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Acetylbenzylamine piperazine derivatives and their application as neuroprotective agents

A technology of acetylbenzylamine piperazine and its derivatives, which is applied in the field of acetylbenzylamine piperazine derivatives, which can solve the problems of low activity, difficulty in penetrating the blood-brain barrier, and high cardiotoxicity, and achieve high activity and significant deficiency tolerance. Oxygen activity and less side effects

Active Publication Date: 2018-04-24
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The technical problem to be solved in the present invention is to disclose a class of acetylbenzylamine piperazine derivatives and their application as brain neuroprotective agents to overcome the low activity of existing anti-stroke drugs and difficulty in penetrating the blood-brain barrier, cardiac Defects such as high toxicity;

Method used

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  • Acetylbenzylamine piperazine derivatives and their application as neuroprotective agents
  • Acetylbenzylamine piperazine derivatives and their application as neuroprotective agents
  • Acetylbenzylamine piperazine derivatives and their application as neuroprotective agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] N-Benzyl-2-(4-{2-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]-2-carbonylethyl}piperazin-1-yl) Acetamide (V-1) and its hydrochloride

[0083] Put 2-amino-5-methyl-3,4-diazathiophene (20mmol), chloroacetyl chloride (24mmol), and triethylamine (30mmol) in 25ml of acetonitrile, react at room temperature for 8h, follow General Method 2 N-(5-methyl-3,4-diazathiophene)-2-chloroacetamide was obtained with a yield of 67%.

[0084] The above-obtained N-(5-methyl-3,4-diazathiophene)-2-chloroacetamide (12.8mmol) and N-acetylbenzylamine piperazine (II) intermediate (19.6mmol) were put into 30ml acetone solution, add K 2 CO 3 (19.6mmol), KI (6.4mmol), reacted at room temperature for 8h. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography to obtain the free base N-benzyl-2-(4-{2-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]-2-carbonyl ethyl Bas...

Embodiment 2

[0089] [4-(2-Benzylamino-2-carbonylethyl)piperazin-1-yl]-N-phenylpropanamide (V-2) and its hydrobromide

[0090] Put aniline (20mmol), 2-chloropropionyl chloride (24mmol), and triethylamine (30mmol) in 25ml of acetonitrile, react at room temperature for 8h, and follow the operation of General Method 2 to obtain N-aniline-2-chloropropane Amide, yield 66%.

[0091] Put the N-aniline-2-chloropropionamide (12.8mmol) obtained above and the N-acetylbenzylamine piperazine (II) intermediate (19.6mmol) into 30ml of acetone solution, and add K 2 CO 3(19.6mmol), KI (6.4mmol), reacted at room temperature for 8h. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography to obtain the free base [4-(2-benzylamino-2-carbonylethyl)piperazin-1-yl]-N-phenylpropanamide (V-2), 4.0g, yield 81.87%.

[0092] Add 8ml of ethanol to the free base and heat to ...

Embodiment 3

[0096] 2-[4-(2-Benzylamino-2-carbonylethyl)piperazin-1-yl]-N-(4-methoxyphenyl)propionamide (V-3) and its sulfate;

[0097] Put p-methoxyaniline (20mmol), 2-chloropropionyl chloride (24mmol), and triethylamine (30mmol) in 25ml of acetonitrile, react at room temperature for 8h, and follow the operation of General Method 2 to obtain N-p-methyl Oxyaniline-2-chloropropionamide, yield 64%.

[0098] The above-obtained N-p-methoxyaniline-2-chloropropionamide (12.8mmol) and N-acetylbenzylamine piperazine (II) intermediate (19.6mmol) were put into 30ml of acetone solution, and K 2 CO 3 (19.6mmol), KI (6.4mmol), reacted at room temperature for 8h. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography to obtain free base 2-[4-(2-benzylamino-2-carbonylethyl)piperazin-1-yl]-N-(4-methoxyphenyl)propionamide (V -3), 3.4g, yield 64.63%.

[0099] ...

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Abstract

The present invention discloses a acetylbenzylamine piperazine derivative and its application as a brain neuroprotectant. Pharmacological experiments show that the compound of the present invention not only exhibits obvious anti-glutamate-induced neuron excitotoxicity in vitro , there is significant hypoxia resistance activity in mice, and the herg test also shows that the compound of the present invention has no risk of cardiotoxicity. Therefore, the compound of the present invention has the advantages of high activity, few side effects, and good druggability. The compound and its pharmaceutical preparations have good curative effect on treating cranial nerve injury diseases, such as cerebral apoplexy and related diseases, and do not have cardiac Toxicity risk. The acetylbenzylamine piperazine derivatives are free bases or salts of compounds with the following general chemical structure:.

Description

technical field [0001] The invention relates to a class of acetylbenzylamine piperazine derivatives and the use of the compound as a protective agent for cranial nerves. Background technique [0002] Stroke (especially ischemic stroke) is a common disease with high morbidity, high mortality, and high disability rate, which has seriously threatened the health of the general public. Stroke is currently the third leading cause of death in humans, second only to cancer and myocardial infarction. According to the statistics of the World Health Organization, the global stroke mortality rate is about 4.6 million people / year, and in my country: about 1.5 million people / year. It is estimated that in the next ten years, 15 million people in my country will face the threat of stroke death. Stroke is also the number one factor leading to long-term severe loss of self-care ability. There are about 5 million stroke survivors in my country, 75% of whom are disabled to varying degrees, an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/22C07D417/12C07D285/135C07D295/15C07D235/02C07D209/34C07D235/26C07D231/40C07D213/75A61K31/496A61K31/454A61P25/00A61P9/10
Inventor 李建其翁志洁崔宁解鹏马潇
Owner SHANGHAI INST OF PHARMA IND CO LTD
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