Polyglycol active derivative with oligopeptide as framework, preparation method thereof and conjugate of the same and pharmaceutical molecule

A technology of polyethylene glycol and drug molecules, which is applied in the fields of genetic material components, chemical instruments and methods, and medical preparations of non-active ingredients, etc., can solve the problems of poor binding stability and low degree of modification, etc.

Active Publication Date: 2008-04-30
JENKEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The existing polyethylene glycol derivatives for modification have disadvantages such as low degree of modification and poor binding stability

Method used

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  • Polyglycol active derivative with oligopeptide as framework, preparation method thereof and conjugate of the same and pharmaceutical molecule
  • Polyglycol active derivative with oligopeptide as framework, preparation method thereof and conjugate of the same and pharmaceutical molecule
  • Polyglycol active derivative with oligopeptide as framework, preparation method thereof and conjugate of the same and pharmaceutical molecule

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Synthesis of active derivatives of double-chain polyethylene glycol formed by polyethylene glycol acetic acid and Gly-Lys dipeptide (1)

[0081]

[0082] Dissolve 20 g of polyethylene glycol monomethyl ether acetate-N-hydroxysuccinimide ester (mPEG-SCM) with a molecular weight of 20,000 in phosphate buffer containing 1 g of Gly-Lys dipeptide, pH=8.5 , stirred at room temperature for three hours. Adjust the pH to 3 with hydrochloric acid, extract three times with dichloromethane, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, evaporate the solvent in vacuo, and add 200 ml of isopropanol to precipitate. The precipitate was filtered and dried in vacuo. Branched PEG acidic products can be further purified by ion-exchange chromatography. Yield: 8 g (40%). NMR (DMSO) 3.50 (br m, hydrogens in PEG), 3.24 (s, 3 hydrogens), 4.15 (t, 2 hydrogens).

[0083] 0.5 g of branched PEG acid (prepared from the previous step) was dissolved in 5 mL o...

Embodiment 2

[0085] Synthesis of active derivatives of double-chain polyethylene glycol formed by polyethylene glycol and Gly-Lys dipeptide (2)

[0086]

[0087] Dissolve 20 g of polyethylene glycol monomethyl ether orthocarbonate-N-hydroxysuccinimide ester (mPEG-SC) with a molecular weight of 20,000 in borate buffer containing 1 g of Gly-Lys dipeptide, pH =10.2, stirred overnight at room temperature. Adjust the pH to 3 with hydrochloric acid, extract three times with dichloromethane, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, evaporate the solvent in vacuo, and add 200 ml of isopropanol to precipitate. The precipitate was filtered and dried in vacuo. Branched PEG acidic products can be further purified by ion-exchange chromatography. Yield: 8 g (40%). NMR (DMSO) 3.50 (br m, hydrogens in PEG), 3.24 (s, 3 hydrogens), 4.32 (t, 2 hydrogens).

[0088]0.5 g of branched PEG acid (prepared from the previous step) was dissolved in 5 mL of dichlorometha...

Embodiment 3

[0090] Synthesis of active derivatives of double-chain polyethylene glycol formed by polyethylene glycol and Gly-Lys (Gly) tripeptide (3)

[0091]

[0092] Dissolve 20 g of polyethylene glycol monomethyl ether orthocarbonate-N-hydroxysuccinimide ester (mPEG-SC) with a molecular weight of 20,000 in borate buffer containing 1.2 g of Gly-Lys (Gly) polypeptide , pH=10.2, stirred overnight at room temperature. Adjust the pH to 3 with hydrochloric acid, extract three times with dichloromethane, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, evaporate the solvent in vacuo, and add 200 ml of isopropanol to precipitate. The precipitate was filtered and dried in vacuo. Branched PEG acidic products can be further purified by ion-exchange chromatography. Yield: 8 g (40%). NMR (DMSO) 3.50 (br m, hydrogens in PEG), 3.24 (s, 3 hydrogens), 4.32 (t, 2 hydrogens).

[0093] 0.5 g of branched mPEG acid (prepared from the previous step) was dissolved in 5 ...

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Abstract

The invention relates to compound formed by polyethylene glycol and oligopeptide and expressed by the general formula I, wherein, i, j, p, and q are integral numbers, i is equal to 1, 2, to j; j is larger than or equal to 2; p is equal to 1, 2, to q; q is larger than or equal to 1; PEGi is a polyethylene glycol chain; Xi is a linking group; A is derived from oligopeptide and composed of 2 to 20 amino acids, and two amino acids are different; Fp is an active group. The compound can link macromolecular protein or polypeptide or micromolecular active constituents of natural drugs through the Fp to improve the physiological action of drug molecular in the human body, or ensure the appropriate drug concentration and provide the slow-releasing function.

Description

technical field [0001] The invention relates to polyethylene glycol active derivatives, in particular to a polyethylene glycol active derivative with an oligopeptide as the backbone, a preparation method thereof, and a combination of the derivative and a drug molecule. Background technique [0002] A variety of natural and recombinant proteins and peptides have some pharmaceutical utility. Various products after purification and separation can be used for various therapeutic indications through parenteral administration. However, proteins administered parenterally may be immunogenic, may be relatively water insoluble, and may have a short pharmacological half-life. Therefore, how to improve and maintain the effective blood drug concentration of these drug molecules in patients has very significant practical significance. [0003] Similarly, various natural pharmaceutical ingredients other than proteins, such as flavonoids, terpenoids, quinones, steroids, and various alkalo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/48A61K48/00A61K47/48
CPCC07K5/1008C07K5/06086C07K5/06026C07K7/02C07K5/0806C07K5/021A61K47/48215A61K47/60
Inventor 赵宣顾强
Owner JENKEM TECH
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