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Methoxy polyethylene glycol-modified erythropoietin mimic peptide derivative

A technology of methoxypolyethylene glycol and erythropoietin, which is applied in the field of cytopoietin receptors or erythropoietin hormones, can solve the problems of short half-life and low EC50, and achieve high bioavailability and biological active effect

Inactive Publication Date: 2014-02-12
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the EC50 of peptides that can stimulate the proliferation and differentiation of red blood cells is very low, and the half-life is short, so the clinical application of these peptides is greatly limited.

Method used

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  • Methoxy polyethylene glycol-modified erythropoietin mimic peptide derivative
  • Methoxy polyethylene glycol-modified erythropoietin mimic peptide derivative
  • Methoxy polyethylene glycol-modified erythropoietin mimic peptide derivative

Examples

Experimental program
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Effect test

reference example

[0035] Reference Example: Preparation of HH-EPO-018(2)

[0036] 1. Synthesis of erythropoietin mimic peptide derivative monomer peptide SEQ ID NO:8

[0037] The synthesis of monomeric peptides of erythropoietin-mimetic peptide derivatives adopts the method of solid-phase peptide synthesis. This type of peptide synthesis method has been reported in many literatures. See stewart, J.M., and Young, J.D., solid phase peptide synthesis 2deditioN, Novabiochem peptide synthesis notes. The erythropoietin mimetic peptide derivative monomer peptide provided by the present invention is manually synthesized, the resin is rink amind resin, the α-amino group of the amino acid derivative used is protected by Fmoc (fluorenylcarbonyl), and the cysteine ​​side Chain sulfhydryl group, glutamine side chain amino group, histidine side chain imidazole group are protected by Trt (trityl), arginine side chain guanidine group is protected by Pbf (2,2,4,6,7-pentamethyl) Dihydrobenzofuran-5-sulfonyl) p...

Embodiment 1

[0052] The preparation of embodiment one HH-EPO-018 (22)

[0053] 1. Synthesis of erythropoietin-mimicking peptide derivative monomer peptide SEQ ID NO: 8: refer to the reference example.

[0054] 2. Preparation of HH-EPO-008: refer to the reference example.

[0055] 3. Preparation of mPEG2-OSU (20kD+20kD)

[0056]

[0057] (1) Preparation of intermediate three

[0058] Add glycerol (15.3mg) into the reactor, dissolve it with boric acid buffer (pH=8), add mPEG-OSU (20KD) (10.0g), stir at room temperature overnight, then add 50ml of deionized water to dilute and adjust with oxalic acid PH≈3, extract completely with dichloromethane (150ml×3), dry over anhydrous magnesium sulfate, concentrate under reduced pressure, settle the residue with ether, filter out the solid, and dry the solid under vacuum to obtain 9.71g of white solid (crude intermediate 3) .

[0059] Dissolve 9.61g of the crude intermediate 3 in 150ml of deionized water and purify it by column chromatography on...

Embodiment 2

[0065] The preparation of embodiment two HH-EPO-018 (31)

[0066]1. Synthesis of erythropoietin-mimicking peptide derivative monomer peptide SEQ ID NO: 8: refer to the reference example.

[0067] 2. Preparation of HH-EPO-008: refer to the reference example.

[0068] 3. Preparation of mPEG2-OSU (30kD+10kD)

[0069]

[0070] (1) Preparation of intermediate four

[0071] Add glycerol (460mg) into the reactor, dissolve it with boric acid buffer (pH=8), add mPEG-OSU (10KD) (2.5g), stir at room temperature overnight, then add 50ml of deionized water to dilute and adjust the pH with oxalic acid ≈3, extracted completely with dichloromethane (150ml×3), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was settled with ether, and the solid was filtered out, and the solid was dried in vacuo to obtain 2.48g of white solid. Dissolve 2.48g of white solid in 5ml of TFA / DCM (1 / 4), stir for 30min, settle into diethyl ether and filter out the solid. ...

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Abstract

The present invention relates to a methoxy polyethylene glycol-modified erythropoietin mimic peptide derivative represented by a general formula (I), a pharmaceutically acceptable salt of the derivative, a preparation method of the derivative and the pharmaceutically acceptable salt, and uses of the derivative and the pharmaceutically acceptable salt in preparation of drugs for treatment of diseases adopting erythropoietin deficiency or red cell mass shortage or defect as characteristics.

Description

technical field [0001] The invention relates to a methoxypolyethylene glycol-modified erythropoietin mimic peptide derivative capable of binding to and activating the erythropoietin receptor or having an agonistic effect on the erythropoietin, Specifically, the present invention relates to the selection of active methoxypolyethylene glycol for modification of erythropoietin mimic peptide derivatives, that is, by comparing red blood cells modified with active methoxypolyethylene glycol with different molecular weights or different structures Based on factors such as the biological activity and stability of the erythropoietin-mimicking peptide, active methoxypolyethylene glycol with a specific structure is selected to modify the erythropoietin-mimicking peptide. Background technique [0002] Polyethylene glycol (PEG) is a hydrophilic polymer with neutral pH, non-toxicity and high water solubility. Its repeating unit is oxyethylene, and its terminal group is two hydroxyl groups...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K17/08C07K1/113A61K38/18A61K47/48A61P13/12A61P7/06A61P37/02A61P25/00A61P35/00
Inventor 吴文涛王瑞军孙长安吕爱锋
Owner JIANGSU HANSOH PHARMA CO LTD
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