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Dihydro nicotinate derivative and application thereof

A technology of dihydronicotinic acid ester and derivatives, which can be used in drug combinations, medical preparations containing active ingredients, cardiovascular system diseases, etc., can solve the problems of inability to improve the distribution of drugs in the central nervous system, lack of stability, etc. Achieving the effect of good brain targeting

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

The inventors have found that if ZL006 is simply linked with dihydronicotinic acid with an amide bond, the obtained compound (compound 4) cannot release ZL006 in vivo, and ZL006 is simply linked with dihydronicotinic acid with an ester bond , the obtained compound (compound 5) lacks stability, releases ZL006 rapidly in the body, and cannot achieve the purpose of improving the distribution of the drug in the central nervous system

Method used

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  • Dihydro nicotinate derivative and application thereof
  • Dihydro nicotinate derivative and application thereof
  • Dihydro nicotinate derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1 Synthesis of dihydronicotinate derivatives (compound 1) of 4-N-(2-hydroxyl-3,5-dichlorobenzyl)aminosalicylic acid

[0021] The synthetic route of target compound is as follows:

[0022]

[0023] 1) Synthesis of 4-[N-(3,5-dichloro-2-hydroxybenzyl)-N-tert-butoxycarbonyl]amino-2-hydroxybenzoic acid (Boc-ZL006)

[0024] Add 5-(3,5-dichloro-2-hydroxybenzyl)amino-2-hydroxybenzoic acid (1.0g, 3.0mmol), 4-dimethylaminopyridine (0.37g, 3.0mmol) into a 50mL eggplant-shaped bottle , di-tert-butyl dicarbonate (0.65g, 3.0mmol) and dichloromethane (3.0mL), stirred at room temperature for 6h. After the reaction, add water (20mL), extract with ethyl acetate (20mL) 3 times, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain white 5-[N-(3,5-dichloro-2-hydroxybenzyl )-N-tert-butoxycarbonyl]amino-2-hydroxybenzoic acid (1.2 g, 91% yield).

[0025] 1H NMR (300MHz, DMSO-d6) δ7.83(s, 1H), 7.77(d, J=8.43Hz, 1H), 7.69(s, 1H), 6.93(s, 1H), 6.84(d, ...

Embodiment 2

[0030] Concentration determination of ZL006 in embodiment 2 brain tissue

[0031] 1. Preparation of sample solution

[0032] Weigh 20 mg of ZL006 dihydronicotinate (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), and add Dilute normal saline to 20mL, and prepare to a concentration of 1mg·mL -1solution.

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Abstract

The invention discloses a dihydro nicotinate derivative and an application thereof. The dihydro nicotinate derivative is the dihydro nicotinate derivative of 4-N-(2-hydroxyl-3,5-dichloro benzyl) amino salicylic acid, and the structure is as shown in a formula 1. The compound has a good brain-targeting effect and can be used for preparing a drug for treating cerebral apoplexy.

Description

technical field [0001] The invention belongs to the field of pharmacy and provides a dihydronicotinate derivative of 4-N-(2-hydroxy-3,5-dichlorobenzyl)aminosalicylic acid and its medicinal 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 itself has strong oxidative properties, and when it is released too much ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90A61K31/625A61P9/10A61P29/00A61P25/00A61P25/04A61P25/08A61P25/18
CPCC07D211/90
Inventor 蒋南李飞熊正新罗宏华施震宇倪凯栋杨磊陈冬寅
Owner NANJING MEDICAL UNIV