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7-amino-1,4-dihydroisoquinoline-3(2H)-one derivative, synthetic method and application thereof

A technology of dihydroisoquinoline and its derivatives, which can be applied in drug combinations, nervous system diseases, organic chemistry, etc., and can solve the problems of low compound activity, increased side effects, undisclosed acetylcholinesterase inhibitory activity, etc.

Inactive Publication Date: 2016-02-10
CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since the above-mentioned acetylcholinesterase can only alleviate the symptoms of AD, and continuous monotherapy will bring the consequences of decreased curative effect and increased side effects, it is meaningful to further discover and develop new and efficient acetylcholinesterase inhibitors for the treatment of Alzheimer's disease
[0004] In 2006, U.S. Patent US2006 / 0135557 disclosed a kind of isoquinoline-1,3,4-triketone compound and its synthesis method and application in medicine, to cysteine-containing aspartic acid protein Hydrolase (Caspase) has inhibitory activity, can delay cell apoptosis, and can be developed as a treatment for neurodegenerative diseases, especially as a drug for the treatment of Alzheimer's disease, stroke and local ischemic injury, but This type of compound has low inhibitory activity on Caspase, and its IC 50 The value is above 80mM, and the inhibitory activity of this type of compound on acetylcholinesterase has not been disclosed
In 2006, Chinese patent CN101356159A disclosed isoquinolin-1,3(2H,4H)-diones, 1-thio-1,4-dihydro-2H-isoquinolin-3-ones and 1, 4-dihydro-3 (2H)-isoquinolinone compounds and their preparation methods and applications in medicine have inhibitory activity on kinases and can be developed as drugs for the treatment of cancer. Esterase inhibitory activity
In 2011, Chinese patent CN101550103B disclosed a 1,2,3,4-tetrahydroisoquinoline compound and its salt, its preparation method and application in medicine. This type of compound has inhibitory activity on acetylcholinesterase and can Further research and development of new drugs for the treatment of Alzheimer's disease, but the activity of this type of compound is not too high, the IC for the inhibition of acetylcholinesterase 50 Values ​​above 7.5nM

Method used

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  • 7-amino-1,4-dihydroisoquinoline-3(2H)-one derivative, synthetic method and application thereof
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  • 7-amino-1,4-dihydroisoquinoline-3(2H)-one derivative, synthetic method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] 2-N-benzoyl-7-N-benzoylamino-1,4-dihydroisoquinolin-3(2H)-one (I 1 ) preparation

[0030] (1) Preparation of 2-indanone (IV)

[0031]Add 140ml of 88% formic acid and 28ml of 30% hydrogen peroxide in a 250ml three-necked bottle equipped with a thermometer and a constant pressure dropping funnel, and control the temperature of the water bath at 35-40°C. Accurately measure 26ml of 90% indene into the bottle through the dropping funnel and slowly add it dropwise, stirring while dropping. After 2 hours, the dropping is completed, wash the dropping funnel with 10ml of formic acid, and continue stirring at 35°C for 20 minutes. Then it was stirred for 7 hours at 25°C. After the reaction, excess formic acid in the reaction system was evaporated by a rotary evaporator (35mmHg / 35-40°C). After the rotary evaporation, the residual liquid will be cooled and a white solid will be precipitated. Before the next step, it can be slightly heated to liquefy it, which is convenient for ad...

Embodiment 2

[0046] 2-N-(3'-chlorobenzoyl)-7-N-benzoylamino-1,4-dihydroisoquinolin-3(2H)-one (I 2 ) preparation

[0047] At room temperature, take 70mgIX 1 Dissolve it with 10ml of dioxane, and add 0.1ml of triethylamine as an acid-binding agent. Dissolve 0.1ml of m-chlorobenzoyl chloride in 10ml of dioxane, and add it dropwise into the reaction system through the dropping funnel. press I 1 Preparation method, 40mg viscous yellow product was obtained with a yield of 39.5%.

[0048] 1 HNMR (500MHz, CDCl 3 )δ7.93(d, J=4.6Hz, 3H, Ar-H), 7.86-7.68(s, 1H, CO-NH-Ar), 7.63-7.24(m, 9H, Ar-H), 4.97(d , J=10.3Hz, 2H, Ar-CH 2 -N), 3.79(d, J=14.5Hz, 2H, Ar-CH 2 -CO)

Embodiment 3

[0050] 2-N-(3'-methylbenzoyl)-7-N-benzoylamino-1,4-dihydroisoquinolin-3(2H)-one (I 3 ) preparation

[0051] At room temperature, take 70mgIX 1 Dissolve it with 10ml of dioxane, and add 0.1ml of triethylamine as an acid-binding agent. Dissolve 0.1ml of m-toluoyl chloride in 10ml of dioxane, and add it dropwise into the reaction system through the dropping funnel. press I 1 Preparation method, 40mg viscous yellow-brown product was obtained with a yield of 39.6%.

[0052] 1 HNMR (500MHz, CDCl 3 )δ7.95-7.84 (m, 2H, Ar-H), 7.79 (s, 1H, CO-NH-Ar), 7.79-7.49 (m, 4H, Ar-H), 7.45-7.29 (m, 4H, Ar-H), 7.16(d, J=7.5Hz, 2H, Ar-H), 4.96(d, J=8.7Hz, 2H, Ar-CH 2 -N), 3.78(d, J=14.1Hz, 2H, Ar-CH 2 -CO), 2.42(s, 3H, Ar-CH 3 ).

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Abstract

A 7-amino-1,4-dihydroisoquinoline-3(2H)-one derivative, a synthetic method and an application thereof. The invention belongs to the technical field of medicines and relates to the 7-amino-1,4-dihydroisoquinoline-3(2H)-one compound, the synthetic method, and the application thereof in medicine The compound is represented as the general formula (I), wherein X is (CH2)<n-1>CO, n = 1-10; or is NH(CH2)<n-2>CO, n = 2-10; or is NHCO(CH2)<n-3>CO, n = 3-10; Y is CO(CH2)<n-1>, n = 1-10; or is CO(CH2)<n-2>NH, n = 2-10; or is CO(CH2)<n-3>CONH, n = 3-10, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 refers to different substituent groups. The invention also discloses the structures and synthetic methods of these compounds and in-vitro acetylcholin esterase inhibition activity of the compounds. The compounds can be further developed into a novel drug for treating Alzheimer's disease.

Description

technical field [0001] The invention belongs to the technical field of medicines, and relates to a class of 7-amino-1,4-dihydroisoquinolin-3(2H)-one derivatives with novel structure, their synthesis method and their application in medicine. Background technique [0002] Alzheimer's disease (Alzheimer's disease, AD), also known as Alzheimer's disease, has become the most common type of dementia in the elderly population, accounting for 50%-56% of anatomical and clinical events. An important cause of death in the elderly worldwide. Alzheimer's disease is a neurodegenerative disease that affects more than 350 million people and causes death within three to nine years of diagnosis. Age growth is the most important factor leading to the disease. The incidence rate of the elderly over 65 years old increases by 5 years, and the incidence rate doubles, and the incidence rate of the elderly over 85 years old is as high as 1 / 3. [0003] At present, based on different perspectives, m...

Claims

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Application Information

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IPC IPC(8): C07D217/24A61P25/28
Inventor 蒋玉仁赵雄杰邓友超王宗成汪金连
Owner CENT SOUTH UNIV
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