JPS5953477A - Coumarin derivative - Google Patents
Coumarin derivativeInfo
- Publication number
- JPS5953477A JPS5953477A JP57164337A JP16433782A JPS5953477A JP S5953477 A JPS5953477 A JP S5953477A JP 57164337 A JP57164337 A JP 57164337A JP 16433782 A JP16433782 A JP 16433782A JP S5953477 A JPS5953477 A JP S5953477A
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Abstract
Description
【発明の詳細な説明】
本発明は、蛇床子に含まれている新規なりマリン誘導体
に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel marine derivative contained in japonica.
蛇床子は、古く神農本草経に収載されている生薬であり
、収れん性消炎薬として使用2されてきているが、その
有効成分は不明であり、有効性自体も薬理学的には積極
的に証明されていない。Snake beetroot is a herbal medicine that has long been listed in the Shennong Bencaojing, and has been used as an astringent anti-inflammatory2, but its active ingredients are unknown, and its effectiveness itself has not been evaluated pharmacologically. Not proven.
本発明者は、天然物から抗アレルギー作用を有する成分
を取り出すことを目的に数多くの実験をおこなううち、
蛇床子のメタノール抽出エキスが軽做ながらも抗アレへ
・キー作用を有するとの知見を得、更に研究の結果、抗
アレルギー作用を有する成分として、下記の新規なりマ
リン誘導体に到CH,−CH= CCCJI、 )2
本発明は、上式の化合物中、比較的構造が互いに類似す
る、(1)式の化合物と(1)式の化合物に係るもので
ある。The present inventor conducted numerous experiments with the aim of extracting components with anti-allergic effects from natural products.
We found that the methanol extract of Jatoko has a mild but key anti-allergic effect, and as a result of further research, we discovered the following new marine derivatives as ingredients with anti-allergic effects: CH, -CH = CCCJI, )2 The present invention relates to a compound of formula (1) and a compound of formula (1), which have relatively similar structures among the compounds of the above formula.
蛇床子から(1)式の化合物及び(1)式の化合物を得
るだめには、蛇床子にアルコール類を抽出溶媒とする常
用の抽出処理を施して抽出エキスを得、次いでこの抽出
エキスを薄層クロマトグラフィーを併用しなからカラム
クロマトグラフィーによって分画して主にクマリン誘導
体を含む分画を得る。In order to obtain the compound of formula (1) and the compound of formula (1) from japonica, the japonica is subjected to a conventional extraction process using alcohol as an extraction solvent to obtain an extract, and then this extracted extract is diluted. Fractionation is performed by column chromatography in combination with layer chromatography to obtain a fraction containing mainly coumarin derivatives.
このクマリン誘導体を主とl−で含む分画には、本発明
の化合物である(1)式の化合物、(1)式の化合νす
の他、前述の(1)式の化合物やこれら新規化合物に構
造的に類似する既知の下式(ff)の化合物が混在して
いるが、
引きRき前記クマリン誘導体を主として含む分画を、薄
層クロマトグラフィーを併用しなからカラムクロマトグ
ラフィーによって分画すれば本発明の化合物−(員)式
の化合物及び(1式の化合物−と、(I)式の化合物と
、(II’)式の化合物とを分取することかでやきる。In addition to the compound of the formula (1) and the compound of the formula (1), which are the compounds of the present invention, the fraction containing mainly l-coumarin derivatives includes the above-mentioned compound of the formula (1) and these novel compounds. Although a known compound of the formula (ff) structurally similar to the compound is present, the fraction mainly containing the coumarin derivative was separated by column chromatography rather than by thin layer chromatography. This can be done by separating the compound of the present invention - the compound of formula (member) and the compound of formula (1), the compound of formula (I), and the compound of formula (II').
蛇床子中の(員)式の化合物と(1)式の化合物とは、
これらを完全に分離して得るよりも、混合物として得る
方が容易であり、また、本発明の化合物を抗アレルギー
剤の有効成分として用いるに際lノCも、(1)式の化
合物と(1)式の化合物の混合物を用いたからといって
何ら薬理的に不都合は生じない。The compound of formula (member) and the compound of formula (1) in Jaboko are:
It is easier to obtain these as a mixture than to obtain them completely separated, and when the compound of the present invention is used as an active ingredient of an antiallergic agent, the compound of formula (1) and ( 1) The use of a mixture of compounds of the formula does not cause any pharmacological disadvantage.
従って、蛇床子を原料として本発明の化合物を得、これ
を抗アレルギー剤の有効成分と1−で用いる場合には、
むしろ(1)式の化合物と(1)式の化合物とは分離す
ることなく混合物として得、これを抗アレルギー剤の有
効成分として用いる方が得策である。Therefore, when the compound of the present invention is obtained using Jatoko as a raw material and is used together with the active ingredient of an antiallergic agent,
Rather, it is better to obtain the compound of formula (1) and the compound of formula (1) as a mixture without separation, and use this mixture as an active ingredient of an antiallergic agent.
その際の有効成分換算での投与量は、前者の単独化合物
を用いた抗アレルギー剤と後者の混合物を用いた抗アレ
ルギー剤とでは同様に設定すtLばよい。In this case, the dosage in terms of active ingredient may be set in the same way for the former anti-allergic agent using a single compound and the latter anti-allergic agent using a mixture.
以下、本発明を製造例、薬理試験例、毒性試験例等によ
り史に具体的に説明する。Hereinafter, the present invention will be explained in detail with reference to production examples, pharmacological test examples, toxicity test examples, etc.
製造例
1)市販の中国産蛇床子を粗粉末化した後、これを50
%メタノール水溶液で3回温浸し、メタノールエキスを
得た。Production example 1) After coarsely powdering a commercially available china beetroot, it was
% methanol aqueous solution three times to obtain a methanol extract.
2)上記で得たメタノールエキスを水−n−ブタノール
とともに振盪1〜、n−ブタノール層に移行した成分を
、シリカゲルを吸着剤とし、ベンゼン蓚アセトン50:
1→5:1を溶出溶媒としてカラムクロマトグラフィー
にかけ、ベンゼン;アセトン4:1を8ジ開溶媒とする
薄層クロマトグラフィーで」一方に現われるスポットの
成分から順に分画して分画■(収率4.5%)、分画菖
(Ily率522%)、分画厘(収率4.0%)、分画
■(収率39.5%)を得た。2) The methanol extract obtained above was shaken with water-n-butanol. The components transferred to the n-butanol layer were mixed with benzene/acetone 50% using silica gel as an adsorbent.
1 → 5:1 as an eluent, and thin layer chromatography using benzene:acetone as an 8-di opening solvent. A fraction (Ily yield: 4.5%), a fraction (Ily yield: 522%), a fraction (yield: 4.0%), and a fraction - (yield: 39.5%) were obtained.
5)上記で得た分画125.98Fを、シリカゲルを吸
着剤とし、n−ヘキサン:酢酸エチ/L/4:1→2:
1を溶出溶媒とする薄層クロマトグラフィーで上方に現
われるスポットの成分から順に分画し、メ第1図〜第4
図は、順に(ff)式の化合物、(1)式の化合物、(
厘)式の化合物、(1)式の化合物のNMRスヘクトル
を、第5図〜第8図はMASBスペクトル(BASS
PEAK i第5図M/B 2440工NT 234.
4、第6図M/m 202.0工NT 715.3、第
7図M/’lRi 19Q、QINT 204.5、第
8図M/l!! 43.0工NT 422.7)を示す
。5) Fraction 125.98F obtained above was mixed with n-hexane:ethyl acetate/L/4:1→2: using silica gel as an adsorbent.
1 as an elution solvent.
The figure shows, in order, a compound of formula (ff), a compound of formula (1), and (
Figures 5 to 8 show the NMR spectra of the compound of formula (Rin) and the compound of formula (1).
PEAK iFigure 5 M/B 2440 NT 234.
4, Fig. 6 M/m 202.0 Engineering NT 715.3, Fig. 7 M/'lRi 19Q, QINT 204.5, Fig. 8 M/l! ! 43.0 engineering NT 422.7).
薬理試験例
1)遅延型皮膚炎に対する効果
体重21前後のBDF、系雄性マウスを1群Il1匹と
し、アレルギー反応惹起物として塩化ピクリルを用いて
実験をおこなった。すなわち、7%塩化ピクリルエタノ
ール溶液を刺毛したマウスの腹部に塗布し、第1回目の
感作をおこない、その後直ちに、蒸留水にとかした被検
薬物を1日2回lO日間経口投与した。Pharmacological Test Example 1) Effect on Delayed Dermatitis An experiment was conducted using picryl chloride as an allergic reaction inducer using 1 group of male BDF mice weighing around 21 mm. That is, a 7% picrylic chloride ethanol solution was applied to the abdomen of a mouse with prickly hair to perform the first sensitization, and immediately thereafter, the test drug dissolved in distilled water was orally administered twice a day for 10 days. .
被検薬物の投与量は次の通りである。The dosage of the test drug was as follows.
ルl造例ノ2)ノ分画1;1100rnΔを分画1 ;
250mfA
分画■;100噌AQ
分iJj y ; 250m1AQ
薬効の判定は、1%塩化ピクリルオリーブ油溶液をマウ
スの両耳にぬり、反応直前及び反応後12.1B、24
並ひに36時間後の1%塩化ピクリル塗布によって惹起
した反旗炎の程度をダイアルシックスゲージ(PEAC
OK−G型、尼崎製作所)で測定することによりおこな
った。Example 2) Fraction 1; Fraction 1 of 1100rnΔ;
250mfA fraction ■; 100ml AQ min iJj y ; 250m1AQ To determine the medicinal efficacy, apply a 1% chlorinated picryl olive oil solution to both ears of a mouse, and immediately before the reaction and after the reaction 12.1B, 24
After 36 hours, the degree of antiflag inflammation caused by applying 1% picryl chloride was measured using a dial six gauge (PEAC).
The measurement was carried out using an OK-G model (Amagasaki Seisakusho).
その結果は第9図に示す通りであり、製造例2)の分画
口図中1の浮腫曲線)及び分画l(図中2の浮腫曲線)
に特に効果がみられた。The results are as shown in Figure 9, and are the edema curve of fraction 1 in the diagram of production example 2) and the edema curve of fraction 1 (edema curve of 2 in the diagram).
Particularly effective was seen.
製造例の2)の分画lについては、被検薬物としての投
与量を550m1〆qとし、上記と同様の試験をおこな
ったところ、第11)図の結果を得た。Regarding fraction 1 of Production Example 2), the same test as above was conducted using a dose of 550 ml as a test drug, and the results shown in Figure 11) were obtained.
更に、製造例の3)の化合物についても、被検薬物とし
ての投与量を100rnlA9とし、上記と同様の試験
をおこなった。比較のため、製造例の2)の分画lにつ
いては、投与量を1oorrnAqとし、再び試験をお
こなった。Furthermore, for the compound of Production Example 3), the same test as above was conducted using a dose of 100rnlA9 as a test drug. For comparison, for fraction 1 of Production Example 2), the test was conducted again at a dose of 1 oorrnAq.
その結果は、第11図に示す通りであり、製造例の2)
の分l!!!Il(図中2の浮腫曲線)及び製造例の3
)の(1)式の化合物(図中6の浮腫曲線)に特に効果
がみられ、i!I!!造例の3)の(1)式の化合物(
図中7の浮腫曲線)及び(1)式の化合物(図中8の浮
ル1【曲線)に前者よりも弱いが、明らかな効果が観察
された。製造例の3)の(IV)式の化合物(図中5の
浮腫曲線)は効果が殆んど認められなかった。The results are as shown in Figure 11, and are shown in Production Example 2)
Minute l! ! ! Il (edema curve 2 in the figure) and Production Example 3
), the compound of formula (1) (edema curve 6 in the figure) was particularly effective, and i! I! ! The compound of formula (1) in Example 3) (
A clear effect, although weaker than the former, was observed for the compound of formula (1) (edema curve 7 in the figure) and edema curve 1 (curve 8 in the figure). In Production Example 3), the compound of formula (IV) (edema curve 5 in the figure) had almost no effect.
2)モルモツ) PCA反応に対する効果抗血清の作成
法逼 牛111清アルブミン(BSA)を2優の割合で
生理食塩水にとかし、これにフロイントのコンブリート
アジエバンドを1:1の割合で十分に乳化混合し1、体
重300g前後の雄性モルモットをエーテルで軽く麻酔
し、前記乳1@液を前後の足肥計4ケ所に0.11妙\
皮下注躬した。この注射の後、300回目背部に2ケ所
0.1mlづ\前述同様抗原BSAを注射し、2回目の
感作ζしt:。2回目のべ
作後14日目に全血を採血し、血清を得、とのものを抗
BSA血清として以下の実験に使用した。2) Effect on PCA reaction Method for preparing antiserum Dissolve bovine 111 serum albumin (BSA) in a ratio of 2 parts in physiological saline, and add enough Freund's Combrete Azierband in a ratio of 1:1. Emulsify and mix 1. A male guinea pig weighing around 300 g was lightly anesthetized with ether, and the milk 1 solution was applied to a total of 4 sites on the front and back legs at 0.11 μm.
Injected subcutaneously. After this injection, the antigen BSA was injected into the back for the 300th time in two places with 0.1 ml in the same manner as described above, and the second sensitization was carried out. On the 14th day after the second cropping, whole blood was collected to obtain serum, which was used as anti-BSA serum in the following experiments.
実験方法; 実験前日に電気バリカンで刺毛した体重3
00g前後のハートレー系雄性モルモットを1群5匹と
し、被検薬物を経口投与後直ちに、背部に前記抗血清希
釈液を0.1m13ケ所に皮肉注射した。注射後3時間
目に抗原であるBSA O,2チ生理食塩水溶液o、5
肩l及びエパンスブ1v−5%生理食塩水溶液O,S
鰐tを混じ、前足静脈より注射する。静脈に注射後30
分に放血致死させ、背部の皮膚を剥離する。皮膚に惹起
された色素斑の面積により抗アレルギー作用の程度をプ
ラニメーターで面積を求め判定した。その結果を第1表
に示した。Experiment method: Hair pricked with electric clippers on the day before the experiment 3
Immediately after oral administration of the test drug to a group of 5 male Hartley guinea pigs weighing approximately 0.00 g, the diluted antiserum was injected subcutaneously into the back at 13 locations of 0.1 m. 3 hours after injection, the antigen BSA O, 2 and physiological saline solution O, 5
Shoulder l and Epansub 1v-5% physiological saline solution O,S
Mix it with crocodile t and inject it through the front leg vein. 30 minutes after intravenous injection
Bleed to death for a minute and peel off the skin on the back. The degree of anti-allergic effect was determined based on the area of pigment spots induced on the skin using a planimeter. The results are shown in Table 1.
口
第1表から明らかなQlく、比牝′5対照薬であるプレ
ドニゾロンに比較しゃ−弱いが、製造例の2)の分11
111にはPCA反応抑制効果が明らかにiHめられた
。まだ、9;!!造例の1)のツクノールエキスも有〃
フであった。It is clear from Table 1 that the QI is weak compared to prednisolone, which is a control drug, but it is still as good as 11 in production example 2).
111 was clearly shown to have a PCA reaction inhibitory effect. Still, 9;! ! We also have the tsukunor extract in example 1).
It was f.
急性母性試験
体重1B −20fの直系雄性マウスを1群15匹とし
て被検薬物の経口投与後3日間の致死穀からLD5oを
求めた。その結果は第2表の通りであった。Acute Maternal Test LD5o was determined from lethal grains 3 days after oral administration of the test drug using 15 lineal male mice weighing 1B-20f per group. The results were as shown in Table 2.
第 2 表
以上の結果から、本発明の化合物である(1)式の化合
物及び(■)式の化合物は、1回400〜600哩、1
日2〜3回の服用で、成人のアレルギー治療に有効と推
定される。特に本発明の化合物は、(り式の化合物との
調合において、顕著な抗アレルギー剤としての効果を発
揮するものと考えられ、その際には分画(璽)または(
1)式の化合物からなる抗アレルギー剤の投与量である
、1回200〜300哩、1日2〜3回の服用、よりも
更に少量の服用で成人のアレルギー治療に有効な、抗ア
レルギー剤となしうるものと推定される。From the results shown in Table 2, it can be seen that the compounds of the formula (1) and the compound of the formula (■), which are the compounds of the present invention, can be used for 400 to 600 m/d, 1
It is estimated to be effective in treating allergies in adults when taken two to three times a day. In particular, the compound of the present invention is thought to exhibit remarkable antiallergic effects when formulated with a compound of formula (2).
1) An anti-allergic agent that is effective for treating allergies in adults when taken in smaller doses than the anti-allergic agent consisting of the compound of formula 200-300 mt/dose, 2-3 times a day. It is estimated that this can be achieved.
以下、更に(1)式の化合物を用いる場合の製剤例を挙
げる。Below, further examples of formulations in which the compound of formula (1) is used are given.
(1)式の化合物をパレイシ書デンプンとよく混合し、
水を加えて練合する。1jIJl×1MMの網目を有す
るスクリーンで造粒して、顆粒状とする。乾燥後&16
メツシー(B、$・)の篩で整粒する。次にこの顆粒を
ステアリン酸マグネシウムと混和し、打錠機で1T30
0暉の錠剤と1〜だ。A compound of formula (1) is thoroughly mixed with Paleisi starch,
Add water and mix. The mixture is granulated using a screen having a mesh size of 1JIJl x 1MM to form granules. After drying &16
Sort the particles using a Metsushi (B, $.) sieve. Next, the granules were mixed with magnesium stearate and 1T30
There are 0 tablets and 1~.
第1図〜第4図は、順に(IV)式の化合物、(■)式
の化合物、(曹)式の化合物、膏式の化合物のNMRス
ペクトルを、第5〜第8図はMA8Bスペクトルを示す
。
第9図〜第11図は、遅延型反省炎(塩化ピクリルによ
る)に対する試験結果を示すグラフであり、図中の符号
中、10は盲検群の浮腫曲線を、加は対照群の浮腫曲線
を意味する。またその能の符号は次の通りの意味を有す
る。
第9図における符号の意味
1;製造例の2)の分画1 (10o#、4Lj投与)
の浮腫曲線2N I 分画1(250躯kq投与
) 13N I 分画I(100mg/に9
投与) 14; l 分画IV(2501q投
与) #第1+1図における符号の意味
2;製造例の2)の分画l (350ml/b投与)の
浮腫曲線第11図における符号の意味
特許出願人
(財)生産開イd科叩′研究所Figures 1 to 4 show the NMR spectra of the compound of the formula (IV), the compound of the formula (■), the compound of the formula (sulfur), and the compound of the plaster formula, and Figures 5 to 8 show the MA8B spectra. show. Figures 9 to 11 are graphs showing the test results for delayed-type relapsing inflammation (due to picryl chloride). In the figures, 10 indicates the edema curve of the blind group, and 10 indicates the edema curve of the control group. means. Also, the sign of the ability has the following meaning. Meaning of symbols in FIG. 9 1; Fraction 1 of 2) of Production Example (10o#, 4Lj administration)
Edema curve of 2N I fraction 1 (250 kgq administration) 13N I fraction I (9 in 100 mg/kg)
Administration) 14; l Fraction IV (2501q administration) #Meaning of the symbols in Figure 1+1 2; Edema curve of fraction l (350ml/b administration) of Production Example 2) Meaning of the symbols in Figure 11 Patent applicant Research Institute for Production Development
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP57164337A JPS5953477A (en) | 1982-09-20 | 1982-09-20 | Coumarin derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP57164337A JPS5953477A (en) | 1982-09-20 | 1982-09-20 | Coumarin derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS5953477A true JPS5953477A (en) | 1984-03-28 |
Family
ID=15791250
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP57164337A Pending JPS5953477A (en) | 1982-09-20 | 1982-09-20 | Coumarin derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5953477A (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6115834A (en) * | 1984-07-02 | 1986-01-23 | Osaka Chem Lab | Antiallergic food |
JPH01100020U (en) * | 1987-12-24 | 1989-07-05 | ||
US5444042A (en) * | 1990-12-28 | 1995-08-22 | Cortex Pharmaceuticals | Method of treatment of neurodegeneration with calpain inhibitors |
EP1486213A4 (en) * | 2002-02-27 | 2006-04-26 | Liping Yang | The use of the total coumarins of cnidium monnieri in preparation of the medicament for treating psoriasis |
KR100792613B1 (en) | 2005-10-25 | 2008-01-09 | 경북대학교 산학협력단 | Methods for increasing coumarin and scopoletin contents in Artemisia Capillaris, and the method for extraction of coumarin and scopoletin having increased contents |
-
1982
- 1982-09-20 JP JP57164337A patent/JPS5953477A/en active Pending
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6115834A (en) * | 1984-07-02 | 1986-01-23 | Osaka Chem Lab | Antiallergic food |
JPH01100020U (en) * | 1987-12-24 | 1989-07-05 | ||
US5444042A (en) * | 1990-12-28 | 1995-08-22 | Cortex Pharmaceuticals | Method of treatment of neurodegeneration with calpain inhibitors |
EP1486213A4 (en) * | 2002-02-27 | 2006-04-26 | Liping Yang | The use of the total coumarins of cnidium monnieri in preparation of the medicament for treating psoriasis |
US8124133B2 (en) | 2002-02-27 | 2012-02-28 | Liping Yang | Use of the total coumarins of Cnidium monnieri in preparation of the medicament for treating psoriasis |
KR100792613B1 (en) | 2005-10-25 | 2008-01-09 | 경북대학교 산학협력단 | Methods for increasing coumarin and scopoletin contents in Artemisia Capillaris, and the method for extraction of coumarin and scopoletin having increased contents |
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