JPS6141515B2 - - Google Patents
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- Publication number
- JPS6141515B2 JPS6141515B2 JP748279A JP748279A JPS6141515B2 JP S6141515 B2 JPS6141515 B2 JP S6141515B2 JP 748279 A JP748279 A JP 748279A JP 748279 A JP748279 A JP 748279A JP S6141515 B2 JPS6141515 B2 JP S6141515B2
- Authority
- JP
- Japan
- Prior art keywords
- general formula
- water
- ethyl
- cis
- nitrogen
- 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
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は新規な窒素含有多環式化合物に関し、
詳しくは下記一般式〔〕であらわされる窒素含
有多環式化合物およびそれらの塩および製法に関
するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel nitrogen-containing polycyclic compound,
Specifically, the present invention relates to nitrogen-containing polycyclic compounds represented by the following general formula [], salts thereof, and production methods.
上記一般式〔〕において、R1，R2は低級ア
ルキル基をあらわし、例えばメチル、エチル、プ
ロピル、ブチル、ペンチル、ヘキシル基があげら
れる。Ｗは酸素原子またはNHをあらわす。 In the above general formula [], R 1 and R 2 represent lower alkyl groups, such as methyl, ethyl, propyl, butyl, pentyl, and hexyl groups. W represents an oxygen atom or NH.
本発明による前記一般式〔〕の窒素含有多環
式化合物は文献未記載の新規化合物であり、優れ
た薬理作用すなわち血管拡張作用、鎭痙作用、脳
代謝賦活作用を有し、血栓などによる動脈硬化
症、脳および冠血管障害の治療剤として有用な化
合物である。また、本発明化合物は優れた脳血管
拡張作用を有するエブルナメニンタイプのアルカ
ロイドエステル（特公昭51−32640号公報）の重
要な中間体でもある。 The nitrogen-containing polycyclic compound of the general formula [] according to the present invention is a new compound that has not been described in any literature, and has excellent pharmacological effects, that is, vasodilatory effect, spasmism effect, and cerebral metabolic activation effect, and is effective in reducing arterial damage due to thrombosis, etc. It is a compound useful as a therapeutic agent for sclerosis, cerebral and coronary vascular disorders. The compound of the present invention is also an important intermediate for eburnamenine type alkaloid esters (Japanese Patent Publication No. 32,640/1983) which have excellent cerebral vasodilatory effects.
なお、一般式〔〕の化合物には各種光学異性
体が存在するが、本発明はその光学活性体および
その混合物を含む。 The compound of general formula [] has various optical isomers, and the present invention includes optically active forms thereof and mixtures thereof.
本発明化合物は以下の合成経路により得られ
る。すなわち下記のインドロキノリジン誘導体
〔〕
と一般式〔〕
Ｘ―CH2CO2R1 〔〕
〔式中、Ｘはハロゲン原子をあらわし、R1，
R2は前記の定義のとおりである。〕
であらわされる化合物を適当な溶媒中、塩基の存
在下反応させ、必要に応じて酸触媒を用い加水分
解することによつて得られる。 The compound of the present invention can be obtained by the following synthetic route. That is, the following indoquinolidine derivatives [] and the general formula [] X—CH 2 CO 2 R 1 [] [In the formula, X represents a halogen atom,
R 2 is as defined above. ] It can be obtained by reacting the compound represented by in an appropriate solvent in the presence of a base, and optionally hydrolyzing it using an acid catalyst.
インドロキノリジン誘導体〔〕と一般式
〔〕の化合物とのアルキル化、閉還反応におい
て用いられる適当な溶媒としてはアミド系溶媒
（たとえばジメチルアミノホルムアミド、ジメチ
ルアミノアセトアミド）があげられ、反応温度と
しては10℃から70℃の範囲が適当である。また、
本反応においては通常適当な塩基を用いるが、適
当な塩基としては金属水素化合物（たとえば水素
化ナトリウム）、金属アミド等があげられる。イ
ミノエステル体の加水分解反応において用いられ
る溶媒としては、水、含水アルコール系溶媒、ア
ルコール系溶媒等があげられ、酸触媒としては鉱
酸（塩酸、硫酸等）あるいは強有機酸を用いる。
反応温度は０℃から室温までが適当である。 Suitable solvents used in the alkylation and closure reactions between the indoquinolidine derivative [] and the compound of the general formula [] include amide solvents (e.g. dimethylaminoformamide, dimethylaminoacetamide), and the reaction temperature A range of 10°C to 70°C is appropriate. Also,
In this reaction, a suitable base is usually used, and suitable bases include metal hydride compounds (eg, sodium hydride), metal amides, and the like. Examples of solvents used in the hydrolysis reaction of imino esters include water, hydrous alcoholic solvents, alcoholic solvents, etc., and mineral acids (hydrochloric acid, sulfuric acid, etc.) or strong organic acids are used as acid catalysts.
The reaction temperature is suitably from 0°C to room temperature.
式〔〕であらわされるインドロキノリジン誘
導体は、例えば下記のアミド誘導体〔〕
をオキシ塩化リン、五酸化リン等を用いて閉環反
応を行い、次いで水素化ナトリウムホウ素還元あ
るいは氷酢酸中亜鉛還元することによつて得られ
る。 The indoquinolidine derivative represented by the formula [] is, for example, the following amide derivative [] It can be obtained by carrying out a ring-closing reaction using phosphorus oxychloride, phosphorus pentoxide, etc., and then reducing it with sodium boron hydride or zinc in glacial acetic acid.
このようにして得られた一般式〔〕の窒素含
有多環式化合物は種々の無機酸および強有機酸に
より製薬上許容される酸付加物に変えることがで
きる。 The nitrogen-containing polycyclic compound of general formula [] thus obtained can be converted into a pharmaceutically acceptable acid adduct with various inorganic acids and strong organic acids.
本発明によつて例えば次に掲げる化合物が容易
に製造される。 According to the present invention, for example, the following compounds can be easily produced.
シス 16―メトキシカルボニル―17―イミノエ
ブルナン
シス 16―エトキシカルボニル―17―イミノエ
ブルナン
シス 16―エトキシカルボニル―17―オキソエ
ブルナン
シス 16―プロポキシカルボニル―17―イミノ
エブルナン
シス 16―プロポキシカルボニル―17―オキソ
エブルナン
シス 16―ブトキシカルボニル―17―イミノエ
ブルナン
シス 16―ペントキシカルボニル―17―イミノ
エブルナン
シス 16―ヘキシルオキシカルボニル―17―イ
ミノエブルナン
および上記化合物のトランス異性体。 cis 16-Methoxycarbonyl-17-iminoeburnane cis 16-ethoxycarbonyl-17-iminoeburnan cis 16-ethoxycarbonyl-17-oxoeburnan cis 16-propoxycarbonyl-17-iminoeburnane cis 16-propoxycarbonyl-17-oxoeburnan cis 16-butoxycarbonyl -17-iminoeburnan cis 16-pentoxycarbonyl-17-iminoeburnan cis 16-hexyloxycarbonyl-17-iminoeburnan and trans isomers of the above compounds.
本発明による一般式〔〕の窒素含有多環式化
合物およびそれらの塩類は各種製剤型で、例えば
錠剤、糖衣錠、顆粒剤、カプセル、坐薬、注射、
アンプル等の形態で種々の天然または合成担体、
希釈剤、安定剤たとえばブドウ糖、庶糖、乳糖、
でん粉、滑石、ステアリン酸マグネシウム、メチ
ルセルロース、エチルセルロース、トラガント、
蒸留水等と組合せて経口、直腸、非経口的または
局所的方法により投与することができる。症状の
重さの函数として活性ある治療投与量は変化する
が、人では１日５mg〜100mgの範囲で経口投与す
る。 The nitrogen-containing polycyclic compounds of the general formula [] and their salts according to the present invention are available in various formulations, such as tablets, sugar-coated tablets, granules, capsules, suppositories, injections,
various natural or synthetic carriers in the form of ampoules and the like;
Diluents, stabilizers such as glucose, sucrose, lactose,
Starch, talc, magnesium stearate, methylcellulose, ethylcellulose, tragacanth,
It can be administered orally, rectally, parenterally or topically in combination with distilled water and the like. The active therapeutic dose varies as a function of the severity of the symptoms, but in humans it ranges from 5 mg to 100 mg orally per day.
次に実施例をあげて本発明の詳細に説明する
が、これはその１例であつて本発明は何らこれら
のみに限定されるものはない。 EXAMPLES Next, the present invention will be explained in detail with reference to Examples, but these are just examples and the present invention is not limited to these in any way.
実施例 １
シス―１―シアノ―１―エチル―１，２，３，
４，６，７，12，12b―オクタヒドロインドロ
〔２，３―ａ〕キノリジン260mgをDMF8mlに溶か
し、室温にて水素化ナトリウム（純度65％）500
mgを投与し、次いで５分後、クロル酢酸エチル
780mgのDMF溶媒３mlを加注、次いで20分撹拌
後、反応混合物を氷水に空け、酢酸エチルにて抽
出し、水洗、乾燥後、減圧下溶媒を留去した。残
渣をｎ―ヘキサンおよびイソプロピルエーテルよ
り結晶化、取し、シス―16―エトキシカルボニ
ル―17―イミノエブルナンを得た。融点 148〜
150℃
実施例 ２
実施例１で得られたシス―16―エトキシカルボ
ニル―17―イミノエブルナン500mgをエタノール
20mlに混ぜ、次いで濃塩酸５ml、水５mlを加え13
分室温にて撹拌した。反応終了後、水に空け飽和
NaHCO3水にて中和次いで酢酸エチル抽出した。
有機層を水洗乾燥後、減圧下溶媒を留去、残渣を
ｎ―ヘキサンにて結晶化し、シス―16―エトキシ
カルボニル―17―オキソエブルナンを得た。融点
139〜142.5℃
実施例 ３
トランス―１―シアノ―１―エチル―１，２，
３，４，６，７，12，12b―オクタヒドロインド
ロ〔２，３―ａ〕―キノリジン250mlをDMF5ml
に溶かし、水素化ナトリウム（69.6％）100mgを
室温にて投入、撹拌５分後、クロル酢酸エチル
250mgを加注し、更に20分撹拌し、反応混合物を
氷水に空け、酢酸エチルにて抽出、水洗、乾燥
後、減圧下溶媒を留去し、残渣をメタノールにて
結晶化、取し、トランス―16―エトキシカルボ
ニル―17―イミノエブルナンを得た。融点152.5
〜157.5℃
実施例 ４
実施例３で得たトランス―16―エトキシカルボ
ニル―17―イミノエブルナン2gをエタノール70
mlに溶かし、濃塩酸30ml、水70mlを加え、室温で
２時間撹拌した。反応終了後、反応混合物を氷水
に空け、アンモニア水にて中和後、酢酸エチルに
て抽出し、水洗、乾燥後、減圧下溶媒を留去し
た。得られた粗生成物をシリカゲルを用いカラム
クロマト法により分離し、トランス―16―エトキ
シカルボニル―17―オキソエブルナンを得た。融
点 130〜131.5℃
参考例 １
１―〔２―（インドール―３―イル）エチル〕
―３―シアノ―３―エチル―２―ピペリドン
0.9g、アセトニトリル30mlにオキシ塩化リン8.2
mlを加注し、次いで20時間還流した。減圧下溶媒
を留去し、メタノールを加え、氷冷下、水素化ホ
ウ素ナトリウムにて還元した。反応混合物を水に
空け酢酸エチルにて抽出し、水洗、乾燥後、減圧
下溶媒を留去し、残渣をメタノールにて結晶化
し、トランス―１―シアノ―１―エチル―１，
２，３，４，６，７，12，12b―オクタヒドロイ
ンドロ〔２，３―ａ〕―キノリジンを得た。融点
139〜141℃
参考例 ２
１―〔２―（インドール―３―イル）エチル〕
―３―シアノ―３―エチル―２―ピペリドン
4.5g、アセトニトリル60mlにオキシ塩化リン60ml
を加注し、次いで7.5時間還流した。減圧下溶媒
を留去し、氷酢酸100mlを加え、80℃から85℃に
て亜鉛末で還元した。不溶物を去後、アンモニ
ア水にて中和、酢酸エチルにて抽出し、水洗、乾
燥後、減圧下溶媒を留去し、残渣をシリカゲルを
用いてカラムクロマト法により精製し、シス―１
―シアノ―１―エチル―１，２，３，４，６，
７，12，12b―オクタヒドロインドロ〔２，３―
ａ〕キノリジンを得た。融点231〜233℃。Example 1 Cis-1-cyano-1-ethyl-1,2,3,
Dissolve 260 mg of 4,6,7,12,12b-octahydroindolo[2,3-a]quinolidine in 8 ml of DMF and add 500 mg of sodium hydride (purity 65%) at room temperature.
mg, then 5 minutes later, ethyl chloroacetate
After adding 780 mg of DMF solvent (3 ml) and stirring for 20 minutes, the reaction mixture was poured into ice water, extracted with ethyl acetate, washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was crystallized and collected from n-hexane and isopropyl ether to obtain cis-16-ethoxycarbonyl-17-iminoeburnane. Melting point 148~
150℃ Example 2 500 mg of cis-16-ethoxycarbonyl-17-iminoeburnan obtained in Example 1 was dissolved in ethanol.
Mix to 20ml, then add 5ml of concentrated hydrochloric acid and 5ml of water13
The mixture was stirred at room temperature for several minutes. After the reaction is complete, drain it into water to saturate it.
The mixture was neutralized with NaHCO 3 water and then extracted with ethyl acetate.
After washing the organic layer with water and drying, the solvent was distilled off under reduced pressure, and the residue was crystallized from n-hexane to obtain cis-16-ethoxycarbonyl-17-oxoeburunane. melting point
139-142.5℃ Example 3 trans-1-cyano-1-ethyl-1,2,
250ml of 3,4,6,7,12,12b-octahydroindolo[2,3-a]-quinolidine and 5ml of DMF
Add 100 mg of sodium hydride (69.6%) at room temperature, stir for 5 minutes, and add ethyl chloroacetate.
250mg was added, stirred for an additional 20 minutes, poured the reaction mixture into ice water, extracted with ethyl acetate, washed with water, dried, the solvent was distilled off under reduced pressure, the residue was crystallized from methanol, collected, and trans. -16-ethoxycarbonyl-17-iminoeburnan was obtained. Melting point 152.5
~157.5℃ Example 4 2 g of trans-16-ethoxycarbonyl-17-iminoeburnan obtained in Example 3 was added to 70% ethanol.
ml, added 30 ml of concentrated hydrochloric acid and 70 ml of water, and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was poured into ice water, neutralized with aqueous ammonia, extracted with ethyl acetate, washed with water, dried, and the solvent was distilled off under reduced pressure. The obtained crude product was separated by column chromatography using silica gel to obtain trans-16-ethoxycarbonyl-17-oxoeburnane. Melting point 130-131.5℃ Reference example 1 1-[2-(indol-3-yl)ethyl]
-3-cyano-3-ethyl-2-piperidone
0.9g, phosphorus oxychloride 8.2 in 30ml acetonitrile
ml and then refluxed for 20 hours. The solvent was distilled off under reduced pressure, methanol was added, and the mixture was reduced with sodium borohydride under ice cooling. The reaction mixture was poured into water and extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off under reduced pressure, and the residue was crystallized from methanol to obtain trans-1-cyano-1-ethyl-1,
2,3,4,6,7,12,12b-octahydroindolo[2,3-a]-quinolidine was obtained. melting point
139-141℃ Reference example 2 1-[2-(indol-3-yl)ethyl]
-3-cyano-3-ethyl-2-piperidone
4.5g, 60ml of phosphorous oxychloride in 60ml of acetonitrile
was added and then refluxed for 7.5 hours. The solvent was distilled off under reduced pressure, 100 ml of glacial acetic acid was added, and the mixture was reduced with zinc powder at 80°C to 85°C. After removing insoluble matter, neutralization with aqueous ammonia, extraction with ethyl acetate, washing with water, drying, distilling off the solvent under reduced pressure, and purifying the residue by column chromatography using silica gel.
-cyano-1-ethyl-1,2,3,4,6,
7,12,12b-octahydroindolo [2,3-
a] Quinolidine was obtained. Melting point 231-233℃.
Claims (1)
素原子またはNHをあらわす。〕 であらわされる窒素含有多環式化合物およびそれ
らの塩。 ２ R1，R2がエチル基である特許請求の範囲第
１項記載の窒素含有多環式化合物およびそれらの
塩。 ３ 式 であらわされるインドロキノリジン誘導体を一般
式 Ｘ―CH2CO2R1 〔式中、Ｘはハロゲン原子、R1，R2は低級ア
ルキル基をあらわす。〕 であらわされる化合物と反応させ、次いで必要に
応じて加水分解することを特徴とする一般式 〔式中、R1およびR2は前記の定義どおりであ
る。Ｗは酸素原子またはNHをあらわす。〕 であらわされる窒素含有多環式化合物の製法。[Claims] 1. General formula [In the formula, R 1 and R 2 represent a lower alkyl group, and W represents an oxygen atom or NH. ] Nitrogen-containing polycyclic compounds and salts thereof. 2. Nitrogen-containing polycyclic compounds and salts thereof according to claim 1, wherein R 1 and R 2 are ethyl groups. 3 formulas The indoquinolidine derivative represented by the general formula: X --CH 2 CO 2 R 1 [wherein, ] A general formula characterized by reacting with a compound represented by and then hydrolyzing as necessary. [In the formula, R 1 and R 2 are as defined above. W represents an oxygen atom or NH. ] A method for producing a nitrogen-containing polycyclic compound represented by
Priority Applications (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP748279A JPS55100382A (en) | 1979-01-24 | 1979-01-24 | Novel nitrogen-containing polycyclic compound and its preparation |
| US06/093,606 US4316028A (en) | 1978-11-20 | 1979-11-13 | Process for producing eburnane derivatives |
| AU52864/79A AU532001B2 (en) | 1978-11-20 | 1979-11-15 | Polycyclic indole derivatives |
| ES486028A ES486028A0 (en) | 1978-11-20 | 1979-11-16 | A PROCEDURE FOR PREPARING DERIVATIVES OF INDOL POLICICLICOS |
| EP79104535A EP0013315B1 (en) | 1978-11-20 | 1979-11-16 | Eburnane derivatives, their synthesis and pharmaceutical compositions containing them |
| EP81104366A EP0042526B1 (en) | 1978-11-20 | 1979-11-16 | Process for producing apovincaminic acid esters and their salts |
| DE7979104535T DE2966204D1 (en) | 1978-11-20 | 1979-11-16 | Eburnane derivatives, their synthesis and pharmaceutical compositions containing them |
| AT79104535T ATE4666T1 (en) | 1978-11-20 | 1979-11-16 | EBURNAN DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| HUSU001041 HU185370B (en) | 1979-01-24 | 1979-11-19 | Process for the production of new 17-substituted-eburnane-derivatives |
| CA000340171A CA1136139A (en) | 1978-11-20 | 1979-11-20 | Polycyclic indole derivatives |
| ES489139A ES489139A0 (en) | 1979-01-24 | 1980-03-03 | A PROCEDURE FOR PREPARING DERIVATIVES OF INDOL POLICICLI-COS |
| US06/259,179 US4382936A (en) | 1978-11-20 | 1981-04-30 | Cerebral vasodilator eburnane derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP748279A JPS55100382A (en) | 1979-01-24 | 1979-01-24 | Novel nitrogen-containing polycyclic compound and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS55100382A JPS55100382A (en) | 1980-07-31 |
| JPS6141515B2 true JPS6141515B2 (en) | 1986-09-16 |
Family
ID=11666976
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP748279A Granted JPS55100382A (en) | 1978-11-20 | 1979-01-24 | Novel nitrogen-containing polycyclic compound and its preparation |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS55100382A (en) |
| ES (1) | ES489139A0 (en) |
-
1979
- 1979-01-24 JP JP748279A patent/JPS55100382A/en active Granted
-
1980
- 1980-03-03 ES ES489139A patent/ES489139A0/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| ES8103084A1 (en) | 1981-02-16 |
| ES489139A0 (en) | 1981-02-16 |
| JPS55100382A (en) | 1980-07-31 |
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