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Thymosin alpha 1 active segment cyclicpeptide analogue and its poly glycol derivative

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

Inactive Publication Date: 2011-07-20
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

[0006] Currently, Tα1 (Zidaxian) in clinical use is a chemical synthetic product, which is expensive, has a large dosage, and a long cycle. Therefore, the research on the structure-activity relationship has found that better analogues have better application prospects.

Method used

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  • Thymosin alpha 1 active segment cyclicpeptide analogue and its poly glycol derivative
  • Thymosin alpha 1 active segment cyclicpeptide analogue and its poly glycol derivative
  • Thymosin alpha 1 active segment cyclicpeptide analogue and its poly glycol derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0572] BocNHCH 2 CH 2 OCH 2 Synthesis of COOH:

[0573]

[0574] ●BocNHCH 2 CH 2 Synthesis of OH

[0575] Add 30ml of water into the 250ml reactor, NH 2 CH 2 CH 2 6.1 g (100 mmol) of OH was added to the reactor and cooled to 0°C. Under ice bath conditions, (Boc) 2 O21.82g (100mmol) dissolved in 30ml of dioxane was added to the reactor, the temperature was controlled below 0℃, 100ml of 1mol / LnaOH solution was added dropwise, after 40 minutes of dripping, it was naturally warmed to room temperature, and the reaction was continued for 12 hours. (Boc) 2 O disappeared, stop the reaction, click the plate to detect, the reaction solution was extracted three times with ethyl acetate, washed with saturated NaCl solution, with anhydrous Na 2 It was dried over SO4 and evaporated to dryness under reduced pressure to obtain 15.6 g of colorless oil with a yield of 97.2%.

[0576] ●BocNHCH 2 CH 2 OCH 2 Synthesis of COOH

[0577] Add 350ml of re-distilled DMF and BocNH to a 500ml three-necked bottle...

Embodiment 2

[0579] Cys-Glu-Val-Val-Glu-SCH 2 CH 2 CONH 2 Synthesis:

[0580] 350mg MBHA resin (loading 0.57mmol / g, 0.2mmol), suspended in DMF, followed by adding 0.12gHOBt, 150μL 3-mercaptopropionic acid (1.2mmol), 160mg DCC, adding a small amount of DCM to dissolve fully, magnetically at room temperature Stir for 4 hours, wash twice with DMF, DCM, MeOH, and DCM for two minutes each time. Ninhydrin test was negative. Then use 50mg of cysteine ​​methyl ester hydrochloride (0.2mmol), 100mg (0.2mmol) of triphenylphosphorus and 120μl of DIEA (0.2mmol) to dissolve in DMF. After five minutes, add to the resin and react at room temperature for two hours. DMF, DCM, MeOH, and DCM were washed twice each, 4 times the amount of BOC-protected amino acid, BOP, and 6 times the amount of DIEA were mixed and dissolved in DMF. After five minutes, the mixture was added to the reactor and reacted at room temperature for 2 hours. Wash with DMF, DCM, MeOH, DCM, and use qualitative Ellman test to test. The negat...

Embodiment 3

[0581] Example 3: Synthesis of ring (CEVVE):

[0582] 350mg MBHA resin (loading 0.57mmol / g, 0.2mmol), suspended in DMF, followed by adding 0.12gHOBt, 150μL 3-mercaptopropionic acid (1.2mmol), 160mg DCC, adding a small amount of DCM to dissolve fully, magnetically at room temperature Stir for 4 hours, wash twice with DMF, DCM, MeOH, and DCM for two minutes each time. Ninhydrin test was negative. Then use 50mg of cysteine ​​methyl ester hydrochloride (0.2mmol), 100mg (0.2mmol) of triphenylphosphorus and 120μl of DIEA (0.2mmol) to dissolve in DMF. After five minutes, add to the resin and react at room temperature for two hours. DMF, DCM, MeOH, and DCM were washed twice each, 4 times the amount of BOC-protected amino acid, BOP, and 6 times the amount of DIEA were mixed and dissolved in DMF. After five minutes, the mixture was added to the reactor and reacted at room temperature for 2 hours. Wash with DMF, DCM, MeOH, DCM, and use qualitative Ellman test. The negative solution resin ...

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PUM

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Abstract

The present invention relates to a kind of cyclopeptide derivative containing natural or artificial amino acid substituted active thymosin alpha-1 segment, and the preparation process thereof, medicine composition and their medicines for treating or preventing diseases related to immune deficiency, hypoimmunity, etc.

Description

Invention field [0001] The present invention relates to active fragments of thymosin α1 and cyclic peptide analogs substituted with natural or unnatural amino acids, and pegylated derivatives thereof, and preparation methods thereof, and pharmaceutical compositions containing them and their use in the treatment or prevention of immunodeficiency , Use in related diseases such as low immune function. Background technique [0002] Thymosin α1 (Tα1) is an important polypeptide immunomodulatory factor, which has a significant effect of enhancing immune function. It is an immune enhancer for T lymphocytes, which can promote the maturation and differentiation of T cells, and promote maturity Lymphocytes secrete a variety of lymphokines (such as interleukin-2 and gamma-interferon, etc.) and can promote the production of interleukin-2 receptors. Tα1 consists of 28 amino acid residues, with a molecular weight of 3108, an isoelectric point of 4.2, and an acetylated structure at the N-termi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/10C07K7/06A61K38/07A61K38/08A61P37/02A61P37/04A23L1/305A23L33/18
Inventor 刘克良蒋志龙王良友梁远军许笑宇吴萍韩寒
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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