JPS6089474A - Morphinan derivative, production thereof and antitumor agent containing said compound - Google Patents
Morphinan derivative, production thereof and antitumor agent containing said compoundInfo
- Publication number
- JPS6089474A JPS6089474A JP19731583A JP19731583A JPS6089474A JP S6089474 A JPS6089474 A JP S6089474A JP 19731583 A JP19731583 A JP 19731583A JP 19731583 A JP19731583 A JP 19731583A JP S6089474 A JPS6089474 A JP S6089474A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- polyolefinyl
- compound
- mono
- 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.)
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Abstract
Description
【発明の詳細な説明】
本発明は、下記式（１）
（式中、Ｘは水素原子又はハロゲン原子を示し、Ｒ１は
アルキル基、モノ若しくはポリオレフイニル基、フェニ
ルＭｔｉしくはメトキシフェニル基の置換したアルキル
基、又はフェニル基の置換したモノ若しくはポリオレフ
イニル基を示し、Ｒ２は水素原子、アルキル基、モノ若
しくはポリオレフイニル基、又はフェニル基の置換した
モノ若しくはポリオレフイニル基を示す。但し、Ｘが水
素原子で、かつＲ１及びＲ２が共にメチル基であるもの
を除く。）
で示される新規なモルフィナン誘導体、その製造方法、
及び該化合物を有効成分とする抗腫瘍剤に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the following formula (1) (wherein, It represents a mono- or polyolefinyl group substituted with an alkyl group or a phenyl group, and R2 represents a hydrogen atom, an alkyl group, a mono- or polyolefinyl group, or a mono- or polyolefinyl group substituted with a phenyl group. Provided, that X is a hydrogen atom, and excluding those in which both R1 and R2 are methyl groups.) A novel morphinan derivative represented by the following, a method for producing the same,
and an antitumor agent containing the compound as an active ingredient.
従来より、抗腫瘍剤として使用される種々の化合物が開
発されているが、本発明者らも抗１匝瘍作用を有する物
質を得るために鋭意研究を行なっているうち、前記（１
）式で示される新規なモルフィナン誘導体が優れた抗腫
瘍作用を有することを見出した。Conventionally, various compounds used as antitumor agents have been developed, and the present inventors have been conducting intensive research to obtain substances with antitumor effects.
We have discovered that a novel morphinan derivative represented by the formula ) has excellent antitumor activity.
即チ、デキストロメトルファン等のモルフィナン系化合
物は、延髄の咳中枢を直接抑制し、優れた鎮咳作用を有
するため、鎮咳薬として多用されているものであるが、
本発明者らは、上記研究において、後述する製造方法等
により前記（０式の新規なモルフィナン誘導体が得られ
ると共に、これらの化合物がｉｎ ｖｉｔｒｏでエール
リッヒ腹水癌、ザルコーマ１８０等の癌細胞に対する阻
害作用をＭすると共に、ｉｎ ｖｉｖｏでマウスに対す
る延命効果を有し、抗腫瘍剤として好適に使用し得るこ
とを知見し、本発明をなすに至ったものである。Morfinan compounds such as dextromethorphan and dextromethorphan are frequently used as antitussives because they directly suppress the cough center in the medulla oblongata and have excellent antitussive effects.
In the above research, the present inventors have obtained novel morphinan derivatives of the formula (0) by the production method described below, and have demonstrated that these compounds have an inhibitory effect on cancer cells such as Ehrlich ascites carcinoma and Sarcoma 180 in vitro. The inventors have discovered that the compound has a survival effect on mice in vivo and can be suitably used as an antitumor agent, leading to the present invention.
以下、本発明につき詳しく説明する。The present invention will be explained in detail below.
本発明に係る新規モルフィナン誘導体は、（０式、即ち
（式中、Ｘは水素原子又はハロダン原子を示し、Ｒ１は
アルキル基、モノ若しくはポリオレフイニル基、フェニ
ル基若しくはメトキシフェニル基の置換したアルキル基
、又はフェニル基の直換したモノ若しくはポリオレフイ
ニル基を示し、Ｒ２は水素原子、アルキル基、モノ若し
くはポリオレフイニル基、又はフェニル基の置換したモ
ノ若しくはポリオレフイニル基金示す。但し、Ｘが水素
原子で、かつＲ１及びＲ２が共にメチル基であるものを
除く。）
で示される化学構造を有するものである。The novel morphinan derivative according to the present invention has the following formula: or represents a mono- or polyolefinyl group directly substituted with a phenyl group, and R2 represents a hydrogen atom, an alkyl group, a mono- or polyolefinyl group, or a mono- or polyolefinyl group substituted with a phenyl group.However, if X is a hydrogen atom, and R1 and (excluding those in which both R2 are methyl groups).
ここで、ハロダン原子としてはＣ１１Ｂｒ、Ｉ等が挙げ
られ、Ｒ１のアルキル基としては炭素数１〜１８のもの
が挙げられる。この場合、アルキル基は直鎖及び分枝鎖
のものが包含される。また、オレフィニル基としては炭
素数３〜１６のものが挙げられ、この場合も直鎖及び分
枝鎖のものが包含される。更に、Ｂ２のアルキル基とし
ては炭素数１〜１８のもの、特に低級アルキル基が、オ
レフイニル基としては炭素数３〜１６のものが挙げられ
、これらは直鎖でも分枝鎖でもよい。Here, examples of the halodane atom include C11Br, I, etc., and examples of the alkyl group of R1 include those having 1 to 18 carbon atoms. In this case, the alkyl group includes both straight chain and branched chain alkyl groups. Further, examples of the olefinyl group include those having 3 to 16 carbon atoms, and in this case, straight chain and branched chains are also included. Further, examples of the alkyl group of B2 include those having 1 to 18 carbon atoms, particularly lower alkyl groups, and examples of the olefinyl group include those having 3 to 16 carbon atoms, and these may be linear or branched.
次に、上記（１）式で示される化合物の製造方法の一例
を挙げると、まず下記式（２）
（式中、Ｘは水素原子又は７１０グン原子を示′ｔｏ）
で示される３−ヒドロキク−１７−メチルモルフィナン
又は２−ハロゲノ−３−ヒドロキシ−１フ＝メチル
％式％（３）
（式中、Ｙはハロダン原子を示し、Ｒ１はアルキル基、
モノ若しくはポリオレフイニル基、フェニル基若しくは
メトキシフェニル基の置換したアルキル基、又はフェニ
ル基の置換したモノ若しくはポリオレフイニル基を示す
。）
で示される化合物を反応させて下記式（１ａ）（式中、
Ｘは水素原子又は）１０グン原子を示し、Ｒ１はアルキ
ル基、モノ若しくはポリオレフイニル基、フェニル基若
しくはメトキシフェニル基の置換したアルキル基、又は
フェニル基の置換したモノ若しくは４？リオレフイニル
基を示す。Next, an example of a method for producing a compound represented by the above formula (1) is first expressed by the following formula (2) (wherein, X represents a hydrogen atom or a 710g atom)
3-hydroxy-17-methylmorphinan or 2-halogeno-3-hydroxy-1-methyl % formula % (3) (wherein, Y represents a halodane atom, R1 represents an alkyl group,
It represents a mono- or polyolefinyl group, an alkyl group substituted with a phenyl group or a methoxyphenyl group, or a mono- or polyolefinyl group substituted with a phenyl group. ) by reacting the compound represented by the following formula (1a) (in the formula,
X represents a hydrogen atom or )10 Gn atom, and R1 is an alkyl group, a mono- or polyolefinyl group, an alkyl group substituted with a phenyl group or a methoxyphenyl group, or a mono- or 4-substituted phenyl group. Indicates a lyolefinyl group.
但し、Ｘが水素原子で、かつＲ１がメチル基であるもの
を除く。）
で示されるモルフィナン銹導体（本発明化合物）を得る
ものである。However, those in which X is a hydrogen atom and R1 is a methyl group are excluded. ) A morphinan rust conductor (compound of the present invention) is obtained.
ここで、上記反応を具体的に例示すると、まず上記（２
） 式の３−ヒドロキシ−１７−メチルモルフィナン３
１ｊ２−ハロゲノ−３−ヒドロキシ−１７−メチルモル
フィナンを低級アルコール類などの適宜な有機溶媒、例
えばエタノールに溶解し、これに水酸化ナトリウム、水
酸化カリウムなどの水酸化アルカリのアルコール溶液を
添加して上記（２）式の化合物をそのアルカリ金属塩に
誘導することが好適である。そして、次にこのアルカリ
金力Ｊ１塩に対し、上記（３）式の化合物を反応させ、
上記（ｌａ）式のモルフィナン誘導体を得るようにする
ことが好ましい。なお、この（２）式の化合物のアルカ
リ金属塩に対する（３）式の化合物の反応ｉ、アルカリ
金属塩を単離してから行なってもよく、また単離するこ
となく行なってもよい。ここで、アルカリ金属塩を単離
する場合は、溶媒を留去することで簡単にその目的を達
することができる。また、この単離したアルカリ金属塩
と上記（３）式の化合物との反応の反応溶媒としては、
アセトン、テトラヒドロ７ランや、低級アルコール類、
特にメタノール又はエタノールが好適に使用し得る。更
に、アルカリ金属塩を単離しない場合は、反応液に直接
（２）式の化合物を添加するもので、反応溶媒としては
アルカリ金属塩を生成させる際に用いた溶媒をそのまま
引続いて使用することができる。なお、上記反応におい
ては、反応温度は通常室温乃至溶媒の沸点の範囲とする
ことができるが、特に溶媒の沸点付近の温度とすること
が好ましい。また、反応時間は特に制限されないが、通
常１〜１２時間、特に３〜６時間程度とすることが好ま
しい。Here, to specifically illustrate the above reaction, first, the above (2
) 3-hydroxy-17-methylmorphinan 3 of the formula
1j2-halogeno-3-hydroxy-17-methylmorphinan is dissolved in an appropriate organic solvent such as lower alcohols, for example, ethanol, and an alcoholic solution of an alkali hydroxide such as sodium hydroxide or potassium hydroxide is added to this. It is preferable to derive the compound of formula (2) above into its alkali metal salt. Then, this alkali Kinriki J1 salt is reacted with the compound of the above formula (3),
It is preferable to obtain a morphinan derivative of the above formula (la). The reaction i of the compound of formula (3) with the alkali metal salt of the compound of formula (2) may be carried out after the alkali metal salt is isolated, or may be carried out without isolation. Here, when the alkali metal salt is to be isolated, the purpose can be easily achieved by distilling off the solvent. In addition, as a reaction solvent for the reaction between this isolated alkali metal salt and the compound of formula (3) above,
Acetone, tetrahydro7ran, lower alcohols,
In particular, methanol or ethanol can be suitably used. Furthermore, when the alkali metal salt is not isolated, the compound of formula (2) is added directly to the reaction solution, and the same solvent used to generate the alkali metal salt is used as the reaction solvent. be able to. In the above reaction, the reaction temperature can be generally in the range from room temperature to the boiling point of the solvent, but it is particularly preferable to set it at a temperature near the boiling point of the solvent. Further, the reaction time is not particularly limited, but it is usually about 1 to 12 hours, particularly preferably about 3 to 6 hours.
なお、本発明製造方法の出発物質である３−ヒドロキシ
−１７−メチルモルフィナン又は２−ハロゲノ−３−ヒ
ドロキシ−１７−メチルモルフィナンは、市販の３−メ
トキシ−１７−メチルモルフィテン（一般名デキストロ
メトルファン）の臭化水素酸塩を出発原料として容易に
得ることができる。即ち、３−メトキシ−１７−メチル
モルフィナンの臭化水素酸塩を５〜３０倍、好ましくは
１０〜２０倍の４７％臭化水素酸に溶解し、その沸点付
近で数時間、好ましくは５〜７時間加熱還流することに
より、７２〜８０多程度の収率で３＝ヒドロキシ−１７
−メチルモルフィナンカ得うれ、更にこれを適宜な極性
溶媒、例えば酢酸に溶解し、これに臭素の酢酸溶液を冷
却下に滴下することによシ、６０〜７０チの収率で２−
プロモー３−ヒドロキシ−１７−メチルモルフィナンヲ
曲ることができる。また、２−アイオド−３−ヒドロキ
シ−１７−メチルモルフィナンは３−ヒドロキシ−１７
−メチルモルフィナンのメタノール溶液にアンモニア水
を少量加え、ヨードのメタノール溶液を水冷下に滴下す
ることによって得ることができ、２−クロロ−３−ヒド
ロキシ−１７−メチルモルフィナンは３−ヒドロキシ−
１７−メチルモルフィナンに塩素全作用させることによ
り得ることかできる。The starting material for the production method of the present invention, 3-hydroxy-17-methylmorphinan or 2-halogeno-3-hydroxy-17-methylmorphinan, is commercially available 3-methoxy-17-methylmorphitene (common name: The hydrobromide salt of dextromethorphan can be easily obtained as a starting material. That is, the hydrobromide of 3-methoxy-17-methylmorphinan is dissolved in 47% hydrobromic acid 5 to 30 times, preferably 10 to 20 times, and heated at around its boiling point for several hours, preferably 5 to 5 times. By heating under reflux for ~7 hours, 3=hydroxy-17 was obtained with a yield of 72 to 80 degrees.
-Methylmorphinanka is obtained, and this is further dissolved in a suitable polar solvent, such as acetic acid, and a bromine acetic acid solution is added dropwise thereto under cooling to obtain 2-2-
The promoter 3-hydroxy-17-methylmorphinane can be bent. In addition, 2-iodo-3-hydroxy-17-methylmorphinan is 3-hydroxy-17
-2-chloro-3-hydroxy-17-methylmorphinan can be obtained by adding a small amount of ammonia water to a methanol solution of methylmorphinan and dropping a methanol solution of iodine under water cooling.
It can be obtained by fully reacting 17-methylmorphinan with chlorine.
上述のようにして得られた上記（１ａ）式の化合物は、
本発明の目的物質であると共に、更に他の本発明モルフ
ィナン誘導体に誘導する中間物質となるものであり、こ
の（１ａ）式の化合物を用いて他のモルフィナン誘導体
を得る場合は、この（１ａ）式の化合物にβ、β、β−
トリクロロエトキシカルボニルクロライドを反応させて
下記式（４）
（式中、Ｘ及びＲ１は前記と同じ。）
で示される１７−（β、β、β−トリクロロエトキシカ
ルボニル）モルフィナン誘導体を得、次いでこの（４）
式の化合物を加水分解して下記式（１ｂ）（式中、Ｘ及
びＲ１は前記と同じ。）
で示されるモルフィナン誘導体（本うｔ間化合物）を得
るものである。The compound of formula (1a) obtained as described above is
In addition to being the target substance of the present invention, it also serves as an intermediate substance for deriving other morphinan derivatives of the present invention, and when using this compound of formula (1a) to obtain other morphinan derivatives, this (1a) β, β, β− in the compound of formula
Trichloroethoxycarbonyl chloride is reacted to obtain a 17-(β,β,β-trichloroethoxycarbonyl)morphinan derivative represented by the following formula (4) (wherein X and R1 are the same as above), and then this ( 4)
The compound of the formula is hydrolyzed to obtain a morphinan derivative (the intermediate compound) represented by the following formula (1b) (wherein X and R1 are the same as above).
この場合、例えば（ｌｂ）式の化合物を８〜１５倍ノヘ
ンゼンに溶解し、これに１〜１．２倍モルのβ。In this case, for example, the compound of formula (lb) is dissolved 8 to 15 times in nohenzene, and 1 to 1.2 times mole of β is added thereto.
β、β−トリクロロエトキシカルボニルクロライドを加
え、１〜３時間還流して（４）式の化合物を得るように
することができる。また、（４）式の化合！吻の加水分
解を行なう場合、（４）式の化合物を溶媒、例えば５〜
７倍の酢酸水浴液に溶解し、これに２〜２．５倍モルの
亜鉛末を加え、約１時間室部下で攪拌して（１ｂ）式の
化合物を得る方法が好適に採用できる。β,β-trichloroethoxycarbonyl chloride may be added and refluxed for 1 to 3 hours to obtain a compound of formula (4). Also, the compound of formula (4)! When hydrolyzing the proboscis, the compound of formula (4) is dissolved in a solvent, e.g.
Preferably, the compound of formula (1b) can be obtained by dissolving it in a 7-fold molar acetic acid water bath, adding 2 to 2.5-fold molar amount of zinc powder, and stirring the mixture in a room for about 1 hour.
上述のようにして得られた上記（ｌｂ）式の化合物は、
本発明の目的物質であると共に１更に他の本発明モルフ
ィナン誘導体に誘導する中間物質であり、（ｌｂ）式の
化合物から更に他のモルフィナン誘導体を得る場合は、
（ｌｂ）式の化合物に下記式（５）Ｒ２−ｙ ・・・（
５）
（式中、Ｙはハロゲン原子を示し ＲＫはアルキル基、
モノ若しくはポリオレフイニル基、又ハフェニル基の置
換したモノ若しくはポリオレフイニル基を示す。）
で示される化合物を反応させて下記式（１）′（式中、
Ｘは水素原子又はハロダン原子を示し、Ｒ１はアルキル
基、モノ若しくはポリオレフィニル基、フェニル基若し
くはメトキシフェニル基の置換したアルキル基、又はフ
ェニル基の置換したモノ若しくは月？リオレフィニル基
を示し、Ｒ６はアルキル基、モノ若しくはポリオレフイ
ニル基、又はフェニル基の置換したモノ若しくはポリオ
レフイニル基をパす。但し、Ｘが水素原子で、かつＲ１
及びＲ６が共にメチル基であるものを除く。）
で示されるモルフィナン誘４体（本発明化合物）を得る
ものである。The compound of formula (lb) obtained as described above is
In addition to being the target substance of the present invention, it is also an intermediate for inducing other morphinan derivatives of the present invention, and when obtaining further morphinan derivatives from the compound of formula (lb),
The compound of formula (lb) has the following formula (5) R2-y...(
5) (In the formula, Y represents a halogen atom, RK is an alkyl group,
It represents a mono- or polyolefinyl group, or a mono- or polyolefinyl group substituted with a haphenyl group. ) is reacted with the compound represented by the following formula (1)' (in the formula,
X represents a hydrogen atom or a halodane atom, and R1 is an alkyl group, a mono- or polyolefinyl group, an alkyl group substituted with a phenyl group or a methoxyphenyl group, or a mono- or mon-substituted phenyl group. It represents a lyolefinyl group, and R6 represents an alkyl group, a mono- or polyolefinyl group, or a phenyl-substituted mono- or polyolefinyl group. However, X is a hydrogen atom, and R1
Excluding those in which both of and R6 are methyl groups. ) A morphinan derivative 4 (compound of the present invention) represented by the following formula is obtained.
ここで１上記反応を具体例に例示すると、まず上記（ｌ
ｂ）式の化合物を８〜１５倍のジメチルホルムアミド等
の溶媒に溶解し、これに（５）式の化合物及び塩基、例
えば炭酸水素す） ＩＪウムを加え、５〜８時間加熱還
流して（１）′式の化合物を得る方法を採用することが
できる。Here, to illustrate the above reaction 1 as a specific example, first, the above (l
The compound of formula b) is dissolved in 8 to 15 times the amount of a solvent such as dimethylformamide, and the compound of formula (5) and a base such as hydrogen carbonate are added thereto, and the mixture is heated under reflux for 5 to 8 hours to obtain ( 1) A method for obtaining a compound of the formula ' can be adopted.
なお、上述した一連の反応の一例を下記反応酸Ａに示す
。An example of the above-mentioned series of reactions is shown in Reaction Acid A below.
反応式Ａ
（２） （１ａ ）
（１ｂ）
（１）′
まだ、本発明化合物の製造方法の他の例を述べると、特
にＲ１がメチル基である下記式（１ｆ）（式甲、Ｘ及び
Ｒ２は前記と同じ。但し、Ｘが水素原子で、かつＲ２か
メチル基であるものを除く。）で示されるモルフィナン
訪導体を得る場合は、下す己式 （１ｄ）
（式中、Ｘは水素原子又はハロダン原子を示も）で示さ
れる３−メトキシ−１７−メチルモルフィナン又は２−
ハロダノ−３−メトキシ−１７−メチルモルフィナンに
臭化シアンを反応させて下記式（６）
（式中、Ｘは前記と同じ。）
で示される化合物を得、更にこの（６）式の化合物を加
水分解して下記式（１ｅ）
（式中、Ｘは前記と同じ。）
テ示すれるモルフィナン誘導体（本発明化合物）を得、
更に必要によ）この（１ｅ）式の化合物に前記（５）式
の化合物を反応させることによりｓ造することができる
。Reaction formula A (2) (1a) (1b) (1)' To describe other examples of the method for producing the compound of the present invention, in particular, the following formula (1f) (Formula A, X and R2 is the same as above.However, to obtain a morphinan visiting conductor represented by 3-methoxy-17-methylmorphinan or 2-
Halodano-3-methoxy-17-methylmorphinan is reacted with cyanogen bromide to obtain a compound represented by the following formula (6) (wherein, X is the same as above), and further a compound of this formula (6) is obtained. is hydrolyzed to obtain a morphinan derivative (compound of the present invention) represented by the following formula (1e) (wherein, X is the same as above),
Furthermore, if necessary, s can be produced by reacting the compound of formula (1e) with the compound of formula (5).
具体的には、上ｈａ（ｉａ）式で示される３−メトキシ
−１７−メチルモルフィナン（７ｊキストロメトルファ
ン）又は２−ハロダン−３−メトキシ−１フーメチル
メトルファン）の１７位脱メチル反応を行なう場合、前
記反応酸Ａにおけると同様にデキストロメトルファン又
は２−ハロゲノデキストロメトルファンにβ，β，βー
トリクロロエトキシカルボニルクロライドを作用させた
後、加水分解するようにしてもよいが、デキストロメト
ルファン又は２−ノ）口ｒノブキストロメトルファンは
３位がメトキシ基であシ、強酸に対して比較的安定であ
るため、デキストロメトルファン又は２−ハロゲノデキ
ストロメトルファンに臭化シアンを作用させて上記（６
）式の化合物を得だ後、これを加水分がトして上記（１
ｅ）式の化合物′＋ｃ得ることが収率等の点でより好ま
しく、そしてこのようにして得られた（１ｅ）式の化合
物に対し、前記反応酸Ａにおけると同本色已に（５）式
の化合物を反応させ、上記（１ｆ）式の化合物を得るよ
うにすることが好ましい。Specifically, the 17-position demethylation reaction of 3-methoxy-17-methylmorphinan (7j-kistromethorphan) or 2-halodan-3-methoxy-1-fumethylmethorphan shown by the above ha(ia) formula In this case, dextromethorphan or 2-halogenodextromethorphan may be treated with β,β,β-trichloroethoxycarbonyl chloride and then hydrolyzed in the same manner as in reaction acid A. Lomethorphan or 2-halogenodextromethorphan has a methoxy group at the 3-position and is relatively stable against strong acids, so cyanogen bromide acts on dextromethorphan or 2-halogenodextromethorphan. Let me do the above (6
) After obtaining the compound of the formula, it was hydrolyzed to give the above (1)
It is more preferable to obtain the compound '+c of the formula e) in terms of yield, etc., and the compound of the formula (1e) obtained in this way has the same color as in the reaction acid A, and the compound of the formula (5) is obtained. It is preferable to react the compound of formula (1f) above to obtain the compound of formula (1f).
ここで、上記（１ｄ）式の化合物の１７位脱メチル反応
を詳述すると、址ず（１ｄ）式の化合物、例えば２−ブ
ロモデキストロメトルファンをクロロポルム等の溶媒に
溶解し、これに例えば等モル量の臭化シアンをクロロホ
ルム等の溶媒に溶解した溶液を好ましくは室温下におい
て滴下し、これを例えば２〜５時間還流する。次いで、
反応液を濃縮乾固して残渣金ベンゼン等にとり、この残
液を例えば希塩酸、炭酸水素す） ＩＪウム水溶液及び
水で洗浄した後、溶媒を留去して（６）式の化金物を得
る。Here, to explain in detail the 17-position demethylation reaction of the compound of formula (1d) above, the compound of formula (1d), for example, 2-bromodextromethorphan, is dissolved in a solvent such as chloroporm, and then A solution of a molar amount of cyanogen bromide in a solvent such as chloroform is added dropwise, preferably at room temperature, and the mixture is refluxed, for example, for 2 to 5 hours. Then,
The reaction solution is concentrated to dryness and the residue is taken up in benzene, etc., and this residual solution is washed with, for example, dilute hydrochloric acid, hydrogen carbonate, an aqueous solution of IJ and water, and the solvent is distilled off to obtain the metal compound of formula (6). .
その後、これを例えば１０〜２５倍の１０係塩酸水溶液
中で６〜１２時間加熱還流して加水分解を行ない、（ｌ
ｅ）式の化合物（１７位脱メチル体）を得るものである
。Thereafter, this is heated under reflux for 6 to 12 hours in a 10 to 25 times aqueous solution of 10% hydrochloric acid to perform hydrolysis.
e) A compound of formula (17-position demethylated form) is obtained.
また、下記式（１ｃ）
（式中、ガはハロダン原子を示す。）
で示されるモルフィナン誘導体である上記の２−ハロゲ
ノデキストロメトルファン（本発明化合物）に滴下する
ことにより得ることができる。It can also be obtained by dropping it onto the above-mentioned 2-halogenodextromethorphan (the compound of the present invention), which is a morphinan derivative represented by the following formula (1c) (in the formula, ``a'' represents a halodane atom).
なお、上述した一連の反応の一例を下記反応式Ｂに示す
。An example of the series of reactions described above is shown in Reaction Formula B below.
反応式Ｂ
（ｌｄ） （６）
前記（１）式の化合物は、優れた抗腫瘍作用を有するた
め、抗１１ａ瘍剤として好適に使用し得る。Reaction formula B (ld) (6) The compound of formula (1) has an excellent antitumor effect and can therefore be suitably used as an anti-11a tumor agent.
本発明に係る抗腫傷創は、（１）式の化合物を有効成分
として常法によシ製剤とすることができ、注射剤、経口
投与剤、座剤等の任意の形態に調製することができる。The anti-tumor wound preparation according to the present invention can be prepared by a conventional method using the compound of formula (1) as an active ingredient, and can be prepared in any form such as an injection, an oral preparation, or a suppository. I can do it.
この場合、（１）式の化合物の投与量は、投与経路や病
状の軽重などによシ異なシ、広範に変えることができる
が、通常の有効投与量は、１日当シ体重１ ｋｇにつき
本発明有効成分１０〜４０ｍ９程度である。In this case, the dosage of the compound of formula (1) can vary widely depending on the route of administration, the severity of the disease, etc., but the usual effective dosage is 1 kg of body weight per day. The amount of the active ingredient of the present invention is about 10 to 40 m9.
本発明の抗腫瘍剤を注射剤に調製する場合、慣用の方法
によって静脈内注射剤、筋肉内注射剤等とすることがで
き、注射用蒸留水に本発明有効成分を乳化或いは懸濁さ
せる方法等を採用することができる。また、本発明抗腫
傷創を錠剤、カプセル剤といった経口投与剤に調製する
場合、適宜な製薬用担体や賦形剤を用いて慣用の方法に
より製造することができる。なお、この場合、製薬用担
体や賦形剤の成分としては、ゼラチン、ポリビニルピロ
リドン、トラガカントガム、アラビヤガム、ソルビット
等の結合剤、プロピレングリコール、無水ケイ酸、リノ
ール酸、蔗糖、乳糖、デンプン、アルミン酸マグネシウ
ム等の賦形剤、タルク、ステアリン酸マグネシウム等の
滑沢剤等の適宜なものを使用し得る。更に、本発明抗１
厘傷剤を座剤等の粘膜適用の製剤に調製する場合、基剤
としてポリエチレングリコール、グリセロゼラチン、ス
テアリン酸ナトリウム、ラウリン脂、カカオ脂、或いは
これらの混合物が使用される。When the antitumor agent of the present invention is prepared as an injection, it can be made into an intravenous injection, an intramuscular injection, etc. by a conventional method, and the active ingredient of the present invention is emulsified or suspended in distilled water for injection. etc. can be adopted. In addition, when the anti-tumor wound preparation of the present invention is prepared into oral preparations such as tablets and capsules, they can be manufactured by conventional methods using appropriate pharmaceutical carriers and excipients. In this case, the pharmaceutical carrier and excipient components include gelatin, polyvinylpyrrolidone, binders such as gum tragacanth, gum arabic, and sorbitol, propylene glycol, silicic anhydride, linoleic acid, sucrose, lactose, starch, and aluminic acid. Appropriate excipients such as magnesium, talc, lubricants such as magnesium stearate, etc. may be used. Furthermore, the anti-1 of the present invention
When the curative agent is prepared as a preparation for mucosal application such as a suppository, polyethylene glycol, glycerogelatin, sodium stearate, lauric butter, cocoa butter, or a mixture thereof is used as a base.
次に、下記第１〜３表に示す本発明化合物の製造例を具
体的に示す。Next, production examples of the compounds of the present invention shown in Tables 1 to 3 below will be specifically shown.
３−ヒドロキシ−１７−メチルモルフィナン１２．１．
９及び苛性ソーダ１．９ｇをエタノール１５０Ｍに溶解
し、これに室温下で攪拌しながらシンナミルクロライド
６、Ｏｇを溶解した５０ｍ１のエタノール溶液を滴下し
、そのまま２時間攪拌した。次に、不溶物を濾過し、溶
媒を減圧下に留去した後、残渣をベンゼン２００ＩＩＬ
ｌに溶解した。このベンゼン溶液を１０チ苛性ソーダ水
溶液で洗浄し、更に水洗した後、無水硫酸マグネシウム
を用いて乾燥し、これを減圧下に濃縮乾固した。得られ
た残渣をエタノールによ）再結晶し、無色針状晶の３−
（シンナミルオキシ）−１７−メチルモルフィナン６．
５．９’ｌｚ得た。この物質の融点、元素分析、マスス
ペクトルは次の通シであった。3-Hydroxy-17-methylmorphinan 12.1.
9 and 1.9 g of caustic soda were dissolved in 150 M ethanol, and 50 ml of an ethanol solution in which cinnamyl chloride 6 and Og were dissolved was added dropwise to the solution while stirring at room temperature, and the mixture was stirred for 2 hours. Next, insoluble materials were filtered, the solvent was distilled off under reduced pressure, and the residue was dissolved in benzene 200IIL.
Dissolved in l. This benzene solution was washed with a 10% aqueous sodium hydroxide solution, further washed with water, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was recrystallized (from ethanol) to give colorless needle-like crystals of 3-
(Cinnamyloxy)-17-methylmorphinan6.
I got 5.9'lz. The melting point, elemental analysis, and mass spectrum of this substance were as follows.
融点二１１１℃〜１１３．５℃
元素分析値： （Ｃ２６Ｈ５１ＮＯ）
計算値 Ｃ：８３．６０．Ｈ：８．３６．Ｎ：３．７５
実測値 Ｃ：８３．８６．Ｈ：８．３８．Ｎ：３．９７
マススペクトル、Ｍ／＝３７３
３−ヒドロキシ−１７−メチルモルフィナン３．０９及
び苛性ソーダ０．５６．！９を６０１ｎ＃）エタ／ −
ルに溶解した後、溶媒を留去して３−ヒドロキシ−１７
−メチルモルフィナンのナトリウム塩を得た。このナト
リウム塩をアセトン７０ｒｎｌに懸濁し、これに７アル
ネシルプロマイド３．７Ｉを添加して、室温で４時間攪
拌した。以下、製造例１と同様の処理を行ない、得られ
た油状の残液をシリカダルカラムクロマトグラフィーに
かり、クロロホルム：メタノール＝２４：１の溶出部を
濃縮乾固して、油状の３−（ファルネシルオキシ）−１
７−メチルモルフィナン１．８０ ＆ ｋ得り。Melting point: 2111°C to 113.5°C Elemental analysis value: (C26H51NO) Calculated value C: 83.60. H:8.36. N: 3.75
Actual value C: 83.86. H:8.38. N: 3.97
Mass spectrum, M/=373 3-hydroxy-17-methylmorphinan 3.09 and caustic soda 0.56. ! 9 to 601n#)eta/-
After dissolving the 3-hydroxy-17
- The sodium salt of methylmorphinan was obtained. This sodium salt was suspended in 70 rnl of acetone, 3.7 I of 7-arnesyl bromide was added thereto, and the mixture was stirred at room temperature for 4 hours. Thereafter, the same treatment as in Production Example 1 was carried out, and the obtained oily residue was subjected to silica dull column chromatography, and the eluate of chloroform:methanol = 24:1 was concentrated to dryness to form an oily 3-( farnesyloxy)-1
7-Methylmorphinan yielded 1.80&k.
この物質の元素分析値、マススペクトルは次の通シであ
った。The elemental analysis values and mass spectrum of this substance were as follows.
元素分析値： （Ｃ３２Ｈ４７ＮＯ）
計算イＩ運Ｃ，Ｃ：８３．２４． Ｈ：１０．２６．
Ｎ：３．０３実演１月直 Ｃ：８３．０７． Ｈ二１０
．４１． Ｎ：３．１３マススペクトル、Ｍ／＝４６１
の製造
製造例２と同様にして、３−ヒドロキシ−１７＝メチル
モルフィナン３．０．ｌｉ＋及び苛性ソーダ０．５６９
より３−ヒドロキシ−１７−メチルモルフィナンのナト
リウム塩を得た。このナトリウム塩をアセトン５０ｍＡ
に懸濁し、これに１−ブロモー５−フェニル−２，４−
ヘンタソエン３．１．９を添加して、室温で１２時間攪
拌した。以下、製造例１と同様の処理を行ない、得られ
た固体残渣ｔ−ｎ−ヘキサンによシ再結晶し、無色プリ
ズム品の３−（５−フェニル−２，４−ペンタジェニル
オキシ）−１７−メチルモルフィナン２．２ｇを得た。Elemental analysis value: (C32H47NO) Calculation I luck C, C: 83.24. H:10.26.
N: 3.03 Performance in January C: 83.07. H210
．． 41. N: 3.13 mass spectrum, M/=461 Production of 3-hydroxy-17=methylmorphinan 3.0. li+ and caustic soda 0.569
The sodium salt of 3-hydroxy-17-methylmorphinan was obtained. Add this sodium salt to acetone at 50 mA.
1-bromo-5-phenyl-2,4-
Hentasoene 3.1.9 was added and stirred at room temperature for 12 hours. Thereafter, the same treatment as in Production Example 1 was carried out, and the obtained solid residue was recrystallized from t-n-hexane to obtain a colorless prism product of 3-(5-phenyl-2,4-pentadienyloxy)- 2.2 g of 17-methylmorphinan was obtained.
この物質の融点、元素分析値、マススペクトルは次の通
シであった。 −
融点：１１０．５〜１１２．５℃
元素分析値： （Ｃ２ｅＨ５５ＮＯ）
計算値 Ｃ：８４．１７．１（：８．３２．Ｎ：３．５
１実測値 Ｃ：８３．９９．Ｈ：８．２１．Ｎ：３．６
５マススペクトル、Ｍ／ ＝３２３
製造
製造例２と同様にして、３−ヒドロキシ−１７−メチル
モルフィナン３．０ｇ及び苛性ソーダ０．５６９よｆｉ
３−ヒドロキシ−１７−メチルモルフィナンのナトリウ
ム塩を得た。このナトリウム塩をアセトン６ＯＮに懸濁
し、これに１−７’ロモー３，３−ジフェニル−２−ノ
ロペン３．９ｇを添加し又、室温で１０時間攪拌した。The melting point, elemental analysis values, and mass spectrum of this substance were as follows. - Melting point: 110.5-112.5°C Elemental analysis value: (C2eH55NO) Calculated value C: 84.17.1 (: 8.32. N: 3.5
1 Actual value C: 83.99. H:8.21. N: 3.6
5 Mass spectrum, M/ = 323 Production In the same manner as in Production Example 2, 3.0 g of 3-hydroxy-17-methylmorphinan and 0.569 g of caustic soda were added.
The sodium salt of 3-hydroxy-17-methylmorphinan was obtained. This sodium salt was suspended in acetone 6ON, and 3.9 g of 1-7' lomo-3,3-diphenyl-2-noropene was added thereto, followed by stirring at room temperature for 10 hours.
以下、製造例１と同様の処理を行ない、得られた油状の
残液をシリカダルカラムクロマトグラフィーにかけ、ク
ロロホルム：エタノール＝２４：１の溶出部を濃縮乾固
し、油状の３− （３，３−ジフェニル−２−フ’ロペ
ニルオキシ）−１７−メチルモルフィナン１．２ｇを得
た。Thereafter, the same treatment as in Production Example 1 was carried out, and the obtained oily residue was subjected to silica dull column chromatography, and the eluate of chloroform:ethanol = 24:1 was concentrated to dryness. 1.2 g of 3-diphenyl-2-furopenyloxy)-17-methylmorphinan was obtained.
この物質の元素分析値、マススペクトルは次の通シであ
った。The elemental analysis values and mass spectrum of this substance were as follows.
元素分析値： （Ｃ３２Ｈ５５ＮＯ）
計算値 Ｃ：８５．４８．Ｈニア、８５．Ｎ：３．１２
実測値 Ｃ：８５．８１．■二８．１０．Ｎ：３．３６
マススペクトル、Ｍ／＝４４９
〔製造例５〜２２〕
製造例１〜４の方法に準じて第１表に示す化合物を合成
した。Elemental analysis value: (C32H55NO) Calculated value C: 85.48. H Near, 85. N: 3.12
Actual value C: 85.81. ■28.10. N: 3.36
Mass spectrum, M/=449 [Production Examples 5 to 22] The compounds shown in Table 1 were synthesized according to the methods of Production Examples 1 to 4.
〔製造例２３〕 ηニブクモ−３−シンナミルオキシ−
１７−メチルモルフィナンの製造２−ゾロモー３−ヒド
ロキシ−１７−メチルモルフィナン３．８ｇ及び苛性ソ
ーダ０．５５，９’１−ｒ−タノール７０ ｍｌに溶解
し、これにシンナミルクロライド２．８ｇを添加して、
６時間還流した。以下製造例１と同様の処理を行ない、
得られた油状の残渣をシリカゲルカラムクロマトグラフ
ィーにかけ、クロロホルム：エタノール＝２４：１の溶
出部を濃縮乾固し、淡黄色油状の２−ブロモ−３−シン
ナミルオキシ−１７−メチルモルフィナン２．６９を得
た。[Production Example 23] ηnibukumo-3-cinnamyloxy-
Preparation of 17-methylmorphinan 3.8 g of 2-zolomo-3-hydroxy-17-methylmorphinan and 70 ml of caustic soda 0.55,9'1-r-tanol were dissolved, and 2.8 g of cinnamyl chloride was added thereto. Add
It was refluxed for 6 hours. The same treatment as in Production Example 1 was carried out below,
The obtained oily residue was subjected to silica gel column chromatography, and the eluate of chloroform:ethanol=24:1 was concentrated to dryness to give 2-bromo-3-cinnamyloxy-17-methylmorphinan as a pale yellow oil. I got 69.
この物質の元素分析値、マススペクトルは次の通シであ
った。The elemental analysis values and mass spectrum of this substance were as follows.
元素分析値（Ｃ２６Ｈ５ｏＢｒＮＯ）
計算値 Ｃ：６９．０２．Ｈ：６．６８．Ｎ：３．１０
実測値 Ｃ：６９．２７．）Ｉニア、１１．Ｎ：３．２
３マススペクトル、Ｍ／ −４５２
２−ブロモー３−ヒドロキシ−１７−メチルモルフィナ
ン４．０ｇ及び苛性ソーダ０．５８ ｇをエタノール８
０ｒｎｌに溶解し、これにファルネシルブロマイド５．
５ｇを添加して、室温で１２時間攪拌した。以下、製造
例１と同様の処理を行ない、得られた油状の残渣をシリ
カｒルカ２ムクロマトグラフィーにかけ、クロロホルム
：エタノール＝２３、＝２の溶出部を濃縮乾固し、油状
の２−プロモー３−ファルネシルオキシ−１７−メチル
モルフィナン１．３Ｉを得た。Elemental analysis value (C26H5oBrNO) Calculated value C: 69.02. H:6.68. N: 3.10
Actual value C: 69.27. ) I near, 11. N: 3.2
3 mass spectrum, M/ -452 4.0 g of 2-bromo-3-hydroxy-17-methylmorphinan and 0.58 g of caustic soda were dissolved in ethanol 8
Dissolve in 0rnl and add farnesyl bromide 5.
5 g was added and stirred at room temperature for 12 hours. Hereinafter, the same treatment as in Production Example 1 was carried out, and the obtained oily residue was subjected to silica 2-mer chromatography, and the eluate of chloroform:ethanol = 23, = 2 was concentrated to dryness, and the oily 2-promoter 3-farnesyloxy-17-methylmorphinan 1.3I was obtained.
この物質の元素分析値、マススペクトルは次の通シであ
った。The elemental analysis values and mass spectrum of this substance were as follows.
元素分析値（Ｃ３２Ｈａ６ＢｒＮＯ）
計算値 Ｃニア１．０９．Ｈ：８．５Ｂ、Ｎ：２．５９
実測値 Ｃニア１．１３．）ｌ：８．７６、Ｎ：２．８
０マススペクトル、Ｍ／＝５４０
３−メトキシ−１７−メチルモルフィナン５．４ｇを酢
酸５（ＩＪに溶解し、５０℃〜７０℃で臭素３．２ｇを
滴加した。次に７０℃〜８０℃で３時間攪拌した後、反
応液を水３００１１Ｊに注入し、苛性ソーダ水溶液で塩
基性として分離した油状物をベンゼンで抽出した。ベン
ゼン層を水洗し、無水硫酸マグネシウムで乾燥した後、
濃縮乾固して５．６Ｉの残渣を得た。これをｎ−ヘキサ
ンより再結晶して無色プリズム晶の２−７′ロモー３−
メトキシ次の通シであった。Elemental analysis value (C32Ha6BrNO) Calculated value C near 1.09. H: 8.5B, N: 2.59
Actual value C near 1.13. )l: 8.76, N: 2.8
0 mass spectrum, M/=540 5.4 g of 3-methoxy-17-methylmorphinan was dissolved in acetic acid 5 (IJ) and 3.2 g of bromine was added dropwise at 50°C to 70°C. Then 70°C to 80°C After stirring at ℃ for 3 hours, the reaction solution was poured into 30011 J of water, made basic with an aqueous solution of caustic soda, and the separated oil was extracted with benzene.The benzene layer was washed with water and dried over anhydrous magnesium sulfate.
Concentration to dryness gave a residue of 5.6I. This was recrystallized from n-hexane to form colorless prismatic crystals of 2-7' Romo 3-
The next step was methoxy.
融点：１３０〜１３２℃
元素分析値（Ｃｌ８Ｈ２４ＢｒＮＯ）
計算値 Ｃ：６１．７２％、）Ｉ：６．９１％、 Ｎ
： ４．００％実ｇ＋り値 Ｃ：６２．２１％、ｌ（ニ
ア、０６％、 Ｎ ： ４．０７％マススペクトル：Ｍ
”／＝３５０
〔製造例２６，２７）
製造例２３．２４の方法に準じて第２表に示す化合物を
合成した。Melting point: 130-132°C Elemental analysis value (Cl8H24BrNO) Calculated value C: 61.72%, )I: 6.91%, N
: 4.00% actual g+resistance value C: 62.21%, l(near, 06%, N: 4.07% mass spectrum: M
”/=350 [Production Examples 26 and 27] The compounds shown in Table 2 were synthesized according to the method of Production Examples 23 and 24.
３−シンナミルオキシ−１７−メチルモルフィナン３．
３１！をベンゼン４０属に溶解し、これにβ、β、β−
トリクロロエトキシカル７にニルクロライド２．１ｇを
添加して、２時間３０分還流した。次に、減圧下に溶媒
を留去し、得られた残渣をエーテルに溶解した後、不溶
物を沖過した。その後、エーテル層を濃縮乾固して、粗
製の３−シンナミルオキシ−１７−（β、β、β−トリ
クロロエトキシ、カルボニル）モルフィナン３．９１！
ｉ得た。3-Cinnamyloxy-17-methylmorphinan3.
31! is dissolved in 40 types of benzene, and β, β, β-
2.1 g of nyl chloride was added to trichloroethoxylic 7, and the mixture was refluxed for 2 hours and 30 minutes. Next, the solvent was distilled off under reduced pressure, the resulting residue was dissolved in ether, and the insoluble matter was filtered off. Thereafter, the ether layer was concentrated to dryness to obtain crude 3-cinnamyloxy-17-(β,β,β-trichloroethoxy,carbonyl)morphinan, 3.91%!
I got it.
次に、この粗製カルバメイトに９０％酢畝水溶液２５ｍ
１に溶解し、これに亜鉛末１．１Ｘｙを〃■えてから１
時間室温下で撹拌した。その後反応溶媒を減圧下に留去
し、上記化合物と酢酸亜鉛との塩（下記式ａ）を得た。Next, add 25 m of a 90% vinegar solution to this crude carbamate.
Dissolve in 1, add 1.1Xy of zinc powder to it, and then add 1
The mixture was stirred at room temperature for an hour. Thereafter, the reaction solvent was distilled off under reduced pressure to obtain a salt of the above compound and zinc acetate (formula a below).
（式中、Ｒはシンナミル基を示す。）
その後、仁の塩をクロロホルム３ｏｍｌＶＩ：、溶解し
、これにＩＮ水酸化ナトリウム水溶液１ｏｏｙ’ｉ加え
て約１時間激しく攪拌した後、クロロホルム層を分離し
、これを水洗してから無水硫酸マグネシウムで乾燥し、
濃縮乾固して２．９ｇの油状物を得た。(In the formula, R represents a cinnamyl group.) Thereafter, 3 oml of IN sodium hydroxide solution was added to the solution, and the mixture was stirred vigorously for about 1 hour, and then the chloroform layer was separated. , this was washed with water and then dried with anhydrous magnesium sulfate,
Concentration to dryness gave 2.9 g of oil.
この油状物をエーテルに溶解し、塩化水素−エーテル溶
液を加えた後エーテルを留去し、残渣を水ニよシ再結晶
して、３−シンナミルオキシモルフィナン塙酸塩１．５
ｇを得た。This oil was dissolved in ether, a hydrogen chloride-ether solution was added thereto, the ether was distilled off, and the residue was recrystallized in water to give 1.5 ml of 3-cinnamyloxymorphinan sulfate.
I got g.
この化合物の融点、元素分析値、マススペクトルは次の
通りであった。The melting point, elemental analysis values, and mass spectrum of this compound were as follows.
一点：２４２〜２４４℃（分解）（塩酸塩）元素分析値
： （ＣｚｓＨｚ９ＮＯ−ＨＣｌ）計算値 Ｃニア５．
８３．Ｈニア、６４．Ｎ：３．５４実測値 Ｃニア５．
５６ 、 Ｈ： ７．６０ 、 Ｎ ： ３．３０マス
スペクトル： Ｍ’；／；、 ＝ ３５９ （塩基）〔
製造例２９〕
製造例２８の方法に準じて第３表に示す化合物を合成し
た。 −
３−メトキシモルフィナン３．０９？：ジメチルホ −
ルムアミド４０＋Ｊに溶解し、これに炭酸水素ナトリウ
ム１．５．９及びシンナミルクロライド２．２ｇを添加
して、６時間還流した。次に、不溶物を濾過し、溶媒を
減圧下に留去し、油状の残液を得た。One point: 242-244°C (decomposition) (hydrochloride) Elemental analysis value: (CzsHz9NO-HCl) Calculated value C Near 5.
83. H Near, 64. N: 3.54 actual value C near 5.
56, H: 7.60, N: 3.30 Mass spectrum: M';/;, = 359 (base) [
Production Example 29] Compounds shown in Table 3 were synthesized according to the method of Production Example 28. - 3-methoxymorphinan 3.09? :dimethylpho-
The mixture was dissolved in Lumamide 40+J, 1.5.9 g of sodium hydrogen carbonate and 2.2 g of cinnamyl chloride were added thereto, and the mixture was refluxed for 6 hours. Next, insoluble matter was filtered, and the solvent was distilled off under reduced pressure to obtain an oily residue.
この残渣をベンゼン１００ ｒｎｌに溶解し、これを水
洗してから無水（＃ｔｆｉ２マグネシウムを用いて乾燥
した後、減圧下に蒸発乾固して、淡黄色清秋物を得だ。This residue was dissolved in 100 rnl of benzene, washed with water, dried over anhydrous (#tfi2 magnesium), and then evaporated to dryness under reduced pressure to obtain a pale yellow clear product.
この油状物をシリカダルカラムクロマトグラフィーにか
け、クロロホルム溶出部よシ油状の３−メトキシ−１７
−シンナミルモルフィナン２．５１７ ｋ 得７’Ｃ０
この物質の元素分析値、マススペクトルは次の通りであ
った・
元素分析値（Ｃ２６Ｈｓ１Ｎｏ ）
計算値 Ｃ：８３．６０．Ｈニア、８４．Ｎ：３．７５
実測値 Ｃ：８３．５５．Ｉ（ニア、８９．Ｎ：４．０
０マススペクトル、Ｍ／＝３７３
〔製造例３１〕
製造例３０の方法に準じて第３表に示す化合物を合成し
た。This oil was subjected to silica dull column chromatography, and the chloroform eluate was extracted with oily 3-methoxy-17.
-Cinnamylmorphinan 2.517k obtained 7'C0
The elemental analysis value and mass spectrum of this substance were as follows: Elemental analysis value (C26Hs1No) Calculated value C: 83.60. H Near, 84. N: 3.75
Actual value C: 83.55. I (Near, 89.N: 4.0
0 mass spectrum, M/=373 [Production Example 31] The compounds shown in Table 3 were synthesized according to the method of Production Example 30.
次に、上記製造例で得た化合物を用いた実験例を挙げ、
本発明化合物のｉｎ ｖｉｔｒｏ及びｉｎ ｖｉｖ。Next, we will give an experimental example using the compound obtained in the above production example,
In vitro and in viv of the compounds of the present invention.
における抗腫瘍作用並びにＬＤ５Ｑを示す。LD5Q and anti-tumor effect of LD5Q.
ｉｎ ｖｌｔｒｏでの本発明化合物のエールリッヒ癌細
胞及びザルコーマ１８０癌細胞に対する阻害作用を下記
方法によシ調べた。The in vitro inhibitory effect of the compounds of the present invention on Ehrlich cancer cells and Sarcoma 180 cancer cells was investigated by the following method.
即ち、５０Ｉｎｌの試験管に２０ｍの各癌細胞懸濁液（
２Ｘ１０６ｃｅｌ１ｇ／ゴ）全それぞれ入れ、これに第
４表に示す製造例應の化合物をそれぞれ１０−５モル、
１０ モル及び１０ モルの濃度で加えたもの並びに無
添〃日のものの計４種の試料を作成し、これらをそれぞ
れ３７℃の湯浴中で振盪しながら３０〜１２０分間培養
する。培養後、遠心分離して集めた癌細胞を生理食塩水
及びｌ１ａｎｋｓ液で洗浄し、Ｈａｎｋｓ液中に懸濁し
て生存している癌細胞ヲトリパンブルーの色素通過試験
によって測定した。結果を第４表に示す。That is, 20 m of each cancer cell suspension (
2×106 cells (1 g/g) were added, and 10 −5 mol of each of the compounds of the production examples shown in Table 4 were added thereto.
A total of four samples were prepared, one added at a concentration of 10 mol and 10 mol, and one without the addition for 1 day, and each sample was incubated for 30 to 120 minutes with shaking in a water bath at 37°C. After culturing, the cancer cells collected by centrifugation were washed with physiological saline and 11anks solution, and the surviving cancer cells suspended in Hanks solution were measured by a trypan blue dye passage test. The results are shown in Table 4.
第４表の結果よシ、本発明の化合物はｉｎ ｖｌｔｒ。According to the results in Table 4, the compounds of the present invention are in vltr.
においてエールリッヒ肋細胞及びザルコーマ１８０癌細
胞１１０−３〜１０−４モル濃度程度の添刃口量で殆ん
−ど死滅させることが認められた。It was found that Ehrlich's costocytes and Sarcoma 180 cancer cells could be almost killed at a 110-3 to 10-4 molar concentration.
次に、ｉｎ ｖｉｖｏ Ｋおける試験として、マウスの
エールリッヒ腹水癌及びザルコーマ１ｓｏ＋ｉ水癌に対
しての延命効果を下記方法によシ調べた。Next, as an in vivo K test, the survival effect on Ehrlich ascites carcinoma and Sarcoma 1so+i water carcinoma in mice was investigated using the following method.
即ち、７〜８周令のｄｄＹ系雌マウス１０匹を１グルー
プとし、それぞれのグループのマウスの腹腔内にエール
リッヒ癌細胞又はザルコーマ１８０癌細胞を接種する。That is, 10 ddY female mice aged 7 to 8 weeks are made into one group, and Ehrlich cancer cells or Sarcoma 180 cancer cells are inoculated intraperitoneally into each group of mice.
２４時間後からマウスの腹腔内に第５．６表に示す各化
合物の投与（１０〜４０■へ〆ｄａｙ ）を始め、その
後５日間連続して１日１回の投与を行ない、マウスの生
存時間を６０日間観察した。なお、比較のため、本発明
化合物を投与しない場合についても同様に調べた。結果
を第５表（エールリッヒ腹水癌の場合）及び第６表（ザ
ルコーマ１８０腹水癌の場合）に示す。After 24 hours, each compound shown in Table 5.6 was intraperitoneally administered to the mice (from 10 to 40 days), and then administered once a day for 5 consecutive days to determine the survival of the mice. The time was observed for 60 days. For comparison, the same study was conducted in the case where the compound of the present invention was not administered. The results are shown in Table 5 (for Ehrlich ascites carcinoma) and Table 6 (for Sarcoma 180 ascites carcinoma).
第５表 マウスのエールリッヒ腹水癌に対しての延命効
果ム（６表 マウスのデルコーマ１８０腹水癌に対して
の延命効果第５表及び第６表の結果より、本発明の化合
物は、マウスのエールリッヒ腹水癌及びザルコーマ１８
０腹水癌に対しての延命効果を有し、ｉｎ ｖｉｖ。Table 5: Survival prolonging effect on Ehrlich ascites cancer in mice Ascites cancer and Sarcoma 18
0 has a survival effect on ascites cancer in viv.
において抗腫瘍作用を有することが認められた。was found to have antitumor effects.
更に、第７表に示す化合物のｄｄＹマウス腹腔腹腔再投
与るＬＤ５．を調べた。結果ｔ−第７表に示す。Furthermore, LD5. I looked into it. The results are shown in Table 7.
第７表 ｄｄＹマウス腹腔腹腔再投与るＬＤ５゜以下、
実施例によシ本発明抗腫瘍剤の製剤例を示す。Table 7 ddY mice peritoneal re-administration LD5° or less,
Examples of formulations of the antitumor agent of the present invention are shown in Examples.
〔実施例１〕 錠 剤 製造例（３）の化合物 ２００１ｎｇ 結晶セルロース ９３即 とうもろこしデンプン ４０■ カル？キシメチルセルロース ２０ｒｎｇタルク ５雫 合 計 ３６０９ 上記成分を用いて常法にょシ錠剤１個を製造した。[Example 1] Tablets Compound of production example (3) 2001 ng Crystalline cellulose 93 instant Corn starch 40■ Cal? 20rng oxymethylcellulose 5 drops talc Total 3609 One tablet was manufactured using the above ingredients using a conventional method.
〔実施例２〕 カプセル剤
’ＪＪ ｍ 例（３） ノ化合物２００ ｎｑ結晶セル
ロース １２ｏＩｎ９
無水ケイ酸 １２７＋ｉｐ
乳 糖 ６３ｍｇ
上記成上記用いて常法にょシヵノセル剤１ ｍを製造し
た。[Example 2] Capsule 'JJm Example (3) Compound 200 nq Crystalline cellulose 12oIn9 Silicic anhydride 127 + ip Lactose 63 mg 1 m of Nyoshicanocell was prepared in a conventional manner using the above composition.
出願人 東洋ファルマー株式会社
代理人 弁理士 小 島 隆 司
手続補正歯（自発）
昭和５８年１２月Ｇ 日
特許庁長官 若 杉 和 夫 殿
１、事件の表示
昭和５８年特許願第１９７３１５号
２、発明の名称
３、補正をする者
事件との関係 特許出願人
代表者 三 １）−雄
５、補正の対象
明ｍ書の［発明の詳細な説明−１の欄
６、補正の内容
（１）明ｍ書第２１真下から第１０行目ｒ（１ｂ）Ｊと
あるのをｒ（１ａ）Ｊと訂正する。Applicant: Toyo Pharma Co., Ltd. Agent, Patent Attorney: Takashi Kojima, Procedural amendment (voluntary): December G, 1980, Commissioner of the Patent Office, Kazuo Wakasugi, 1, Indication of the case, 1988 Patent Application No. 197315, 2, Title of the invention 3, Relationship with the case of the person making the amendment Representative 3 of the patent applicant 1) - Male 5, Column 6 of [Detailed description of the invention - 1] of the statement of subject matter of the amendment, Contents of the amendment (1) The 10th line from the bottom of Book M, 21st line, r(1b)J, is corrected to r(1a)J.
〈２）同第４１頁第１３行目の化学式（ａ ）が「 」 とあるのを ［ と訂正する。<2) The chemical formula (a) on page 41, line 13 of the same page is “ ” There is a certain thing [ I am corrected.
以 上that's all
Claims (1)
はアルキル基、モノ若しくはポリオレフイニル基、フェ
ニル基若しくはメトキ７フエニル基の置換したアルキル
基、又はフェニル基の置換したモノ若しくはポリオレフ
（二Ｊし基を示し、Ｒ２は水素原子、アルキル基、モノ
若しくはポリオレフイニル基、又はフェニル基の置換し
たモノ若しくはポリオレフイニル基を示す。但し、Ｘが
水素原子で、かつＲ１及びＲ２が共にメチル基であるも
のを除く。） で示される化合物から選ばれるモルフィナン誘導体。 ２、下記式（２） （式中、Ｘは水素原子又はハロゲン原子を示′ｔｏ）で
示される３−ヒドロキシ−１７−メチルモルフィナン又
は２−ハロゲノ−３−ヒドロ千シー１７−メチルモルフ
ィナンに下記式（３） ％式％（３） （式中、Ｙはハロゲン原子を示し、Ｒ１はアルキル基、
モノ若しくはポリオレフイニル基、フェニル基若しくは
メトキシフェニル基の置換したアルキル基、又はフェニ
ル基の置換したモノ若しくはポリオレフイニル基を示す
。） で示される化合物を反応させて下記式（ｌａ）（式中、
Ｘ及びＲ１は前記と同じ。但し、Ｘが水素原子で、かつ
Ｒ１がメチル基であるものを除く。）で示されるモルフ
ィナン誘導体を得ることを特徴とするモルフィナン誘導
体の製造方法。 ３、（２）式の化合物を有機溶媒に溶解すると共に、こ
れに水酸化アルカリを加えて（２）式の化合物のアルカ
リ金属塩を得、このアルカリ金属塩に（３）式の化合物
を反応させて（ｌａ）式の化合物を得るようにした特許
請求の範囲第２項記載の製造方法。 ４、 有機溶媒として低級アルコール類を用いた特許請
求の範囲第３項記載の製造方法。 ５、 下記式（１ａ） （式中、Ｘは水素原子又はハロゲン原子を示し、Ｒ１は
アルキル基、モノ若しくはポリオレフイニル基、フェニ
ル基若しくはメトキシフェニル基の置換したアルキル基
、又はフェニル基の置換したモノ若しくはポリオレフイ
ニル基を示す。）で示されるモルフィナン誘導体にβ、
β、β−トリクロロエトキシカルボニルクロライドを反
応させて下記式（４） （式中、Ｘ及びＲ１は前記と同じ。） で示される１７−（β、β、β−トリクロロエトキシカ
ルボニル）モルフィナン誘導体を得、次いでこの（４）
式の化合物を加水分解して下記式Ｑｂ）（式中、Ｘ及び
Ｒ１は前記と同じ。） で示されるモルフィナン誘導体を得ることを特徴とする
モルフィナン誘導体の製造方法。 ６、（４）式の化合物を酢酸の存在下で亜鉛により加水
分解して（１ｂ）式の化合物を得るようにした特許請求
の範囲第５項記載の製造方法。 ７、 下記式Ｑｂ） （式中、Ｘは水素原子又はハロゲン原子を示し、Ｒ１は
アルキル基、モノ若しくはポリオレフイニル基、フェニ
ル基若しくはメトキンフェニル基の置換したアルキル基
、又はフェニル基の置換したモノ若しくはポリオレフイ
ニル基ヲ示す。）で示されるモルフィナン誘導体に下記
式（５）％式％（５） （式中、Ｙは）・ログン原子を示し、ＲＬ２はアルキル
基、モノ若しくはポリオレフイニル基、又はフェニル基
の置換したモノ若しくはポリオレフイニル基を示す。） で示される化合物を反応させて下記式（１）′（式中、
Ｘは水素原子又はハロゲン原子を示し、Ｒ１はアルキル
基、モノ若しくはポリオレフイニル基、フェニル基若し
くはメトキノフェニル基の置換したアルキル基、又はフ
ェニル基の置換したモノ若しくはポリオレフイニル基を
示し、幅はアルキル基、モノ若しくはポリオレフイニル
基、又はフェニル基の置換したモノ若しくはポリオレフ
イニル基を示す。但し、Ｘが水素原子で、かつＲ１及び
ＲＫが共にメチル基であるもで示されるモルフィナン誘
導体金得ることを特徴とするモルフィナン誘導体の製造
方法。 ８．３〜メトキシ−１７−メチルモルフィナンにハロダ
ン分子を作用させて下記式（ｉｃ）Ｘ′ （式中、Ｘ′はハロダン原子を示す。）で示されるモル
フィナン誘導体を得ることを特数とするモルフィナン誘
導体の製造方法。 ９、 下記式（ｌｄ） （式中、Ｘは水素原子又はハロゲン原子を示も）で示さ
れる３−メトキシ−１７−メチルモルフィナン又は２−
ハロゲノ−３−メトキシ−１７−メチルモルフィナンに
臭化シアンを反応させて下記式（６） （式中、Ｘは前記と同じ。） で示される化合物を得、更にこの（６）式の化合物を加
水分解して下記式（１ｅ） （式中、Ｘは前記と同じ。） で示されるモルフィナン誘導体を得ることを特徴とする
モルフィナン誘導体の製造方法。 １０、（ｌｄ）式の化合物として２−ブロモ−３−メト
キシ−１７−メチルモルフィナンを用いた特許請求の範
囲第９項記載の製造方法。 １１、下記式（１） Ｘ （式中、Ｘは水素原子又はハロゲン原子を示し、Ｒ１は
アルキル基、モノ若しくはポリオレフイニル基、フェニ
ル基若しくはメトキシフェニル基の置換したアルキル基
、又はフェニル基の置換したモノ若しくはポリオレフイ
ニル基を示し、Ｒ２は水素原子、アルキル基、モノ若し
くはポリオレフイニル基、又はフェニル基の置換したモ
ノ若しくはポリオレフイニル基を示す。但し、Ｘが水素
原子で、かつＲ１及びＲ２が共にメチル基であるものを
除欠。） で示される化合物から選ばれるモルフィナン誘導体を有
効成分とすることを特徴とする抗腫瘍剤。[Claims] 1. The following formula (1) (wherein, X represents a hydrogen atom or) a rogone atom, and R1
represents an alkyl group, a mono- or polyolefinyl group, an alkyl group substituted with a phenyl group or a methoxyphenyl group, or a mono- or polyolefinyl group substituted with a phenyl group, where R2 is a hydrogen atom, an alkyl group, a mono- or polyolefinyl group; or a mono- or polyolefinyl group substituted with a phenyl group (excluding those in which X is a hydrogen atom and R1 and R2 are both methyl groups). 2. 3-hydroxy-17-methylmorphinan or 2-halogeno-3-hydro-17-methylmorphinan represented by the following formula (2) (wherein, X represents a hydrogen atom or a halogen atom) is the following formula (3) % formula % (3) (wherein, Y represents a halogen atom, R1 is an alkyl group,
It represents a mono- or polyolefinyl group, an alkyl group substituted with a phenyl group or a methoxyphenyl group, or a mono- or polyolefinyl group substituted with a phenyl group. ) by reacting the compound represented by the following formula (la) (in the formula,
X and R1 are the same as above. However, those in which X is a hydrogen atom and R1 is a methyl group are excluded. ) A method for producing a morphinan derivative, the method comprising obtaining a morphinan derivative represented by: 3. Dissolve the compound of formula (2) in an organic solvent, add alkali hydroxide to it to obtain an alkali metal salt of the compound of formula (2), and react the compound of formula (3) with this alkali metal salt. 3. The manufacturing method according to claim 2, wherein the compound of formula (la) is obtained by 4. The manufacturing method according to claim 3, using lower alcohols as the organic solvent. 5. The following formula (1a) (wherein, or a polyolefinyl group), β,
A 17-(β,β,β-trichloroethoxycarbonyl)morphinan derivative represented by the following formula (4) (wherein X and R1 are the same as above) was obtained by reacting β,β-trichloroethoxycarbonyl chloride. , then this (4)
A method for producing a morphinan derivative, which comprises hydrolyzing a compound of the formula to obtain a morphinan derivative represented by the following formula Qb) (wherein X and R1 are the same as above). 6. The manufacturing method according to claim 5, wherein the compound of formula (1b) is obtained by hydrolyzing the compound of formula (4) with zinc in the presence of acetic acid. 7. The following formula Qb) (wherein, X represents a hydrogen atom or a halogen atom, and R1 is an alkyl group, a mono- or polyolefinyl group, an alkyl group substituted with a phenyl group or a methquin phenyl group, or a monosubstituted phenyl group) or a polyolefinyl group) to a morphinan derivative represented by the following formula (5) % formula % (5) (in the formula, Y represents a logan atom), and RL2 is an alkyl group, a mono- or polyolefinyl group, or a phenyl group. represents a substituted mono- or polyolefinyl group. ) is reacted with the compound represented by the following formula (1)' (in the formula,
X represents a hydrogen atom or a halogen atom, R1 represents an alkyl group, a mono- or polyolefinyl group, an alkyl group substituted with a phenyl group or a methquinophenyl group, or a mono- or polyolefinyl group substituted with a phenyl group, and the width is the alkyl group. , a mono- or polyolefinyl group, or a mono- or polyolefinyl group substituted with a phenyl group. However, a method for producing a morphinan derivative, which is characterized in that a gold morphinan derivative is obtained, wherein X is a hydrogen atom, and R1 and RK are both methyl groups. 8.3 ~ The special feature is to react methoxy-17-methylmorphinan with a halodan molecule to obtain a morphinan derivative represented by the following formula (ic)X' (wherein, X' represents a halodan atom). A method for producing a morphinan derivative. 9. 3-methoxy-17-methylmorphinan or 2-methoxy-17-methylmorphinan represented by the following formula (ld) (wherein, X represents a hydrogen atom or a halogen atom)
Halogeno-3-methoxy-17-methylmorphinane is reacted with cyanogen bromide to obtain a compound represented by the following formula (6) (wherein, X is the same as above), and further a compound of this formula (6) A method for producing a morphinan derivative, which comprises hydrolyzing morphinan derivative to obtain a morphinan derivative represented by the following formula (1e) (wherein, X is the same as above). 10. The manufacturing method according to claim 9, wherein 2-bromo-3-methoxy-17-methylmorphinan is used as the compound of formula (ld). 11. The following formula (1) It represents a mono- or polyolefinyl group, and R2 represents a hydrogen atom, an alkyl group, a mono- or polyolefinyl group, or a mono- or polyolefinyl group substituted with a phenyl group.However, when X is a hydrogen atom, and R1 and R2 are both methyl groups, An antitumor agent characterized by containing as an active ingredient a morphinan derivative selected from the compounds shown in (with some exceptions).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19731583A JPS6089474A (en) | 1983-10-20 | 1983-10-20 | Morphinan derivative, production thereof and antitumor agent containing said compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19731583A JPS6089474A (en) | 1983-10-20 | 1983-10-20 | Morphinan derivative, production thereof and antitumor agent containing said compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS6089474A true JPS6089474A (en) | 1985-05-20 |
Family
ID=16372407
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19731583A Pending JPS6089474A (en) | 1983-10-20 | 1983-10-20 | Morphinan derivative, production thereof and antitumor agent containing said compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6089474A (en) |
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