Method for synthesizing brain targeting head modification cyclodextrin (CD) derivative

A synthesis method and cyclodextrin technology, applied in the field of biomedicine, can solve problems such as brain-targeted molecular modification that has not yet been seen, and achieve the effect of improving brain transfer rate, simple method, and mild reaction conditions

Inactive Publication Date: 2011-01-05
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there have been no reports on the modification of brain-targeting molecules to cyclodextrin carriers

Method used

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  • Method for synthesizing brain targeting head modification cyclodextrin (CD) derivative
  • Method for synthesizing brain targeting head modification cyclodextrin (CD) derivative
  • Method for synthesizing brain targeting head modification cyclodextrin (CD) derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0031]Disperse 60g of β-cyclodextrin evenly in water, add 20ml of 8.25mol / L sodium hydroxide solution at 20°C, drop it in 6 minutes, and the solution becomes clear during the process. After the reaction continued for 1 hour, the reaction temperature was lowered to 2° C., and 15 g of p-toluenesulfonyl chloride acetonitrile solution was added, resulting in a white precipitate. The reaction solution was stirred at room temperature for 2 h, filtered, washed, and the filtrate was adjusted to pH 8 with 10% HCl, and a white solid was precipitated, which was left overnight at 4°C. Filtrate, collect two precipitates, recrystallize three times, and vacuum-dry at 50°C for 6 hours to obtain 6-p-toluenesulfonyl chloride-β-cyclodextrin with a yield of 10%.

[0032] Dissolve 6.5g of 6-p-toluenesulfonyl chloride-β-cyclodextrin in 30ml of anhydrous ethylenediamine, mix well, and react for 4 hours at 80°C under nitrogen protection. After the reaction is completed, cool to room temperature, and ...

Embodiment 2

[0037] Disperse 60g of β-cyclodextrin evenly in water, add 20ml of 8.25mol / L sodium hydroxide solution at 20°C, drop it in 6 minutes, and the solution becomes clear during the process. After the reaction lasted for 1 hour, the reaction temperature was lowered to 2° C., and 20 g of p-toluenesulfonyl chloride acetonitrile solution was added to produce a white precipitate. The reaction solution was stirred at room temperature for 2 h, filtered, washed, and the filtrate was adjusted to pH 8 with 10% HCl, and a white solid was precipitated, which was left overnight at 4°C. Filtrate, collect two precipitates, recrystallize three times, and vacuum-dry at 50°C for 6 hours to obtain 6-p-toluenesulfonyl chloride-β-cyclodextrin with a yield of 7.8%, and a small amount of 2-p-toluenesulfonyl chloride-β- Cyclodextrin by-products.

[0038] Dissolve 6.5g of 6-p-toluenesulfonyl chloride-β-cyclodextrin in 30ml of anhydrous ethylenediamine, mix well, and react for 4 hours at 80°C under nitroge...

Embodiment 3

[0043] Disperse 60g of β-cyclodextrin evenly in water, add 20ml of 8.25mol / L sodium hydroxide solution at 20°C, drop it in 6 minutes, and the solution becomes clear during the process. After the reaction continued for 1 hour, the reaction temperature was lowered to 2° C., and 15 g of p-toluenesulfonyl chloride acetonitrile solution was added, resulting in a white precipitate. The reaction solution was stirred at room temperature for 2 h, filtered, washed, and the filtrate was adjusted to pH 8 with 10% HCl, and a white solid was precipitated, which was left overnight at 4°C. Filtrate, collect two precipitates, recrystallize three times, and vacuum-dry at 50°C for 6 hours to obtain 6-p-toluenesulfonyl chloride-β-cyclodextrin with a yield of 10%.

[0044] Dissolve 6.5g of 6-p-toluenesulfonyl chloride-β-cyclodextrin in 30ml of anhydrous ethylenediamine, mix well, and react for 4 hours at 80°C under nitrogen protection. After the reaction is completed, cool to room temperature, and...

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Abstract

The invention relates to a method for synthesizing a brain targeting head modification cyclodextrin (CD) derivative. The method comprises the following steps of: preparing an intermediate, namely, a mono-6-p-methylbenzene sulfonic acid-beta-cyclodextrin ester from beta-CD by an alkali aqueous solution method and introducing active amino into the reaction of the mono-6-p-methylbenzene sulfonic acid-beta-cyclodextrin ester to obtain amino-modified beta-cyclodextrin; and connecting the amino-modified beta-cyclodextrin with a mercapto brain targeting head through iso-functional group disubstituted polyethylene glycol derivative N-hydroxysuccinimide polyethylene glycol-maleimide maleinimide to prepare the brain targeting head modification cyclodextrin derivative. The method has the advantages that: the method for preparing the brain targeting head modification cyclodextrin derivative is simple and convenient, a reaction condition is mild and the derivative is taken as a medicament carrier and is easy for industrial production; a polyethylene glycol (PEG) long-chain structure is contained, so that long circulation effect is achieved and a carrier is prevented from being phagocytosed by a netlike endothelial system; and the structure is connected with a brain targeting head Tf or Lf, so that the brain transport rate of the structure serving as a medicament conveying carrier is increased.

Description

【Technical field】 [0001] The invention relates to the technical field of biomedicine, in particular to a method for synthesizing brain-targeting base-modified cyclodextrin derivatives. 【Background technique】 [0002] The blood-brain barrier (BBB) ​​is mainly composed of capillary endothelial cells, basement membrane and glial cell protrusions, which is a structure with defensive function, so that useful nutrients and metabolites of the brain can pass through freely. And prevent harmful substances from the outside world from entering the brain. However, it is difficult for various drugs, especially protein and peptide drugs, to break through the BBB and enter the central nervous system to exert their therapeutic effects. In the past, methods such as transcranial drug delivery or lipidation of water-soluble small molecules by chemical methods to increase the efficiency of drug brain transport will be abandoned due to various deficiencies. [0003] In recent years, great prog...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/16A61K47/42A61K47/40
Inventor 高峰孙怡蓝闽波赵红利曹海付栋君
Owner EAST CHINA UNIV OF SCI & TECH
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