KR800001702B1 - Process for preparing homophthalimides - Google Patents

Process for preparing homophthalimides Download PDF

Info

Publication number
KR800001702B1
KR800001702B1 KR1019800000824A KR800000824A KR800001702B1 KR 800001702 B1 KR800001702 B1 KR 800001702B1 KR 1019800000824 A KR1019800000824 A KR 1019800000824A KR 800000824 A KR800000824 A KR 800000824A KR 800001702 B1 KR800001702 B1 KR 800001702B1
Authority
KR
South Korea
Prior art keywords
dimethyl
isoquinolyl
dioxo
dihydro
compound
Prior art date
Application number
KR1019800000824A
Other languages
Korean (ko)
Inventor
하르트 쿠터 에베르
아우스텔 플크하르트
에베르라인 볼프강
하이더 요아힘
코빙거 발터
리리에 크리스티안
카다쯔 루돌프
Original Assignee
닥터. 칼토매 지엠 비 에이치
쿠터, 좀머
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 닥터. 칼토매 지엠 비 에이치, 쿠터, 좀머 filed Critical 닥터. 칼토매 지엠 비 에이치
Priority to KR1019800000824A priority Critical patent/KR800001702B1/en
Application granted granted Critical
Publication of KR800001702B1 publication Critical patent/KR800001702B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Title compds.(I; A and B are optionally Me or Ph substituted C2-4 alkylene; R1, R2, R3 and R4 are H, halo, OH, NH2, alkoxy, alkylthio; R5, R6, R7 and R8 are H, alkyl, Ph ; R5R6 and R7R8 = (CH2)n; n = 2-5) were prepd. by reaction of II(Z = halogen) and III. Thus, 2.7 g 4.4-dimethyl-w-(3-chloropropy1-2,3,4-tetrahydro-isoquinolyl-dione-1,3,2.8 g 4,4-dimethy1-2-(2-methylaminoethyl)-1,2,3,4-tetrahydro-isoquinolinedione-1,3-hydrochloride were heated with 2.24 g potassium-tert-bu-thoxide in glycol at 1600C, followed by addn. of fumaric acid to give I.

Description

호모프탈이미드류의 제조방법Manufacturing Method of Homophthalimides

본 발명은 부정맥 치료에 유효한 작용을 갖는 다음 구조식(Ⅰ)화합물 및 이의 산부가염의 제조방법에 관한 것이다.The present invention relates to the following formula (I) compound having an effective action in the treatment of arrhythmia and a method for preparing acid addition salts thereof.

Figure kpo00001
Figure kpo00001

상기 구조식에서In the above structural formula

A와 B는 메틸 또는 페닐그룹으로 임의로 치환된 탄소수 2 내지 4인 직쇄 포화 알킬렌그룹이며, 같거나 다를 수 있고A and B are straight chain saturated alkylene groups having 2 to 4 carbon atoms optionally substituted with methyl or phenyl groups, and may be the same or different.

R1, R2, R3와 R4는 수소, 불소, 염소 또는 브롬, 하이드록시, 아미노, 니트로 또는 아세틸아미노, 알킬부분의 탄소수가 1 내지 3인 알킬, 알콕시 또는 알킬티오그룹이며 같거나 다를 수 있고,R 1 , R 2 , R 3 and R 4 are hydrogen, fluorine, chlorine or bromine, hydroxy, amino, nitro or acetylamino, alkyl, alkoxy or alkylthio groups having 1 to 3 carbon atoms in the alkyl moiety and are the same or different. Can,

R5, R6R7과 R8는 수소, 페닐 또는 메톡시페닐그룹으로 임의로 치환된 탄소수 1 내지 4인 알킬이며, 같거나 다를 수 있고 R5는 R6과 함께, R7은 R8과 함께 탄소수 2 내지 5인 직쇄인 포화 알킬렌그룹이고,R 5 , R 6 R 7 and R 8 are alkyl having 1 to 4 carbon atoms optionally substituted with hydrogen, phenyl or methoxyphenyl group, may be the same or different and R 5 together with R 6 , R 7 with R 8 Together are a saturated alkylene group having 2 to 5 carbon atoms,

R9은 수소 또는 페닐로 임의로 치환된 탄소수 1 내지 6인 알킬이다.R 9 is alkyl having 1 to 6 carbon atoms optionally substituted with hydrogen or phenyl.

본 발명에 따른 바람직한 화합물에는 R1및／또는 R3가 수소 또는 메톡시그룹인 화합물류, R2및／또는 R4가 수소, 불수 또는 브롬, 메틸, 메톡시, 에톡시, 이소프로폭시 메틸티오, 니트로, 아미노 또는 아세틸아미노 그룹인 화합물류, R5,R6,R7및／또는 R8이 수소, 메틸, 에틸, 프로필, 이소프로필, 부틸, 벤질, P-메톡시벤질 또는 페닐프로필그룹인 화합물류와 R5가 R6와 함께 또는 R7이 R8과 함께 에틸렌, 부틸렌 또는 펜틸렌그룹인 화합물류, A 및／또는 B가 에틸렌, 1-메틸-에틸렌, 1-페닐-에틸렌, 프로필렌, 1-또는 3-메틸-프로필렌 또는 부틸렌그룹인 화합물류와 R9은 수소, 메틸 에틸, 프로필, 이소프로필, 부틸, n-헥실, 벤질, 페닐에틸 또는 페닐프로필 그룹인 화합물류이다.Preferred compounds according to the invention include compounds in which R 1 and / or R 3 are hydrogen or methoxy groups, R 2 and / or R 4 is hydrogen, insoluble or bromine, methyl, methoxy, ethoxy, isopropoxy methyl Compounds which are thio, nitro, amino or acetylamino groups, R 5 , R 6 , R 7 and / or R 8 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, benzyl, P-methoxybenzyl or phenylpropyl Compounds which are groups and compounds in which R 5 is together with R 6 or R 7 together with R 8 is an ethylene, butylene or pentylene group, A and / or B is ethylene, 1-methyl-ethylene, 1-phenyl- Compounds which are ethylene, propylene, 1- or 3-methyl-propylene or butylene groups, and R 9 is hydrogen, methyl ethyl, propyl, isopropyl, butyl, n-hexyl, benzyl, phenylethyl or phenylpropyl groups to be.

구조식(Ⅰ)화합물과 그의 산부 가염류는 약학적 활성을 지니고 있으며 특히 부정맥 치료작용을 갖는다.Structural Formula (I) compounds and their acid salts have pharmaceutical activity, particularly arrhythmia treatment.

구조식(Ⅰ)인 새로운 화합물은 다음 구조식(Ⅱ)의 이소퀴놀린-디온을 다음 구조식(III)의 호모프탈이마이드와 반응시켜 제조한다.A new compound of formula (I) is prepared by reacting isoquinoline-dione of formula (II) with homophthalimide of formula (III).

Figure kpo00002
Figure kpo00002

상기 구조식에서In the above structural formula

R1, R2, R5, R6와 A는 상기와 같고,R 1 , R 2 , R 5 , R 6 and A are the same as above,

Z는 할로겐원자와 같은 친핵 치환할 수 있는 그룹이고,Z is a nucleophilic substitutable group such as a halogen atom,

R3, R4, R7, R8,R9과 B는 상기와 같다.R 3 , R 4 , R 7 , R 8 , R 9 and B are the same as above.

반응은 임의로 메탄올, 에테르, 테트라하이드로푸란, 디메틸포름아마이드,디메틸설폭사이드, 에틸렌글라이콜 또는 벤젠과 같은 용매존재하에서, 그룹의 반응성에 따라 변화시킬 수 있는 -50 내지 250℃의 온도에서, 그러나 바람직하기로는 사용된 용매의 비점에서 반응을 진행시킨다. 알코올레이트, 수산화알카리금속 또는 탄산 알카리금속염과 같은 산 결합제 또는 피리딘과 같은 3급 유기염기 존재하에서 반응시키는 것이 유용하다.The reaction is optionally at a temperature of -50 to 250 ° C., which may vary depending on the reactivity of the group, in the presence of a solvent such as methanol, ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, ethylene glycol or benzene. Preferably the reaction proceeds at the boiling point of the solvent used. It is useful to react in the presence of an acid binder such as an alcoholate, an alkali metal hydroxide or an alkali metal carbonate salt or a tertiary organic base such as pyridine.

적어도 R5-R9그룹중의 하나가 수소이거나 또는 R1-R4가 하이드롭시그룹인 구조식(Ⅰ)화합물은 본 발명에 따라 얻으면 이 화합물을 알킬화에 의해 알킬화된 구조식(Ⅰ)화합물로 전환시킬 수 있으며 R1-R4중의 적어도 하나가 수소인 구조식(Ⅰ)화합물을 얻으면 이 화합물을 니트로화에 의해 구조식(Ⅰ)인 니트로화합물로 전환시킬 수 있으며 니트화된 화합물은 환원에 의해 아미노화합물로 전환시킬 수 있으며 이어서 아세틸화하여 상응하는 아세틸아미노 아미노 화합물로 전환시킬 수 있다.A compound of formula (I) wherein at least one of the groups R 5 -R 9 is hydrogen or R 1 -R 4 is a hydroxy group, when obtained according to the invention, converts this compound to a compound of formula (I) alkylated by alkylation. Once a compound of formula (I) is obtained in which at least one of R 1 -R 4 is hydrogen, the compound can be converted to a nitro compound of formula (I) by nitration, and the nitrated compound is amino by reduction. The compound can be converted and then acetylated to the corresponding acetylamino amino compound.

알킬화는 상응하는 알킬할라이드 또는 디알킬설페이트로 실시하는 것이 바람직하며 에탄올, 디메틸포름아마이드, 디메틸설폭사이드 또는 헥사메틸-인산 트리아마이드와 같은 용매중에서, 탄산칼슘, 수산화나트륨, 나트륨에톡사이드 또는 칼륨 3급-부톡사이드와 같은 염기 존재하가 바람직하며 온도는 20 내지 200℃이나 바람직한 온도는 60 내지 160℃이다. R9이 수소인 메틸화될 수 있는 구조식(Ⅰ)화합물은 반응혼합물의 비점하에서 포름알데히드／포름산으로 반응하여 또한 메틸화할 수 있다.The alkylation is preferably carried out with the corresponding alkyl halide or dialkylsulfate and in a solvent such as ethanol, dimethylformamide, dimethylsulfoxide or hexamethyl-phosphate triamide, calcium carbonate, sodium hydroxide, sodium ethoxide or potassium 3 Presence of a base such as a but-butoxide is preferred and the temperature is from 20 to 200 ° C. but the preferred temperature is from 60 to 160 ° C. The methylated compound of formula (I) wherein R 9 is hydrogen can also be methylated by reacting with formaldehyde / formic acid under the boiling point of the reaction mixture.

더욱이 본 발명에 따른 구조식(Ⅰ)화합물은 필요에 따라 무기 또는 유기산으로 약학적 무독한 산부가염으로 전환시킬 수 있다. 산으로서 예를 들면 염산, 브롬화수소산, 황산, 락트산, 시트르산, 타타르산, 말레인산 또는 푸마르산이 적합하다.Furthermore, the compound of formula (I) according to the present invention can be converted into inorganic or organic acids into pharmaceutically harmless acid addition salts as necessary. Suitable acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, lactic acid, citric acid, tartaric acid, maleic acid or fumaric acid.

출발물질로 사용 사용된 화합물은 문헌에 알려진 기지의 방법 또는 실시예에 기술된 방법에 따라 얻는다. 상기에서 언급된 바와 같이, 구조식(Ⅰ)화합물과 그의 산부 가염은 약학적으로 유효한 작용을 가졌으며 특히 부정맥치료작용을 갖는다.The compounds used as starting materials are obtained according to known methods known in the literature or according to the methods described in the examples. As mentioned above, the structural formula (I) compound and its acid salts have a pharmaceutically effective action, in particular arrhythmia.

부정맥 치료작용을 시험한 화합물의 예를 들면 다음과 같다.Examples of compounds tested for arrhythmia treatment are as follows.

A＝비스-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민A = bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine

B＝비스-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로핀]-아민,B = bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyn] -amine,

C＝비스-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-비스]-에틸아민,C = bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -bis] -ethylamine,

D＝[2-(3,4-디하이드로-7-메톡시-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-에틸]-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민,D = [2- (3,4-Dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3, 4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine,

E＝[2-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-에틸]-[3-(3,4-디하이드로-7-메톡시-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민,E = [2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3,4-dihydro- 7-methoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine,

F＝비스-[2-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-에틸]-메틸아민,F = bis- [2- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl] -methylamine,

G＝[2-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-에틸]-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-아민,G = [2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3,4-dihydro- 4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine,

H＝[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-[4-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-부틸]-아민,H = [3- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-[4- (3,4-dihydro- 4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -butyl] -amine,

I＝비스-[2-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-에틸]-아민,I = bis- [2- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl] -amine,

J＝[2-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴-에틸]-[4-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-부틸]-아민,J = [2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl-ethyl]-[4- (3,4-dihydro-4 , 4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -butyl] -amine,

1. 모르모트의 분리해낸, 전기적으로 자극을 준 심장의 왼쪽심이(心耳)의 유효 불응기에 대한 작용1. The action of effective mortality of the left ventricle of the electrically stimulated heart, isolated from mormot

[방법][Way]

성별의 구별없이 모르모트를 목에 일격을 가하여 죽인다. 흉부를 절개한 후 심장을 재빨리 제거하여 37℃의 티로이드용액(Tyrode)속에 옮겨 놓는다. 심이를 절개하여 왼쪽심이만을 사용한다. 전기적 자극은 그라스 자극기 S4G로 10-3초 동안의 구(矩)형과 자극과 12V의 자극으로 행해진다.Mormor is killed by striking a neck, regardless of gender. After the incision in the chest, the heart is quickly removed and transferred to Tyrode at 37 ° C. Cut the seam and use only the left seam. Electrical stimulation is carried out with a glass stimulator S4G, with a spherical shape for 10 -3 seconds and a stimulus of 12V.

심이를 NaCl 136.8 ; KCl 2.68 ; MgCl20.2625 ; NaH2PO40.417 ; NaHCO311.9 ; CaCl 1.8(mval/ℓ) ; 포도당 3g을 함유한 37℃의 티로이드 용액중에 현탁시킨다. 용액은 98％의 산소와 2％ 탄산가스로 끊임없이 산화시킨다. 수축현상을 힘전환장치로 측정하여 그라스-풀리그라프(P5)에 기록한다.Shim NaCl 136.8; KCl 2.68; MgCl 2 0.2625; NaH 2 PO 4 0.417; NaHCO 3 11.9; CaCl 1.8 (mval / L); It is suspended in a 37 ° C. thyroid solution containing 3 g of glucose. The solution is constantly oxidized with 98% oxygen and 2% carbon dioxide. Shrinkage is measured with a force converter and recorded on a glass-plygraph (P5).

심이는 0.5헤르쯔로 수축을 한다. 최고 박동수를 매 10초마다 자극율을 1헤르쯔씩 증가시켜 측정한다. 측정은 시험 약물을 가하기전 매 5분마다 3회 행하고 가한 후 5분과 10분에 측정한다. 측정시간 간격동안의 자극율을 0.5헤르쯔이다. 약물의 효과는 약물을 가한 후 5분과 10분의 최고 박동수의 변화를 계산하여서 한다. 약물은 농도를 증가시켜가며 시험하여 용량-반응곡선을 작성하여 EC50을 계산해낸다.Sims contract at 0.5 hertz. The maximum heart rate is measured by increasing the stimulus rate by 1 hertz every 10 seconds. The measurement is made three times every 5 minutes before the test drug is added and at 5 and 10 minutes after the addition. The stimulation rate during the measurement time interval is 0.5 Hz. The effect of the drug is calculated by calculating the change in the maximum heart rate for 5 and 10 minutes after the drug is added. Drugs are tested at increasing concentrations to create a dose-response curve to calculate EC 50 .

[원리][principle]

최고 박동수는 자극율을 증가시켜가며 측정한다. 두 번의 자극사이의 기간이 짧을 때 매초마다의 자극으로 앞의 자극에 대한 수축후의 불응기에 해당되어 다음의 자극에 대해서는 반응이 나타나지 않는다. 그래서 최고 박동수는 유효한 불응기에 대한 측정이며 최고 박동수를 감소시키는 화합물은 불응기를 길게 연장시키는 화합물이다.Peak beats are measured with increasing stimulation rate. When the period between two stimuli is short, every second stimulus corresponds to post-contraction refractory to the previous stimulus, and no response occurs for the next stimulus. Thus, the highest beat rate is a measure of the effective refractory, and the compound that reduces the highest beat rate is a compound that prolongs the refractory.

[결과][result]

용량-반응 곡선으로부터 다음의 농도는 최고 박동수를 50％ 감소시키는 용량이며 이는 그래프로 처리하여 얻은 것이다.The next concentration from the dose-response curve is the dose that reduces the highest heart rate by 50%, which is obtained by treating the graph.

Figure kpo00003
Figure kpo00003

2. 쥐의 클로로포름으로 유도시킨 심실 세동에 대한 부정맥 치료효과2. Effect of Arrhythmia on Chloroform-Induced Ventricular Fibrillation in Rats

[방법][Way]

쥐를 클로로포름 기체로 포화된 곳에 놓은 후 40초후에 쥐는 마취되어지며 동시에 호흡기관이 멈추고 다시 20초후에는 헐떡거리는 것을 볼 수 있다. 호흡이 완전히 억제되었을 때 쥐를 클로로포름 기체가 있는 곳에서 꺼내서 흉부를 절개하고 재빨리 심장을 절당해내어 심장운동을 조사한다. 흉부를 절개한 후의 1분간은 거의 모든 동물에서 심실세동현상을 볼 수 있거나 이러한 현상이 없는 것일지라도 심장을 건드려서 이 현상을 유발시킬 수 있다.After placing the rat in a saturated area with chloroform gas, the rat is anesthetized 40 seconds later, and the respiratory system stops, and again, gasping 20 seconds later. When breathing is completely suppressed, the rat is removed from the presence of chloroform gas, incised to the chest, and quickly struck the heart to investigate cardiac movement. One minute after the incision of the chest, ventricular fibrillation can be seen in almost all animals, or even if it is not present, it can be caused by touching the heart.

부정맥 치료작용을 갖는 화합물로의 전처리는 용량에 따라 심실세동을 보이는 동물의 수를 감소시킨다. 심실 세동을 보이는 동물의 수를 50％ 감소시키는 용량은 용량-반응-곡선으로 계산하며 표준오차를 졔산한다.Pretreatment with a compound having an arrhythmic treatment reduces the number of animals showing ventricular fibrillation with dose. Doses that reduce the number of animals with ventricular fibrillation by 50% are calculated as dose-response-curve and estimate standard error.

[참조 : Miller. L. C. 와 Trinter, M.L, Proc. Soc. Exp. Biol. Med. 57, 261(1944)][Reference: Miller. L. C. and Trinter, M. L, Proc. Soc. Exp. Biol. Med. 57, 261 (1944)]

실험은 체중이 20 내지 25g인 숫컷쥐를 사용한다. 각용량을 10마리 쥐에 대해 시험한다.Experiments use male rats weighing 20-25 g. Each dose is tested on 10 rats.

약물은 심실 세동을 유발시키기 1분전에 정맥주사한다.The drug is injected intravenously 1 minute before triggering the ventricular fibrillation.

Figure kpo00004
Figure kpo00004

3. 급성 독성 시험3. Acute Toxicity Test

문제시 되는 화합물의 급성 독성은 경구 또는 정맥주사후 쥐를 사용하여 결정할 수 있다. (관찰시간 : 14일)Acute toxicity of the compound in question can be determined using oral or intravenous mice. (Observation time: 14 days)

LD50은 관찰시간내의 여러 용량 투여후의 치사율로부터 계산해낸다. (참조 : J.Pharmacol. ExP. Therap. 96, 99(1949))LD 50 is calculated from the mortality rate after administration of several doses within the observation time. (See J. Pharmacol. ExP. Therap. 96, 99 (1949))

Figure kpo00005
Figure kpo00005

그러므로 본 발명에 따른 구조식Ⅰ)화합물과 그의 약학적 무독염은 특히 심장의 부정맥 치료에 적합하며 약학적 투여는 통상의 약학적 제제인 정제, 코팅정, 현탁액, 좌제 또는 안정제로 다른 활성물질과 임의로 혼합하여 제조된 제제로 할 수 있다. 어른의 일회 복용량은 25 내지 50㎎이다.Therefore, the compound of formula I) and pharmaceutical non-toxic salt thereof according to the present invention are particularly suitable for the treatment of arrhythmia of the heart, and the pharmaceutical administration is optionally used with other active substances as tablets, coated tablets, suspensions, suppositories or stabilizers which are conventional pharmaceutical preparations. It can be made into the formulation prepared by mixing. The single dose for adults is 25-50 mg.

다음 실시예는 본 발명을 상술한다.The following examples detail the invention.

[실시예 1]Example 1

[2-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴-에틸]-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴프로필]-메틸아민,[2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl-ethyl]-[3- (3,4-dihydro-4,4 -Dimethyl-1,3-dioxo-2 (1H) -isoquinolylpropyl] -methylamine,

2.7g (0.01몰)의 4.4-디메틸-2-(3-클로로프로필)-1,2,3,4-테트라하이드로-이소퀴놀린-디온 1,3, 2.8g(0.01몰)의 4,4-디메틸-2-(2-메틸아미노-에틸)-1,2,3,4-테트라하이드로-이소퀴놀린-디온 1,3-하이드로클로라이드와 2.24g (0.02몰)의 칼륨-3급-부톡사이드를 30ml의 글라이콜중에서 5시간 동안 160℃까지 가열해준다. 냉각한후 물을 가하고 여러차례 클로로포름으로 추출한다. 유기층을 탈수하고 증발하고 실리카겔로 칼럼크로마토그라피하여 정제한다. 증발시킨 획분을 소량의 아세톤에 녹이고 200ml에 녹인 1ℓ의 푸마르산 용액과 혼합하고 20ml용량으로 증발 농축하여 에테르로 침전시킨다.2.7 g (0.01 mole) of 4.4-dimethyl-2- (3-chloropropyl) -1,2,3,4-tetrahydro-isoquinoline-dione 1,3, 2.8 g (0.01 mole) of 4,4- 2.24 g (0.02 mol) of potassium tert-butoxide with dimethyl-2- (2-methylamino-ethyl) -1,2,3,4-tetrahydro-isoquinoline-dione 1,3-hydrochloride Heat to 160 ° C. for 5 hours in 30 ml of glycol. After cooling, water is added and extracted with chloroform several times. The organic layer is dehydrated, evaporated and purified by column chromatography on silica gel. The evaporated fraction was dissolved in a small amount of acetone, mixed with 1 L of fumaric acid solution dissolved in 200 ml, concentrated to 20 ml, and precipitated with ether.

수율 : 37.2% (2.2g)Yield: 37.2% (2.2g)

융점 : 150 내지 151℃Melting Point: 150 ~ 151 ℃

[실시예 2]Example 2

[2-(3,4-디하이드로-7-메톡시-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-에틸]一[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민[2- (3,4-Dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl] 一 [3- (3,4- Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine

실시예 1과 유사한 방법으로 2.7g(0.01몰)의 4.4-디메틸-2-(3-클로로프로필)-1,2,3,4-테트라하이드로-이소퀴놀린-디온-1,3, 3.1g(0.01몰)의 4,4-디메틸-7-메톡시-2-(2-메틸아미노-에틸)-1,2,3,4-테트라하이드로-이소퀴놀린-디온-1,3-하이드로클로라이드와 2.24g(0.02몰)의 칼륨-3급-부톡사이드로부터 30ml의 글라이콜중에서 제조한다.In a similar manner to Example 1, 2.7 g (0.01 mol) of 4.4-dimethyl-2- (3-chloropropyl) -1,2,3,4-tetrahydro-isoquinoline-dione-1,3, 3.1 g ( 0.01 mole) of 4,4-dimethyl-7-methoxy-2- (2-methylamino-ethyl) -1,2,3,4-tetrahydro-isoquinoline-dione-1,3-hydrochloride and 2.24 Prepared in 30 ml of glycol from g (0.02 mol) potassium tert-butoxide.

수율 : 24.1 (1.5g)Yield: 24.1 (1.5 g)

융점 : 103 내지 105℃(분해)Melting Point: 103-105 ° C (Decomposition)

[실시예 3]Example 3

[2-(3,4-디하이드로-7-메톡시-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-에틸]-[3-(3,4-디하이드로-7-메톡시-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민[2- (3,4-Dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3,4- Dihydro-7-methoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine

실시예 1)과 유사한 방법으로 30ml의 글라이콜 중의 3g(0.01몰)의 4.4-디메틸-7-메톡시-2-(3-클로로프로필)-1,2,3,4-테트라하이드로-이소퀴놀린-디온-1,3, 3.1g(0.01몰)의 4,4-디메틸-7-메톡시-2-(2-메틸아미노-에틸)-1,2,3,4-테트라하이드로-이소퀴놀린-디온-1,3-하이드로클로라이드와 2.24g(0.02몰)의 칼륨-3급-부톡사이드로부터 제조되어 진다.3 g (0.01 mol) of 4.4-dimethyl-7-methoxy-2- (3-chloropropyl) -1,2,3,4-tetrahydro-iso in 30 ml of glycol in a similar manner to Example 1) Quinoline-dione-1,3, 3.1 g (0.01 mol) of 4,4-dimethyl-7-methoxy-2- (2-methylamino-ethyl) -1,2,3,4-tetrahydro-isoquinoline It is prepared from dione-1,3-hydrochloride and 2.24 g (0.02 mol) of potassium tert-butoxide.

수율 : 16.9 (1.1g)Yield: 16.9 (1.1 g)

융점 : 142 내지 143℃Melting Point: 142-143 ℃

[실시예 4]Example 4

[2-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-에틸]-[3-(3,4-디하이드로-7-메톡시-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민[2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3,4-dihydro-7- Methoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine

실시예 1과 유사한 방법으로 30ml의 글라이콜 중의 3g(0.01몰) 4.4-디메틸-7-메톡시-2-(3-클로로프로필)-1,2,3,4-테트라하이드로-이소퀴놀린-디온-1,3, 2.8g(0.01몰)의 4,4-디메틸-2-(2-메틸아미노-에틸)-1,2,3,4-테트라하이드로-이소퀴놀린-디온-1,3과 2.24g(0.02몰)의 칼륨-3급-부톡사이드로부터 제조된다.3 g (0.01 mole) 4.4-dimethyl-7-methoxy-2- (3-chloropropyl) -1,2,3,4-tetrahydro-isoquinoline- in 30 ml of glycol in a similar manner to Example 1 Dione-1,3, 2.8 g (0.01 mol) of 4,4-dimethyl-2- (2-methylamino-ethyl) -1,2,3,4-tetrahydro-isoquinoline-dione-1,3 Prepared from 2.24 g (0.02 mol) of potassium tert-butoxide.

실시예 1내지 4에 따라 다음 화합물을 제조한다.The following compounds are prepared according to Examples 1-4.

[2-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-에틸]-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-(2-페닐에틸)-아민[2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3,4-dihydro-4, 4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-(2-phenylethyl) -amine

무색의 기름Colorless oil

계산치 : C 74.31, H 6.95, N 7.43Calculated Value: C 74.31, H 6.95, N 7.43

실측치 : C 74.10, H 7.06, N 7.41Found: C 74.10, H 7.06, N 7.41

비스-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-벤질아민Bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -benzylamine

융점 : 108℃Melting Point: 108 ℃

비스-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민Bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine

융점 : 156 내지 158℃Melting Point: 156 to 158 ° C

비스-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-아민Bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine

융점 : 170 내지 172℃Melting Point: 170-172 ° C

비스-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-에틸아민Bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -ethylamine

융점(푸마르산염) : 141 내지 142℃Melting Point (Fumarate): 141 to 142 ° C

[2-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-에틸]-[3-(3,4-디하이드로-7-메톡시-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민[2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3,4-dihydro-7- Methoxy-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine

융점 : 158℃Melting Point: 158 ℃

비스-[2-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-에틸]-메틸아민Bis- [2- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl] -methylamine

융점 : 106 내지 107℃Melting Point: 106 to 107 ° C

[2-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-에틸]-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-아민[2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3,4-dihydro-4, 4-Dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine

융점(푸마르산염) : 205 내지 206℃Melting Point (Fumarate): 205 to 206 ° C

[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-[4-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1)-이소퀴놀릴)-부틸]-아민[3- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-[4- (3,4-dihydro-4, 4-dimethyl-1,3-dioxo-2 (1) -isoquinolyl) -butyl] -amine

융점(푸마르산염) : 90 내지 95℃Melting Point (Fumarate): 90-95 ° C

비스-[2-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-에틸]-아민Bis- [2- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl] -amine

융점(푸마르산염) : 207 내지 208℃Melting Point (Fumarate): 207 to 208 ° C

[2-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-에틸]-[4-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-부틸]-아민[2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[4- (3,4-dihydro-4, 4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -butyl] -amine

융점(푸마르산염) : 181 내지 182℃Melting Point (Fumarate): 181 to 182 ° C

[실시예 5]Example 5

[2-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴에틸]-[3(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-(2-페닐에틸)-아민[2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolylethyl]-[3 (3,4-dihydro-4,4-dimethyl -1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-(2-phenylethyl) -amine

5.8g의 [2-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)- 에틸]-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-암모늄-푸마르산 염을 100ml의 디메틸포름 아마이드에 녹이고 2.8g의 탄산칼륨과 1.85g의 2-페닐-에틸브로마이드와 혼합하고 4시간 동안 환류 시킨다. 디메틸포름아마이드를 증발시킨 후에 물을 가하고 혼합물을 클로로포름으로 추출하고 실리카겔로 정제한다(용출제 : 클로로포름／아세톤＝19 : 1) 무색인 기름상 물질을 얻는다.5.8 g of [2- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -ethyl]-[3- (3,4-dihydro -4,4-Dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -ammonium-fumaric acid salt was dissolved in 100 ml of dimethylformamide and 2.8 g of potassium carbonate and 1.85 g of 2- Mix with phenyl-ethyl bromide and reflux for 4 hours. After evaporating dimethylformamide, water is added and the mixture is extracted with chloroform and purified by silica gel (eluent: chloroform / acetone = 19: 1) to give a colorless oily substance.

수율 : 55％(3.1g)Yield: 55% (3.1 g)

분석analysis

계산치 : C 74.31, H 6.95, N 7.43Calculated Value: C 74.31, H 6.95, N 7.43

실측치 : C 74.10, H 7.06, N 7.41Found: C 74.10, H 7.06, N 7.41

[실시예 6]Example 6

비스-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민Bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine

2.35g의 비스-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀 릴)-프로필]-메틸아민-염산염과 5.42g의 에틸 요다이드를 100㎖ 에탄올 중에서 가열 환류시키고 10㎖ 물에 녹인 108g의 수산화나트륨 용액을 적가 해준다. 혼액을 60℃에서 1.5시간 더 교반해준 후 용매를 증발 제거하고 물을 가한다. 혼액을 에틸 아세테이트로 추출한다. 실리카겔을 충진한 컬럼으로 정제한 후 (용출제 : 클로로포름 ／ 에탄올＝19 : 1) 염산염을 에테르성 염산으로 아세톤 중에서 침전시킨다.2.35 g of bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine-hydrochloride with 5.42 g Ethyl iodide was heated to reflux in 100 ml ethanol and 108 g of sodium hydroxide solution dissolved in 10 ml water was added dropwise. The mixture was stirred at 60 ° C. for 1.5 hours more, the solvent was then evaporated off and water was added. The mixture is extracted with ethyl acetate. After silica gel was purified by a packed column (eluent: chloroform / ethanol = 19: 1) hydrochloride was precipitated in acetone with etheric hydrochloric acid.

수율 : 5.8％(0.17g)Yield: 5.8% (0.17 g)

응융점(염산염) : 135내지 140℃(70℃부터 반융상태)Freezing point (hydrochloride): 135-140 ℃ (semi-melting from 70 ℃)

[실시예 7]Example 7

[3-(3,4-디하이드로-4,4-디메틸-7-에톡시-1,3-디옥소-2(1)-이소퀴놀릴)-프로필]-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민[3- (3,4-Dihydro-4,4-dimethyl-7-ethoxy-1,3-dioxo-2 (1) -isoquinolyl) -propyl]-[3- (3,4- Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine

1.3g의 [3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민을 10ml의 무수에탄올에 녹여서 10ml 무수 에탄올에 녹인 0.06g의 나트륨 용액을 가하고 0.42g의 에틸요다이드와 혼합한다. 혼합물을 0.5시간 동안 환류시키고 동량의 에틸 요다이드를 가하고 다시 0.5시간동안 환류시킨다. 생성물을 실리카겔 컬럼으로 정제하고 (용출제 : 클로로포름／에탄올＝25 : 1) 염산염을 에테르성 염산으로 아세톤 중에서 침전시킨다.1.3 g of [3- (3,4-Dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-[3- (3,4-dihydro -4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine was dissolved in 10 ml of anhydrous ethanol, 0.06 g of sodium solution dissolved in 10 ml of anhydrous ethanol was added, and 0.42 g of Mix with ethyl iodide. The mixture is refluxed for 0.5 h, the same amount of ethyl iodide is added and refluxed again for 0.5 h. The product is purified by silica gel column (eluent: chloroform / ethanol = 25: 1) hydrochloride to precipitate in acetone with etheric hydrochloric acid.

수율 : 35％(0.5g)Yield: 35% (0.5 g)

반융점(염산염) : 45℃이상Semi-melting point (hydrochloride): 45 ℃ or more

[실시예 8]Example 8

비스-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-n-헥실-아민Bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -n-hexyl-amine

실시예 5와 유사한 방법으로 2.6g의 비스-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-아민과 1g의 n-헥실브로마이드로부터 제조되어 진다.2.6 g bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine in a similar manner to Example 5 And 1 g of n-hexylbromide.

수율 : 50％(1.7g)Yield: 50% (1.7 g)

융점(푸마르산염) : 137 내지 138℃Melting Point (Fumarate): 137 to 138 ° C

[실시예 9]Example 9

비스-[3-(1,2,3,4-테트라하이드로-1,3-디옥소-이소퀴놀릴)-4-스피로사이클로헥신-2-일)-프로필]-메틸아민Bis- [3- (1,2,3,4-tetrahydro-1,3-dioxo-isoquinolyl) -4-spirocyclohexyn-2-yl) -propyl] -methylamine

실시예 5와 유사한 방법으로 비스-[3-(3,4-디하이드로-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민과 4.0g의 1,5-디브로모펜탄으로부터 제조되어진다.In a manner similar to Example 5, 4.0 g of 1,5- with bis- [3- (3,4-dihydro-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine It is prepared from dibromopentane.

수율 : 2.6％(0.12g)Yield: 2.6% (0.12 g)

융점(염산염) : 183 내지 185℃Melting point (hydrochloride): 183 to 185 ° C

[실시예 10]Example 10

비스-[3-(3,4-디하이드로-4-이소프로필-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민Bis- [3- (3,4-dihydro-4-isopropyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine

실시예 9와 유사한 방법으로 4.7g의 비스-[3-(3,4-디하이드로-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필-메틸아민과 3.05g의 이소프로필 브로마이드로부터 제조되어진다.In a similar manner to Example 9, 4.7 g of bis- [3- (3,4-dihydro-1,3-dioxo-2 (1H) -isoquinolyl) -propyl-methylamine and 3.05 g of isopropyl Prepared from bromide.

수율 : 2.2％(0.12g)Yield: 2.2% (0.12 g)

융점(염산염) : 204 내지 206℃Melting point (hydrochloride): 204-206 degreeC

[실시예 11]Example 11

비스-[3-(1,2,3,4-테트라하이드로-1,3-디옥소-이소퀴놀린-4-스피로사이클로프로판-2-일)-프로필]-메틸아민Bis- [3- (1,2,3,4-tetrahydro-1,3-dioxo-isoquinolin-4-spirocyclopropan-2-yl) -propyl] -methylamine

실시예 6과 유사한 방법으로 3.6g의 비스-[3-(3,4-디하이드로-1,3-디옥소-2(1JH)-이소퀴놀릴)-프로필]-메틸아민과 3.3g의 1,2-디브로모에탄이 제조된다.In a similar manner to Example 6, 3.6 g of bis- [3- (3,4-dihydro-1,3-dioxo-2 (1JH) -isoquinolyl) -propyl] -methylamine and 3.3 g of 1 , 2-dibromoethane is prepared.

수율 : 1.3％(0.05g)Yield: 1.3% (0.05 g)

융점(염산염) : 192 내지 196℃Melting point (hydrochloride): 192 to 196 ° C

[실시예 12]Example 12

비스-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-(3-페닐프로필)-아민Bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl]-(3-phenylpropyl) -amine

1.8g의 3-페닐 브로모프로판과 20㎖ 물에 녹인 0.96g의 수산화나트륨용액을 소량씩 70℃에서 2.56g의 비스-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-아민의 염산염용액을 가해준다. 16시간후 혼액을 물에 가하고 에틸아세테이트로 추출한 후 증발시키고 얻어진 잔사를 실리카겔로 정제한다.(용출액 : 클로로포름／에탄올＝19 : 1)1.8 g of 3-phenyl bromopropane and 0.96 g of sodium hydroxide solution dissolved in 20 ml of water were added in small portions at 70 ° C. to 2.56 g of bis- [3- (3,4-dihydro-4,4-dimethyl-1 A hydrochloride solution of, 3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine is added. After 16 hours, the mixed solution was added to water, extracted with ethyl acetate and evaporated. The obtained residue was purified by silica gel (eluate: chloroform / ethanol = 19: 1).

염산염을 에테르성 염산으로 에틸 아세티이트중에서 침전시킨다.Hydrochloride is precipitated in ethyl acetate with etheric hydrochloric acid.

수율 : 4.2％(0.13g)Yield: 4.2% (0.13 g)

융점(염산염) : 135℃Melting Point (HCl): 135 ℃

[실시예 13]Example 13

비스-[3-(3,4-디하이드로-4,4-디메틸-7-아세트아미노-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민Bis- [3- (3,4-dihydro-4,4-dimethyl-7-acetamino-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine

3.25g의 비스-[3-(3,4-디하이드로-4,4-디메틸-7-아미노-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민-트리하이드라이드를 70㎖의 무수 아세트산중에 현탁시키고 실온에서 2시간동안 교반해준다. 혼약을 얼음에 가하고 암노니아성으로 해준 후 클로로포름으로 추출하고 증발한 후 얻어진 잔사를 실리카겔을 사용한 컬럼크로마토그라피로 정제한다.(용출제 : 클로로포름／메탄올＝9 : 1)3.25 g Bis- [3- (3,4-Dihydro-4,4-dimethyl-7-amino-1, 3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine-tri The hydride is suspended in 70 ml of acetic anhydride and stirred at room temperature for 2 hours. The mixture was added to ice, made ammonia, extracted with chloroform, evaporated, and the residue was purified by column chromatography using silica gel (eluent: chloroform / methanol = 9: 1).

염산염은 에테르성 염산으로 에탄올중에서 침전시키며 이소프로판올로 재결정한다.Hydrochloride is precipitated in ethanol with etheric hydrochloric acid and recrystallized from isopropanol.

수율 : 54％(1.8g)Yield: 54% (1.8 g)

융점(염산염) : 175℃Melting Point (HCl): 175 ℃

[실시예 14]Example 14

비스-[3-(3,4-디하이드로-4,4-디메틸-7-아미노-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸아민Bis- [3- (3,4-dihydro-4,4-dimethyl-7-amino-1, 3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylamine

5.3g의 비스-[3-(3,4-디하이드로-4,4-디메틸-7-니트로-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸암모늄-나이트레이트를 100㎖의 메탄올에 녹이고 10㎖의 메탄올성 염산과 0.6g의 10％ 팔라듐／목탄을 가하고 혼합물을 5기압 수소압, 실온에서 환원시킨다. 촉매를 흡인여과하고 용매를 제거하고 잔사를 물로 처리한다. 용액을 메틸렌 클로라이드로 추출하고 암모니아성으로 해준 후 다시 메틸렌 클로라이드로 추출한다. 메틸렌 클로라이드층을 증발하고 잔사를 에탄올에 녹이고 3염산염을 에테르성 염산으로 침전시킨다.5.3 g bis- [3- (3,4-dihydro-4,4-dimethyl-7-nitro-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylammonium-knight The rate is dissolved in 100 ml of methanol, 10 ml of methanolic hydrochloric acid and 0.6 g of 10% palladium / charcoal are added, and the mixture is reduced at 5 atmospheres of hydrogen pressure and room temperature. The catalyst is suction filtered, the solvent is removed and the residue is treated with water. The solution is extracted with methylene chloride and ammonia is extracted again with methylene chloride. The methylene chloride layer is evaporated and the residue is taken up in ethanol and the trichloride is precipitated with etheric hydrochloric acid.

수율 : 63％(3.25g)Yield: 63% (3.25 g)

융점(3염산염) : 225℃Melting Point (Trihydrochloride): 225 ℃

[실시예 15]Example 15

비스-[3-(3,4-디하이드로-4,4-디메틸-7-니트로-2(1H)-이소퀴놀릴)-프로필]-메틸아민Bis- [3- (3,4-dihydro-4,4-dimethyl-7-nitro-2 (1H) -isoquinolyl) -propyl] -methylamine

5g의 비스-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-메틸암묘늄-푸마르산염을 50ml의 발연질산에 -20°내지 30℃에서 가해주고 -25℃에서 40분간 교반해준다.50 ml of 5 g of bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -methylammonium-fumarate Add fuming nitric acid at -20 ° to 30 ° C and stir at -25 ° C for 40 minutes.

용액을 얼음에 가하고 침전된 질산염을 흡인여과 한다.The solution is added to ice and the precipitated nitrate is suction filtered.

수율 : 100％(5.3g)Yield: 100% (5.3 g)

융점(질산염) : 135℃Melting Point (Nitrate): 135 ℃

[실시예 16]Example 16

비스-[3-(3,4-디하이드로-4,4-디메틸-7-나이트로-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-아민Bis- [3- (3,4-dihydro-4,4-dimethyl-7-nitro-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine

실시예 15와 유사한 방법으로 10g의 비스-3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필-아민의 염산염으로부터 제조된다.From 10 g of hydrochloride of bis-3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl-amine in a similar manner to Example 15 Are manufactured.

수율 : 83％(10.2g)Yield: 83% (10.2 g)

융점(질산염) : 197℃Melting Point (Nitrate): 197 ℃

[실시예 17]Example 17

비스-[3-(3,4-디하이드로-4,4-디메틸-7-아미노-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-아민Bis- [3- (3,4-dihydro-4,4-dimethyl-7-amino-1, 3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine

실시예 14과 유사한 방법으로 비스-[3-(3,4-디하이드로-4,4-디메틸-7-나이트로-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-암모늄-나이트레이트로부터 제조된다.Bis- [3- (3,4-Dihydro-4,4-dimethyl-7-nitro-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] in a similar manner to Example 14] Prepared from ammonium-nitrate.

수율 : 41％(1g)(염산염)Yield: 41% (1 g) (hydrochloride)

융점(염산염) : 300℃이상(285℃부터 반응상태)Melting point (hydrochloride): 300 ℃ or higher (reaction state from 285 ℃)

[실시예 18]Example 18

비스-[3-(3,4-디하이드로-4,4-디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-벤질아민Bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -benzylamine

실시예 12와 유사한 방법으로 5.12g의 비스-[3-(3,4-디하이드로- 4,4- 디메틸-1,3-디옥소-2(1H)-이소퀴놀릴)-프로필]-아민과 염산염과 1.75g의 벤질브로마이드로부터 염기인 나트륨에톡사이드를 사용하여 제조된다.5.12 g of bis- [3- (3,4-dihydro-4,4-dimethyl-1,3-dioxo-2 (1H) -isoquinolyl) -propyl] -amine in a similar manner to Example 12 Perchlorate and 1.75 g of benzyl bromide are prepared using the base sodium ethoxide.

수율 : 65％(3.7g)Yield: 65% (3.7 g)

융점 : 108℃Melting Point: 108 ℃

Claims (1)

다음 구조식(I)의 카보닐 화합물을 다음 구조식(Ⅲ)의 호모프탈이미드와 반응시킴을 특징으로하고 필요에 따라 R5-R9그룹중의 적어도 하나가 수소 또는 R1-R4중의 적어도 하나가 하이드록시그룹인 생성물을 알킬화시켜 상응하는 알킬화된 화합물을 만들거나, R1-R4중의 적어도 하나가 수소인 생성물을 니트로화시킨 뒤, 이 니트로 화합물을 환원시켜 상응하는 아미노 화합물로 전환하고 이 아미노화합물을 아세틸화하여 상응하는 아세틸아미노화합물로 전환시켜 구조식(Ⅰ)의 화합물 및 이의 산부가염의 제조방법.Of the following structural formula (I) carbonyl compound the following structural formula (Ⅲ) of the call de-morph imide and reacting characterized in that at least one of R 5 -R 9 group as needed is hydrogen or an R 1 -R 4 Alkylation of the product of at least one hydroxy group to form the corresponding alkylated compound or nitration of the product of at least one of R 1 -R 4 to hydrogen, followed by reduction of the nitro compound to the corresponding amino compound And acetylating this amino compound to convert it to the corresponding acetylamino compound to prepare a compound of formula (I) and an acid addition salt thereof.
Figure kpo00006
Figure kpo00006
 상기 구조식에서, A와 B는 임의로 메틸 또는 페닐그룹으로 치환된 탄소수 2 내지 4인 직쇄 포화 알킬렌그룹이며 같거나 서로 다를 수 있고, R1, R2, R3와 R4는 수소, 불소, 염소, 또는 취소, 하이드록시, 아미노, 니트로 또는 아세틸아미노그룹, 탄소수 1 내지 3인 알킬, 알콕시 또는 알킬티오 그룹이며, 같거나 서로 다를 수 있고, R5, R6, R7과 R8는 수소, 임의로 페닐 또는 메톡시페닐로 치환된 탄소수 1 내지 4인 알킬이며, 같거나 서로 다를 수 있고, R5는 R6와 함께, R7은 R8와 함께 탄소수 2 내지 5인 직쇄 포화 알킬렌이며, R9은 수소 또는 임의로 페닐로 치환된 탄소수 1 내지 6인 알킬이고, Z는 할로 겐원자와 같은 친핵 치환할 수 있는 그룹이다.Wherein A and B are straight chain saturated alkylene groups of 2 to 4 carbon atoms, optionally substituted with methyl or phenyl groups, and may be the same or different, and R 1 , R 2 , R 3 and R 4 are hydrogen, fluorine, Chlorine, or cancelled, hydroxy, amino, nitro or acetylamino group, alkyl, alkoxy or alkylthio group having 1 to 3 carbon atoms, which may be the same or different, and R 5 , R 6 , R 7 and R 8 are hydrogen , Optionally substituted with phenyl or methoxyphenyl, alkyl having 1 to 4 carbons, which may be the same or different, R 5 together with R 6 , R 7 together with R 8 straight chain saturated alkylene with 2 to 5 carbon atoms R 9 is hydrogen or alkyl having 1 to 6 carbon atoms optionally substituted with phenyl, and Z is a nucleophilic substitutable group such as a halogen atom.
KR1019800000824A 1980-02-28 1980-02-28 Process for preparing homophthalimides KR800001702B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1019800000824A KR800001702B1 (en) 1980-02-28 1980-02-28 Process for preparing homophthalimides

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1019800000824A KR800001702B1 (en) 1980-02-28 1980-02-28 Process for preparing homophthalimides

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
KR7601728A Division KR800000906B1 (en) 1976-07-15 1976-07-15 Process for preparing homophthalimides

Publications (1)

Publication Number Publication Date
KR800001702B1 true KR800001702B1 (en) 1980-12-31

Family

ID=19215704

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1019800000824A KR800001702B1 (en) 1980-02-28 1980-02-28 Process for preparing homophthalimides

Country Status (1)

Country Link
KR (1) KR800001702B1 (en)

Similar Documents

Publication Publication Date Title
US3585198A (en) Homopyrimidazole derivatives,process for the preparation thereof and pharmaceutical compositions containing same
EP0113778B1 (en) Aryl substituted aminomethyl benzene derivatives useful as antiarrhythmic agents
US5346904A (en) Sulphonyl compound
NO763724L (en)
EP0310155A1 (en) Heteroaryl substituted aminomethyl benzene derivatives, compositions and use
DK159114B (en) BENZYLDIHYDROFUROPYRIDINE DERIVATIVES AND PREPARATIONS CONTAINING THESE COMPOUNDS
US4086353A (en) Certain azolinylamino (azolidinylimino) indazoles
US4025607A (en) Propargyl-substituted 2-phenylamino-2-imidazolines and salts thereof
US3632587A (en) Piperazino methyl isatinylidine 3 acetates
US3050553A (en) Disulfamylbenzoic acids
US4163785A (en) Benzothiazepine compounds and compositions
KR100352899B1 (en) Pharmaceuticals containing novel 3-phenylsulfonyl-3,7-diazabicyclo [3,3,1] nonan-compounds
Cannon et al. Congeners of the. alpha. conformer of dopamine derived from octahydrobenz [h] isoquinoline
US4124587A (en) 4-Hydroxy-3-sulfinyl-quinolin-2(1H)-ones
KR800001702B1 (en) Process for preparing homophthalimides
EP0000355B1 (en) New indole derivatives, processes for their preparation, and pharmaceutical compositions containing them.
US4143143A (en) Substituted imidazo[5,1-a]isoquinolines
US4181657A (en) 2-Aminooctahydroindolo[2,3-a]quinolizines useful in treating cardiovascular disorders
US5070094A (en) N-benzyltropaneamides
EP0105458B1 (en) Alpha-aryl-alpha-pyridylalkanoic acid derivatives, process for preparation thereof and pharmaceutical composition comprising the same
KR800001703B1 (en) Process for preparing homophtalimides
GB1598628A (en) Guanidine derivatives
EP0076559B1 (en) Antiallergic imidosulfamides
US4438121A (en) Isoquinoline amidoxime derivatives
KR850000126B1 (en) Process for preparing novel imidazole derivatives