Thiol-ene click chemistry based preparation and characterization of fatty acid modified heparin

An alkene click, chemical technology, applied in material analysis by observing the influence of chemical indicators, analysis by chemical reaction of materials, scientific instruments, etc., can solve the problem of unstable quality, poor patient compliance, and cannot replace each other. and other problems to achieve the effect of expanding the scope of applications and great attraction

Active Publication Date: 2017-02-22
广州脉和药业有限公司
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AI Technical Summary

Problems solved by technology

[0010] Low-molecular-weight heparin and chemically synthesized heparin drugs have been used in more and more therapeutic fields as new anticoagulant drugs, and they all overcome the short half-life and low bioavailability of unfractionated heparin to varying degrees.
However, low-molecular-weight heparin still needs to be injected twice a day, and patient compliance is poor; in addition, the production technology of low-molecular-weight heparin needs to be strictly controlled to avoid introducing foreign matter during the separation and depolymerization process or changing or even disappearing the anticoagulant active site of heparin ;The products obtained by different degradation methods have different characteristics and unstable quality, and they cannot be substituted for each other in clinical practice, and different research tests are required【Fareed J, Jeske W, Fareed D, et al.Are all low molecularweight heparins equivalent in the management of venous thromboembolism? [J].Clinical&Applied Thrombosis/hemostasis Official Journal of the International Academy of Clinical&Applied Thrombosis/hemostasis, 2008,14(4):385-392], so th

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  • Thiol-ene click chemistry based preparation and characterization of fatty acid modified heparin
  • Thiol-ene click chemistry based preparation and characterization of fatty acid modified heparin
  • Thiol-ene click chemistry based preparation and characterization of fatty acid modified heparin

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preparation example Construction

[0061] In combination with the above synthetic circuit diagram, the preparation method of the fatty acidated heparin based on thiol-ene click chemistry comprises the following steps:

[0062] 1) Take the structural formula as (n=10, 12, 14, 16, 18) five different long-chain saturated fatty acids of lauric acid, myristic acid, palmitic acid, stearic acid and arachidic acid with cystamine Under alkaline conditions, an acylation reaction occurs to generate the structural formula (n=10, 12, 14) compound 2a and structural formula are Compound 2b of (n=16, 18);

[0063] 2) Reducing the disulfide bonds of compounds 2a and 2b to generate a structural formula of Compound 3 of (n=10, 12, 14, 16, 18);

[0064] 3) the structural formula is Allyl glycidyl ether with heparin (M and N are other polysaccharide sequences in the heparin structure) Under the alkaline condition of sodium hydroxide, the ring-opening reaction of ethylene oxide occurs, and the resulting structural formu...

Embodiment 1

[0085] Example 1: Preparation of Fattylated Heparin Conjugates Modified by Lauric Acid

[0086] (1) Preparation of mercaptolated lauric acid (12 carbons):

[0087] ① Preparation of intermediates containing disulfide bonds: Take 5g of lauric acid (25mmol) and 11g of Carter condensing agent (25mmol) and dissolve them with 100mL of N'N-dimethylformamide; then add 12.4mL of N'N-Dimethylformamide Isopropylethylamine (75mmol), mixed and stirred for about 10min; finally, 1.8mL of cystamine (13.75mmol) was slowly added dropwise, stirred and reacted for 8h, until the reaction was complete as detected by thin-layer chromatography. About 500 mL of water was added to the reaction solution to precipitate a solid, which was collected by filtration, heated and dissolved in ethanol at 70°C, reprecipitated, filtered again, and dried to obtain a white solid, which was an intermediate containing a disulfide bond (compound 2a, n =10), mass 5.2g, productive rate 80.5%, its mass spectrum is attach...

Embodiment 2

[0091] Example 2: Preparation of fatty acidated heparin conjugates modified with palmitic acid

[0092] (1) Preparation of mercapto-palmitic acid (16 carbons):

[0093] ①Preparation of intermediates containing disulfide bonds: Take 5g of palmitic acid (19.5mmol) and 8.6g of Carter condensing agent (19.5mmol) and dissolve them with 100mL of N'N-dimethylformamide; then add 9.7mL of N'N-Diisopropylethylamine (58.5mmol), mixed and stirred for about 10min; finally, 1.4mL of cystamine (10.7mmol) was slowly added dropwise, stirred for 8h, until the reaction was complete as detected by thin-layer chromatography. About 500 mL of water was added to the reaction solution to precipitate a solid, which was collected by filtration, heated and dissolved in ethanol at 70°C, reprecipitated, filtered again, and dried to obtain a white solid, which was an intermediate containing a disulfide bond (compound 2a, n =14), mass 4.4g, productive rate 71.8%, its mass spectrum is attached Figure 4 sho...

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Abstract

The invention discloses thiol-ene click chemistry based preparation and characterization of fatty acid modified heparin. A preparation method comprises steps as follows: two compounds including sulfhydrylated fatty acid and a double-bond heparin-allyl conjugate are synthesized respectively, sulfydryl in the sulfhydrylated fatty acid and double bonds in the heparin-allyl conjugate are enabled to be subjected to a reaction with thiol-ene click chemistry, and then fatty acid is linked to a heparin structure, so that a fatty acid modified heparin conjugate modified with different long-chain saturated fatty acids is prepared. The invention further discloses characterization for fatty acid modified heparin on the basis of nuclear magnetic resonance hydrogen spectrum detection, anti-Xa activity determination, elemental analysis, grain-size analysis and gel permeation chromatography molecular-weight determination. According to advantages and characteristics of the thiol-ene click chemistry reaction, the long-chain saturated fatty acids are applied to heparin structure modification for the first time, anticoagulant activity of heparin is reserved, so that a new idea is provided for heparin modification, and the preparation and the characterization have great significance in research and development of novel long-acting heparin anticoagulant drugs.

Description

technical field [0001] The invention relates to the preparation and characterization of fatty acidated heparin based on thiol-ene click chemistry, and belongs to the field of biomedicine. Background technique [0002] Fatty acidation of drugs refers to the modification of drugs with fatty acids (saturated / unsaturated) to improve certain properties of drugs and better meet clinical needs. At present, there are not many studies on fatty acid modification drugs, and some existing studies mainly focus on the modification of protein and polypeptide drugs. The use of fatty acids to modify protein polypeptide drugs can effectively prolong their half-life in the body. In addition, compared with other modifiers, fatty acids are important components of cell membrane phospholipids and human fats and lipids, and directly participate in the composition of cell membranes and protein ligands. Combination with membrane receptors, so fatty acid modification is more helpful to improve the fa...

Claims

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Application Information

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IPC IPC(8): C08B37/10G01N30/90G01N21/78
CPCC08B37/0075G01N21/78G01N30/90
Inventor 高泳胡碧煌
Owner 广州脉和药业有限公司
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