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Brain-targeted compound and application thereof

A compound, brain-targeting technology, applied in organic chemistry, drug combination, medical preparations containing active ingredients, etc., can solve the problems of unfavorable drug distribution in the central nervous system, no significant increase in ZL006, etc., and achieve good brain-targeting effect. Effect

Inactive Publication Date: 2017-06-13
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the high hydrophilicity of this type of uncoupling agent, it is not conducive to the distribution of drugs in the central nervous system.
Although ZL006 ethyl ester (compound 3) can increase the distribution of the drug in the central nervous system, the ZL006 produced in the brain tissue does not increase significantly (Bioorganic&Medicinal Chemistry Letters 2016,158:494-506)

Method used

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  • Brain-targeted compound and application thereof
  • Brain-targeted compound and application thereof
  • Brain-targeted compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] 3-(2-ethyl)dithio-4-N-methylformamido-3-pentenol 4-(3,5-dichloro-2-hydroxybenzyl)amino-2-hydroxybenzoate preparation

[0021]

[0022] 1) Preparation of sodium ethyl thiosulfate

[0023] Add ethyl bromide (1.0g, 9.3mmol), PEG 400 (0.05mL) and ethanol (10mL) in a 50mL eggplant-shaped bottle, stir, and add sodium thiosulfate pentahydrate (2.6g, 10.3mmol) in water (10mL) solution, after the dropwise addition, under nitrogen protection, the temperature was raised to 110°C, and the reaction was carried out for 6h. After the reaction was completed, it was concentrated under reduced pressure and dried to obtain yellow sodium ethylthiosulfate (1.44 g, yield 95%).

[0024] 2) Preparation of N,4-dimethyl-5-[2-(hydroxyl)ethyl]thiazole iodide

[0025] Add 4-methyl-5-(β-hydroxyethyl)thiazole (1.0g, 7.0mmol), methyl iodide (1.0g, 7.0mmol) and acetonitrile (10mL) into a 50mL eggplant-shaped bottle, stir, and heat to reflux for 1.5 h. After the reaction was completed, cool to r...

Embodiment 2

[0043] 1) Preparation of sample solution

[0044] Weigh 20 mg of compound 1 sample, dissolve it in a very small amount of DMSO (less than 1% of the total volume), add Tween 80 (less than 5% of the total volume), add normal saline in a hot water bath and dilute to 20 mL, and prepare The concentration is 1mg·mL -1 solution.

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Abstract

The invention discloses a brain-targeted compound and an application thereof. The name of the brain-targeted compound is 4-(3,5-dichloro-2-hydroxybenzyl) amino-2-hydroxybenzoic acid 3-(2-ethyl)dithio-4-N-methyl formamido-3-, and the structure is as shown in a formula I. The brain-targeted compound can be used for preparing a drug for treating stroke, neuropathic pain and inflammatory pathological pain. Meanwhile, due to the unique action mechanism of the drug, the brain-targeted compound can also be used for preparing a drug for treating epilepsy, affective disorder and various neurodegenerative diseases.

Description

technical field [0001] The invention belongs to the field of pharmacy and provides a class of 4-(3,5-dichloro-2-hydroxybenzyl)amino-2-hydroxybenzoic acid 3-(2-ethyl)dithio-4-N-methylformamide Base-3-pentenol ester and its preparation method and pharmaceutical use. Background technique [0002] Stroke has the characteristics of high mortality, high disability rate, and high recurrence rate, which seriously endanger human health. Due to the fine and complex structure of brain tissue, it is particularly sensitive and fragile to ischemic and hypoxic injury, so far there are few clinically effective therapeutic drugs. Studies have shown that under the condition of cerebral ischemia, excessive release of excitatory amino acids (such as glutamate) causes excessive activation of N-methyl-D-aspartate receptors (NMDAR), through the NMDAR-PSD-95-nNOS Signaling pathways pathologically release nitric oxide (NO) (Science, 1999, 284, 1845-1848; Nature Medicine 2010, 16, 1439-1443). NO i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/25A61K31/618A61P9/10A61P29/00A61P25/28A61P25/08A61P25/00
CPCC07C323/25
Inventor 陈冬寅李飞孙炎施震宇熊正新李婷杨磊蒋南
Owner NANJING MEDICAL UNIV