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Double-chain structured polyethylene active derivatives, and ligature with other molecules

A polyethylene glycol and derivative technology, applied in dipeptide components, cyclic peptide components, peptide/protein components, etc., can solve the problems of linking group hydrolysis, fragmentation, protein inactivation, etc.

Inactive Publication Date: 2007-10-03
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are several problems with the above method of forming PEG-protein conjugates and the conjugates resulting from said method, one is that the method of forming these conjugates will inactivate 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 active derivatives, and ligature with other molecules
  • Double-chain structured polyethylene active derivatives, and ligature with other molecules
  • Double-chain structured polyethylene active derivatives, and ligature with other molecules

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Preparation of N, N-bispolyethylene glycol acetamido-butyric acid succinimidyl ester 1000

[0028] 2g N,N-dipolyethylene glycol acetamide 1000 (0.002mol) and 0.53g 4-chlorobutyric acid (0.005mol) were dissolved in 50ml of dichloromethane, refluxed at room temperature for 2 hours, and the mixture was concentrated under reduced pressure to 20ml, add 200ml of cooling diethyl ether, filter the resulting precipitate and dry under reduced pressure to obtain 1.75g ​​of the product N,N-bispolyethylene glycol acetamidobutyric acid 1000.

[0029] Get above-mentioned obtained product and 0.58g N-hydroxysuccinimide (0.005mol) and dissolve in 50ml dichloromethane, in the presence of dimethylaminopyridine (DMAP) and dicyclohexylcarbodiimide (DCC), temperature- 20~10℃, react for 4 hours or overnight. The mixture was precipitated with ether, recrystallized from ethanol, and further purified through a Sephadex G-25 column to obtain 1.7 g of pure N,N-bispolyethylene glycol ac...

Embodiment 2

[0030] Embodiment 2: the preparation of N, N-dipolyethylene glycol acetamido-butyric acid maleimide ester 20000

[0031]2g N, N-dipolyethylene glycol acetamide 1000 (0.002mol) and 0.53g 1-methyl-4-chlorobutyric acid (0.005mol) were dissolved in 50ml of dichloromethane, refluxed at room temperature for 2 hours, and The mixture was concentrated under reduced pressure to 20 ml, 200 ml of diethyl ether was added for cooling, and the obtained precipitate was filtered and then dried under reduced pressure to obtain 1.75 g of the product N,N-bispolyethylene glycol acetamidomethyl butyric acid 1000. The above product and 0.57g N-hydroxyl maleimide (0.005mol) were dissolved in 50ml of methylene chloride, in the presence of dimethylaminopyridine (DMAP) and dicyclohexylcarbodiimide (DCC), the temperature- 20~10℃, react for 4 hours or overnight. The mixture was precipitated with ether, recrystallized from ethanol, and further purified by Sephadex G-25 column to obtain pure N,N-bispolyeth...

Embodiment 3

[0032] Example 3: Preparation of N,N-bispolyethylene glycol acetamidoacetic acid-6-aminocaproic acid succinimidyl ester 60000

[0033] Get 60g N, N-bispolyethylene glycol acetamidoacetic acid 40000 (0.001mol), 0.65g aminon-hexanoic acid (0.005mol) and 1.03g dicyclohexylcarbodiimide (DCC, 0.005mol) are dissolved in 100ml of dichloromethane, stirred and refluxed at room temperature for 16 hours. The mixture was filtered, the obtained filtrate was concentrated to 20ml under reduced pressure, 200ml of cooling diethyl ether was added, the obtained precipitate was filtered and then dried under reduced pressure to obtain the product N,N-dipolyethylene glycol acetamidoacetic acid-6-aminocaproic acid 40000 52.5 g.

[0034] Get above-mentioned gained product and 0.58g N-hydroxysuccinimide (0.005mol) and dissolve in 50ml methylene chloride, in the presence of dimethylaminopyridine (DMAP) and dicyclohexylcarbodiimide (DCC), Temperature -20~10°C, react for 4 hours or overnight. The mixt...

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Abstract

An active polyethanediol derivative with double chain structure, its preparing process, and its compound with other moleculae (protein and polypeptide) are disclosed.

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 the pharmacokinetic properties of b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K45/00A61K38/05A61K38/08A61K38/12A61K38/20A61K38/21A61K38/28A61K39/395C08G65/329A61K47/60
Inventor 姚文兵田浤高向东陈阳建陆涛
Owner CHINA PHARM UNIV