Active fragment of thymosin alphal and its polyethylene glycol derivatives

A technology of derivatives and peptide derivatives, applied in the field of law, can solve the problems of large dosage, long cycle and high price

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

[0010] Tα currently in clinical use 1 It is a chemical synthetic product, expensive, with large dosage and long cycle

Method used

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  • Active fragment of thymosin alphal and its polyethylene glycol derivatives
  • Active fragment of thymosin alphal and its polyethylene glycol derivatives
  • Active fragment of thymosin alphal and its polyethylene glycol derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0126] Example 1 Phe(4-F) 21 Tα 1 Synthesis of (17-24)

[0127] Dissolve 0.285g of H-Phe(4-F)-OH.HCl (1.3mmol) in 10mL of methanol, 10mL of acetone and 10mL of water, add 0.218g of NaHCO 3 (2.6mmol), stirred to dissolve the solid and then added 0.438g Fmoc-OSu (1.3mmol), stirred at room temperature for reaction. After the completion of the reaction monitored by TLC, the organic solvent was removed by rotary evaporation, the pH was adjusted to 2-3 with 6N hydrochloric acid, the aqueous phase was extracted 3 times with ethyl acetate, the organic phase was combined, and anhydrous MgSO 4 dry. The desiccant was filtered off, and the filtrate was rotary evaporated to remove the solvent to obtain a white solid. Then recrystallized from ethyl acetate-petroleum ether to obtain 0.320 g of Fmoc-Phe(4-F)-OH, with a yield of 61.5%.

[0128] With 100mg Wang resin (0.05mmol) as solid phase carrier, Fmoc-Lys(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Val-OH as raw material, DCC-HOBT as condensatio...

Embodiment 2

[0130] Implementation of 2 mPEG 2000 -NHCOCH 2 CH 2 CO-Tα 1 Synthesis of (17-24)

[0131] Weigh mPEG 2000 -OH 20g (10mmol) was placed in a 250ml reaction bottle, and 50ml CH was added 2 Cl 2 , the solid dissolved and then added 7.5ml Et 3 N (50mmmol) and 9.5g Ts-Cl (50mmol), 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 18.9 g of mPEG 2000 -OTs, yield 94%

[0132] 12g mPEG 2000 -OTs (6mmol) was dissolved in 30ml DMF, 3.36g (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 50ml of absolute ethanol, 4.0ml 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 CH 2 Cl 2 , filtered off the insoluble matter, and ...

Embodiment 3

[0136] Implementation of 3 Cys (mPEG 2000 -MAL)-Tα 1 Synthesis of (17-24)

[0137] 1.0g mPEG 2000 -NH 2 Dissolve in 10ml of dioxane, add 0.4g of maleic anhydride, stir and react at 80°C for 30min. The solvent was evaporated under reduced pressure, 50ml of anhydrous diethyl ether was added, and a solid was precipitated by cooling. The solid was collected by filtration and dried to obtain 0.95g. The obtained solid was dissolved in 15ml of acetic anhydride, 1.0g of sodium acetate was added, and the reaction was stirred at 100°C for 45min. Evaporate the solvent under reduced pressure, dissolve the residue with dichloromethane, filter off the insoluble matter, add an appropriate amount of activated carbon to the filtrate, let it stand for 30 minutes, filter out the activated carbon, concentrate the filtrate to dryness, add anhydrous ether, precipitate a solid, filter After collection and drying, light yellow solid 0.55g mPEG was obtained 2000 -MAL, yield 55%.

[0138] With 1...

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PUM

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Abstract

The present invention relates to active fragment of natural or artificial amino acid substituted thymosin alpha-1 and its polyethylene glycol derivatives, 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 substituted with natural or unnatural amino acids 1 Active fragments and their PEGylated derivatives, their preparation methods, their pharmaceutical compositions and their use in medicines for the treatment or prevention of diseases related to immunodeficiency and immunodeficiency, including hepatitis B, C Applications in the treatment or prevention of hepatitis, 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 generation of interleukin-2 receptor. Tα 1 It consists of 28 amino a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/08A61K38/32A61P1/16A61P31/12C07K7/06C07K14/66C07K17/02C08F290/06C08G65/48
Inventor 刘克良王良友梁远军吴萍许笑宇刘尚义齐春会赵修南
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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