added may be impaired. Therefore, it is preferable to determine the addition amount in consideration of these circumstances. From this viewpoint, the amount of the composition added is about 0.01% to 20%, preferably about 0.01% to 5% of the mass of the food or drink to be added.
以下、実施例を示し、本発明を具体的に説明するが、本発明は下記の各例に何ら制限されるものではない。 EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated concretely, this invention is not restrict | limited to each following example at all.
「実施例1」クロロゲン酸エチルエステルの合成
エタノール50mLと試薬級クロロゲン酸0.1g、希硫酸1mLを混合し、暗中条件下、40℃で3時間加熱、反応させた。酢酸エチル50mLと精製水50mLを添加して攪拌後酢酸エチル層を採取した。酢酸エチル層を精製水を用いて3回洗浄し、得られた酢酸エチル層の溶媒を留去し、濃縮物を凍結乾燥することにより、化学式(1)においてR1位にエチル基を導入したクロロゲン酸エチルエステルを合成した。収率は48.6%であった。
クロロゲン酸エチルエステルの確認
LC/MS 直接MSに注入して
ESI+ 水素付加イオンである383.1を確認
ESI− 水素脱離イオンである381.1を確認
NMR (100MHz、CD3OD)
13.0, 36.4, 36.6, 36.6, 61.3, 69.0, 70.8, 71.2, 74.4, 113.7, 113.7, 115.2, 121.7, 126.3, 145.5, 145.9, 148.4, 167.0, 173.6
Example 1 Synthesis of Chlorogenic Acid Ethyl Ester 50 mL of ethanol, 0.1 g of reagent grade chlorogenic acid, and 1 mL of dilute sulfuric acid were mixed and heated and reacted at 40 ° C. for 3 hours under dark conditions. 50 mL of ethyl acetate and 50 mL of purified water were added and stirred, and the ethyl acetate layer was collected. The ethyl acetate layer was washed three times with purified water, the solvent of the obtained ethyl acetate layer was distilled off, and the concentrate was freeze-dried to introduce an ethyl group at the R 1 position in the chemical formula (1). Chlorogenic acid ethyl ester was synthesized. The yield was 48.6%.
Confirmation of chlorogenic acid ethyl ester LC / MS Direct injection into MS confirms ESI + hydrogen addition ion 383.1 ESI- confirms hydrogen desorption ion 381.1 NMR (100 MHz, CD3OD)
13.0, 36.4, 36.6, 36.6, 61.3, 69.0, 70.8, 71.2, 74.4, 113.7, 113.7, 115.2, 121.7, 126.3, 145.5, 145.9, 148.4, 167.0, 173.6
「実施例2」クロロゲン酸2−エチルヘキシルエステルの合成
2−エチルヘキサノール125mLと試薬級クロロゲン酸0.1g、希硫酸1mLを混合し、暗中条件下、40℃で3時間加熱、反応させた。酢酸エチル50mLと精製水50mLを添加して攪拌後酢酸エチル層を採取した。酢酸エチル層を精製水を用いて3回洗浄し、得られた酢酸エチル層の溶媒を留去し、濃縮物を凍結乾燥することにより、化学式(1)においてR1位に2−エチルヘキシル基を導入したクロロゲン酸2−エチルヘキシルエステルを合成した。収率は42.8%であった。
エチルヘキシルクロロゲン酸の確認
LC/MS 直接MSに注入して
ESI+ 水素付加イオンである467.2を確認
ESI− 水素脱離イオンである465.2を確認
NMR(100MHz、C5D5N)
10.8, 10.9, 14.0, 23.0, 23.7, 28.9, 28.9, 30.3, 30.4, 38.5, 38.8, 67.4, 67.4, 72.0, 114.9, 115.6, 116.5, 121.9, 126.6, 145.9, 147.5, 150.4, 166.8, 174.5
[Example 2] Synthesis of 2-ethylhexyl chlorogenic acid 125 mL of 2-ethylhexanol, 0.1 g of reagent grade chlorogenic acid and 1 mL of dilute sulfuric acid were mixed, and heated and reacted at 40 ° C for 3 hours under dark conditions. 50 mL of ethyl acetate and 50 mL of purified water were added and stirred, and the ethyl acetate layer was collected. The ethyl acetate layer was washed 3 times with purified water, the solvent of the obtained ethyl acetate layer was distilled off, and the concentrate was lyophilized to give a 2-ethylhexyl group at the R 1 position in chemical formula (1). The introduced chlorogenic acid 2-ethylhexyl ester was synthesized. The yield was 42.8%.
Confirmation of ethylhexyl chlorogenic acid LC / MS Direct injection into MS confirms 467.2 which is ESI + hydrogen addition ion ESI- Confirms 465.2 which is hydrogen desorption ion NMR (100 MHz, C5D5N)
10.8, 10.9, 14.0, 23.0, 23.7, 28.9, 28.9, 30.3, 30.4, 38.5, 38.8, 67.4, 67.4, 72.0, 114.9, 115.6, 116.5, 121.9, 126.6, 145.9, 147.5, 150.4, 166.8, 174.5
「実施例3」クロロゲン酸アセチルエステルの合成
試薬級クロロゲン酸0.1gと無水酢酸−ピリミジン混液(1:2)1mLを混合し、暗中条件下室温で12時間反応させた。精製水10mLと酢酸エチル10mLを攪拌後酢酸エチル層を採取した。酢酸エチル層を精製水を用いて3回洗浄し、得られた酢酸エチル層の溶媒を留去し、濃縮物を凍結乾燥することにより、クロロゲン酸アセチルエステルを合成した。収率は68.6%であった。
アセチルクロロゲン酸の確認
LC/MS 直接MSに注入して
ESI+ 水素付加イオンである565.0を確認
ESI− 水素脱離イオンである563.0を確認
NMR(100MHz、CD3OD)
19.1, 19.1, 19.3, 19.6, 19.9, 31.3, 36.4, 67.0, 68.1, 71.6, 79.1, 118.1, 122.9, 123.9, 126.4, 133.1, 142.8, 143.9, 144.1, 165.7, 168.3, 168.5, 170.2, 170.3, 170.4, 172.2
"Example 3" Synthesis of chlorogenic acid acetyl ester 0.1 g of reagent grade chlorogenic acid and 1 mL of acetic anhydride-pyrimidine mixed liquid (1: 2) were mixed and reacted at room temperature for 12 hours under dark conditions. After stirring 10 mL of purified water and 10 mL of ethyl acetate, the ethyl acetate layer was collected. The ethyl acetate layer was washed three times with purified water, the solvent of the obtained ethyl acetate layer was distilled off, and the concentrate was freeze-dried to synthesize chlorogenic acid acetyl ester. The yield was 68.6%.
Confirmation of acetylchlorogenic acid LC / MS Direct injection into MS confirms ESI + hydrogen addition ion 565.0 ESI- confirms hydrogen elimination ion 563.0 NMR (100 MHz, CD3OD)
19.1, 19.1, 19.3, 19.6, 19.9, 31.3, 36.4, 67.0, 68.1, 71.6, 79.1, 118.1, 122.9, 123.9, 126.4, 133.1, 142.8, 143.9, 144.1, 165.7, 168.3, 168.5, 170.2, 170.3, 170.4, 172.2
「ヒアルロニダーゼ阻害作用」
市販のヒアルロン酸カリウム塩(ヒト臍の緒由来)を0.9mg/mLになるように、0.1Mリン酸緩衝液(pH7.0)に溶解し、基質溶液とした。市販のヒアルロニダーゼ(ウシ精巣由来)を5,3000unit/mLとなるように、0.1Mリン酸緩衝液(pH7.0)に溶解し、酵素溶液とした。なお酵素溶液は用時調製とした。試験管に、緩衝液で各濃度に調製したサンプル溶液0.1mL、及び酵素溶液0.03mLをとり、37℃で20分間反応させた。次に活性化剤を0.06mL加え、37℃で20分間反応させた。さらに基質溶液を0.15mL加え、37℃で1時間反応させた。0.4規定のNaOHを0.06mL加え反応を停止させた後すぐに氷冷し、ホウ酸緩衝液(pH9.1)を0.06mL添加し、3分間煮沸した後さらに氷冷した。p−ジメチルベンズアルデヒド(p−DABA)溶液溶液を2.0mL添加し、37℃で20分間反応させた後、各試験管から96ウェルマイクロプレートに移しかえ、マイクロプレートリーダーを用いて585nmにおける吸光度を測定した。コントロールには、サンプルを溶かすのに用いた緩衝溶液のみを加えたものを用いた。ヒアルロニダーゼの活性が阻害されると分解産物であるN−アセチルグルコサミンが減少し。p−DABAによる吸光度が低くなる。このことを利用し、阻害活性は次式より求めた。結果を表2にまとめる。
阻害率(%)=(コントロール吸光度−サンプル吸光度)/コントロール吸光度×100
"Hyaluronidase inhibitory action"
Commercially available hyaluronic acid potassium salt (derived from human umbilical cord) was dissolved in 0.1 M phosphate buffer (pH 7.0) to a concentration of 0.9 mg / mL to obtain a substrate solution. A commercially available hyaluronidase (derived from bovine testis) was dissolved in 0.1 M phosphate buffer (pH 7.0) so as to be 5,3000 units / mL to obtain an enzyme solution. The enzyme solution was prepared at the time of use. In a test tube, 0.1 mL of a sample solution adjusted to each concentration with a buffer solution and 0.03 mL of an enzyme solution were taken and reacted at 37 ° C. for 20 minutes. Next, 0.06 mL of an activator was added and reacted at 37 ° C. for 20 minutes. Further, 0.15 mL of the substrate solution was added and reacted at 37 ° C. for 1 hour. 0.06 mL of 0.4N NaOH was added to stop the reaction, and the mixture was immediately cooled with ice. Then, 0.06 mL of borate buffer (pH 9.1) was added, and the mixture was boiled for 3 minutes and further cooled with ice. After 2.0 mL of p-dimethylbenzaldehyde (p-DABA) solution was added and reacted at 37 ° C. for 20 minutes, the solution was transferred from each test tube to a 96-well microplate, and the absorbance at 585 nm was measured using a microplate reader. It was measured. As a control, a solution to which only the buffer solution used for dissolving the sample was added was used. When the activity of hyaluronidase is inhibited, the degradation product N-acetylglucosamine decreases. Absorbance by p-DABA is lowered. Utilizing this fact, the inhibitory activity was obtained from the following equation. The results are summarized in Table 2.
Inhibition rate (%) = (control absorbance−sample absorbance) / control absorbance × 100
表1に示した通り、本発明の実施例1〜3は、高いヒアルロニダーゼ阻害作用を示した。これに対し、クロロゲン酸においては有意なヒアルロニダーゼ阻害作用は認められなかった。したがって、本願発明の化学式(1)に示した化合物は、高いヒアルロニダーゼ阻害作用をを示し、抗炎症剤、ヒアルロニダーゼ阻害剤、抗アレルギー剤として有用である。 As shown in Table 1, Examples 1 to 3 of the present invention showed high hyaluronidase inhibitory action. In contrast, chlorogenic acid did not have a significant hyaluronidase inhibitory effect. Therefore, the compound represented by the chemical formula (1) of the present invention exhibits a high hyaluronidase inhibitory action and is useful as an anti-inflammatory agent, a hyaluronidase inhibitor, and an antiallergic agent.
Claims (6)
(式1中R1は、H若しくは炭素数1〜12の直鎖若しくは分岐鎖を有する、飽和若しくは不飽和のアルキル基を示し、R2〜R6は同一若しくは異なってもよくH若しくは炭素数2〜12の直鎖若しくは分岐鎖を有する、飽和若しくは不飽和のアシル基を示し、R1〜R6が全てHであることはない)を有効成分とする抗炎症剤。 Compound represented by the following chemical formula (1)
(In Formula 1, R 1 represents H or a saturated or unsaturated alkyl group having a straight chain or branched chain having 1 to 12 carbon atoms, and R 2 to R 6 may be the same or different, and H or carbon number. An anti-inflammatory agent comprising 2 to 12 straight or branched chain saturated or unsaturated acyl groups, wherein R 1 to R 6 are not all H).
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JP2007161632A (en) * | 2005-12-13 | 2007-06-28 | Ucc Ueshima Coffee Co Ltd | Hyaluronidase inhibitor |
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JPS60192555A (en) * | 1984-03-13 | 1985-10-01 | Osaka Chem Lab | Antiallergic food |
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FR3057772A1 (en) * | 2016-10-26 | 2018-04-27 | Plant Advanced Technologies Pat | POLYSUBSTITUTED QUINIC ACID DERIVATIVES AND USES THEREOF |
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