JP2860385B2 - Bisbenzyl isoquinoline derivative - Google Patents

Bisbenzyl isoquinoline derivative

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Publication number
JP2860385B2
JP2860385B2 JP20479689A JP20479689A JP2860385B2 JP 2860385 B2 JP2860385 B2 JP 2860385B2 JP 20479689 A JP20479689 A JP 20479689A JP 20479689 A JP20479689 A JP 20479689A JP 2860385 B2 JP2860385 B2 JP 2860385B2
Authority
JP
Japan
Prior art keywords
compound
formula
group
acid
acyl group
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
Application number
JP20479689A
Other languages
Japanese (ja)
Other versions
JPH0368557A (en
Inventor
通範 赤須
一哉 小玉
淳司 大木
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.)
Kaken Shoyaku Co Ltd
Original Assignee
Kaken Shoyaku Co Ltd
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 Kaken Shoyaku Co Ltd filed Critical Kaken Shoyaku Co Ltd
Priority to JP20479689A priority Critical patent/JP2860385B2/en
Publication of JPH0368557A publication Critical patent/JPH0368557A/en
Application granted granted Critical
Publication of JP2860385B2 publication Critical patent/JP2860385B2/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

【発明の詳細な説明】 本発明は新規なビスベンジルイソキノリン誘導体及び
それを有効成分とする抗がん剤に関する。
The present invention relates to a novel bisbenzylisoquinoline derivative and an anticancer agent containing the same as an active ingredient.

つづらふじ科その他の植物に含有されるビスベンジル
イソキノリン系アルカロイド、例えばテトランドリン、
セフアランチン等に抗がん作用のあることは知られてい
る(Chem.Pharm.Bull.第24巻2413〜2420頁1976年参
照)。本発明者らは、ベンゼン環に水酸基を有するビス
ベンジルイソキノリン系アルカロイド例えばイソリエン
シニン及びネフエリンの水酸基にアシル基を導入して各
種誘導体を合成し、それら化合物について薬理作用を検
討した。その結果、ある種のビスベンジルイソキノリン
誘導体が優れたがん細胞増殖抑制作用を示すことを見出
した。
Bisbenzylisoquinoline-based alkaloids contained in other plants such as serrata, such as tetrandrine,
It is known that cepharanthin and the like have an anticancer effect (see Chem. Pharm. Bull. Vol. 24, 2413-2420, 1976). The present inventors synthesized various derivatives by introducing an acyl group into a hydroxyl group of a bisbenzylisoquinoline-based alkaloid having a hydroxyl group on a benzene ring, for example, isoliensinine and nepheline, and examined the pharmacological action of these compounds. As a result, they have found that certain bisbenzylisoquinoline derivatives exhibit an excellent cancer cell growth inhibitory action.

本発明はこの知見に基くもので、一般式 (式中R1はC3〜C10−アシル基又はメトキシ基、R2はC3
〜C10−アシル基を示す)で表わされるビスベンジルイ
ソキノリン誘導体又はその酸付加塩である。
The present invention is based on this finding, and has the general formula (Wherein R 1 is a C 3 -C 10 -acyl group or a methoxy group, R 2 is a C 3
To a C 10 -acyl group) or an acid addition salt thereof.

式Iの化合物は文献未載の新規化合物であつて、例え
ば下記のものがあげられる。7,12−O,O−ジプロピオニ
ルイソリエンシニン(化合物1)、7,12−O,O−ジ−n
−カプロイルイソリエンシニン(化合物2)、12−O−
n−バレリルネフエリン(化合物3)、12−O−n−カ
プリルネフエリン(化合物4)など。
The compound of the formula I is a novel compound which has not been described in the literature, and examples thereof include the following. 7,12-O, O-dipropionyl isoliencinine (compound 1), 7,12-O, O-di-n
-Caproyl isoliencinin (compound 2), 12-O-
n-valeryl nepheline (compound 3), 12-On-caprynephrine (compound 4) and the like.

式Iの化合物は、一般式 (式中Xは水酸基又はメトキシ基を示す)で表わされる
化合物を一般式 R−Y (III) (式中RはC3〜C10−アシル基を示し、Yはハロゲン原
子又は水酸基を示す)で表わされる化合物、又は一般式 R−O−R (IV) (式中Rは前記の意味を有する)で表わされる化合物と
反応させることによつて得られる。
Compounds of formula I have the general formula (Wherein X represents a hydroxyl group or a methoxy group) by converting a compound represented by the general formula RY (III) (wherein R represents a C 3 -C 10 -acyl group, and Y represents a halogen atom or a hydroxyl group) Or a compound represented by the general formula R-O-R (IV) (wherein R has the above-mentioned meaning).

すなわちXが水酸基である式IIの化合物を用いると、
R1及びR2が同一のC3〜C10−アシル基である式Iの化合
物が得られる。この場合は式III及び式IVの化合物のR
と式Iの化合物のR1及びR2は同一である。またXがメト
キシ基である式IIの化合物を用いると、R1がメトキシ
基、R2がC3〜C10−アシル基である式Iの化合物が得ら
れる。
That is, when a compound of the formula II in which X is a hydroxyl group is used,
R 1 and R 2 are identical C 3 -C 10 - compound of formula I is an acyl group can be obtained. In this case, the R of the compound of formulas III and IV
And R 1 and R 2 of the compound of formula I are identical. Also the use of a compound of formula II X is a methoxy group, R 1 is methoxy, R 2 is C 3 -C 10 - compound of formula I is an acyl group can be obtained.

式IIの化合物としてはイソリエンシニン(X=−O
H)、ネフエリン(X=−OCH3)があげられる。式IIの
化合物にはSS体、SR体、RS体及びRR体の4種の立体異性
体が存在するが、これらの異性体を用いてもよい。
Compounds of formula II include isoliencinin (X = -O
H), Nefuerin (X = -OCH 3), and the like. There are four types of stereoisomers of the compound of formula II: SS, SR, RS and RR, and these isomers may be used.

式IIIの化合物の置換基Yのためのハロゲン原子とし
ては例えば塩素原子、沃素原子、臭素原子があげられ
る。式III及び式IVの置換基RのためのC3〜C10−アシル
基としては例えばプロピオニル基、ブチリル基、バレリ
ル基、カプロイル基、カプリル基があげられる。直鎖状
のアシル基が好ましい。
Halogen atoms for substituent Y in compounds of formula III include, for example, chlorine, iodine and bromine. Examples of the C 3 -C 10 -acyl group for the substituent R in the formulas III and IV include a propionyl group, a butyryl group, a valeryl group, a caproyl group, and a capryl group. Linear acyl groups are preferred.

式IIの化合物とYがハロゲン原子である式IIIの化合
物又は式IVの化合物との反応は塩基性溶媒中で行うこと
が好ましい。塩基性溶媒としてはピリジン、トリエチル
アミンなどが用いられるが、エーテル、ベンゼン、ジク
ロルメタンなどの溶媒を混合してもよい。
The reaction of the compound of formula II with the compound of formula III or the compound of formula IV wherein Y is a halogen atom is preferably carried out in a basic solvent. As the basic solvent, pyridine, triethylamine or the like is used, but a solvent such as ether, benzene or dichloromethane may be mixed.

式IIの化合物とYが水酸基である式IIIの化合物の反
応は縮合剤の存在下、溶媒中で行うことが好ましい。縮
合剤としては例えばジシクロヘキシルカルボジイミドが
用いられる。溶媒としては例えばジクロルメタン、テト
ラヒドロフラン、ジオキサン等が用いられる。
The reaction of the compound of the formula II with the compound of the formula III wherein Y is a hydroxyl group is preferably carried out in the presence of a condensing agent in a solvent. As the condensing agent, for example, dicyclohexylcarbodiimide is used. As the solvent, for example, dichloromethane, tetrahydrofuran, dioxane and the like are used.

式Iの化合物は定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、
硝酸、燐酸等の無機酸、酢酸、フマル酸、りんご酸、く
えん酸等の有機酸が好ましい。
Compounds of formula I can be derivatized to acid addition salts by conventional methods. Physiologically harmless acids such as hydrochloric acid, sulfuric acid,
Preferred are inorganic acids such as nitric acid and phosphoric acid, and organic acids such as acetic acid, fumaric acid, malic acid and citric acid.

式Iの化合物は優れたがん細胞増殖抑制作用を示す。
したがつて本発明はさらに式Iの化合物を有効成分とす
る抗がん剤である。
The compounds of the formula I show an excellent inhibitory action on cancer cells.
Therefore, the present invention is further an anticancer agent comprising a compound of the formula I as an active ingredient.

式Iの化合物は抗がん剤としてそのまま用いてもよい
が、通常は賦形剤、結合剤、滑沢剤、溶剤、安定剤等を
添加し、錠剤、散剤、顆粒剤、カプセル剤、注射剤等に
製剤化して用いられる。賦形剤としては例えば殿粉、乳
糖、メチルセルロース、合成珪酸アルミニウム等、結合
剤としては例えばヒドロキシプロピルセルロース、ポリ
ビニルピロリドン等、滑沢剤としては例えばタルク、ス
テアリン酸マグネシウム、ステアリン酸カルシウム等が
あげられる。
The compound of the formula I may be used as it is as an anticancer agent, but usually, excipients, binders, lubricants, solvents, stabilizers and the like are added, and tablets, powders, granules, capsules and injections are added. It is used after being formulated into an agent. Excipients include, for example, starch, lactose, methylcellulose, synthetic aluminum silicate, etc., binders, for example, hydroxypropylcellulose, polyvinylpyrrolidone, etc., and lubricants, for example, talc, magnesium stearate, calcium stearate and the like.

本発明の薬剤の投与量は、経口投与の場合は1日当り
有効成分として10〜1000mg好ましくは30〜300mgであ
る。
The dose of the drug of the present invention is 10 to 1000 mg, preferably 30 to 300 mg, per day as an active ingredient in the case of oral administration.

製造例1 イソリエンシニン100mgをピリジン−ジクロルメタン
(1:1)の混合溶媒2mlに溶かし、氷冷下プロピオニルク
ロライド100mgを加える。室温で2時間反応後水20mlを
加えエーテルで抽出する。抽出物を分取し、カラムクロ
マト〔シリカゲル;クロロホルム−メタノール(5:
1)〕で精製すると、化合物1が融点55〜58℃の無晶状
粉末として得られる。
Production Example 1 100 mg of isoliencinine was dissolved in 2 ml of a mixed solvent of pyridine and dichloromethane (1: 1), and 100 mg of propionyl chloride was added under ice cooling. After reacting at room temperature for 2 hours, 20 ml of water is added and extracted with ether. The extract was separated and subjected to column chromatography [silica gel; chloroform-methanol (5:
Purification in 1)] gives compound 1 as an amorphous powder having a melting point of 55-58 ° C.

同様にして化合物2及び3が得られる。 Compounds 2 and 3 are obtained in a similar manner.

化合物2:融点37〜40℃無晶状粉末 化合物3:〃 47〜52℃ 〃 製造例2 ネフエリン100mg、カプリル酸25mgをジクロルメタン2
mlに溶解した溶液に、氷冷下N,N′−ジシクロヘキシル
カルボジイミド34mgを加える。室温で1時間反応後不溶
物を去する。液を減圧濃縮後、残留物をカラムクロ
マト〔シリカゲル;クロロホルム−メタノール(5:
1)〕で精製すると、化合物4が融点40〜43℃の無晶状
粉末として得られる。
Compound 2: Amorphous powder having a melting point of 37 to 40 ° C. Amorphous compound 3: {47 to 52 ° C.} Preparation Example 2 100 mg of nepheline and 25 mg of caprylic acid in dichloromethane
34 mg of N, N'-dicyclohexylcarbodiimide is added to the solution dissolved in ml under ice-cooling. After reacting at room temperature for 1 hour, the insoluble matter is removed. After the solution was concentrated under reduced pressure, the residue was subjected to column chromatography [silica gel; chloroform-methanol (5:
Purification in 1)] gives compound 4 as an amorphous powder with a melting point of 40-43 ° C.

実験例 ヒト大腸ガン由来培養細胞株RPMI4788細胞を用い、山
崎らのdye−uptake法(Jpn.J.Med.Sci.Biol.第39巻105
〜118頁1986年参照)によつて被験物質のがん細胞増殖
抑制の程度を測定した。
Experimental Example Using the human colon cancer-derived cultured cell line RPMI4788 cells, the dye-uptake method of Yamazaki et al. (Jpn. J. Med. Sci. Biol. Vol. 39, 105
, P. 118, 1986), the degree of suppression of cancer cell growth of the test substance was measured.

がん細胞の増殖を50%抑制する被験物質の濃度(I
C50)を下記表に示す。
Test substance concentration that inhibits cancer cell growth by 50% (I
C50 ) is shown in the table below.

製剤例1 化合物1の500mg、乳糖3.0g、とうもろこし殿粉1.28
g、ヒドロキシプロピルセルロース200mg及びステアリン
酸マグネシウム20mgをよく混合し、造粒したのち打錠し
て1錠当り100mgの錠剤とする。
Formulation Example 1 500 mg of compound 1, lactose 3.0 g, corn starch 1.28
g, 200 mg of hydroxypropylcellulose and 20 mg of magnesium stearate are mixed well, granulated, and tableted to give a tablet of 100 mg per tablet.

製剤例2 化合物2の500mg、乳糖2.5g、ばれいしよ殿粉1.75g、
結晶セルロース240mg及びステアリン酸カルシウム10mg
をよく混合し、この混合物をカプセルに充填して1カプ
セル中有効成分10mgを含有するカプセル剤とする。
Formulation Example 2 500 mg of compound 2, lactose 2.5 g, potato starch 1.75 g,
240mg crystalline cellulose and 10mg calcium stearate
Are mixed well, and the mixture is filled into capsules to give capsules containing 10 mg of the active ingredient in one capsule.

製剤例3 化合物3の塩酸塩500mg及びD−マンニトール1.0gを
注射用蒸留水に溶解して全量100mlとする。この溶液を
0.2μのメンブレンフイルターで過し、2mlのアンプル
に分注し、溶封したのち加熱滅菌して注射剤とする。
Formulation Example 3 500 mg of the hydrochloride of Compound 3 and 1.0 g of D-mannitol are dissolved in distilled water for injection to make a total volume of 100 ml. This solution
The mixture is passed through a 0.2 μm membrane filter, dispensed into 2 ml ampules, sealed, and then heat-sterilized to prepare an injection.

Claims (2)

(57)【特許請求の範囲】(57) [Claims] 【請求項1】一般式 (式中R1はC3〜C10−アシル基又はメトキシ基、R2はC3
〜C10−アシル基を示す)で表わされるビスベンジルイ
ソキノリン誘導体又はその酸付加塩。
(1) General formula (Wherein R 1 is a C 3 -C 10 -acyl group or a methoxy group, R 2 is a C 3
~ C 10 -acyl group) or a bisbenzylisoquinoline derivative or an acid addition salt thereof.
【請求項2】第1請求項に記載のビスベンジルイソキノ
リン誘導体又はその酸付加塩を有効成分とする抗がん
剤。
2. An anticancer agent comprising the bisbenzylisoquinoline derivative according to claim 1 or an acid addition salt thereof as an active ingredient.
JP20479689A 1989-08-09 1989-08-09 Bisbenzyl isoquinoline derivative Expired - Lifetime JP2860385B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP20479689A JP2860385B2 (en) 1989-08-09 1989-08-09 Bisbenzyl isoquinoline derivative

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP20479689A JP2860385B2 (en) 1989-08-09 1989-08-09 Bisbenzyl isoquinoline derivative

Publications (2)

Publication Number Publication Date
JPH0368557A JPH0368557A (en) 1991-03-25
JP2860385B2 true JP2860385B2 (en) 1999-02-24

Family

ID=16496505

Family Applications (1)

Application Number Title Priority Date Filing Date
JP20479689A Expired - Lifetime JP2860385B2 (en) 1989-08-09 1989-08-09 Bisbenzyl isoquinoline derivative

Country Status (1)

Country Link
JP (1) JP2860385B2 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113214154B (en) * 2020-02-04 2023-10-20 中国医学科学院药物研究所 Tribenzyl isoquinoline alkaloid, preparation method, pharmaceutical composition and application thereof

Also Published As

Publication number Publication date
JPH0368557A (en) 1991-03-25

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