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Double-chain structured polyethylene glycol derivative preparation and its combination with pharmaceutical molecule

A technology of polyethylene glycol and drug molecules, applied in the field of active derivatives of polyethylene glycol, can solve the problems of protein inactivation, hydrolysis of linking groups, loss of favorable properties, etc.

Inactive Publication Date: 2011-11-09
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] There are several problems with the above methods of forming PEG-protein conjugates and the conjugates resulting from said methods, one is that the method of forming these conjugates inactivates the protein
In addition, some linking groups used in the formation of these PEG-protein conjugates are prone to hydrolysis and fragmentation in vivo. When such fragmentation occurs after administration, these conjugates lose the beneficial properties brought about by PEG.

Method used

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  • Double-chain structured polyethylene glycol derivative preparation and its combination with pharmaceutical molecule
  • Double-chain structured polyethylene glycol derivative preparation and its combination with pharmaceutical molecule
  • Double-chain structured polyethylene glycol derivative preparation and its combination with pharmaceutical molecule

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Preparation of Dipolyethylene Glycol Thio S-ester Lipoic Acid Succinimide Ester

[0035] Reaction formula:

[0036]

[0037]Take 10g of monomethoxy polyethylene glycol acid 5000 (0.002mol) and dissolve it in 50ml of dichloromethane, add an appropriate amount of thionyl chloride, stir at room temperature for 5-7 hours, and remove the solvent and the remaining thionyl chloride by rotary evaporation , Dissolve the obtained solid in 75ml of dichloromethane, then add 0.21g lipoic acid (reduced form) (0.001mol) and 0.40g pyridine (0.005mol), stir and reflux for 16-24 hours. Filtrate and evaporate the resulting filtrate to dryness under reduced pressure, dissolve the solid in 50ml of dichloromethane, then add 0.58g of N-hydroxysuccinimide (0.005mol), in dimethylaminopyridine (DMAP) and dicyclohexylcarbodi In the presence of imine (DCCI), react at -20~10°C for 4 hours or overnight. Use a water separator to remove water, continue to reflux overnight, and then remove the dic...

Embodiment 2

[0039] Preparation of Dipolyethylene Glycol Thio S-ester Lipoic Acid Maleimide Ester

[0040] Reaction formula:

[0041]

[0042] Take 16g of monomethoxy polyethylene glycol acid 8000 (0.002mol) and dissolve it in 50ml of dichloromethane, add an appropriate amount of thionyl chloride, stir at room temperature for 5-7 hours, and remove the solvent and the remaining thionyl chloride by rotary evaporation , The resulting solid matter was dissolved in 75ml of dichloromethane, then added 0.21g of lipoic acid (reduced form) (0.001mol) and 0.40g of pyridine (0.005mol), and stirred and refluxed for 16 hours. Filtrate and evaporate the resulting filtrate to dryness under reduced pressure, dissolve the solid in 50ml of dichloromethane, then add 0.57g of N-hydroxy maleimide (0.005mol), in dimethylaminopyridine (DMAP) and dicyclohexyl carbon In the presence of diimine (DCCI), react at -20~10°C for 4 hours or overnight. Use a water separator to remove water, continue to reflux overnig...

Embodiment 3

[0044] Preparation of Dipolyethylene glycol thioether lipoic acid succinimidyl ester

[0045] Reaction formula:

[0046]

[0047] Take 20g of monomethoxypolyethylene glycol 10000 (0.002mol) and dissolve it in 50ml of dichloromethane, add an appropriate amount of thionyl chloride, stir at room temperature for 5-7 hours, remove the solvent and the remaining thionyl chloride by rotary evaporation, The obtained solid matter was dissolved in 75ml of dichloromethane, and then 20ml of ethanol solution of 0.21g lipoic acid (reduced form) (0.001mol) and 0.20g NaOH (0.005mol) was added, and the pH was adjusted with hydrochloric acid after stirring and reflux for 18-24 hours value to 5.0. The mixture solvent was evaporated to dryness under reduced pressure, and the solid was dissolved in 50ml of dichloromethane, and then 0.58g of N-hydroxysuccinimide (0.005mol) was added, and in dimethylaminopyridine (DMAP) and dicyclohexylcarbodiimide In the presence of (DCCI), react at -20~10°C fo...

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Abstract

Many drug molecules with biological activities, especially proteins and peptides biological macromolecules, have been successfully used in a broad treatment. However, these biological macromolecules in clinical application also have many disadvantages, such as easy immune rejection, poor stability and less solubility, and faster clearance rate. Polyehylene glycol (PEG) technology developing in recent years is a very effective improvement of biological macromolecules pharmacokinetics. This invention relates to a new type of polyethylene glycol derivatives with lipoic acid as a connector and double-chain structure, their preparation methods and combination with drug molecules. The referred derivatives can be used for connecting drug molecules, especially amino groups and sulfhydryl groups of proteins and peptides biological macromolecules, so as to improve the pharmacokinetics nature of drug molecules. The invention also relates to drug compositions including the combinations.

Description

technical field [0001] The present invention relates to active derivatives of polyethylene glycol with a double-chain structure, a preparation method thereof, and a conjugate with drug molecules, the drug molecules are especially macromolecules such as proteins and polypeptides, and the present invention also relates to a compound comprising the conjugate pharmaceutical composition. Background technique [0002] Numerous biologically active drug molecules, especially biomacromolecules such as proteins and peptides, have been widely used in therapy and achieved success. However, these biomacromolecules also have many disadvantages in clinical application, such as prone to immune rejection, poor stability and solubility, and fast clearance rate. Therefore, people have adopted various methods to eliminate the above-mentioned unfavorable factors, among which PEGylation technology is a very effective method developed in recent years to improve t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G65/48A61K47/48A61K47/60
Inventor 姚文兵田浤陈阳建宋潇达高向东
Owner CHINA PHARM UNIV