JPH0753359A - Lipoxygenase inhibitor - Google Patents

Lipoxygenase inhibitor

Info

Publication number
JPH0753359A
JPH0753359A JP6118098A JP11809894A JPH0753359A JP H0753359 A JPH0753359 A JP H0753359A JP 6118098 A JP6118098 A JP 6118098A JP 11809894 A JP11809894 A JP 11809894A JP H0753359 A JPH0753359 A JP H0753359A
Authority
JP
Japan
Prior art keywords
group
methanol
piceatannol
liquid
derivative
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.)
Pending
Application number
JP6118098A
Other languages
Japanese (ja)
Inventor
Takatoshi Murase
孝利 村瀬
Tadashi Hase
正 長谷
Yusuke Shibuya
祐輔 渋谷
Yoshinori Nishizawa
義則 西澤
Yukihiro Yada
幸博 矢田
Genji Imokawa
玄爾 芋川
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kao Corp
Original Assignee
Kao Corp
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Kao Corp filed Critical Kao Corp
Priority to JP6118098A priority Critical patent/JPH0753359A/en
Publication of JPH0753359A publication Critical patent/JPH0753359A/en
Pending legal-status Critical Current

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Abstract

PURPOSE:To provide a lipoxygenase inhibitor having excellent lipoxygenase inhibiting action and useful as an anti-inflammatory agent, anti-allergic agent, etc., by using piceatannol existing in flat-sedge belonging to the family Cyperaceae or its derivative as the active component. CONSTITUTION:Dried flat-sedge is crushed and extracted with methanol, the extracted liquid is concentrated under reduced pressure, the concentrated liquid is subjected to liquid-liquid partition with ethyl acetate-water, the obtained organic layer is concentrated under reduced pressure and partitioned with hexane-90% methanol, the 90% methanol layer is concentrated, dried and subjected to silica gel chromatography, the adsorbed material is eluted with chloroform-methanol and the eluate is collected and subjected to high- performance liquid chromatography to obtain piceatannol of the formula (R<1> to R<4> are each OH, an alkyl, alkoxy, alkanoyl, etc.) or its derivative. The compound is used as an active component, compounded with a carrier and formed in the form of a pharmaceutical preparation to obtain the objective preparation for anti-inflammatory agent, anti-allergic agent, etc., having excellent lipoxygenase inhibiting action.

Description

【発明の詳細な説明】Detailed Description of the Invention

【0001】[0001]

【産業上の利用分野】本発明は、抗炎症剤及び抗アレル
ギー剤として有用なリポキシゲナーゼ阻害剤に関する。
TECHNICAL FIELD The present invention relates to a lipoxygenase inhibitor useful as an anti-inflammatory agent and an antiallergic agent.

【0002】[0002]

【従来の技術】近年、食生活や生活環境の変化、及び大
気汚染等の公害の発生に伴い、気管支喘息や花粉症等の
アレルギー性疾患患者が増加し大きな社会問題となりつ
つある。
2. Description of the Related Art In recent years, the number of patients with allergic diseases such as bronchial asthma and hay fever has increased with the changes in eating habits and living environment, and pollution such as air pollution, which is becoming a big social problem.

【0003】このうち、喘息は気道過敏性の高い患者が
気道に対する外界からのアレルゲンや非特異的な刺激に
よって血管透過性の亢進や気管支平滑筋の収縮、分泌亢
進等を惹起し、呼吸困難を引き起こし、重度の場合は死
に至る疾病である。現在喘息の治療薬としては薬物療
法、転地療法、減感作療法、心理療法などが行われてい
るが、未だ十分な治療効果を奏する方法は確立されてい
ない。喘息治療薬としてはステロイド剤や抗ヒスタミン
剤などが用いられているがそれらには重篤な副作用があ
るためその克服が重要な課題となっている。
Among them, asthma is a patient with high airway hypersensitivity, which causes vascular permeability increase, bronchial smooth muscle contraction, secretion increase, etc. due to external allergens or nonspecific stimulation to the airway, resulting in respiratory distress. It is a disease that causes and, in severe cases, death. Currently, as therapeutic agents for asthma, drug therapy, translocation therapy, desensitization therapy, psychotherapy, etc. are performed, but a method that produces a sufficient therapeutic effect has not yet been established. Steroids and antihistamines have been used as therapeutic agents for asthma, but since they have serious side effects, overcoming them is an important issue.

【0004】近年喘息に対する基礎研究が進むにつれ、
アラキドン酸代謝系のうち特にリポキシゲナーゼ系代謝
物が喘息の病態において重要な役割を果していることが
明らかになってきた。
With the progress of basic research on asthma in recent years,
It has become clear that, among the arachidonic acid metabolism systems, especially the lipoxygenase metabolites play an important role in the pathological condition of asthma.

【0005】このアラキドン酸は種々の刺激に応じて細
胞膜から遊離される炭素数20の不飽和脂肪酸でそれは
更にシクロオキシゲナーゼ系によりプロスタグランジン
類へ、リポキシゲナーゼ系によりロイコトリエンやHE
TE(ヒドロキシエイコサテトラエン酸)類へと代謝さ
れ、各代謝物は種々のアレルギー性疾患や炎症性疾患に
深く関与していることが知られている。
This arachidonic acid is an unsaturated fatty acid having 20 carbon atoms which is released from the cell membrane in response to various stimuli. It is further converted into prostaglandins by the cyclooxygenase system and leukotriene or HE by the lipoxygenase system.
It is known that these metabolites are metabolized to TE (hydroxyeicosatetraenoic acid) s, and that each metabolite is deeply involved in various allergic diseases and inflammatory diseases.

【0006】また皮膚病の一種である乾せんは表皮の増
殖と炎症性細胞の浸潤をきたす難治性の慢性炎症性角化
症である。乾せん発症の原因は未だ明らかにされていな
いが、病変部でリポキシゲナーゼ系代謝物のロイコトリ
エンやHETE類の量が増大していたことなどより、乾
せんの病変形成とアラキドン酸代謝異常の関連が強く示
唆されている。
Psoriasis, which is a type of skin disease, is a refractory chronic inflammatory keratosis that causes proliferation of the epidermis and infiltration of inflammatory cells. Although the cause of psoriasis has not been clarified yet, the amount of lipoxygenase metabolites leukotriene and HETEs increased in the lesions, which strongly suggests the relationship between psoriasis lesion formation and abnormal arachidonic acid metabolism. Has been done.

【0007】従って、アラキドン酸代謝物は、種々のア
レルギー性疾患及び炎症性疾患において極めて重要な役
割を果していると考えられ、このアラキドン酸の代謝酵
素であるリポキシゲナーゼは、主要な代謝酵素であるこ
とから、この酵素を阻害する物質は、上記の種々の疾患
の治療に有用であると考えられる。
[0007] Therefore, arachidonic acid metabolites are considered to play an extremely important role in various allergic and inflammatory diseases, and lipoxygenase, which is a metabolizing enzyme of arachidonic acid, is a major metabolic enzyme. Therefore, substances that inhibit this enzyme are considered to be useful for treating the above-mentioned various diseases.

【0008】[0008]

【発明が解決しようとする課題】従って本発明の目的
は、種々のアレルギー性疾患及び炎症性疾患の治療に有
用なリポキシゲナーゼ阻害剤を提供することにある。
Therefore, an object of the present invention is to provide a lipoxygenase inhibitor useful for treating various allergic diseases and inflammatory diseases.

【0009】[0009]

【課題を解決するための手段】斯かる実情に鑑み、本発
明者らは、リポキシゲナーゼ阻害作用を有する物質を得
るべく鋭意研究を重ねた結果、従来、抗カビ、抗菌活性
(Chem.Pharm.Bull.32(1)213
−218(1984))、ラット肥満細胞からのヒスタ
ミン遊離の阻害作用(Chem.Pharm.Bul
l.39(12)3276−3278(1991))を
有することが知られていたカヤツリ草科のカヤツリ草
(Cyperus microiria)に含まれるピ
セアタンノール及びその誘導体がリポキシゲナーゼ阻害
作用を有することを新たに見出し本発明を完成した。
In view of such circumstances, the inventors of the present invention have conducted earnest studies to obtain a substance having a lipoxygenase inhibitory action, and as a result, conventionally, antifungal activity and antibacterial activity (Chem. Pharm. Bull. .32 (1) 213
-218 (1984)), an inhibitory effect of histamine release from rat mast cells (Chem. Pharm. Bul.
l. 39 (12) 3276-3278 (1991)), which was known to have a new finding that piceatannol and its derivatives contained in Cyperus microiria of the family Cyperaceae have a lipoxygenase inhibitory action. Completed the invention.

【0010】すなわち本発明は、次の一般式(1)That is, the present invention provides the following general formula (1):

【0011】[0011]

【化2】 [Chemical 2]

【0012】(式中、R1、R2、R3 及びR4 は、同一
又は異なっていてもよく、水酸基、アルキル基、アルコ
キシ基、アルカノイル基又はアルカノイルオキシ基を示
す)で表わされるピセアタンノール又はその誘導体を有
効成分とするリポキシゲナーゼ阻害剤、並びにこれを有
効成分とする抗アレルギー剤及び抗炎症剤を提供するも
のである。
(Wherein R 1 , R 2 , R 3 and R 4 may be the same or different and represent a hydroxyl group, an alkyl group, an alkoxy group, an alkanoyl group or an alkanoyloxy group) The present invention provides a lipoxygenase inhibitor containing a norl or its derivative as an active ingredient, and an antiallergic agent and an anti-inflammatory agent containing this as an active ingredient.

【0013】上記一般式(1)中、R1、R2、R3 及び
4 で示されるアルキル基としては炭素数1〜6の直鎖
又は分岐鎖のアルキル基、例えばメチル基、エチル基、
n−プロピル基、イソプロピル基、n−ブチル基、se
c−ブチル基、n−ペンチル基、n−ヘキシル基等が挙
げられる。また、アルコキシ基としては炭素数1〜6の
直鎖又は分岐鎖のアルコキシ基、例えばメトキシ基、エ
トキシ基、n−プロピルオキシ基、イソプロピルオキシ
基、n−ブチルオキシ基、sec−ブチルオキシ基、n
−ペンチルオキシ基、n−ヘキシルオキシ基等が挙げら
れる。アルカノイル基としては炭素数1〜6の直鎖又は
分岐鎖のアルカノイル基、例えばホルミル基、アセチル
基、プロピオニル基、n−ブタノイル基、イソブタノイ
ル基、n−ペンタノイル基、n−ヘキサノイル基等が挙
げられる。アルカノイルオキシ基としては炭素数1〜6
の直鎖又は分岐鎖のアルカノイルオキシ基、例えばアセ
トキシ基、プロピオニルオキシ基、イソブタノイルオキ
シ基、n−ブタノイルオキシ基、n−ペンタノイルオキ
シ基、n−ヘキサノイルオキシ基等が挙げられる。R1
〜R4 としては、水酸基、アルコキシ基、アルカノイル
オキシ基が好ましい。
In the general formula (1), the alkyl group represented by R 1 , R 2 , R 3 and R 4 is a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group or an ethyl group. ,
n-propyl group, isopropyl group, n-butyl group, se
A c-butyl group, an n-pentyl group, an n-hexyl group and the like can be mentioned. As the alkoxy group, a linear or branched alkoxy group having 1 to 6 carbon atoms such as methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, sec-butyloxy group, n
Examples include -pentyloxy group and n-hexyloxy group. Examples of the alkanoyl group include linear or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl group, acetyl group, propionyl group, n-butanoyl group, isobutanoyl group, n-pentanoyl group and n-hexanoyl group. . The alkanoyloxy group has 1 to 6 carbon atoms.
And a linear or branched alkanoyloxy group such as acetoxy group, propionyloxy group, isobutanoyloxy group, n-butanoyloxy group, n-pentanoyloxy group, n-hexanoyloxy group. R 1
The to R 4, a hydroxyl group, an alkoxy group, alkanoyloxy group.

【0014】本発明の有効成分たるピセアタンノール又
はその誘導体(1)は、公知の方法(Rev.Lati
noamer.Quim.18,79−80(198
7),J.Nat.Prod.,50(1),36−4
0(1987)など)で合成することができるが、ピセ
アタンノール(一般式(1)中、R1 〜R4 =OH)は
カヤツリ草から抽出することもできる。抽出の場合は、
まずジエチルエーテル、酢酸エチル、アセトン、メタノ
ール、エタノール、ヘキサン、酢酸エチル、水より選ば
れる溶媒から抽出する。次いで得られた抽出液から溶媒
を留去して得られた残渣を、適宜メタノール、エタノー
ル、酢酸エチル等の溶媒に溶解し、更に水、メタノー
ル、エタノール、酢酸エチル、クロロホルム、ジクロロ
メタン、ヘキサン、アセトン、ベンゼン等を溶出溶媒と
して、アンバーライトXAD−2、ダイアイオンHP−
20、TSKゲルHW−40等の親水性ポリマーやセフ
ァデックスLH−20等のセファデックス、逆相系シリ
カゲルやシリカゲル、セルロース等を担体に用いたカラ
ムクロマトグラフィーに付し、薄層クロマトグラフィー
などで目的成分を確認しながら分画することにより目的
物を得ることができる。また、場合によりベンゼン、エ
ーテル、ヘキサン、アセトン、メタノール、エタノー
ル、水等の適当な溶媒を用いて再結晶することにより精
製してもよい。
The active ingredient piceatannol or its derivative (1) of the present invention can be prepared by a known method (Rev. Lati).
noamer. Quim. 18, 79-80 (198
7), J. Nat. Prod. , 50 (1), 36-4
No. 0 (1987)), but piceatannol (R 1 to R 4 = OH in the general formula (1)) can also be extracted from cypress grass. For extraction,
First, extraction is performed from a solvent selected from diethyl ether, ethyl acetate, acetone, methanol, ethanol, hexane, ethyl acetate, and water. Then, the residue obtained by distilling off the solvent from the obtained extract is appropriately dissolved in a solvent such as methanol, ethanol and ethyl acetate, and further water, methanol, ethanol, ethyl acetate, chloroform, dichloromethane, hexane and acetone. , Benzene, etc. as elution solvents, Amberlite XAD-2, Diaion HP-
20, hydrophilic polymer such as TSK gel HW-40, Sephadex such as Sephadex LH-20, column chromatography using reversed phase silica gel, silica gel, cellulose, etc. as a carrier, and thin layer chromatography etc. The target product can be obtained by fractionating while checking the target component. In some cases, it may be purified by recrystallization using a suitable solvent such as benzene, ether, hexane, acetone, methanol, ethanol and water.

【0015】ピセアタンノール又はその誘導体(1)
は、そのまま又は慣用の製剤単体と共に動物及び人に投
与することができる。この投与量は、患者又は動物の年
齢、性別、疾患の程度等により適宜決定すればよいが、
通常1日当たり体重1kgにつき0.002〜20mg、特
に0.05〜5mgの範囲とすることが好ましい。
Piceatannol or its derivative (1)
Can be administered to animals and humans as is or together with conventional formulations alone. This dose may be appropriately determined depending on the age of the patient or animal, sex, degree of disease, etc.
Usually, it is preferable to set the range of 0.002 to 20 mg, especially 0.05 to 5 mg per 1 kg of body weight per day.

【0016】また、ピセアタンノール又はその誘導体
(1)の投与形態は特に制限はなく、必要に応じて適宜
選択することができ、剤型も錠剤、カプセル剤、顆粒
剤、散剤等の経口剤、注射剤、坐剤、軟膏等の非経口剤
の中から適宜選択することができる。
The dosage form of piceatannol or its derivative (1) is not particularly limited and can be appropriately selected as needed, and the dosage form is an oral preparation such as tablets, capsules, granules and powders. , Parenteral preparations such as injections, suppositories, ointments and the like.

【0017】錠剤の形態にする場合は、担体としては、
この分野で公知のものを広く使用できる。これには、例
えば澱粉、乳糖、ショ糖、カルボキシメチルセルロー
ス、コーンスターチ、無機塩類、尿素等の賦形剤;水、
エタノール、プロパノール、単シロップ、ブドウ糖、澱
粉液、ゼラチン溶液、カルボキシメチルセルロース、セ
ラック、メチルセルロース、リン酸カリウム、ポリビニ
ルピロリドン等の結合剤;乾燥澱粉、アルギン酸ナトリ
ウム、カンテン末、ラミナラン末、炭酸水素ナトリウ
ム、炭酸カルシウム、ポリオキシエチレンソルビタン脂
肪酸エステル類、ラウリル硫酸ナトリウム、ステアリン
酸モノグリセライド、澱粉、乳糖等の崩壊剤;白糖、ス
テアリン、カカオバター、水素添加油等の崩壊抑制剤;
ラウリル硫酸ナトリウム、第4級アンモニウム塩等の吸
収促進剤;グリセリン、澱粉等の保湿剤;澱粉、乳糖、
カオリン、ベントナイト、コロイド状ケイ酸等の吸着
剤;ステアリン酸塩、ホウ酸末、精製タルク、ポリエチ
レングリコール等の滑沢剤等が挙げられる。更に錠剤は
必要に応じて通常の剤皮を施した錠剤、例えば糖衣錠、
ゼラチン被包錠、腸溶包錠、フィルムコーティング錠あ
るいは二重錠、多層錠とすることができる。
In the case of tablets, the carrier is
A wide variety of materials known in the art can be used. This includes excipients such as starch, lactose, sucrose, carboxymethyl cellulose, corn starch, inorganic salts, urea; water,
Binders such as ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone; dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, carbonate Disintegrators such as calcium, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch and lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter and hydrogenated oils;
Absorption enhancers such as sodium lauryl sulfate and quaternary ammonium salts; moisturizers such as glycerin and starch; starch, lactose,
Adsorbents such as kaolin, bentonite, colloidal silicic acid; stearates, boric acid powder, purified talc, lubricants such as polyethylene glycol and the like. Further, the tablets are tablets coated with a usual coating as necessary, for example, sugar-coated tablets,
It may be a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multi-layer tablet.

【0018】丸剤の形態にする場合には、担体としては
この分野で公知のものを広く使用でき、これには、例え
ば澱粉、乳糖、ブドウ糖、カカオ脂、硬化植物油、カオ
リン、タルク等の賦形剤、アラビアゴム末、トラガント
末、ゼラチン、エタノール等の結合剤、ラミナランカン
テン等の崩壊剤等が挙げられる。
In the case of pills, a wide variety of carriers known in the art can be used, and examples thereof include starch, lactose, glucose, cocoa butter, hydrogenated vegetable oil, kaolin, talc and the like. Examples include shaping agents, gum arabic powder, tragacanth powder, binders such as gelatin and ethanol, and disintegrating agents such as laminaranthantene.

【0019】坐剤の形態にする場合は、担体としてはこ
の分野で公知のものを広く使用でき、これには例えばカ
カオ脂、ゼラチン、ポリエチレングリコール、高級アル
コール、高級アルコールのエステル類、半合成グリセリ
ド等を挙げることができる。
When in the form of suppositories, those widely known in the art can be widely used as the carrier, and examples thereof include cocoa butter, gelatin, polyethylene glycol, higher alcohols, esters of higher alcohols, and semisynthetic glycerides. Etc. can be mentioned.

【0020】注射剤として調製する場合は、液剤及び懸
濁剤は殺菌され、かつ血液と等張であることが望まし
く、これら液剤、懸濁剤及び乳剤の形態にする場合は、
希釈剤としては、この分野において慣用されているもの
を利用することができる。例えば水、エチルアルコー
ル、プロピレングリコール、エトキシ化イソステアリル
アルコール、ポリオキシエチレン化イソステアリルアル
コール、ポリオキシエチレンソルビタン脂肪酸エステル
類等を挙げることができる。尚、この場合等張性の水溶
液を調製するに十分な量の食塩、ブドウ糖、グリセリン
等を医薬製剤中に含有せしめてもよく、また通常の溶解
補助剤、緩衝剤、無痛化剤等を添加してもよい。更に必
要に応じて着色剤、保存剤、香料、風味剤、甘味剤や他
の医薬品を医薬製剤中に含有せしめてもよい。
When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood. When these solutions, suspensions and emulsions are prepared,
As the diluent, those commonly used in this field can be used. Examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylenated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, the pharmaceutical preparation may contain a sufficient amount of salt, glucose, glycerin, etc. to prepare an isotonic aqueous solution, and a usual solubilizing agent, buffer, soothing agent, etc. are added. You may. Further, if necessary, a colorant, a preservative, a flavor, a flavoring agent, a sweetening agent and other pharmaceuticals may be contained in the pharmaceutical preparation.

【0021】また、本化合物を噴霧剤の形態にする場合
には、分散剤及び噴射剤はこの分野で公知のものを広く
使用でき、分散剤としては例えば大豆レシチン、卵黄レ
シチン類、オレイン酸、リノール酸、リノレン酸等の脂
肪酸、ソルビタントリオレート、ソルビタンモノオレー
ト等のソルビタン類等を用いることができる。また噴射
剤として例えばフレオン11、フレオン12、フレオン
114等の通常不燃性液化ガスを用いることができる。
When the present compound is in the form of a spray, those widely known in the art can be used as the dispersant and the propellant. Examples of the dispersant include soybean lecithin, egg yolk lecithins, oleic acid, Fatty acids such as linoleic acid and linolenic acid, and sorbitans such as sorbitan trioleate and sorbitan monooleate can be used. Further, as the propellant, for example, a normally incombustible liquefied gas such as Freon 11, Freon 12, Freon 114 can be used.

【0022】本化合物を軟膏の形態にする場合にもこの
分野で公知のものを広く使用でき、例えば水、エタノー
ル、イソプロピルアルコール、グリセリン、ポリエチレ
ングリコール、ソルビトール、ポリビニルアルコール等
の多価アルコール、動物性油脂、植物性油脂、鉱物油、
硬化油、ミツロウ等のワックス、液状パラフィン、パラ
フィンロウ等の高級炭化水素、ステアリン酸等の脂肪
酸、乳化剤、アニオン界面活性剤、カチオン界面活性
剤、両性界面活性剤といった界面活性剤、キサンタンガ
ム、アルギン酸ナトリウム、メチルセルロース、ヒドロ
キシエチルセルロース、カルボキシビニルポリマー等の
水溶性高分子化合物等を使用することができる。また、
色素、保存剤、香料等も必要に応じて配合してもよい。
When the present compound is in the form of an ointment, a wide variety of compounds known in the art can be used, and examples thereof include water, ethanol, isopropyl alcohol, glycerin, polyethylene glycol, sorbitol, polyvinyl alcohol, and other polyhydric alcohols, and animal products. Oils, vegetable oils, mineral oils,
Hardened oil, waxes such as beeswax, higher hydrocarbons such as liquid paraffin and paraffin wax, fatty acids such as stearic acid, emulsifiers, surfactants such as anionic surfactants, cationic surfactants and amphoteric surfactants, xanthan gum, sodium alginate. Water-soluble polymer compounds such as methyl cellulose, hydroxyethyl cellulose and carboxyvinyl polymer can be used. Also,
Dyes, preservatives, fragrances, etc. may be added as required.

【0023】ピセアタンノール及びその誘導体(1)が
医薬製剤中に配合されるべき量としては特に限定され
ず、広範囲に適宜選択されるが、通常医薬製剤中0.0
01〜70重量%、好ましくは0.1〜30重量%であ
る。
The amount of piceatannol and its derivative (1) to be blended in the pharmaceutical preparation is not particularly limited and may be appropriately selected within a wide range.
It is from 01 to 70% by weight, preferably from 0.1 to 30% by weight.

【0024】上記医薬製剤の投与方法は特に制限はな
く、各種製剤形態、患者の年齢、性別、その他の条件、
患者の程度に応じた方法で投与される。例えば錠剤、丸
剤、液剤、懸濁剤、乳剤、顆粒剤、カプセル剤の場合に
は経口投与される。また注射の場合には単独であるいは
ブドウ糖、アミノ酸等の通常の補液と混合して静脈内投
与され、更には必要に応じて単独で筋肉内、皮内、皮下
もしくは腹腔内投与される。坐剤の場合には直腸内投与
される。また噴霧剤の場合には口又は鼻より噴霧して気
管支へ投与される。軟膏の場合には直接病変部位へ塗布
される。
The administration method of the above-mentioned pharmaceutical preparation is not particularly limited, and various preparation forms, patient's age, sex, other conditions,
It is administered according to the degree of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of injection, it is intravenously administered alone or in admixture with a normal replacement fluid such as glucose or amino acid, and further, if necessary, is intramuscularly, intradermally, subcutaneously or intraperitoneally administered alone. In the case of suppositories, it will be administered rectally. In the case of a spray, it is sprayed from the mouth or nose and administered to the bronchi. In the case of ointment, it is applied directly to the lesion site.

【0025】[0025]

【実施例】以下、実施例、製造例、試験例を挙げて本発
明を更に詳細に説明するが、本発明はこれらに限定され
るものではない。
The present invention will be described in more detail with reference to Examples, Production Examples and Test Examples, but the present invention is not limited to these.

【0026】製造例1 乾燥カヤツリ草(Cyperus microiri
a)(重量1kg)を粉砕し、メタノール1lで抽出す
る。抽出液は減圧濃縮した後、酢酸エチル−水で液−液
分配し、得られた有機層は減圧濃縮後更にヘキサン−9
0%メタノールで分配する。90%メタノール層を濃縮
乾固後(16g)シリカゲルカラムクロマトグラフィー
(Wakogel C−200)に供し、クロロホルム
−メタノール系で溶出した。クロロホルム:メタノール
=9:1溶出部を集め、更に高速液体クロマトグラフィ
ー(ODS;アセトニトリル:3%酢酸水=2:3)に
供し、60mgのピセアタンノールを得た。
Production Example 1 Dried cypress grass (Cyperus microiri)
a) (1 kg in weight) is ground and extracted with 1 l of methanol. The extract was concentrated under reduced pressure and then liquid-liquid partitioned with ethyl acetate-water. The obtained organic layer was concentrated under reduced pressure and further hexane-9.
Partition with 0% methanol. The 90% methanol layer was concentrated to dryness (16 g), and subjected to silica gel column chromatography (Wakogel C-200), and eluted with a chloroform-methanol system. Chloroform: methanol = 9: 1 eluate was collected and further subjected to high performance liquid chromatography (ODS; acetonitrile: 3% acetic acid water = 2: 3) to obtain 60 mg of piceatannol.

【0027】試験例1 ラット好塩基性白血病細胞株(Rat Basophi
lic Leukemia Cell:RBL−1)を
D−PBS(+)に浮遊させる。プラスチックチューブ
に各チューブ2×105 個の細胞をとり、種々の濃度の
ピセアタンノールと37℃で15分間インキュベートし
た後、カルシウムイオノフォアA23187(最終濃度
2.5μM)を加えた。更に15分間インキュベートし
た後EDTA(最終濃度4mM)を加えて氷冷し、20
00rpm で5分間遠心し、上清を分取した。次に上清中
に含まれるロイコトリエンC4 (LTC4 )とプロスタ
グランジンD2 (PGD2 )をラジオイムノアッセイ法
を用いて定量し、その産生阻害効果を評価した。その結
果を表1に示す。
Test Example 1 Rat basophilic leukemia cell line (Rat Basophi)
lic Leukemia Cell: RBL-1) is suspended in D-PBS (+). 2 × 10 5 cells of each tube were placed in a plastic tube and incubated with various concentrations of piceatannol at 37 ° C. for 15 minutes, and then calcium ionophore A23187 (final concentration 2.5 μM) was added. After incubating for another 15 minutes, EDTA (final concentration 4 mM) was added and the mixture was ice-cooled.
The mixture was centrifuged at 00 rpm for 5 minutes, and the supernatant was collected. Next, leukotriene C 4 (LTC 4 ) and prostaglandin D 2 (PGD 2 ) contained in the supernatant were quantified using a radioimmunoassay method, and their production inhibitory effect was evaluated. The results are shown in Table 1.

【0028】[0028]

【表1】 [Table 1]

【0029】試験例2 正常ヒト多形核白血球を4.0×107 個/mlになるよ
う1mM−EDTA及び0.1%−ゼラチンを含む50m
Mリン酸緩衝液に浮遊させ、20kHz の超音波に30秒
間さらして細胞を破砕し、10000Gで10分、10
5000Gで60分間遠心分離を行い、その上清を酵素
標品とした。次に試験管に上記酵素と試験化合物(最終
濃度10μM)をとり、37℃で10分間インキュベー
トした後、14Cで標識したアラキドン酸(0.1μC
i)を加え更に10分間反応させた。反応後、クエン酸
を加え酸性にして酢酸エチルにより抽出し、濃縮後RI
−HPLCに供し(ODSC18カラム250×4mm,M
eCN:MeOH:H2O:AcOH=350:15
0:250:1,流速1.5ml/min)、5−HET
E,12−HETE,15−HETEの放射活性を測定
した。試験化合物を加えない場合のHETE量を100
%としてリポキシゲナーゼ阻害活性を評価した。その結
果を表2に示す。
Test Example 2 Normal human polymorphonuclear leukocytes containing 50 mM of 1 mM EDTA and 0.1% -gelatin so as to have a concentration of 4.0 × 10 7 cells / ml.
Suspend in M phosphate buffer, sonicate at 20kHz for 30 seconds to crush the cells, and at 10 000G for 10 minutes, 10
Centrifugation was performed at 5000 G for 60 minutes, and the supernatant was used as an enzyme preparation. Next, the enzyme and test compound (final concentration 10 μM) were placed in a test tube, incubated at 37 ° C. for 10 minutes, and then 14 C-labeled arachidonic acid (0.1 μC) was added.
i) was added and the reaction was continued for 10 minutes. After the reaction, add citric acid to acidify, extract with ethyl acetate, concentrate and then RI
-Subjected to HPLC (ODSC 18 column 250 x 4 mm, M
eCN: MeOH: H 2 O: AcOH = 350: 15
0: 250: 1, flow rate 1.5 ml / min), 5-HET
The radioactivity of E, 12-HETE, 15-HETE was measured. The amount of HETE is 100 when the test compound is not added.
The lipoxygenase inhibitory activity was evaluated as%. The results are shown in Table 2.

【0030】[0030]

【表2】 [Table 2]

【0031】以上の結果よりピセアタンノール又はその
誘導体(1)の優れたリポキシゲナーゼ阻害作用が確認
された。
From the above results, excellent lipoxygenase inhibitory action of piceatannol or its derivative (1) was confirmed.

【0032】試験例3 正常ヒト繊維芽細胞を、10%FCSを含むDMEM培
地に懸濁して12穴の培養プレートに播き、コンフルエ
ントになった時点で血清を含まないDMEM培地に交換
する。その24時間後に被験物質を含む培地に交換し、
30分間培養後インターロイキン1α(10ユニット/
ml)加えて更に6時間培養する。6時間後に培地を分取
し、培地中に遊離されたプロスタグランジンE2 (PG
2 )を酵素免疫測定法により定量した。その結果を表
3に示す。
Test Example 3 Normal human fibroblasts were suspended in DMEM medium containing 10% FCS, seeded on a 12-well culture plate, and when confluent, replaced with serum-free DMEM medium. 24 hours later, exchange the medium with the test substance,
After incubation for 30 minutes, interleukin 1α (10 units /
ml) and incubate for another 6 hours. After 6 hours, the medium was collected, and prostaglandin E 2 (PG
E 2 ) was quantified by enzyme immunoassay. The results are shown in Table 3.

【0033】[0033]

【表3】 [Table 3]

【0034】一方、化合物a、b、c又はdをマウスに
投与した場合300mg/kgの経口投与または200mg/
kgの腹腔内投与でも死亡したマウスはいなかった。
On the other hand, when compound a, b, c or d is administered to mice, it is orally administered at 300 mg / kg or 200 mg / kg.
None of the mice died even after intraperitoneal administration of kg.

【0035】試験例4 ハートレー系白色モルモットの背部を毛刈りし、0.1
%クロトン油を塗布して炎症を惹起させた。炎症惹起2
時間前及び6時間後にサンプルとしてピセアタンノール
のエタノール溶液(100mM)25μl/(1.5cm×
1.5cm)を塗布し、炎症惹起24時間後に紅斑の程度
を判定した。判定は下記の日本皮膚科学会基準に準じて
行った。その結果を図1に示す。
TEST EXAMPLE 4 Hartley white guinea pigs were shaved on the back to give 0.1.
% Croton oil was applied to induce inflammation. Inflammation induction 2
Before and after 6 hours, as a sample, 25 μl / (1.5 cm ×) of a solution of piceatannol in ethanol (100 mM)
1.5 cm) was applied, and the degree of erythema was judged 24 hours after the induction of inflammation. The judgment was made according to the following Japanese Dermatological Association standards. The result is shown in FIG.

【0036】日本皮膚科学会基準 0 (−) 反応なし。 0.5(±) 軽度又は部分的紅斑。 1.0(+) 明らかな全面紅斑。 2.0(++) 紅斑と浮腫。 3.0(+++)紅斑と浮腫と小水泡。Japanese Dermatological Association Standard 0 (−) No reaction. 0.5 (±) Mild or partial erythema. 1.0 (+) Clear erythema on the whole surface. 2.0 (++) Erythema and edema. 3.0 (+++) Erythema, edema and small blisters.

【0037】[0037]

【表4】 [Table 4]

【0038】表4より、クロトン油誘導炎症モデルにお
けるピセアタンノールの優れた抗炎症効果が確認され
た。
From Table 4, it was confirmed that the excellent anti-inflammatory effect of piceatannol in the croton oil-induced inflammation model.

【0039】試験例5 ハートレー系白色モルモットの背部を毛刈りし、100
mMピセアタンノールのエタノール溶液(サンプル)25
μl/(1.5cm×1.5cm)を塗布した。2時間後に
70%エタノールでサンプルを拭き取り、UVB(1.
7mW/cm2 ×9分)を照射し、その直後にサンプル25
μl/(1.5cm×1.5cm)を塗布した。UVB照射
6時間後に再びサンプル25μlを塗布した。照射6時
間後及び24時間後の時点で、試験例4と同様に紅斑の
程度を判定した。その結果を表5に示す。
Test Example 5 Hurtley-type white guinea pigs were shaved on the back and cut to 100
Ethanol solution of mM piceatannol (sample) 25
μl / (1.5 cm × 1.5 cm) was applied. After 2 hours, the sample was wiped with 70% ethanol and UVB (1.
7 mW / cm 2 × 9 minutes), and immediately after that, sample 25
μl / (1.5 cm × 1.5 cm) was applied. After 6 hours of UVB irradiation, 25 μl of the sample was applied again. At 6 hours and 24 hours after irradiation, the degree of erythema was evaluated in the same manner as in Test Example 4. The results are shown in Table 5.

【0040】[0040]

【表5】 [Table 5]

【0041】表5より、UV炎症モデルにおけるピセア
タンノールの優れた抗炎症効果が確認された。
From Table 5, it was confirmed that the excellent anti-inflammatory effect of piceatannol in the UV inflammation model was confirmed.

【0042】試験例6 7週齢のBalb/c系雄性マウスの背部を剃毛し、7
%の塩化ピクリル/アセトン・オリーブ油(4・1)溶
液100μlを塗布して感作させた。感作6日後に1%
の塩化ピクリル/アセトン・オリーブ油(4・1)溶液
20μlを右耳介両面に塗布してアレルギー炎症を惹起
させた。惹起24時間後に屠殺し、両耳介切断後パンチ
(φ=7mm)にて打ち抜き、左右の耳介片の重量を測定
し、その差を浮腫量とした。尚、惹起前日、惹起時、惹
起6時間後に100mMピセアタンノールのエタノール溶
液(サンプル)を20μlずつ右耳介に塗布し、対象群
は被験物質の代わりに溶媒(エタノール)のみを塗布し
た。その結果を表6に示す。
Test Example 6 Balb / c male mice aged 7 weeks were shaved on the back and
100 μl of a picryl chloride / acetone / olive oil (4. 1) solution was applied for sensitization. 6% after sensitization 1%
20 μl of a solution of picryl chloride / acetone / olive oil (4. 1) was applied to both surfaces of the right auricle to induce allergic inflammation. After 24 hours of induction, the animals were sacrificed, punched with a punch (φ = 7 mm) after cutting both auricles, the weight of the left and right auricle pieces was measured, and the difference between them was taken as the amount of edema. 20 μl of 100 mM piceatannol ethanol solution (sample) was applied to the right auricle on the day before induction, 6 hours after the induction, and only the solvent (ethanol) was applied to the target group instead of the test substance. The results are shown in Table 6.

【0043】[0043]

【表6】 [Table 6]

【0044】表6より、アレルギー炎症モデルにおける
ピセアタンノールの優れた抗炎症効果が確認された。
From Table 6, the excellent anti-inflammatory effect of piceatannol in the allergic inflammation model was confirmed.

【0045】実施例1 下記の処方に従って各成分を均一に混合し、打錠機にて
圧縮成形し、一錠200mgの錠剤を得た。
Example 1 The ingredients were uniformly mixed according to the following formulation, and the mixture was compression-molded with a tableting machine to give 200 mg tablets.

【0046】[0046]

【表7】 本化合物a(表2) 10g コーンスターチ 30g 澱粉 30g カルボキシメチルセルロース 5g マグネシウムステアレート 5g 乳糖 20g 計 100g[Table 7] Compound a (Table 2) 10 g Corn starch 30 g Starch 30 g Carboxymethyl cellulose 5 g Magnesium stearate 5 g Lactose 20 g Total 100 g

【0047】実施例2 下記の処方に従って各成分を均一に混合し、ねつ和し
た。押し出し造粒機により造粒後乾燥し、篩別して顆粒
剤を得た。
Example 2 According to the following formulation, the respective components were uniformly mixed and blended. After granulating with an extrusion granulator, it was dried and sieved to obtain granules.

【0048】[0048]

【表8】 本化合物b(表2) 10g 結晶セルロース 50g 10%ヒドロキシプロピルセルロース 40g エタノール溶液 計 100gTable 8 The present compound b (Table 2) 10 g Crystalline cellulose 50 g 10% Hydroxypropyl cellulose 40 g Ethanol solution total 100 g

【0049】実施例3 常法により下記組成のものをボンベに詰め、噴霧剤を製
造した。
Example 3 A propellant was prepared by filling a cylinder with the following composition by a conventional method.

【0050】[0050]

【表9】 本化合物a(表2) 1g オレイン酸 3g フレオン11 1.2g フレオン12 2.5g フレオン114 1.3g 計 9gTable 9 The present compound a (Table 2) 1 g Oleic acid 3 g Freon 11 1.2 g Freon 12 2.5 g Freon 114 1.3 g Total 9 g

【0051】実施例4 下記の処方により各成分を均一に混合し、軟膏剤を得
た。
Example 4 The components were uniformly mixed according to the following formulation to obtain an ointment.

【0052】[0052]

【表10】 本化合物c(表2) 10g スクワラン 20g グリセリン 20g セチルアルコール 5g マグネシウムステアレート 3g プロピレングリコール 5g 水 20g エタノール 7g 計 90gTable 10 The present compound c (Table 2) 10 g Squalane 20 g Glycerin 20 g Cetyl alcohol 5 g Magnesium stearate 3 g Propylene glycol 5 g Water 20 g Ethanol 7 g Total 90 g

【0053】[0053]

【発明の効果】本発明のリポキシゲナーゼ阻害剤は、優
れたリポキシゲナーゼ阻害作用を有し、抗炎症剤、抗ア
レルギー剤等の医薬として有用である。従って、気管支
炎、喘息、アレルギー性鼻炎、痛風、関節炎、腎炎、肝
炎、乾せん、じんましん、接触皮膚炎、アトピー性皮膚
炎等の予防・治療に広く用いることができる。
INDUSTRIAL APPLICABILITY The lipoxygenase inhibitor of the present invention has an excellent lipoxygenase inhibitory action and is useful as a medicine such as an anti-inflammatory agent and an antiallergic agent. Therefore, it can be widely used for the prevention and treatment of bronchitis, asthma, allergic rhinitis, gout, arthritis, nephritis, hepatitis, psoriasis, urticaria, contact dermatitis, atopic dermatitis and the like.

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 FI 技術表示箇所 A61K 31/22 ADA 9454−4C (72)発明者 矢田 幸博 栃木県芳賀郡二宮町久下田西1丁目115− 1 (72)発明者 芋川 玄爾 栃木県宇都宮市氷室町1022−89─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. 6 Identification number Internal reference number FI Technical indication location A61K 31/22 ADA 9454-4C (72) Inventor Yukihiro Yada 1-chome Kushita Nishi, Ninomiya Town, Haga-gun, Tochigi Prefecture 115-1 (72) Inventor Genji Imokawa 1022-89 Himurocho, Utsunomiya City, Tochigi Prefecture

Claims (3)

【特許請求の範囲】[Claims] 【請求項1】 次の一般式(1) 【化1】 (式中、R1、R2、R3 及びR4 は、同一又は異なって
いてもよく、水酸基、アルキル基、アルコキシ基、アル
カノイル基又はアルカノイルオキシ基を示す)で表わさ
れるピセアタンノール又はその誘導体を有効成分とする
リポキシゲナーゼ阻害剤。
1. The following general formula (1): (Wherein R 1 , R 2 , R 3 and R 4 may be the same or different and represent a hydroxyl group, an alkyl group, an alkoxy group, an alkanoyl group or an alkanoyloxy group) or a piceatannol thereof. A lipoxygenase inhibitor containing a derivative as an active ingredient.
【請求項2】 請求項1記載のピセアタンノール又はそ
の誘導体を有効成分とする抗アレルギー剤。
2. An anti-allergic agent comprising the piceatannol or the derivative thereof according to claim 1 as an active ingredient.
【請求項3】 請求項1記載のピセアタンノール又はそ
の誘導体を有効成分とする抗炎症剤。
3. An anti-inflammatory agent comprising the piceatannol or the derivative thereof according to claim 1 as an active ingredient.
JP6118098A 1993-06-11 1994-05-31 Lipoxygenase inhibitor Pending JPH0753359A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP6118098A JPH0753359A (en) 1993-06-11 1994-05-31 Lipoxygenase inhibitor

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP5-140654 1993-06-11
JP14065493 1993-06-11
JP6118098A JPH0753359A (en) 1993-06-11 1994-05-31 Lipoxygenase inhibitor

Publications (1)

Publication Number Publication Date
JPH0753359A true JPH0753359A (en) 1995-02-28

Family

ID=26456095

Family Applications (1)

Application Number Title Priority Date Filing Date
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Country Status (1)

Country Link
JP (1) JPH0753359A (en)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999056737A1 (en) * 1998-05-05 1999-11-11 Institut National De La Sante Et De La Recherche Medicale (Inserm) Arylhydrocarbon receptor ligand antagonists
WO2000038620A3 (en) * 1998-12-24 2000-10-19 1333366 Ontario Inc A composition useful to treat periodontal disease
WO2001042231A3 (en) * 1999-12-06 2001-11-01 Welichem Biotech Inc Polyhydroxystilbenes and stilbene oxides as antisoriatic agents and protein kinase inhibitors
WO2001008671A3 (en) * 1999-07-30 2002-05-02 Procter & Gamble Method and composition for prophylaxis and treatment of symptoms associated with cold and influenza-like illnesses
JP2004529085A (en) * 2001-01-18 2004-09-24 ウェリケム バイオテック インコーポレーテッド Novel 1,2-diphenylethene derivatives for treating immune diseases
KR100523753B1 (en) * 1997-12-23 2005-12-28 주식회사 엘지생활건강 Anti-inflammatory composition containing mountain mirror extract
AU2003268599B2 (en) * 1998-05-05 2007-03-15 Casper, Robert Frederic Arylhydrocarbon Receptor Ligand Antagonists
US7321050B2 (en) 1999-12-06 2008-01-22 Welichem Biotech Inc. Anti-inflammatory and psoriasis treatment and protein kinase inhibition by hydroxy stilbenes and novel stilbene derivatives and analogues
JP2009528330A (en) * 2006-03-03 2009-08-06 サントル・ナシオナル・ドゥ・ラ・ルシェルシュ・シアンティフィーク(セーエヌエールエス) Hydroxylated long chain resveratrol derivatives useful as neurotrophic agents
US7629375B2 (en) 2001-07-23 2009-12-08 Johnson & Johnson Consumer Companies, Inc. Cytoprotective compounds, pharmaceutical and cosmetic formulations, and methods
US7714161B2 (en) 2004-01-20 2010-05-11 Brigham Young University Sirtuin activating compounds and methods for making the same
JP2012046448A (en) * 2010-08-26 2012-03-08 Maruzen Pharmaceut Co Ltd Agent for recovery from ultraviolet damage
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Cited By (20)

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KR100523753B1 (en) * 1997-12-23 2005-12-28 주식회사 엘지생활건강 Anti-inflammatory composition containing mountain mirror extract
FR2778337A1 (en) * 1998-05-05 1999-11-12 Inst Nat Sante Rech Med ARYLHYDROCARBON RECEPTOR LIGAND ANTAGONISTS
WO1999056737A1 (en) * 1998-05-05 1999-11-11 Institut National De La Sante Et De La Recherche Medicale (Inserm) Arylhydrocarbon receptor ligand antagonists
AU2003268599B2 (en) * 1998-05-05 2007-03-15 Casper, Robert Frederic Arylhydrocarbon Receptor Ligand Antagonists
WO2000038620A3 (en) * 1998-12-24 2000-10-19 1333366 Ontario Inc A composition useful to treat periodontal disease
WO2001008671A3 (en) * 1999-07-30 2002-05-02 Procter & Gamble Method and composition for prophylaxis and treatment of symptoms associated with cold and influenza-like illnesses
WO2001042231A3 (en) * 1999-12-06 2001-11-01 Welichem Biotech Inc Polyhydroxystilbenes and stilbene oxides as antisoriatic agents and protein kinase inhibitors
CN1319959C (en) * 1999-12-06 2007-06-06 天济药业(深圳)有限公司 Polyhydroxystilbenes and stibene oxides as antisoriatic agents and protein kinase inhibitors
US7321050B2 (en) 1999-12-06 2008-01-22 Welichem Biotech Inc. Anti-inflammatory and psoriasis treatment and protein kinase inhibition by hydroxy stilbenes and novel stilbene derivatives and analogues
US7868047B2 (en) 1999-12-06 2011-01-11 Welichem Biotech Inc. Anti-inflammatory and psoriasis treatment and protein kinase inhibition by hydroxy stilbenes and novel stilbene derivatives and analogues
JP2004529085A (en) * 2001-01-18 2004-09-24 ウェリケム バイオテック インコーポレーテッド Novel 1,2-diphenylethene derivatives for treating immune diseases
US7629375B2 (en) 2001-07-23 2009-12-08 Johnson & Johnson Consumer Companies, Inc. Cytoprotective compounds, pharmaceutical and cosmetic formulations, and methods
US8841477B2 (en) 2004-01-20 2014-09-23 Brigham Young University Sirtuin activating compounds and processes for making the same
US7714161B2 (en) 2004-01-20 2010-05-11 Brigham Young University Sirtuin activating compounds and methods for making the same
JP2009528330A (en) * 2006-03-03 2009-08-06 サントル・ナシオナル・ドゥ・ラ・ルシェルシュ・シアンティフィーク(セーエヌエールエス) Hydroxylated long chain resveratrol derivatives useful as neurotrophic agents
JP2012046448A (en) * 2010-08-26 2012-03-08 Maruzen Pharmaceut Co Ltd Agent for recovery from ultraviolet damage
CN102507830A (en) * 2011-11-21 2012-06-20 昆明制药集团股份有限公司 High performance liquid chromatograph method for measuring content of Quzhazhigan in Rheum lhasaense
US10647649B2 (en) 2017-11-10 2020-05-12 Dermavant Sciences GmbH Process for preparing tapinarof
US10961175B2 (en) 2017-11-10 2021-03-30 Dermavant Sciences GmbH Process for preparing tapinarof
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