JPS60248645A - Caffeic acid derivative - Google Patents
Caffeic acid derivativeInfo
- Publication number
- JPS60248645A JPS60248645A JP10499884A JP10499884A JPS60248645A JP S60248645 A JPS60248645 A JP S60248645A JP 10499884 A JP10499884 A JP 10499884A JP 10499884 A JP10499884 A JP 10499884A JP S60248645 A JPS60248645 A JP S60248645A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- caffeic acid
- caffeic
- acid derivative
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
Description
【発明の詳細な説明】
〔技術分野〕
本発明は、リポキシゲナーゼ阻害作用を有する新規カフ
ェー酸誘導体に関する６
〔従来技術・発明の背景〕
リポキシゲナーゼは、アレルギー症、喘息、炎症等の発
症に関与すると考えられているロイコトリエン類、５−
ヒドロキシエイコサテトラエン酸（５−）ＩＥ、ＴＥ＞
の生体内合成に関与する酵素である。[Detailed Description of the Invention] [Technical Field] The present invention relates to a novel caffeic acid derivative having a lipoxygenase inhibitory effect. [Prior Art/Background of the Invention] Lipoxygenase is thought to be involved in the onset of allergic diseases, asthma, inflammation, etc. Leukotrienes, 5-
Hydroxyeicosatetraenoic acid (5-) IE, TE>
It is an enzyme involved in the biosynthesis of
従って、リポキシゲナーゼ阻害作用を有する化合物は、
アレルギー症、喘息、炎症等の治療、予防に有用なもの
である。Therefore, compounds with lipoxygenase inhibitory action are
It is useful for treating and preventing allergies, asthma, inflammation, etc.
かかるリポキシゲナーゼ阻害作用物質としては、カフェ
ー酸及びそのメチルエステルが知られているＣＢ、Ｂ、
Ａ、１Ｊ２．９２ （１９８４））が、そのリポキシゲ
ナーゼ阻害作用は充分なものとはいえない。Such lipoxygenase inhibitory substances include CB, B, which is known as caffeic acid and its methyl ester;
A, 1J2.92 (1984)), but its lipoxygenase inhibitory action cannot be said to be sufficient.
かかる観点から、本発明者らはさらに優れたりポキシケ
ナーゼ阻害作用を存する化合物を得るべく種々研究を重
ねてきたところ、カフェー酸の炭素数３〜５のアルキル
エステル、即ち、一般式（式中、Ｒはハロゲン原子で置
換されていてもよい炭素数３〜１０のアルキルを示す）
で表わされるカフェーＶ誘導体が特に優れたりボキシゲ
ナーゼ阻害作用を有することを見出して本発明を完成す
るに至った。From this point of view, the present inventors have conducted various studies in order to obtain compounds with even better poxykenase inhibitory effects, and have found that alkyl esters of caffeic acid having 3 to 5 carbon atoms, i.e., compounds with the general formula (in the formula R The inventors have completed the present invention by discovering that a caffeine V derivative represented by the following formula (indicates an alkyl group having 3 to 10 carbon atoms which may be substituted with a halogen atom) is particularly effective and has a boxygenase inhibitory effect.
本発明は、カフェー＠誘導体（１）を提供するものであ
る。The present invention provides a Caffe@ derivative (1).
Ｒに関して、炭素数３〜１０のアルキルは、直鎖状、分
岐状のいずれでもよく、たとえばｎ−プロピル、１ｓｏ
−プロピル、ｎ−ブチル、１ｓｏ−ブチル、ｔ−ブチル
、ｎ−ペンチル、ｎ−ヘプチル、ｎ−。Regarding R, the alkyl having 3 to 10 carbon atoms may be linear or branched, such as n-propyl, 1so
-propyl, n-butyl, 1so-butyl, t-butyl, n-pentyl, n-heptyl, n-.
オクチル等が挙げられる。Examples include octyl.
置換基としてのハロゲン原子としては、クロル、ブロム
等があげられ、クロルが特に好ましい。ハロゲンで置換
されたアルキルとしては、例えば、−Ｃｏ−０−（ＣＨ
２）３−ＣＨ２−ＣＡ！−Ｃｏ−０（ＣＨ２）３ ＣＨ
Ｃｊ！２などが挙げられる。Examples of the halogen atom as a substituent include chlorine and bromine, with chlorine being particularly preferred. Examples of alkyl substituted with halogen include -Co-0-(CH
2) 3-CH2-CA! -Co-0(CH2)3CH
Cj! 2 etc.
本発明のカフェー酸誘導体（１）は、たとえばカフェー
酸又はその反応性誘導体をエステル化することによって
製造することが出来る。The caffeic acid derivative (1) of the present invention can be produced, for example, by esterifying caffeic acid or a reactive derivative thereof.
カフェー酸の反応性誘導体としては、たとえば酸ハライ
ド（酸クロライド、酸ブロマイド等）、混合酸無水物（
クロル炭酸エチル、トリエチルアミン等）などがあげら
れる。Examples of reactive derivatives of caffeic acid include acid halides (acid chloride, acid bromide, etc.), mixed acid anhydrides (
Examples include chloroethyl carbonate, triethylamine, etc.).
本反応は、通常のエステル化反応に準じて行われる。即
ち、通常カフェー酸及び所定のアルコールを、好ましく
は酸触媒存在下加熱攪拌させることによって実施される
。This reaction is carried out according to a normal esterification reaction. That is, it is usually carried out by heating and stirring caffeic acid and a specified alcohol, preferably in the presence of an acid catalyst.
反応溶媒としては所定のアルコールを用い、酸触媒とし
てはパラトルエンスルホン酸無水塩酸等が用いられるが
、無水塩酸が望ましい。A predetermined alcohol is used as the reaction solvent, and para-toluenesulfonic acid anhydride or the like is used as the acid catalyst, but anhydrous hydrochloric acid is preferable.
反応温度は８０〜１００℃程度、反応時間は３〜４時間
程度である。The reaction temperature is about 80 to 100°C, and the reaction time is about 3 to 4 hours.
薬理実験Ｊ
モルモットより採取した多形核白血球を酵素源とし、反
応液中に当該酵素と１４Ｇでラベルしたアラキドン酸と
を加えて一定時間反応させ、この反応液中に各種濃度の
各種カフェー酸誘導体（ｊ）を加えた。１４Ｇ−アラキ
ドン酸から５−リボキシゲナーゼにより合成された５Ｉ
４ＥＴＥおよびロイコトリエンＢを薄層クロマトグラフ
ィーにより分離し、そのカウントを測定することによっ
て酵素活性をめ、酵素活性阻害曲線から＋Ｄ５０をめた
。その結果は第１図に示す通りである。Pharmacological Experiment J Using polymorphonuclear leukocytes collected from guinea pigs as an enzyme source, the enzyme and 14G-labeled arachidonic acid were added to the reaction solution and reacted for a certain period of time, and various caffeic acid derivatives at various concentrations were added to the reaction solution. (j) was added. 5I synthesized from 14G-arachidonic acid by 5-riboxygenase
4ETE and leukotriene B were separated by thin layer chromatography, and the enzyme activity was determined by measuring their counts, and +D50 was determined from the enzyme activity inhibition curve. The results are shown in FIG.
薬理実験２
薬理実験１と同様にして、カフェー酸誘導体（Ｉ）の各
種リポキシゲナーゼに対する酵素活性阻害効果を調べ、
その結果をそれぞれ第２〜４図に示した。Pharmacological Experiment 2 In the same manner as Pharmacological Experiment 1, the enzyme activity inhibitory effect of caffeic acid derivative (I) on various lipoxygenases was investigated.
The results are shown in Figures 2 to 4, respectively.
なお、第２図は５−リポキシゲナーゼ（モルモットの多
形核白血球）、第３及び４図は１２−リポキシゲナーゼ
（ヒトの血小板）に対する効果を示すものである。In addition, FIG. 2 shows the effect on 5-lipoxygenase (guinea pig polymorphonuclear leukocytes), and FIGS. 3 and 4 show the effect on 12-lipoxygenase (human platelets).
毒性実験
本発明の化合物のマウスに対する毒性は、いずれも経口
投与でＬＤｓｏ値が１００ ｍｇ／ ｋｇ以上であり、
投与量にくらべて極めて大きく、安今域の広い化合物で
ある。Toxicity experiment The toxicity of the compounds of the present invention to mice is that the LDso value is 100 mg/kg or more when administered orally.
It is a compound that is extremely large compared to the dose and has a wide safety range.
このように、カフェー酸誘導体（１）は、５゛−リポキ
シゲナーゼ阻害作用を有し、ヒト、ウマ、イヌ、モルモ
ット、マウス、ラット等の哺乳動物における生体内での
ロイコトリエン、５−ＨＥＴＥ合成阻害作用を有し、ア
レルギー症、喘息、炎症等の治療・予防剤として有用で
あると考えられる。Thus, the caffeic acid derivative (1) has a 5'-lipoxygenase inhibitory effect, and has an inhibitory effect on leukotriene and 5-HETE synthesis in vivo in mammals such as humans, horses, dogs, guinea pigs, mice, and rats. It is considered to be useful as a therapeutic/preventive agent for allergies, asthma, inflammation, etc.
カフェー酸誘導体（１）は１、適当かつ富用の製薬上許
容されるキャリアとの医薬製剤の形で経口的または非経
口的に投与される。The caffeic acid derivative (1) is administered orally or parenterally in the form of a pharmaceutical formulation with a suitable and commonly used pharmaceutically acceptable carrier.
医薬製剤は錠剤、カプセル剤、散剤、坐剤、注射剤等の
常用の形を取りうる。Pharmaceutical formulations may take conventional forms such as tablets, capsules, powders, suppositories, injections and the like.
カフェー酸誘導体（Ｉ）は、たとえば、経口投与の場合
、通常１０・〜３００ｍｇを１日１回または数回にわた
って投与されるが、年齢、体重、および／または処置す
べき病状の重度や治療に対する反応によりその投与量は
変わりうる。For example, in the case of oral administration, caffeic acid derivative (I) is usually administered at a dose of 10 to 300 mg once or several times a day; The dosage may vary depending on response.
製剤処方例１
カフェー酸プロピルエステル、
カフェー酸ブチルエステル又は
カフェー酸ペンチルエステル ５０ｍｇステアリン酸マ
グネシウム ５０ｍｇ
乳糖 ５０ｍｇ
上記の各成分を配合し、１錠１’５０ｍｇの錠剤を得た
。Formulation Example 1 Caffeic acid propyl ester, caffeic acid butyl ester, or caffeic acid pentyl ester 50 mg Magnesium stearate 50 mg Lactose 50 mg Each of the above components was blended to obtain a tablet weighing 1'50 mg.
実施例１〜３
あらかじめ塩化水素ガスを１０分間程度吹き込んだブタ
ノール５０ｍ１中にカフェー酸２ｇを加える。この混合
物を９０〜１００℃に加熱し、３時間攪拌を行った。反
応生成物を減圧下濃縮し、残留物をクロマトグラフィー
により精製した後、エーテルへキサンより再結晶すると
、カフェー酸ブチルエステル１．４ｇを得た。Examples 1 to 3 2 g of caffeic acid is added to 50 ml of butanol into which hydrogen chloride gas has been blown for about 10 minutes. This mixture was heated to 90-100°C and stirred for 3 hours. The reaction product was concentrated under reduced pressure, the residue was purified by chromatography, and then recrystallized from ether hexane to obtain 1.4 g of caffeic acid butyl ester.
以下、同様の手法によりカフェー酸プロピルエステル、
カフェー酸ペンチルエステルの合成を行った。Hereinafter, caffeic acid propyl ester, caffeic acid propyl ester,
Caffeic acid pentyl ester was synthesized.
Ｂｒ
Ｉ ＲＶ ｍａｘ’
カフェー酸プロピルエステル
３５００、３３００． １６８０． １６０２ ｃｍ−
’カフェー酸ブチルエステル
３４９０、３３２０．１６８２．１６０３ ｃｍ−’カ
フェー酸ペンチルエステル
３５００、３３５０．１６８３．１６０５ ｃｍ ’Br I RV max' Caffeic acid propyl ester 3500, 3300. 1680. 1602 cm-
'Caffeic acid butyl ester 3490, 3320.1682.1603 cm - 'Caffeic acid pentyl ester 3500, 3350.1683.1605 cm'
第１〜４図は、それぞれカフェー酸誘導体（Ｉ）の各種
リポキシゲナーゼに対する酵素活性阻害作用を示すグラ
フである。
第１図
第２図
第３図
円
第４図
手 続 ネ甫 正 書（自発） ６゜
昭和５９年７月２７日
特許庁長官 殿
昭和５９年特許願第１０４９９８号
２、発明の名称
カフェー酸誘導体
３、補正をする者
事件との関係 特許出願人
氏名（名称） 株式会社 ミドリ十字
４、代理人 ■５４１
住 所 大阪市東区平野町４丁目５３番地３ニューライ
フ平野町４０６号
電話（０６） ２２７−１１５６
明細書の１発明の詳細な説明」の欄
）、
補正の内容
（１１明細書第５頁、第１行の「アラキドン酸と」の次
に「各種濃度の各種カフェー酸誘導体’（Ｉ）Ｊを加入
する。
（２）同書第５頁、第１行の「させ、」を「させた。」
に訂正する。
（３）同書第５頁、第１〜３行の「この反応液中に各種
濃度の各種カフェー酸誘導体（Ｉ）を加えた。」を削除
する。Figures 1 to 4 are graphs showing the enzyme activity inhibitory effect of caffeic acid derivative (I) on various lipoxygenases. Figure 1 Figure 2 Figure 3 Circle Figure 4 Procedure Written by Masaru Nebo (spontaneous) 6゜July 27, 1980 Director General of the Patent Office Patent Application No. 104998 2, Name of the Invention: Caffeic Acid Derivative 3, relationship with the amended person case Patent applicant name Midori Juji Co., Ltd. 4, agent ■541 Address 406 New Life Hirano-cho, 4-53-3 Hirano-cho, Higashi-ku, Osaka Telephone (06) 227-1156 "Detailed Description of the Invention" column in the specification), contents of the amendment (11, page 5, line 1 of the specification, next to "arachidonic acid""various caffeic acid derivatives at various concentrations" ( I) Add J. (2) On page 5, line 1 of the same book, "Let" is replaced with "Let".
Correct. (3) Delete "Various concentrations of various caffeic acid derivatives (I) were added to this reaction solution." from lines 1 to 3 on page 5 of the same book.
Claims (1)
数３〜１０のアルキルを示す） で表わされるカフェー酸誘導体。[Scope of Claims] A caffeic acid derivative represented by the general formula (wherein R represents an alkyl having 3 to 10 carbon atoms which may be substituted with a halogen atom).
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10499884A JPS60248645A (en) | 1984-05-23 | 1984-05-23 | Caffeic acid derivative |
| KR1019850003513A KR870002016B1 (en) | 1984-05-23 | 1985-05-22 | Process for preparation of substituted styrene derivatives |
| ES544108A ES8705840A1 (en) | 1984-05-23 | 1985-05-23 | 5-Lipoxygenase inhibitors for treating asthma and inflammation |
| EP91111945A EP0466198A1 (en) | 1984-05-23 | 1985-05-23 | A lipoxygenase inhibitor |
| EP85106390A EP0163270A3 (en) | 1984-05-23 | 1985-05-23 | A lipoxygenase inhibitor |
| EP91111944A EP0466197A1 (en) | 1984-05-23 | 1985-05-23 | A lipoxygenase inhibitor |
| EP91111943A EP0464858A1 (en) | 1984-05-23 | 1985-05-23 | A lipoxygenase inhibitor |
| US06/737,005 US4733002A (en) | 1984-05-23 | 1985-05-23 | Lipoxygenase inhibitor |
| EP91111977A EP0464859A1 (en) | 1984-05-23 | 1985-05-23 | A lipoxygenase inhibitor |
| CN198585104804A CN85104804A (en) | 1984-05-23 | 1985-06-19 | The method for preparing substituted styrene derivative |
| ES557441A ES8801540A1 (en) | 1984-05-23 | 1987-03-13 | 5-Lipoxygenase inhibitors for treating asthma and inflammation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10499884A JPS60248645A (en) | 1984-05-23 | 1984-05-23 | Caffeic acid derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS60248645A true JPS60248645A (en) | 1985-12-09 |
Family
ID=14395764
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10499884A Pending JPS60248645A (en) | 1984-05-23 | 1984-05-23 | Caffeic acid derivative |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS60248645A (en) |
| CN (1) | CN85104804A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5216024A (en) * | 1987-07-28 | 1993-06-01 | Baylor College Of Medicine | Cell growth inhibitors and methods of treating cancer and cell proliferative diseases |
| JPH1192410A (en) * | 1997-09-25 | 1999-04-06 | Naohiko Sato | Antioxidatively active substance |
| DE10215055A1 (en) * | 2002-04-03 | 2003-10-30 | Univ Schiller Jena | Antiinflammatory or pre-neoplastic lesion inhibiting medicaments containing caffeic acid triterpene or sterol esters having radical scavenging action, also useful in cosmetic or nutraceutical compositions |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103936577A (en) * | 2013-01-18 | 2014-07-23 | 北京大学 | Preparation method of E-3,4-dihydroxyphenylvinyl ketone and application thereof as nerve protection drug |
-
1984
- 1984-05-23 JP JP10499884A patent/JPS60248645A/en active Pending
-
1985
- 1985-06-19 CN CN198585104804A patent/CN85104804A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5216024A (en) * | 1987-07-28 | 1993-06-01 | Baylor College Of Medicine | Cell growth inhibitors and methods of treating cancer and cell proliferative diseases |
| JPH1192410A (en) * | 1997-09-25 | 1999-04-06 | Naohiko Sato | Antioxidatively active substance |
| DE10215055A1 (en) * | 2002-04-03 | 2003-10-30 | Univ Schiller Jena | Antiinflammatory or pre-neoplastic lesion inhibiting medicaments containing caffeic acid triterpene or sterol esters having radical scavenging action, also useful in cosmetic or nutraceutical compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| CN85104804A (en) | 1986-12-17 |
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