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Fucosylated glycosaminoglycan derivative and preparation method thereof

A technology of glycosaminoglycan carboxylate and glycosylamine, which is applied in the field of fucosylated glycosaminoglycan carboxylate and its preparation, can solve the problems of large individual differences and slow onset of action

Inactive Publication Date: 2012-01-25
KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main anticoagulant drugs, including coumarins (oral VitK-dependent protease inhibitors) and heparins (thrombin and factor X inhibitors), have been in clinical use for more than 60 years. These drugs have relatively clear efficacy and Pharmacological mechanism of action, but there are also obvious clinical application defects: the main targets of heparin drugs are factors IIa and Xa (f.IIa, f.Xa), which are located in the common pathway of blood coagulation cascade, and the application defects of such drugs Including target-related severe bleeding tendency, thrombocytopenia, bone and lipid metabolism effects, etc.; the defects of coumarin anticoagulant drugs include severe bleeding tendency, slow onset, and individual differences caused by inhibiting the synthesis of a series of coagulation factors Big and so on
At present, there is no public report on the esterification modification of the carboxyl group of fucosylated glycosaminoglycans and the study of its biological activity

Method used

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  • Fucosylated glycosaminoglycan derivative and preparation method thereof
  • Fucosylated glycosaminoglycan derivative and preparation method thereof
  • Fucosylated glycosaminoglycan derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] [Example 1] Preparation of FGAG carboxyethyl esterification product

[0054] 1.1 Materials

[0055] Prunus ginseng (Thelenata ananas Jaeger), commercially available, eviscerated and dried body wall;

[0056] h 2 o 2 , CH 3 COONa·3H 2 O, NaCl, NaOH, Cu(CH 3 COO) 2 ·H 2 O, tetrabutylammonium hydroxide, ethyl bromide, N, N-dimethylformamide, sodium hydroxide, sodium chloride and ethanol were commercially available analytical reagents.

[0057] 1.2 Method

[0058] (1) Extraction and preparation of fucosylated glycosaminoglycans (FGAG): Take the dried body wall of Echinodermata ginseng, and prepare FGAG according to the literature method (J Biol Chem, 1991, 266(21): 13530-6). The yield 0.75%, purity 98% (HPGPC, area normalization method), weight average molecular weight (Mw), 65,960.

[0059] (2) Preparation of low-molecular-weight fucosylated glycosaminoglycan (FGAG): 5.0 g of FGAG obtained in step (1) was prepared according to the method of patent CN 201110114860...

Embodiment 2

[0070] [Example 2] Preparation of FGAG-carboxyallyl esterification product

[0071] 2.1 Materials

[0072] Haitian melon (Acaudiina molpadioides Sepmper) is commercially available, the internal organs are removed and the body wall is dried; allyl bromide is a commercially available analytical reagent, and the rest of the reagents are the same as in Example 1.

[0073] 2.2 Method

[0074] (1) Preparation of FGAG quaternary ammonium salt

[0075] According to the preparation of steps (1) to (3) in the method of [Example 1], 253.1 mg of ammonium salt was obtained.

[0076] (2) Preparation of FGAG-carboxyallyl esterification product

[0077] Get the quaternary ammonium salt 253.1mg that step (1) gained is placed in the reaction test tube, add 3ml DMF to dissolve, add reactant propylene bromide 120 μ l, in N 2 Protected, protected from light, reacted at 30°C for 24h under stirring (450r / min). After the reaction, add 3ml of 0.5M NaCl to the reaction solution, add 15ml of absolu...

Embodiment 3

[0078] [Example 3] Preparation of FGAG-carboxy n-butyl esterification product

[0079] 3.1 Materials

[0080] Sea cucumber (Apostichopus japonicus Selenka, 1867), commercially available, eviscerated and dried body wall; bromo-n-butane and tributylamine are commercially available reagents of analytical grade, and the rest of the reagents are the same as [Example 1].

[0081] 3.2 Method

[0082] (1) Preparation of FGAG quaternary ammonium salt

[0083] According to the method of [Example 1] steps (1) to (3), tributylamine was used to prepare to obtain 166.6 mg of ammonium salt.

[0084] (2) Preparation of FGAG-carboxy n-butyl ester product

[0085] Get the quaternary ammonium salt 166.6mg that step (1) gained is placed in reaction test tube, add 2ml DMSO to dissolve, add reactant n-bromobutane 150 μ l, in N 2 Protected and reacted at 30°C for 20h. After the reaction was completed, 2ml of 0.5M NaCl was added to the reaction solution, and 20ml of absolute ethanol was added, a...

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Abstract

The invention discloses a carboxylic ester of fucosylated glycosaminoglycan (CEFG) with anticoagulation activity, a pharmaceutically acceptable salt thereof, a preparation method of the CEFG and the pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the CEFG or the salt thereof, and application of the pharmaceutical composition in preparation of anticoagulants. The monosaccharides for preparing the CEFG comprise D-glucuronic acid or D-glucuronate (D-GlcU), D-2-deoxy-2-acetyl galactosamine sulfate (D-GalNAcS) and L-fucose sulfate (L-FucS), wherein the molar ratio of D-GlcU to D-GalNAc to L-Fuc to -OSO3<-> is 1:(1+ / -0.3):(1+ / -0.3):(3.5+ / -0.5); the esterification degree of the D-GlcU is not lower than 20%; and the weight average molecular weight of the CEFG is 3000-20000 Da. The glycosylated chondroitin sulfate esterification derivative has strong anticoagulation activity, and can be applied in preparation of drugs for preventing and / or treating thrombotic diseases.

Description

technical field [0001] The invention relates to a fucosylated glycosaminoglycan carboxylate (Carboxylic ester of the Fucosylated Glycosaminoglycans, CEFG) with anticoagulant activity, a preparation method thereof, and a pharmaceutical combination containing the CEFG or a pharmaceutically acceptable salt thereof thing. Background technique [0002] Cardiovascular and cerebrovascular diseases are the most important cause of human death, killing 12 million people every year, which is close to 1 / 4 of the total death toll in the world. Thrombosis is one of the main causes of cardiovascular and cerebrovascular diseases. Antithrombotic drugs, including anticoagulant drugs, are extremely widely used and important therapeutic drugs for cardiovascular and cerebrovascular diseases, and occupy an important position in the domestic and international pharmaceutical markets. The main anticoagulant drugs, including coumarins (oral VitK-dependent protease inhibitors) and heparins (thrombin ...

Claims

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Application Information

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IPC IPC(8): C08B37/00A61K31/726A61P7/02
Inventor 赵金华吴明一高娜文丹丹连武李姿
Owner KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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