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Functional modification method for branched polyethylene glycol (PEG) derivative

A polyethylene glycol, branching technology, applied in the fields of biomedicine and protein chemistry, to achieve the effect of improving biological properties

Inactive Publication Date: 2012-06-13
XIEHE HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI & TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Acryloyl and vinyl sulfone groups have been widely used as the active groups of PEG derivatives in the modification of proteins and peptide drugs, but so far, the related modifiers have one or two active end groups linear PEG, branched PEG modifiers with multiple active end groups have not been reported yet

Method used

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  • Functional modification method for branched polyethylene glycol (PEG) derivative
  • Functional modification method for branched polyethylene glycol (PEG) derivative
  • Functional modification method for branched polyethylene glycol (PEG) derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Take 5g dry PEG 3400 Dissolve in 50 mL of anhydrous dichloromethane, add 3.34 mL of triethylamine and 0.45 mL of methanesulfonyl chloride under the protection of argon, and react at room temperature for 12 hours (the reaction process is shown in the figure below). The reaction solution was washed three times with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, recrystallized with glacial ether, and filtered. The filtered solid was washed three times with glacial ether and dried in vacuo to obtain 5.17 g of a white powdery substance. The substance was tested by infrared spectroscopy and 1 H nuclear magnetic resonance detection and analysis, the results are as follows: IR (NaCl): 2883, 1467, 1280, 1114, 1061, 946, 842cm -1 ; 1 H NMR (CDCl 3 ): 2.84 (6H, CH 3 ), 3.63-3.75 ((OCH 2 CH 2 )n), 3.85-3.90 (4H, CH 2 OSO 2 ). Analysis of the results confirmed that the white powder was polyethylene g...

Embodiment 2

[0026] Dissolve 5.0 g of dry polyethylene glycol methanesulfonate in 50 mL of dimethylformamide, and add 2.74 g of Cs respectively under the protection of argon 2 CO 3 With 1.76g methyl 5-hydroxyisophthalate, react at room temperature for 24h, the reaction process is as follows:

[0027]

[0028] Dimethylformamide was distilled off under reduced pressure, the residue was dissolved in 50 mL of dichloromethane, and insoluble matter was removed by filtration. The filtered solid was washed three times with glacial ether and dried in vacuo to obtain 5.31 g of white powder. The substance was tested by infrared spectroscopy and 1 H nuclear magnetic resonance detection and analysis, the results are as follows: IR (NaCl): 2885, 1725, 1466, 1280, 1111, 963, 842, 760cm -1 ; 1 H NMR: 3.60-3.96 (CH 3 , (OCH 2 CH 2 )n), 4.22 (4H, CH 2 OAr), 7.77 (4H, Ar), 8.28 (2H, Ar). Analysis of the results confirmed that the white powder substance was bis(3,5-dimethoxycarbonyl)phenyl polyeth...

Embodiment 3

[0030] Take 4.85g of dry bis(3,5-dimethoxycarbonyl)phenyl polyethylene glycol and dissolve in 50mL of anhydrous tetrahydrofuran, slowly add 0.29g of lithium aluminum hydride (LiAlH 4 ), stirred overnight, the reaction equation is as follows:

[0031]

[0032] Slowly add 2.5 mL of 10% HCl dropwise under ice-bath stirring, filter, and wash with dichloromethane three times. The washed filtrate was concentrated under reduced pressure to obtain a white solid, which was then dissolved in dichloromethane, washed three times with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, recrystallized with glacial ether, and filtered. The filtered solid was washed three times with glacial ether and dried in vacuo to obtain 4.36 g of white powder. The substance was tested by infrared spectroscopy and 1 H nuclear magnetic resonance detection and analysis, the results are as follows: IR (NaCl): 3459, 2882, 1467, 1280, 1115, 946, ...

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Abstract

The invention provides two kinds of new branched PEGs which realize fixed-point modification of protein and polypeptide medicines and have a plurality of active groups and a preparation method thereof. Compared with the conventional linear PEG modifier, the branched PEGs have a plurality of functional groups and can carry a plurality of biologically active molecules to further improve the biological performance of the modified medicines.

Description

technical field [0001] The invention belongs to the fields of biomedicine and protein chemistry, and particularly relates to branched polyethylene glycol and a preparation method thereof. technical background [0002] Polyethylene glycol (PEG) is a long-chain macromolecular polymer based on repeated ethylene glycol oxide. It has the advantages of good biocompatibility, non-toxicity to the human body, and can reduce the antigenicity of the modified substance. It is widely used in the modification of proteins, polypeptide drugs and biomedical materials. However, in practical applications, there are still some problems in polyethylene glycol modification (PEGylation), especially the biological activity of protein drugs is often reduced after PEGylation. Recent studies have shown that when a PEG with a special structure is used for modification, the loss of drug activity after modification can be significantly reduced. This PEG with a special structure is called branched PEG (B...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G65/48C08G65/334C08G65/332C08H1/00C07K1/107A61K47/48A61K38/00A61K47/60
Inventor 卢翠芬董念国史嘉玮洪昊陈思邹明晖周建良
Owner XIEHE HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI & TECH UNIV
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