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Chemically modified thymopentin and synthetic method thereof

A technology of chemical modification and synthesis method, which is applied in the field of biochemical drug synthesis, can solve the problems of high molecular weight of PEG, difficulty in obtaining modified site products, and decreased biological activity of drugs, so as to achieve high bioavailability, overcome repeated repeated and long-term Injection, the effect of prolonging the half-life

Inactive Publication Date: 2014-07-02
SHENZHEN INST OF ADVANCED TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of PEG modification in the chemical modification method is that since PEG itself is a polymer, it is difficult to obtain a product with a precise modification site and a unique chemical structure of the product
In addition, the molecular weight of PEG is large, and the biological activity of the modified drug is greatly reduced.

Method used

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  • Chemically modified thymopentin and synthetic method thereof
  • Chemically modified thymopentin and synthetic method thereof
  • Chemically modified thymopentin and synthetic method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The synthetic method of the Thymopentin of embodiment 1 chemical modification

[0035] Include the following steps:

[0036] (1) Weigh 200 mg of Fmoc-protected tyrosine king resin (Fmoc-Tyr(tBu)-Wang Resin

[0037] 0.25 mmol / g) in a manual solid-phase peptide synthesizer, adding DCM (dichloromethane) to swell for 30 minutes. Sequentially with Fmoc-Val-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Lys(Boc)-OH and

[0038]Fmoc-Arg(Pbf)-OH is the amino acid raw material, with benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and diisopropylethylamine (DIEA) As a polypeptide condensing agent, the equivalent ratio of the resin to each protected amino acid and polypeptide condensing agent is Tyrosine King Resin: Amino Acid: HBTU: DIEA=1: 3: 3: 6, according to the standard Fmoc strategy to synthesize Fmoc-protected loaded thymus Wang resin of the pentapeptide (compound 1).

[0039] (2) After removing the terminal amino Fmoc protecting group with 2 ml of piperidine deprot...

Embodiment 2

[0044] The synthetic method of the Thymopentin of embodiment 2 chemical modifications

[0045] Include the following steps:

[0046] (1) Weigh 200 mg of Fmoc-protected tyrosine king resin (Fmoc-Tyr(tBu)-Wang Resin

[0047] 0.25 mmol / g) in a manual solid-phase peptide synthesizer, adding DCM (dichloromethane) to swell for 30 minutes.

[0048] Sequentially with Fmoc-Val-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Lys(Dde)-OH and

[0049] Boc-Arg(Pbf)-OH is used as amino acid raw material, with benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and diisopropylethylamine (DIEA) As a polypeptide condensing agent, the equivalent ratio of the resin to each protected amino acid and polypeptide condensing agent is Tyrosine King Resin: Amino Acid: HBTU: DIEA=1: 3: 3: 6, and Thymopentin is synthesized according to the standard Fmoc strategy. Wang resin (compound 3).

[0050] (2) After reacting 2% dimethylformamide (DMF) solution at room temperature with the volume percentage of 2m...

Embodiment 3

[0056] The synthetic method of the Thymopentin of embodiment 3 chemical modifications

[0057] Include the following steps:

[0058] (1) Myristic acid (460 mg, 2mmol) was dissolved in 100 ml of dichloromethane (DCM), activated with equivalent HBTU (759 mg, 2mmol) and DIEA (260 mg, 2mmol) for 2 minutes,

[0059] Add Fmoc-Lys-OH (736 mg, 2 mmol), react at room temperature for 1 hour, evaporate DCM under reduced pressure, and purify the crude product by HPLC to obtain Fmoc-protected myristic acid-modified side chain lysine

[0060] (Fmoc-Lys(Myr)-OH) 872 mg, yield 76%.

[0061] The reaction equation is as follows:

[0062]

[0063] (2) Weigh 200 mg of Fmoc-protected tyrosine king resin (Fmoc-Tyr(tBu)-Wang Resin

[0064] 0.25 mmol / g) in a manual solid-phase peptide synthesizer, adding DCM (dichloromethane) to swell for 30 minutes.

[0065] Sequentially with Fmoc-Val-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Lys(Myr)-OH and

[0066] Boc-Arg(Pbf)-OH is used as amino acid raw material, wit...

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Abstract

The invention discloses a chemically modified thymopentin and a synthetic method thereof. The structure of the chemically modified thymopentin is shown as follows: A-Arg-Lys-Asp-Val-Try-OH or H-Arg-Lys(A)-Asp-Val-Try-OH. The A is a micromolecule ligand. The micromolecule ligand is an aliphatic acid bonding in affinity with human serum albumin, or is a maleimide derivative coupled with free sulfydryl of human serum albumin. The chemically modified thymopentin has characteristics of precision modification sites, a definite chemical structure and a simple and concise synthetic process. The chemically modified thymopentin after being injected intravenously bonds immediately with the serum albumin of the human body and adopts the serum albumin of the human body as a controlled-release vector, thus prolonging the half-life period largely, and significantly prolonging the time of duration of the effective medicine concentration. The bioavailability is high.

Description

technical field [0001] The invention belongs to the field of biochemical drug synthesis, and more specifically, the invention relates to a chemically modified thymopentin and a synthesis method thereof. Background technique [0002] Thymopentin is the first chemically synthesized peptide drug independently developed in my country, and it is also one of the chemically synthesized peptide drugs with the highest sales in hospitals, and the scale of drug use in my country's pharmaceutical market is growing rapidly year by year. Thymopentin can be used clinically for the immunotherapy of various malignant tumors, as well as the adjuvant therapy of surgery, radiotherapy and chemotherapy, and effectively prevent and treat complications such as secondary infection. In addition, Thymopentin is also clinically used for chronic viral hepatitis, major surgical operations and severe infections, autoimmune diseases (such as rheumatoid arthritis and lupus erythematosus, etc.), severe burns...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/107C07K1/06C07K1/04
Inventor 粟武
Owner SHENZHEN INST OF ADVANCED TECH
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