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Bivalirudin-polyethylene glycol compound

A technology of polyethylene glycol and bivalirudin, applied in drug combinations, medical preparations of non-active ingredients, blood diseases, etc.

Inactive Publication Date: 2012-08-22
承德医学院中药研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the present invention, cysteine ​​is introduced into the structure of bivalirudin to realize the method and application of bivalirudin for site-directed pegylation modification, which has not been reported in the literature.

Method used

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  • Bivalirudin-polyethylene glycol compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Embodiment 1 [Cys (mPEG 2000 -MAL)] 7 - Preparation of BVLD

[0059] 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 14.2g, yield 71%.

[0060] Dissolve mPEG-OTs 14g (7mmol) in 30mL DMF, add phthalimide potassium salt 3.8...

Embodiment 2

[0066] Embodiment 2[Cys(mPEG 5000 -MAL)] 7 - Preparation of BVLD

[0067] 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 TLC detection reaction is complete, remove the solvent by rotary evaporation, add 150 mL of anhydrous ether to precipitate a solid, add water to dissolve the solid, separate the liquid, 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, and anhydrous ether was added to precipitate a solid, which was filtered and dried to obtain mPEG 5000 -OTs 21.6g, yield 86%.

[0068] mPEG 5000 -OTs 20g (4mmol) was dissolved in 30mL DMF, phthalimid...

Embodiment 3

[0072] Embodiment 3 [Cys (mPEG 10000 -MAL)] 7 - Preparation of BVLD

[0073] Weigh mPEG 10000 -OH 25g (2.5mmol) was placed in a reaction flask, dichloromethane 100mL was added, and the solid was dissolved, then triethylamine 3.75mL (2.5mmol) and p-toluenesulfonyl chloride 4.75g (Ts-Cl, 25mmol) were added, and stirred at room temperature reaction. After the TLC detection reaction is complete, remove the solvent by rotary evaporation, add 150 mL of anhydrous ether to precipitate a solid, add water to dissolve the solid, separate the liquid, 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 10000 -OTs 24g, yield 92%.

[0074] mPEG 10000 -OTs 20g (2mmol) was dissolved in 30mL DMF, phthalimide pota...

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Abstract

The invention relates to a bivalirudin-polyethylene glycol compound and a preparation method thereof, a medicinal composition containing the compound and application. The bivalirudin-polyethylene glycol compound is a new structural compound which is obtained by cysteine substitution for any glycine from the 5th site to the 8th site in a bivalirudin sequence and polyethylene glycol modification, keeps the activity of bivalirudin and prolongs the half-life period of the bivalirudin. The application of the bivalirudin-polyethylene glycol compound in medicaments for treating or preventing thrombus diseases comprises application in medicaments for unstable angina pectoris, peripheral artery intervention therapy, hearth and lung transplantation and thrombus preventing treatment.

Description

【Technical field】 [0001] The present invention relates to PEGylated complexes of bivalirudin, their preparation methods, pharmaceutical compositions containing them and their application in medicines for treating or preventing thrombotic diseases, including unstable angina pectoris, peripheral arterial intervention The application of drugs in heart and lung transplantation and antithrombotic therapy. 【Background technique】 [0002] Thrombosis caused by atherosclerosis has become the first cause of death in the world, and its incidence is on the rise in my country, and anticoagulant drugs are extremely important in the treatment of this disease. Among the many anticoagulants currently available, Medicines’ bivalirudin (Angiomax TM ) is a new anticoagulant drug approved by the FDA in 2000, and its anticoagulant component is a hirudin analog (fragment). This drug is a direct, specific and reversible inhibitor of thrombin, whether thrombin is in the blood circulation or bound ...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K38/10A61P7/02A61P9/10
Inventor 王良友王小青尹志峰李云峰高杨赵红玲
Owner 承德医学院中药研究所
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