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Polyethylene glycol derivatives of thymosin alphal

A technology of derivatives and compounds, applied in the field of pegylated derivatives of thymosin α1, which can solve the problems of long cycle, high price, and large dosage

Inactive Publication Date: 2004-09-29
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Tα currently in clinical use 1 It is a chemical synthetic product, which is expensive, has a large dosage and a long cycle

Method used

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  • Polyethylene glycol derivatives of thymosin alphal
  • Polyethylene glycol derivatives of thymosin alphal
  • Polyethylene glycol derivatives of thymosin alphal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Example 1 Cys(mPEG 5000 Preparation of -MAL)-Tα1

[0091] 1.1 mPEG 5000 -Synthesis of MAL

[0092] Weigh mPEG 5000 -OH 20g (4mmol) was placed in a 250ml reaction bottle, and 100ml CH was added 2 Cl 2 , after the solid dissolved, add 3.0ml Et 3 N (20mmmol) and 3.8g Ts-Cl (20mmol), stirred at room temperature. After TLC monitors that the reaction is complete, the solvent is removed by rotary evaporation, and 100 ml of anhydrous ether is added to precipitate a solid to obtain 15.2 g of mPEG 5000 -OTs, yield 70%.

[0093] 15g mPEG 5000 -OTs (3mmol) was dissolved in 30ml DMF, 1.68g (18mmol) phthalimide potassium salt was added, and reacted at 120°C for 4 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in 50 ml of absolute ethanol, 2.0 ml of hydrazine hydrate was added, and the mixture was refluxed for 4 hours. The solvent was removed by rotary evaporation and the residue was dissolved in 30 ml CH 2 Cl 2 , filtered off the in...

Embodiment 2

[0100] Example 2 Tα 1 (17-24)-Cys(mPEG 5000 -MAL)-NH 2 preparation of

[0101] 2.1 Tα 1 (17-24)-Cys-NH 2 Synthesis

[0102] With 0.1mmol Rink amide resin as carrier, Fmoc-AA-OH (0.2mmol) as raw material, HBTU (0.2mmol)-NMM (0.3mmol) as condensation agent, according to Tα 1 The amino acid sequence of (17-24) was synthesized into a fully protected peptide resin. Use EDT-m-cresol-TFA as the lysate, react at 0°C for 90 minutes, filter off the resin, remove the TFA by rotary evaporation of the filtrate, add anhydrous ether to precipitate a white solid, collect the solid, dissolve in water, freeze-dry to obtain a white Dry powder 20mg. RP-HPLC purification, FAB-MS analysis, M+1 peak: 1091 (theoretical value: 1090).

[0103] 2.2 Tα 1 (17-24)-Cys(mPEG 5000 -MAL)-NH 2 Synthesis

[0104] Tα purified by RP-HPLC 1 (17-24)-Cys-NH 2 Dissolve in water, adjust pH to 7-8 with sodium bicarbonate, add 3 times the equivalent of mPEG 5000 -MAL, reacted at room temperature for 2 hour...

Embodiment 3

[0106] Example 3 Tα 1 Induction of IFN-γ produced by mouse splenocytes and its analogues

[0107] The mice were sacrificed by decapitation and bloodletting, and the spleen was quickly removed under aseptic conditions and placed in RPMI1640 solution. Put the spleen on a 100-mesh stainless steel net or nylon net and grind it with a needle core or a triangular glass rod to make a spleen cell suspension. After the splenocytes were centrifuged and washed once with culture medium, Tris-NH was added 4 Cl buffer (0.16M NH 4 Cl and 0.17M Tris were mixed at a ratio of 9:1, pH7.2) to act for 3-5 minutes to dissolve RBC, and then centrifuged and washed twice with culture medium. With trypan blue staining, the number of viable cells should be above 95%. Adjust the cell concentration to 1.25×10 with 10% calf serum 1640 7 A / mL spare. Add splenocytes to a sterile 48-well culture plate, 800 μL per well; then add 100 μL of the samples to be tested at different concentrations shown in Tabl...

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Abstract

The present invention relates to polyethylene glycol derivatives of thymosin alpha-1, their preparation process, the medicine composition containing them, and their application in the medicine for preventing and treating diseases related with immune deficiency and hypoimmunity, including hepatitis B, hepatitis C, malignant melanoma, non-small cell lung carcinoma, SARS, etc.

Description

field of invention [0001] The present invention relates to thymosin alpha 1 Pegylated derivatives, their preparation methods, pharmaceutical compositions containing them, and their use in medicines for the treatment or prevention of diseases related to immunodeficiency and immunodeficiency, including hepatitis B, hepatitis C, Application in the treatment or prevention of malignant melanoma, non-small cell lung cancer, SARS (severe acute respiratory syndrome) and other related diseases caused by coronavirus. Background technique [0002] thymosin alpha 1 (Tα 1 ) is an important polypeptide secreted by the thymus. It is an immune enhancer for T lymphocytes, which can promote the maturation and differentiation of T cells, and promote the secretion of various lymphokines (such as interleukin-2 and γ-interferon, etc.), can also promote the production of interleukin-2 receptors. Tα 1 Composed of 28 amino acid residues, the molecular weight is 3108, the isoelectric point is 4....

Claims

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Application Information

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IPC IPC(8): A61K38/00A61K38/08A61K38/32C07K5/00C07K7/06C07K14/66C07K17/02C08F290/06C08G65/48
Inventor 刘克良王良友刘尚义吴萍赵修南董泄建
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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