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Polyethylene glycol derivatives of antitumor small peptides FpAT

A technology of polyethylene glycol and acetyl polyethylene glycol, which is applied in the field of PEGylated derivatives and can solve the problems of short half-life of small peptides

Inactive Publication Date: 2013-06-26
苏州中科天马肽工程中心有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Small peptides with small molecular weight are easily filtered by the glomerulus during the metabolic process, and are easily partially degraded by proteases in the renal tubules and excreted from the urine. Therefore, most small peptides have a short half-life. Requires high-dose repeated medication

Method used

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  • Polyethylene glycol derivatives of antitumor small peptides FpAT
  • Polyethylene glycol derivatives of antitumor small peptides FpAT
  • Polyethylene glycol derivatives of antitumor small peptides FpAT

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1 Cys(mPEG 2000 -MAL)-FpAT Preparation

[0068] Weigh mPEG 2000 -OH 20g (10mmol) was placed in a reaction flask, dichloromethane 50mL was added, and the solid was dissolved, then triethylamine 7.5mL (50mmol) and p-toluenesulfonyl chloride 9.5g (Ts-Cl, 50mmol) were added, and the reaction was stirred at room temperature. After the reaction is complete as detected by TLC, remove the solvent by rotary evaporation, add 50 mL of anhydrous ether to precipitate a solid, add water to dissolve the solid, separate the liquid, separate the water layer, wash twice with 50 mL of anhydrous ether, and then wash the water phase with 75 mL of dichloromethane Extracted twice, collected the organic phase and dried overnight. The solvent was removed by rotary evaporation, and anhydrous diethyl ether was added to precipitate a solid. mPEG after drying 2000 -OTs 15.4g, yield 77%.

[0069] Dissolve mPEG-OTs 14g (7mmol) in 30mL DMF, add phthalimide potassium salt 3.88g (21mmol), a...

Embodiment 2

[0075] Example 2 Preparation of Cys(PEG5000-MAL)-FpAT

[0076] Weigh mPEG 5000 -OH 25g (5mmol) was placed in a reaction flask, dichloromethane 100mL was added, and the solid was dissolved, then triethylamine 7.5mL (5mmol) and p-toluenesulfonyl chloride 9.5g (Ts-Cl, 50mmol) were added, and the reaction was stirred at room temperature. After the reaction is complete as detected by TLC, remove the solvent by rotary evaporation, add 150 mL of anhydrous ether to precipitate a solid, add water to dissolve the solid, separate the liquids, separate the water layer, wash twice with 100 mL of anhydrous ether, and then wash the water phase with 150 mL of dichloromethane Extracted twice, collected the organic phase and dried overnight. The solvent was removed by rotary evaporation, the solid was precipitated by adding anhydrous ether, filtered, and dried to obtain mPEG 5000 -OTs 21.6g, yield 86%.

[0077] mPEG 5000 -OTs 20g (4mmol) was dissolved in 30mL DMF, phthalimide potassium salt...

Embodiment 3

[0081] Example 3 FpAT-Cys(PEG 2000 -MAL) preparation

[0082] Weigh 2-CTC Resin (10mmol) into the reactor, add an appropriate amount of DMF to wash, remove the solution, add an appropriate amount of DCM to swell for about 30min. Weigh 9.6g of Fmoc-Cys(Trt)-OH into a beaker, add an appropriate amount of DMF to dissolve, add 2.8mL of DIPEA to the above amino acid solution, stir evenly, and bathe in ice water for 10-15min. After the resin swells, remove the DCM, pour the dissolved protected amino acid solution into the reactor, react for 10-15 minutes, add DIPEA 5.7mL, and react at room temperature for 3-4 hours. After the reaction, remove the reaction solution, add an appropriate amount of DMF to wash 3 times, add a mixed solution of DCM, methanol, and DIPEA with a volume ratio of 17:2:1 to block unreacted groups, and block twice, about 20 min each time. . After blocking, add an appropriate volume of DMF to wash 3 times, and then wash and shrink twice with anhydrous methanol,...

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Abstract

The invention relates to polyethylene glycol derivatives of antitumor small peptides FpAT, preparation methods of the derivatives, medicinal compositions containing the derivatives, and uses of the derivatives. The polyethylene glycol derivatives of the antitumor small peptides FpAT comprise new-structure compounds obtained through modifying the N-terminal, C-terminal or the aspartic acid and glutamic acid side chains of FpAT by polyethylene glycol to prolong the half-life period of the FpAT. The polyethylene glycol derivatives of the antitumor small peptides FpAT can be used for preparing medicines for treating tumors comprising tumors of the liver cancer, the lung cancer, the stomach cancer, the colon cancer, myeloma and the like.

Description

technical field [0001] The present invention relates to PEGylated derivatives of small peptide FpAT, their preparation method, pharmaceutical composition containing them and their application in medicines for treating or preventing tumors, including in the treatment of liver cancer, lung cancer, stomach cancer, colon cancer, bone marrow Application in drugs for tumors such as tumors. Background technique [0002] Tumor is one of the most serious diseases that endanger human life and health. At present, there are many methods for treating tumors, such as surgery, radiotherapy, chemotherapy, and tumor blood vessel blocking therapy. Among them, anti-angiogenesis is a hot field in the research of tumor biotherapy in recent years. Anti-tumor angiogenesis therapy has many advantages: (1) High efficiency, destroying a small amount of blood vessels can cause ischemic necrosis of a large number of tumor cells that rely on it to grow; Cells often express the same specific protein mo...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K38/10C07K17/08A61P35/00
Inventor 王良友孙锋陆丹
Owner 苏州中科天马肽工程中心有限公司
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