JP2577215B2 - Benzyl isoquinoline derivative - Google Patents
Benzyl isoquinoline derivativeInfo
- Publication number
- JP2577215B2 JP2577215B2 JP62006205A JP620587A JP2577215B2 JP 2577215 B2 JP2577215 B2 JP 2577215B2 JP 62006205 A JP62006205 A JP 62006205A JP 620587 A JP620587 A JP 620587A JP 2577215 B2 JP2577215 B2 JP 2577215B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- benzyloxy
- formula
- acid
- methoxy
- 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.)
- Expired - Lifetime
Links
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- Other In-Based Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 本発明は、新規なベンジルイソキノリン誘導体に関す
る。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel benzylisoquinoline derivatives.
つづらふじ科その他の植物に含まれるビスベンジルイ
ソキノリン系アルカロイド、例えばセフアランチン、ベ
ルバミン、テトランドリン等が血小板凝集抑制作用を有
することは知られている（セル・ストラクチヤー・アン
ド・フアンクシヨン第６巻263〜267頁1981年参照）。特
にセフアランチンの血小板凝集抑制作用については臨床
的にも検討されており、その力価は10余種の抗血小板凝
集剤の中でほぼ中間に位置すると報告されている（基礎
と臨床第16巻291頁1982年参照）。しかしセフアランチ
ンはつづらふじ科植物から抽出されるもので、原料植物
の制約から大量生産が困難である。セフアランチンの合
成法も知られているが、この方法は工程が長く、工業的
実施には不適当である。本発明者らは、構造のより簡単
な単一ベンジルイソキノリン誘導体を創製し、これらの
化合物が優れた血小板凝集抑制作用を有することを見出
した。It is known that bisbenzylisoquinoline-based alkaloids, such as cepharanthin, berbamine, tetrandrine, etc., contained in plants of the family Aphididae and other plants have a platelet aggregation inhibitory action (Cell Structure and Function Vol. 6, 263-267). 1981). In particular, the inhibitory effect of cepharanthin on platelet aggregation has been studied clinically, and its titer is reported to be approximately in the middle of more than 10 anti-platelet aggregating agents (Basic and Clinical Volume 16, 291 1982). However, cefalanthin is extracted from a spellfish plant, and it is difficult to mass-produce it due to the limitation of a raw material plant. Although a method for synthesizing cepharanthin is also known, this method has long steps and is unsuitable for industrial practice. The present inventors have created single benzyl isoquinoline derivatives having a simpler structure, and found that these compounds have an excellent platelet aggregation inhibitory action.
本発明は、一般式 （式中Ｒは水素原子又はメチル基、R1とR2及びR3とR4は
それぞれ一方が水素原子、他方がベンジルオキシ基を示
し、ただしR2及びR3がベンジルオキシ基であり、かつＲ
が水素原子である場合を除く）で表わされるベンジルイ
ソキノリン誘導体である。The present invention has the general formula (Wherein R is a hydrogen atom or a methyl group, R 1 and R 2 and R 3 and R 4 are each a hydrogen atom and the other is a benzyloxy group, provided that R 2 and R 3 are a benzyloxy group, And R
Excluding the case where is a hydrogen atom).
式Ｉの化合物は、文献未載の新規化合物であつて、優
れた血小板凝集抑制作用を有し、抗血小板凝集剤として
有用である。The compound of the formula I is a novel compound which has not been described in the literature, has an excellent platelet aggregation inhibitory action, and is useful as an antiplatelet aggregation agent.
式Ｉの化合物は下記の方法により製造することができ
る。置換基Ｒが水素原子である式Ｉの化合物は、一般式 （式中の各記号は前記の意味を有する）で表わされる化
合物にオキシ塩化燐を作用させたのち、還元することに
より得られる。Compounds of formula I can be prepared by the following methods. Compounds of the formula I in which the substituent R is a hydrogen atom have the general formula (Each symbol in the formula has the same meaning as described above), which is obtained by allowing phosphorus oxychloride to act on the compound and reducing the compound.
式IIの化合物は、次式 （式中の各記号は前記の意味を有する）で表わされる化
合物を、一般式 （式中R3及びR4は前記の意味を有し、Ｘはハロゲン原子
又は水酸基を示す）で表わされる化合物と反応させるこ
とにより得られる。Compounds of formula II have the formula (Wherein each symbol has the meaning described above), a compound represented by the general formula (Wherein R 3 and R 4 have the above-mentioned meanings, and X represents a halogen atom or a hydroxyl group).
式IIの化合物とオキシ塩化燐との反応は溶媒中で行う
ことが好ましい。溶媒としては例えばベンゼン、トルエ
ン、キシレン等が用いられる。反応温度は80〜130℃好
ましくは80〜90℃である。反応は通常２〜４時間で終了
する。The reaction of the compound of formula II with phosphorus oxychloride is preferably carried out in a solvent. As the solvent, for example, benzene, toluene, xylene and the like are used. The reaction temperature is from 80 to 130 ° C, preferably from 80 to 90 ° C. The reaction is usually completed in 2 to 4 hours.
反応終了後、反応生成物を還元すると、Ｒが水素原子
である式Ｉの化合物が得られる。還元法としては接触還
元法、還元剤例えばシアノ水素化硼素ナトリウムを用い
る方法などがあげられる。After completion of the reaction, the reaction product is reduced to obtain a compound of the formula I wherein R is a hydrogen atom. Examples of the reduction method include a catalytic reduction method and a method using a reducing agent such as sodium cyanoborohydride.
Ｒがメチル基である式Ｉの化合物は、Ｒが水素原子で
ある式Ｉの化合物にホルムアルデヒドを作用させたの
ち、還元することにより得られる。A compound of the formula I in which R is a methyl group is obtained by reacting a compound of the formula I in which R is a hydrogen atom with formaldehyde and then reducing the compound.
Ｒが水素原子である式Ｉの化合物とホルムアルデヒド
との反応は、溶媒例えばメタノール、エタノール、水な
どの存在下に行われる。本反応は室温で行うことができ
る。反応生成物の還元法としては前記の方法が用いられ
る。The reaction of the compound of formula I wherein R is a hydrogen atom with formaldehyde is carried out in the presence of a solvent such as methanol, ethanol, water and the like. This reaction can be performed at room temperature. The above-mentioned method is used as a method for reducing the reaction product.
式Ｉの化合物は常法により酸付加塩に導くことができ
る。酸としては生理的に無害な酸例えば塩酸、硫酸、燐
酸等の無機酸、酢酸、フマル酸、りんご酸、くえん酸、
こはく酸等の有機酸が好ましい。The compounds of the formula I can be converted into acid addition salts by customary methods. As the acid, physiologically harmless acids such as hydrochloric acid, sulfuric acid, inorganic acids such as phosphoric acid, acetic acid, fumaric acid, malic acid, citric acid,
Organic acids such as succinic acid are preferred.
製造例１ ２−ベンジルオキシ−３−メトキシ−β−フエネチル
アミン2g、ジクロルメタン100ml及び10％NaOH水溶液40m
lの混合物中に２−ベンジルオキシフエニル酢酸2g及び
塩化チオニル2mlより製造した酸塩化物を氷冷下に滴下
する。室温で30分間攪拌したのち、ジクロルメタン層を
水洗し、乾燥すると、Ｎ−（２−ベンジルオキシ−３−
メトキシフエネチル）−２−（２−ベンジルオキフエニ
ル）アセトアミド3.6gが得られる。このアミド3.6gにベ
ンゼン100ml及びオキシ塩化燐6mlを加え、２時間加熱攪
拌する。次いで室温に放冷したのち、減圧下にベンゼン
及びオキシ塩化燐を留去し、残留物をメタノール100ml
に溶解する。この溶液にシアノ水素化硼素ナトリウム1.
0gを加え、室温で３時間還元する。メタノールを留去し
たのち、５％アンモニア水50mlを加え、酢酸エチル100m
lで２回抽出し、抽出液を水洗したのち乾燥すると、５
−ベンジルオキシ−６−メトキシ−1,2,3,4−テトラハ
イドロ−１−（２−ベンジルオキシベンジル）−イソキ
ノリン1.5gが得られる。この化合物を塩酸で処理したの
ち酢酸エチル−エーテルから再結晶すると、無色結晶性
粉末として塩酸塩が得られる。融点192〜194℃。Production Example 1 2 g of 2-benzyloxy-3-methoxy-β-phenethylamine, 100 ml of dichloromethane, and 40 m of a 10% aqueous NaOH solution
The acid chloride prepared from 2 g of 2-benzyloxyphenylacetic acid and 2 ml of thionyl chloride is added dropwise to the mixture of 1 under ice-cooling. After stirring at room temperature for 30 minutes, the dichloromethane layer was washed with water and dried to give N- (2-benzyloxy-3-
3.6 g of (methoxyphenethyl) -2- (2-benzyloxyphenyl) acetamide are obtained. To 3.6 g of this amide are added 100 ml of benzene and 6 ml of phosphorus oxychloride, and the mixture is heated and stirred for 2 hours. Then, after allowing to cool to room temperature, benzene and phosphorus oxychloride were distilled off under reduced pressure, and the residue was treated with 100 ml of methanol.
Dissolve in To this solution sodium cyanoborohydride 1.
Add 0 g and reduce at room temperature for 3 hours. After distilling off methanol, 50 ml of 5% aqueous ammonia was added, and 100 ml of ethyl acetate was added.
l, extract twice, wash the extract with water and dry it.
1.5 g of -benzyloxy-6-methoxy-1,2,3,4-tetrahydro-1- (2-benzyloxybenzyl) -isoquinoline are obtained. This compound is treated with hydrochloric acid and then recrystallized from ethyl acetate-ether to give the hydrochloride as a colorless crystalline powder. Mp 192-194 ° C.
製造例２ 製造例１で得られた５−ベンジルオキシ−６−メトキ
シ−1,2,3,4−テトラハイドロ−１−（２−ベンジルオ
キシベンジル）−イソキノリン0.2g、メタノール10ml及
び37％ホルマリン水溶液1mlの混合物を室温で16時間攪
拌する。次いで水素化硼素ナトリウム1gを徐々に加え、
室温で30分間攪拌したのち、2N塩酸を加えて過剰の水素
化硼素ナトリウムを分解し、減圧下にメタノールを留去
する。残留物に2N−NaOH水50mlを加え、ジエチルエーテ
ル50mlで３回抽出し、抽出液を水洗したのち乾燥する
と、５−ベンジルオキシ−６−メトキシ−1,2,3,4−テ
トラハイドロ−１−（２−ベンジルオキシベンジル）−
２−メチルイソキノリン0.1gが得られる。この化合物の
塩酸塩は無色板状晶であり、融点は185℃（分解）であ
る。Production Example 2 0.2 g of 5-benzyloxy-6-methoxy-1,2,3,4-tetrahydro-1- (2-benzyloxybenzyl) -isoquinoline obtained in Production Example 1, 10 ml of methanol and 37% formalin The mixture of 1 ml of the aqueous solution is stirred at room temperature for 16 hours. Then, slowly add 1 g of sodium borohydride,
After stirring at room temperature for 30 minutes, 2N hydrochloric acid is added to decompose excess sodium borohydride, and methanol is distilled off under reduced pressure. To the residue was added 2N-NaOH aqueous solution (50 ml), extracted three times with diethyl ether (50 ml), and the extract was washed with water and dried to give 5-benzyloxy-6-methoxy-1,2,3,4-tetrahydro-1. -(2-benzyloxybenzyl)-
0.1 g of 2-methylisoquinoline is obtained. The hydrochloride of this compound is a colorless plate-like crystal, and has a melting point of 185 ° C. (decomposition).
製造例３ ３−メトキシ−４−ベンジルオキシ−β−フエネチル
アミン2.5g及び３−ベンジルオキシフエニル酢酸2gを用
い、製造例１と同様に処理すると、６−メトキシ−７−
ベンジルオキシ−1,2,3,4−テトラハイドロ−１−（３
−ベンジルオキシベンジル）−イソキノリン0.4gが得ら
れる。この化合物の塩酸塩は無晶形粉末であり、融点は
75〜77℃である。Production Example 3 When 2.5 g of 3-methoxy-4-benzyloxy-β-phenethylamine and 2 g of 3-benzyloxyphenylacetic acid were used and treated in the same manner as in Production Example 1, 6-methoxy-7-
Benzyloxy-1,2,3,4-tetrahydro-1- (3
0.4 g of -benzyloxybenzyl) -isoquinoline are obtained. The hydrochloride salt of this compound is an amorphous powder with a melting point
75-77 ° C.
製造例４ 製造例３で得られた６−メトキシ−７−ベンジルオキ
シ−1,2,3,4−テトラハイドロ−１−（３−ベンジルオ
キシベンジル）−イソキノリン0.2gを用い、製造例２と
同様に処理すると、６−メトキシ−７−ベンジルオキシ
−1,2,3,4−テトラハイドロ−１−（３−ベンジルオキ
シベンジル）−２−メチルイソキノリン0.2gが得られ
る。この化合物の塩酸塩は無色針状晶であり、融点は10
6〜107℃である。Production Example 4 Using 0.2 g of 6-methoxy-7-benzyloxy-1,2,3,4-tetrahydro-1- (3-benzyloxybenzyl) -isoquinoline obtained in Production Example 3, A similar treatment gives 0.2 g of 6-methoxy-7-benzyloxy-1,2,3,4-tetrahydro-1- (3-benzyloxybenzyl) -2-methylisoquinoline. The hydrochloride of this compound is colorless needles, mp 10
6-107 ° C.
製造例５ ３−メトキシ−４−ベンジルオキシ−β−フエネチル
アミン1g及び２−ベンジルオキシフエニル酢酸0.8gを用
い、製造例１と同様に処理すると、６−メトキシ−７−
ベンジルオキシ−1,2,3,4−テトラハイドロ−１−（２
−ベンジルオキシベンジル）−イソキノリン1.1gが得ら
れる。この化合物0.2gを用い、製造例２と同様に処理す
ると、６−メトキシ−７−ベンジルオキシ−1,2,3,4−
テトラハイドロ−１−（２−ベンジルオキシベンジル）
−２−メチルイソキノリン0.2gが得られる。この化合物
の塩酸塩は無色針状晶であり、融点は102〜103℃であ
る。Production Example 5 When 1 g of 3-methoxy-4-benzyloxy-β-phenethylamine and 0.8 g of 2-benzyloxyphenylacetic acid were used and treated in the same manner as in Production Example 1, 6-methoxy-7-
Benzyloxy-1,2,3,4-tetrahydro-1- (2
1.1 g of -benzyloxybenzyl) -isoquinoline are obtained. When 0.2 g of this compound was treated in the same manner as in Production Example 2, 6-methoxy-7-benzyloxy-1,2,3,4-
Tetrahydro-1- (2-benzyloxybenzyl)
0.2 g of -2-methylisoquinoline is obtained. The hydrochloride of this compound is colorless needles and has a melting point of 102-103 ° C.
Claims (1)
それぞれ一方が水素原子、他方がベンジルオキシ基を示
し、ただしR2及びR3がベンジルオキシ基であり、かつＲ
が水素原子である場合を除く）で表わされるベンジルイ
ソキノリン誘導体。(1) General formula (Wherein R is a hydrogen atom or a methyl group, R 1 and R 2 and R 3 and R 4 are each a hydrogen atom and the other is a benzyloxy group, provided that R 2 and R 3 are a benzyloxy group, And R
Benzylisoquinoline derivatives represented by the following formula:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62006205A JP2577215B2 (en) | 1987-01-16 | 1987-01-16 | Benzyl isoquinoline derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62006205A JP2577215B2 (en) | 1987-01-16 | 1987-01-16 | Benzyl isoquinoline derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63174974A JPS63174974A (en) | 1988-07-19 |
| JP2577215B2 true JP2577215B2 (en) | 1997-01-29 |
Family
ID=11632031
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62006205A Expired - Lifetime JP2577215B2 (en) | 1987-01-16 | 1987-01-16 | Benzyl isoquinoline derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2577215B2 (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3905982A (en) * | 1973-07-23 | 1975-09-16 | Searle & Co | 1-Aryl-n-dialkylaminoalkyl-3,4-dihydro-2(1H)-isoquinolinecarboxamides and related compounds |
-
1987
- 1987-01-16 JP JP62006205A patent/JP2577215B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63174974A (en) | 1988-07-19 |
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