JPS63154660A - 1,3,4,5-tetrahydrobenz(cd)indole derivative - Google Patents
1,3,4,5-tetrahydrobenz(cd)indole derivativeInfo
- Publication number
- JPS63154660A JPS63154660A JP29970786A JP29970786A JPS63154660A JP S63154660 A JPS63154660 A JP S63154660A JP 29970786 A JP29970786 A JP 29970786A JP 29970786 A JP29970786 A JP 29970786A JP S63154660 A JPS63154660 A JP S63154660A
- Authority
- JP
- Japan
- Prior art keywords
- tetrahydrobenz
- formula
- methylene chloride
- compound
- indole
- 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.)
- Granted
Links
- GESDFCMCXNVUOI-UHFFFAOYSA-N 1,3,4,5-tetrahydrobenzo[cd]indole Chemical class C1=CC(CCC2)=C3C2=CNC3=C1 GESDFCMCXNVUOI-UHFFFAOYSA-N 0.000 title claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 150000002475 indoles Chemical class 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 3
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229960003133 ergot alkaloid Drugs 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000015554 Dopamine receptor Human genes 0.000 description 2
- 108050004812 Dopamine receptor Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 206010034010 Parkinsonism Diseases 0.000 description 2
- 102000003946 Prolactin Human genes 0.000 description 2
- 108010057464 Prolactin Proteins 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- -1 lithium aluminum hydride Chemical compound 0.000 description 2
- 229940097325 prolactin Drugs 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 229940030225 antihemorrhagics Drugs 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000005978 brain dysfunction Effects 0.000 description 1
- 238000000262 chemical ionisation mass spectrometry Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 239000002874 hemostatic agent Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Indole Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
この発明は医薬品の製造中間体として有用な新規なＬ
３．４．５−ｆトラヒドロベンズ［：ｃｄ ：］インド
ール誘導体に関するものである。[Detailed description of the invention] Industrial application field This invention is a novel L useful as an intermediate in the production of pharmaceuticals.
3.4.5-f Concerning trahydrobenz[:cd:]indole derivatives.
従来の技術
従来より麦角アルカロイド類は種々の医薬品として用い
られている。例えば偏頭痛治療剤、末梢血管障害治療剤
、老人性脳機能不全治療剤、子宮収縮剤、子宮止血剤、
降圧剤、高プロラクチン症治療剤などである。BACKGROUND OF THE INVENTION Ergot alkaloids have been used in various pharmaceutical products. For example, a migraine treatment agent, a peripheral vascular disorder treatment agent, a senile brain dysfunction treatment agent, a uterine contractile agent, a uterine hemostatic agent,
These include antihypertensive agents and hyperprolactinism treatment agents.
これらの麦角アルカロイド類はいずれも基本骨格として
エルゴレン構造を有し、しかも側鎖にペプチド鎖を有す
るペプチド型の化合物が殆どである。近年、比較的簡単
な側鎖をもつクラビン型の化合物で活性のあるものが見
出され用いられているが、これらもなお基本骨格として
エルゴレン構造を有している。これまで麦角アルカロイ
ド類の活性発現にはこのエルゴレン構造が必須テあり、
この骨格が開裂した化合物は活性を有しないとされてい
た。All of these ergot alkaloids have an ergolene structure as a basic skeleton, and most of them are peptide-type compounds having a peptide chain in the side chain. In recent years, active clavine-type compounds with relatively simple side chains have been discovered and used, but these still have an ergolene structure as their basic skeleton. Until now, this ergolene structure was essential for the expression of activity of ergot alkaloids.
Compounds with this skeleton cleaved were thought to have no activity.
発明が解決しようとする問題点
この発明の目的は医薬品の製造中間体として有用な新規
な１．３．４．５−テトラヒドロベンズ（ｃｄ ）イン
ドール誘導体を提供することである。Problems to be Solved by the Invention An object of the present invention is to provide a novel 1,3,4,5-tetrahydrobenz (cd) indole derivative useful as an intermediate in the production of pharmaceuticals.
問題点を解決するための手段
本発明者らはエルゴレン骨格が開裂した簡単な構造の１
．３．４．５−テトラヒドロベンズ〔ｃｄ〕インドール
誘導体で従来の麦角アルカロイド類と同様の活性を有す
る化合物を見出すべく研究した結果、４位にアルキルア
ミノ基を有し、５位に２−メチル−１−プロペニル基を
有する化合物がドーパミン受容体刺激作用を有し、パー
キンソン症候群治療剤、ハンチントン舞踏病治療剤、プ
ロラクチン分泌抑制剤などとして有用であることを見出
した。Means for Solving the Problems The present inventors have developed a simple structure in which the ergolene skeleton is cleaved.
．． 3.4.5-Tetrahydrobenz[cd]indole derivatives, which have an alkylamino group at the 4-position and a 2-methyl- It has been found that a compound having a 1-propenyl group has a dopamine receptor stimulating effect and is useful as a therapeutic agent for Parkinson's syndrome, a therapeutic agent for Huntington's chorea, a prolactin secretion inhibitor, and the like.
本発明はこれらの化合物の製造中間体として有用な、一
般式
（式中のＲ１は炭素数１〜５の低級アルキル基であり、
Ｒ２は水素原子または炭素数１〜６の低級アルキル基で
ある）で表される１、 ３．４．５−テトラヒドロベン
ズＩ：ｃｄ ）インドール誘導体を提供するものである
。The present invention provides compounds useful as intermediates for the production of these compounds, which have the general formula (wherein R1 is a lower alkyl group having 1 to 5 carbon atoms,
R2 is a hydrogen atom or a lower alkyl group having 1 to 6 carbon atoms.
本発明の一般式（Ｉ）の化合物は新規化合物であり、以
下のような方法で製造することができる。The compound of general formula (I) of the present invention is a new compound and can be produced by the following method.
例えば、一般式
（式中のＲ２は前記と同じ意味をもつ）で表される化合
物と、一般式
％式％）
（式中のＲ＋は前記と同じ意味をもつ）で表されるカル
ボン酸の反応性官能的誘導体とを反応させることにより
製造することができる。For example, a compound represented by the general formula (R2 in the formula has the same meaning as above) and a carboxylic acid represented by the general formula (% formula %) (R+ in the formula has the same meaning as above). It can be produced by reacting with a reactive functional derivative.
本発明の一般式（■）の化合物の製造方法において出発
原料として用いられる一般式（ＩＩ）の化合物でＲ２が
水素原子である化合物は公知化合物であり、文献記載の
方法により製造することができる〔日本特許出願・昭６
１−８５３６１号公報〕。The compound of general formula (II) used as a starting material in the method for producing the compound of general formula (■) of the present invention, in which R2 is a hydrogen atom, is a known compound and can be produced by the method described in the literature. [Japanese patent application, 1939
1-85361].
また、一般式（ＩＩ）の化合物でＲ２が低級アルキル基
である化合物は、一般式（ＩＩ）の化合物でＲ２が水素
原子である化合物を適当なアシル化剤と反応させてＮ−
アシル誘導体とし、これを適当な還元剤、例えば水素化
リチウムアルミニウムを用いて還元することなどにより
製造することができる。In addition, a compound of general formula (II) in which R2 is a lower alkyl group can be prepared by reacting a compound of general formula (II) in which R2 is a hydrogen atom with an appropriate acylating agent.
It can be produced by reducing the acyl derivative using an appropriate reducing agent such as lithium aluminum hydride.
本発明の一般式（Ｉ）の化合物の製造方法でもう一方の
出発原料として用いられる一般式（Ｉ）の化合物は公知
化合物であり、市販品としであるいは公知の方法に従い
製造することにより容易に入手することができる。The compound of general formula (I) used as the other starting material in the method for producing a compound of general formula (I) of the present invention is a known compound, and can be easily obtained as a commercially available product or by manufacturing according to a known method. can be obtained.
本発明の一般式（１）の化合物は４位および５位の炭素
が不斉炭素であり、それらの炭素上の置換基の配置によ
って４種の立体異性体が存在する。In the compound of general formula (1) of the present invention, carbons at the 4th and 5th positions are asymmetric carbons, and four stereoisomers exist depending on the arrangement of substituents on these carbons.
また、これらの異性体は４位および５位の置換基の配置
関係により２種ずつの４，５−シス体（４Ｓ、 ５Ｓ；
４Ｒ，５Ｒ）と４．５−）ランス体（４Ｓ、５Ｒ； ４
Ｒ，５Ｓ）に分類されるが本発明の一般式（Ｉ）化合物
はそのいずれかに特に限定されるものではない。Furthermore, these isomers consist of two types of 4,5-cis forms (4S, 5S;
4R, 5R) and 4.5-) lance form (4S, 5R; 4
R, 5S), but the compound of general formula (I) of the present invention is not particularly limited to any of them.
発明の効果
本発明の一般式（１）で表される化合物はこれを適当な
還元剤を用いて還元することにより医薬品として有用な
、一般式
（式中のＲ３は炭素数２〜６の低級アルキル基であり
Ｒ２は前記と同じ意味をもつ）で表される化合物に導く
ことができる。Effects of the Invention The compound represented by the general formula (1) of the present invention can be made useful as a pharmaceutical by reducing it with a suitable reducing agent. is an alkyl group
R2 has the same meaning as above).
これらの化合物はドーパミン受容体刺激作用を有し、パ
ーキンソン症候群の治療剤、ハンチントン舞踏病治療剤
、プロラクチン分泌抑制剤などに有用である。These compounds have a dopamine receptor stimulating effect and are useful as therapeutic agents for Parkinson's syndrome, therapeutic agents for Huntington's chorea, prolactin secretion inhibitors, and the like.
実施例
本発明の内容を以下の実施例によってさらに詳細に説明
する。なお、各実施例中における化合物の融点はすべて
未補正である。EXAMPLES The content of the present invention will be explained in more detail with reference to the following examples. Note that all melting points of compounds in each example are uncorrected.
実施例 １
ル）−４−プロピオニルアミノ−１，３，４，５−テト
ラヒト４．５−）ランス−４−アミノ−５−（２−メチ
ル−１−プロペン−１−イル）−１，３，４，５−テト
ラヒドロベンズ［：ｃｄ ：１インドール２．１８６０
ｇを塩化メチレン２４．０ｍｇに溶解した。これにプ
ロピオン酸クロリド１゜００８ｇを塩化メチレン１．０
−に溶解した液を室温攪拌下に加え、さらにトリエチル
アミン２．Ｏｎ＋１を加え室温下３０分間攪拌した。反
応液に飽和炭酸水素ナトリウム水溶液を加えて有機層を
分離し、水層を塩化メチレン−メタノール（９５：５．
ｖ／ｖ）混合溶媒で抽出した。有機層を合わせて飽和
食塩水で洗浄し、無水硫酸す）ＩＪウムで乾燥した。減
圧下に溶媒を留去し、得られた結晶を塩化メチレン−〇
−へキサンから再結晶して２Ｊ４０８ ｇ （８５，８
％）の４．５−）ランス−５−（２−メチル−１−プロ
ペン−１−イル）−４−プロピオニルアミノ−１，３，
４，５−テトラヒドロベンズ［ｃｄ ］インドールを得
た。Example 1 l)-4-propionylamino-1,3,4,5-tetrahydro4.5-)lan-4-amino-5-(2-methyl-1-propen-1-yl)-1,3 ,4,5-tetrahydrobenz[:cd:1indole2.1860
g was dissolved in 24.0 mg of methylene chloride. Add 1.008 g of propionic acid chloride to this and 1.0 g of methylene chloride.
A solution dissolved in - was added to the solution under stirring at room temperature, and further triethylamine 2. On+1 was added and stirred at room temperature for 30 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to separate the organic layer, and the aqueous layer was mixed with methylene chloride-methanol (95:5.
v/v) Extracted with a mixed solvent. The organic layers were combined, washed with saturated brine, and dried over anhydrous sulfuric acid. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from methylene chloride-〇-hexane to give 2J408 g (85,8
%) of 4.5-) lance-5-(2-methyl-1-propen-1-yl)-4-propionylamino-1,3,
4,5-tetrahydrobenz[cd]indole was obtained.
無色針状晶 （塩化メチレン−ｎ−ヘキサン）融 点
： ２０６〜２１０℃
ＩＲ（ＫＢｒ）
ｖ、、、： ３２００． １６５４．１５１６ ｃ
ｍ−’’Ｈ−ＮＭＲ（ＣＤＣ１３）
δ： １．０５（３Ｈ，ｔ、 Ｊ＝７Ｈｚ）、
１．７２（３）１． ｄ、 Ｊ＝ＩＨｚ）、 １
．８９（３）１． ｄ、 Ｊ＝ＩＨｚ）、 ２．
０２（２ｆｔ。Colorless needle-like crystals (methylene chloride-n-hexane) Melting point: 206-210°C IR (KBr) v: 3200. 1654.1516 c
m-''H-NMR (CDC13) δ: 1.05 (3H, t, J=7Hz),
1.72(3)1. d, J=IHz), 1
．． 89(3)1. d, J=IHz), 2.
02 (2ft.
Ｑ、 Ｊ＝７Ｈｚ）、 ２．７８（１）１． ｄ
ｄ、 Ｊ＝１５．６ ａｎｄ５．２Ｈｚ＞、３．２
４（ＩＨ，ｄｄ、Ｊ４５．６ ａｎｄ４．２ｔ（ｚ）
、 ３．９０（ＩＨ，ｄｄ、 Ｊ＝９ ａｎｄ５
．５１１ｚ）、 ４．２２〜４．５２（ＩＨ，ｍ）、
５．０４（ＬＨ。Q, J=7Hz), 2.78(1)1. d
d, J=15.6 and5.2Hz>, 3.2
4 (IH, dd, J45.6 and4.2t(z)
, 3.90 (IH, dd, J=9 and5
．． 511z), 4.22-4.52 (IH, m),
5.04 (LH.
ｂｒ−ｄ、Ｊ＝９゜５ｆｌｚ） 、 ５．３６ （Ｉ
Ｈ，ｂｒ−ｄ、 Ｊ＝９）１ｚ）、 ６．７０〜６
．９４（２Ｈ，ｍ）、 ７．００〜７．１８（２Ｈ，
ｍ） 、 ８．４８ （ＬＨ，ｂｒ−ｓ）ＭＳ ：
ｍ／ｚ ２０９ （Ｍ”−ＮＨＣＯＣＨ２Ｃ
）＋３）元素分析値： （Ｃ＋ａｌ１２２Ｎ２０ と
して）０％ Ｎ％ Ｎ％
計算値 ７６．５６ ７．８５ ９．９２実
測値 ７６．５８ ７．９５ ９．９６実施
例 ２
４−プロピオニルアミノ−１，３，４，５−テトラヒド
ロベ４，５−シスー４−アミノ−５−（２−メチル−１
−プロペン−１−イル）−１，３，４，５−テトラヒド
ロベンズ〔ｃｄ〕インドール３７．０■を塩化メチレン
２．０−に溶解し、これにプロピオン酸クロリド０．１
ｍｊ２、）リエチルアミン０．２ａｉ！を氷冷下に加え
た。室温で約１時間攪拌した後反応液に飽和炭酸水素ナ
トリウム水溶液を加え、塩化メチレン−メタノール（９
５：５． ｖ／ｖ）混合溶媒で抽出した。有機層を飽和
食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下
に溶媒を留去した。残留物をシリカゲル分取薄層クロマ
トグラフィー（展開溶媒：塩化メチレン／メタノール−
９７／３． ｖ／ｖ）で精製して４１．７ｍｇ （９０
，３％）の４．５−シス−５−（２−メチル−１−プロ
ペン−１−イル）−４−プロピオニルアミノ−１，３，
４，５−テトラヒドロベンズ（ｃｄ ）インドールを得
た。br-d, J=9゜5flz), 5.36 (I
H,br-d, J=9)1z), 6.70~6
．． 94 (2H, m), 7.00-7.18 (2H,
m), 8.48 (LH,br-s)MS:
m/z 209 (M”-NHCOCH2C
)+3) Elemental analysis value: (as C+al122N20) 0% N% N% Calculated value 76.56 7.85 9.92 Actual value 76.58 7.95 9.96 Example 2 4-propionylamino-1,3 ,4,5-tetrahydrobe4,5-cis-4-amino-5-(2-methyl-1
37.0 μm of -propen-1-yl)-1,3,4,5-tetrahydrobenz[cd]indole was dissolved in 2.0 μm of methylene chloride, and 0.1 μm of propionic acid chloride was dissolved in the solution.
mj2,) ethylamine 0.2ai! was added under ice cooling. After stirring at room temperature for about 1 hour, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and methylene chloride-methanol (9
5:5. v/v) Extracted with a mixed solvent. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography (developing solvent: methylene chloride/methanol).
97/3. v/v) to produce 41.7 mg (90
, 3%) of 4.5-cis-5-(2-methyl-1-propen-1-yl)-4-propionylamino-1,3,
4,5-tetrahydrobenz (cd) indole was obtained.
無色プリズム晶
（塩化メチレン−ｎ−ヘキサン）
融 点： １２３．０ 〜１２５．０℃１Ｒ（Ｋ
Ｂｒ）
ν□、 ： ３３６０． ３２７０． １６３１．
１５２０ ｃｍ−’’＋１−ＮＭＲ（ＣＤＣＩ３）
δ： １．０８（３Ｈ，ｔ、 Ｊ＝７．６Ｈｚ）、
Ｃ７９（３ｆｌ、 ｄ、 Ｊ−１、２Ｈｚ）、
１．８０（３１１，ｄ、 Ｊ＝１．２１（ｚ）、
２．０９（２Ｈ，Ｑ、 Ｊ＝７．６Ｈｚ）、
２．８６（ＩＨ，ｄｄｄ、 Ｊ＝１５．５． ７．０
ａｎｄ １．０）１ｚ）、 ３．１０（ＬＨ，ｄ
ｄｄ。Colorless prism crystal (methylene chloride-n-hexane) Melting point: 123.0 ~ 125.0℃ 1R (K
Br) ν□, : 3360. 3270. 1631.
1520 cm-''+1-NMR (CDCI3) δ: 1.08 (3H, t, J=7.6Hz),
C79 (3fl, d, J-1, 2Hz),
1.80(311,d, J=1.21(z),
2.09 (2H, Q, J=7.6Hz),
2.86 (IH, ddd, J=15.5. 7.0
and 1.0)1z), 3.10(LH,d
dd.
Ｊ＝１５．５． ４．５ ａｎｄ １．０Ｈｚ）、
４゜０５（ｉｌｌ、 ｄｄ。J=15.5. 4.5 and 1.0Hz),
4゜05(ill, dd.
Ｊ４０．Ｏａｎｄ ４゜ＯＨｚ＞、 ４．４５〜４．
７５（１）１゜ｍ）、 ５．１９（ＩＮ、 ｂｒ−
ｄ、 Ｊ＝１０．０１１ｚ）、 ５．４６（ＬＨ，
ｂｒ−ｄ、 Ｊ＝９．０Ｈｚ； ＮＨ）、 ６．
８３（ｉｔ（。J40. Oand 4゜OHz>, 4.45~4.
75(1)1゜m), 5.19(IN, br-
d, J=10.011z), 5.46(LH,
br-d, J=9.0Hz; NH), 6.
83(it(.
ｂｒ−ｓ）、 ６．６７〜６．８０（ｉｌｌ、 ｍ
＞、 ６．９７〜７．１７（２ｔ（、ｍＬ ８．０
４．（’ＬＨ，ｂｒ−ｓ）ＭＳ ： ｍ／ｚ
２８２ （Ｍ”）元素分析値＋ （ＣＩ８８２２Ｎ
２０ として）０％ ８％ Ｎ％
計算値 ７６．５６ ７．８５ ９．９２実
測値 ７６．２７ ７．９４ ９．９８１
つ
実施例 ３
４．５−）ランス−５−（２−メチル−１−プロペン−
１−イル）−４−プロピオニルアミノ−１，３，４，５
−テトラヒドロベンズ（ｃｄ）インドール１．１０２ｇ
を無水テトラヒドロフラン２０゜Ｏｄに溶解し、これに
水素化リチウムアルミニウム１．９２６ｇを加え７．５
時間還流攪拌した。反応終了後、反応液にメタノールを
加えて過剰の試薬を分解し、１０％ロッシェル塩水溶液
を加えて塩化メチレン−メタノール（９５：５． ｖ／
ｖ）混合溶媒で抽出した。有機層を飽和食塩水で洗浄し
、無水硫酸ナトリウムで乾燥後、減圧下に溶媒を留去し
た。残留結晶を塩化メチレン−ｎ−ヘキサンから再結晶
して４．５−）ランス−５−（２−メチル−１＝プロペ
ン−１−イル）−４−プロピルアミノ−１，３，４，５
−テトラヒドロベンズ［ｃｄ ］インドールを６９９．
２ｍｇ（６６、８％）を得た。br-s), 6.67-6.80(ill, m
>, 6.97-7.17 (2t (, mL 8.0
4. ('LH,br-s)MS: m/z
282 (M”) Elemental analysis value + (CI8822N
20) 0% 8% N% Calculated value 76.56 7.85 9.92 Actual value 76.27 7.94 9.981
Example 3 4.5-) lance-5-(2-methyl-1-propene-
1-yl)-4-propionylamino-1,3,4,5
-Tetrahydrobenz (cd) indole 1.102g
was dissolved in 20°Od of anhydrous tetrahydrofuran, and 1.926g of lithium aluminum hydride was added thereto to give a solution of 7.5
Stir at reflux for an hour. After the reaction, methanol was added to the reaction solution to decompose excess reagent, 10% Rochelle salt aqueous solution was added, and methylene chloride-methanol (95:5.v/
v) Extracted with mixed solvent. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The remaining crystals were recrystallized from methylene chloride-n-hexane to give 4.5-) lance-5-(2-methyl-1=propen-1-yl)-4-propylamino-1,3,4,5
-tetrahydrobenz[cd]indole at 699.
2 mg (66, 8%) was obtained.
無色針状晶 （塩化メチレン−叶へキサン）１と
融 点＋ １３８．５ 〜１４０．０℃ＩＲ（Ｋ
Ｂｒ）
ｖ、、、： ３１５０，３１００． １６０５． １
４４３ ｃｍ−’’Ｈ−ＮＭＲ（ＣＤＣＩ、）
δ： ０．９２（３８，ｔ、Ｊ＝７Ｈｚ）、 １．
５２（２Ｈ，ｓｅｘ、Ｊ＝７Ｈｚ）、 １．７４（Ｉ
Ｈ，ｂｒ−ｓ）、 １．８４（３ｆｔ、 ｄ、
Ｊ−１Ｈｚ）、 １．８８（３Ｈ，ｄ、 、Ｊ＝Ｉ
Ｈｚ）、 ２．３６〜３．００（３Ｈ，ｍ＞、 ２
．７４（ｌｔｌ、 ｂｒ−ｄ、 Ｊ＝１１）１ｚ）
。Colorless needle-like crystals (methylene chloride-Kohexane) 1 and melting point + 138.5 ~ 140.0℃ IR (K
Br) v,,: 3150,3100. 1605. 1
443 cm-''H-NMR (CDCI,) δ: 0.92 (38, t, J=7Hz), 1.
52 (2H, sex, J=7Hz), 1.74 (I
H, br-s), 1.84 (3ft, d,
J-1Hz), 1.88 (3H, d, , J=I
Hz), 2.36-3.00 (3H, m>, 2
．． 74 (ltl, br-d, J=11)1z)
.
３．２８（ＩＨ，ｂｒ−ｄ、 Ｊ＝１１Ｈｚ）、３．
８４（０１，ｔ。3.28 (IH, br-d, J=11Hz), 3.
84 (01, t.
Ｊ＝８．８Ｈｚ）、 ５．１１（ＬＨ，ｂｒ−ｄ、
Ｊ＝９．５ｔｌｚ）。J=8.8Hz), 5.11(LH,br-d,
J=9.5tlz).
６．６４〜６．９０（２Ｎ、 ｍ）、 ７．００〜
７．２０（２ｔｌ、ｍ）。6.64~6.90 (2N, m), 7.00~
7.20 (2tl, m).
７、８７ （ｉｔ（、ｂｒ−ｓ）
ＭＳ’ ： ｍ／ｚ ２６８ （Ｍ”）元
素分析値： （Ｃ１１１Ｈ２４Ｎ４・１／２＋４２０
として）０％ ８％ Ｎ％
計算値 ？７．９３ ９．０８ １０．１０実
測値 ７７．８４ ８．７６ １０．０３４．
５−）ランス−５−（２−メチル−１−プロペン−１−
イル）−４−プロピルアミノ−１，３，４，５−テトラ
ヒドロベンズ［：ｃｄ ：］インドール１２５．０ｍｇ
を塩化メチレン４．０ｍｌに溶解し、これにプロピオン
酸クロリド５０．０ｍｇ、 トリエチルアミン０．２
屁を加えて室温下２．５時間攪拌した。反応液に塩化メ
チレン−メタノール（９５：５． ｖ／ｖ）混合溶媒を
加え有機層を飽和炭酸水素ナトリウム水溶液および水で
順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下に溶
媒を留去した。残留物をシリカゲルカラムクロマトグラ
フィー（溶出溶媒：クロロホルム／メタノール／アンモ
ニア水／ｎ−ヘキサン−１８０／１０／１／６４． ｖ
／ｖ）で精製Ｌテ４．５−）ランス−５−（２−メチル
−１−プロペン−１−イル）−４−ＩＮ−プロピオニル
−Ｎ−プロピルアミノ）−１、３，４，５−テトラヒド
ロベンズ（ｃｄ）インドール７９、８ ｍｇ （５２，
８％）を得た。7,87 (it(,br-s) MS': m/z 268 (M") Elemental analysis value: (C111H24N4・1/2+420
)0% 8% N% Calculated value? 7.93 9.08 10.10 Actual value 77.84 8.76 10.034.
5-) Lance-5-(2-methyl-1-propene-1-
yl)-4-propylamino-1,3,4,5-tetrahydrobenz[:cd:]indole 125.0mg
was dissolved in 4.0 ml of methylene chloride, and 50.0 mg of propionic acid chloride and 0.2 ml of triethylamine were dissolved therein.
A fart was added and the mixture was stirred at room temperature for 2.5 hours. A mixed solvent of methylene chloride and methanol (95:5. v/v) was added to the reaction solution, and the organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. . The residue was subjected to silica gel column chromatography (elution solvent: chloroform/methanol/aqueous ammonia/n-hexane-180/10/1/64.v
/v) purified with Lte4.5-) lance-5-(2-methyl-1-propen-1-yl)-4-IN-propionyl-N-propylamino)-1,3,4,5- Tetrahydrobenz (cd) indole 79.8 mg (52,
8%).
無色プリズム晶 （メタノール−水）融 点 ＋
１７９．０ 〜１８０．０℃ＩＲ（ＫＢｒ）
シー、ｌ’ ３２６３．１６１６ ｃｍ−’’Ｈ−Ｎ
ＭＲ（ＣＤＣｌ２）
δ： ０．９１（３ｆｔ、 ｔ、 Ｊ＝７Ｈｚ＞、 １
．０９ ａｎｄ １．１６（１：ｌ、 ｔｏｔａｌ ３
）１． ｅａｃｈ ｔ、 Ｊ＝７Ｈｚ）、 １．３８〜
１．８８（２）１． ｍ）、 １．７４（３ｔ（、ｂ
ｒ−ｓ）、 １．８２（３ｆｔ、 ｂｒ−ｓ）、 ２
．３２（２Ｈ，Ｑ、 Ｊ＝７ｔｌｚ）、 ２．６８〜３
．６８ （４）１． ｍ） 、 ３．９２〜４．６０
（２８，ｍ） 。Colorless prismatic crystal (methanol-water) Melting point +
179.0 ~ 180.0℃ IR (KBr) Sea, l' 3263.1616 cm-''H-N
MR (CDCl2) δ: 0.91 (3ft, t, J=7Hz>, 1
．． 09 and 1.16 (1:l, total 3
)1. each t, J=7Hz), 1.38~
1.88(2)1. m), 1.74(3t(,b
r-s), 1.82 (3ft, br-s), 2
．． 32 (2H, Q, J=7tlz), 2.68~3
．． 68 (4)1. m), 3.92-4.60
(28, m).
４．９２〜５．２０（ＩＨ，ｍ＞、 ６．６０〜６．９
０（２Ｈ。4.92-5.20 (IH, m>, 6.60-6.9
0 (2H.
ｍ）、 ６．９６〜７．１７（２ｔｌ、 ｍ）、 ７．
９２ ａｎｄ ８、ｏ５（１：ｌ ｔｏｔａｌ ＩＩＬ
ｅａｃｈ ｂｒ−ｓ、 ＮＨ）ＣＩＭＳ ：
ｍ／ｚ ３２４ （Ｍ＋１）元素分析値’
（Ｃ２＋ｔ１２ｅＮ＊０ トＬ テ）６％ Ｎ
％ Ｎ％m), 6.96-7.17 (2tl, m), 7.
92 and 8, o5 (1:l total IIL
each br-s, NH) CIMS:
m/z 324 (M+1) Elemental analysis value'
(C2+t12eN*0 トL TE)6% N
%N%
Claims (5)
、Ｒ＾２は水素原子または炭素数１〜６の低級アルキル
基である）で表される１，３，４，５−テトラヒドロベ
ンズ〔ｃｄ〕インドール誘導体。(1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. A 1,3,4,5-tetrahydrobenz[cd]indole derivative represented by
）で表される特許請求の範囲第１項記載の１，３，４，
５−テトラヒドロベンズ〔ｃｄ〕インドール誘導体。(2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^1 in the formula is a lower alkyl group having 1 to 5 carbon atoms) 1, 3, 4,
5-tetrahydrobenz[cd]indole derivative.
−テトラヒドロベンズ〔ｃｄ〕インドール誘導体。(3) 1, 3, 4, 5 described in claim 1 expressed by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
-Tetrahydrobenz[cd]indole derivative.
−テトラヒドロベンズ〔ｃｄ〕インドール誘導体。(4) 1, 3, 4, 5 described in claim 2 expressed by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
-Tetrahydrobenz[cd]indole derivative.
−テトラヒドロベンズ〔ｃｄ〕インドール誘導体。(5) 1, 3, 4, 5 described in claim 2 expressed by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
-Tetrahydrobenz[cd]indole derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29970786A JPS63154660A (en) | 1986-12-16 | 1986-12-16 | 1,3,4,5-tetrahydrobenz(cd)indole derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP29970786A JPS63154660A (en) | 1986-12-16 | 1986-12-16 | 1,3,4,5-tetrahydrobenz(cd)indole derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63154660A true JPS63154660A (en) | 1988-06-27 |
| JPH0569825B2 JPH0569825B2 (en) | 1993-10-01 |
Family
ID=17875994
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP29970786A Granted JPS63154660A (en) | 1986-12-16 | 1986-12-16 | 1,3,4,5-tetrahydrobenz(cd)indole derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63154660A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0737670A1 (en) * | 1995-04-14 | 1996-10-16 | Adir Et Compagnie | Tricyclic amides, processes for their preparation, and pharmaceutical compositions containing them |
-
1986
- 1986-12-16 JP JP29970786A patent/JPS63154660A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0737670A1 (en) * | 1995-04-14 | 1996-10-16 | Adir Et Compagnie | Tricyclic amides, processes for their preparation, and pharmaceutical compositions containing them |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0569825B2 (en) | 1993-10-01 |
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