Application of Dicarboxylic Acid and Its Esters

A compound and drug technology, applied in the application field of preparing neuroprotective drugs, can solve the problems of clinical application, poor effect, side effects, etc.

Inactive Publication Date: 2015-11-18
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, many protective reagents developed for different links of the cerebral infarction cascade reaction, except for the free radical scavenger Edaravone, are all effective in animals, clinically ineffective or poorly effective, or cannot be used in clinical practice due to serious side effects

Method used

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  • Application of Dicarboxylic Acid and Its Esters
  • Application of Dicarboxylic Acid and Its Esters
  • Application of Dicarboxylic Acid and Its Esters

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] The protective effect of the compound of Example 1 on primary neuronal cell injury induced by glutamate

[0027] Experimental principle:

[0028] This experiment uses lactated dehydrogenase (Lactatedehydrogenase, LDH) assay. LDH exists in the cell, and its extracellular content is low under normal circumstances. When the cell is damaged, LDH will be released outside the cell. Therefore, the leakage rate of LDH can be used to determine the degree of cell damage. LDH can catalyze lactic acid to generate pyruvate, and the reaction of pyruvate with 2,4-dinitrophenylhydrazine to generate pyruvate dinitrophenylhydrazone, which is brown-red in alkaline solution. Enzyme activity can be obtained by colorimetry.

[0029] Extraction of primary neurons from mouse cortex:

[0030] Take ICR pregnant mice with a gestational age of 15-16 days. After cervical dislocation, the uterus is separated from the placenta, and the fetuses taken out are placed in 0.1% neocerin solution and 75% alcohol f...

Embodiment 2

[0056] Example 2 N-(2-Methoxycarbonylacetyl)-D-valine methyl ester (ZLc-002) (1) Neuroprotective effect on animal models

[0057] Preparation of N-(2-methoxycarbonylacetyl)-D-valine methyl ester (ZLc-002):

[0058] Add 1.50g (9mmol) of D-valine methyl ester hydrochloride to 35mL of dichloromethane at -15°C to dissolve, add 2.03mL (18.45mmol) of N-methylmorpholine dropwise, and stir for 5 minutes after dropping , Then add 1.02 mL (9.45 mmol) of malonate monomethyl chloride dropwise, stir for 30 minutes, and then continue stirring at 30°C for 22 hours. Stop the reaction, evaporate the solvent to dryness, add 8 mL of water, 50 mL of ethyl acetate × 4 extractions, 10% wt citric acid 25 mL × 2 washes, saturated sodium chloride wash, then 5% wt sodium bicarbonate 25 mL × 2 washes, Then washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness, and the concentrated solution was yellow. Column chromatography was performed...

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Abstract

The invention provides an application of dicarboxylic acid and ester compounds thereof and in particular relates to an application of the compounds to preparation of neuroprotective drugs. In a chemical formula in the specification, R1 is hydrogen or methyl; R2 is isopropyl or isobutyl; R3 is carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, borneol oxycarbonyl or 5-tetrazole; a is 0 or 1; b is 0 or 1; c is an integer from 1 to 4; b is 0 when a is 0; b is 0 or 1 when a is 1. The compounds have relatively strong protective effects on glutamate-induced neuron damages.

Description

Technical field [0001] The invention belongs to the field of pharmacy and provides applications of a class of dicarboxylic acids and their ester compounds in the preparation of neuroprotective drugs. Background technique [0002] Neuroprotective agents are a hot spot in the development of therapeutic drugs for ischemic stroke. At present, many protective reagents developed for different stages of the cerebral infarction cascade, except for the free radical scavenger edaravone, are all effective in animals, and are clinically ineffective or poorly effective, or cannot be used in clinical practice due to severe side effects. Therefore, the development and screening of new neuroprotective agents is the focus of current research. [0003] Glutamate is released in large quantities when cerebral ischemia occurs. A large amount of released glutamate activates N-methylaspartate (NMDA) receptors, and calcium ions flowing from NMDA receptors activate neuronal nitric oxide synthase (nNOS) a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/225A61K31/22A61K31/20A61K31/198A61P25/00
Inventor 厉廷有丁屹蔡鋆鑫常磊李飞朱东亚
Owner NANJING MEDICAL UNIV
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