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Heparin alendronate sodium conjugate synthetic method and drugs

A technology for the synthesis of sodium alendronate and sodium allenphosphate, which is applied in the field of synthesis of heparin-alendronate sodium conjugates, can solve the problems of inability to produce on a large scale, high preparation cost, cumbersome operation, etc., and achieve convenience for large-scale production and high synthesis efficiency High, simple synthesis process effect

Active Publication Date: 2019-08-16
YANGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the problems of high preparation cost, complicated process and cumbersome operation in these existing technologies, it cannot be mass-produced

Method used

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  • Heparin alendronate sodium conjugate synthetic method and drugs
  • Heparin alendronate sodium conjugate synthetic method and drugs
  • Heparin alendronate sodium conjugate synthetic method and drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] In this example, heparin alendronate sodium conjugates were first synthesized through the following process:

[0037] 1) Dissolve 23g of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in 300ml of tetrahydrofuran (THF);

[0038] 2) Add 13.2ml of 4-methylmorpholine (NMM) into the solution in step 1), and stir vigorously for 1 hour; collect the solid by filtration and wash the solid with THF 5 times, and dry it in vacuum for 48 hours to obtain the DMT-MM condensing agent;

[0039] 3) Dissolve 1g of heparin and 0.874g of the DMT-MM condensing agent prepared in step 2) in 50ml of ultrapure water, and stir for 1h;

[0040] 4) Dissolve 2g of alendronate sodium in 100ml of ultrapure water;

[0041] 5) Add alendronate sodium solution into the mixed solution of heparin and condensing agent in step 3), react for 24 hours, dialyze the solution through a dialysis bag with a molecular weight of 300 for 48 hours, and change the water every 4 hours, filter out the condensing agent and ...

Embodiment 2

[0043]Synthesis of heparin alendronate sodium conjugates in this example:

[0044] 1) Dissolve 40g of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in 400ml of tetrahydrofuran (THF);

[0045] 2) Add 22ml of 4-methylmorpholine (NMM) to the solution in step 1), and stir vigorously for 1.5h; collect the solid by filtration and wash the solid with THF 5 times, and dry it in vacuum for 48h to obtain the DMT-MM condensate of this example. mixture;

[0046] 3) Dissolve 1.5g of heparin and 1.4g of the DMT-MM condensing agent obtained in step 2) in 50ml of ultrapure water, and stir for 1.5h;

[0047] 4) Dissolve 3g of alendronate sodium in 200ml of ultrapure water;

[0048] 5) Add the alendronate sodium solution in step 4) to the mixed solution of heparin and DMT-MM condensing agent in step 3), react for 24-48 hours, dialyze the solution through a dialysis bag with a molecular weight of 800 for 60 hours, and The water was changed every 4 hours, the condensing agent and excess reactan...

Embodiment 3

[0050] In this example, heparin alendronate sodium conjugates were first synthesized

[0051] 1) Dissolve 55g of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in 500ml of tetrahydrofuran (THF);

[0052] 2) Add 30ml of 4-methylmorpholine (NMM) into the solution in step 1), and stir vigorously for 2 hours; collect the solid by filtration, wash the solid with THF for 5 times, and dry it in vacuum for 48 hours to obtain the DMT-MM condensing agent;

[0053] 3) Dissolve 2g of heparin and 2g of the DMT-MM condensing agent in step 2) in 50ml of ultrapure water, and stir for 2 hours;

[0054] 4) Dissolve 5g of alendronate sodium in 300ml of ultrapure water;

[0055] 5) Add the alendronate sodium solution in step 4) to the mixed solution of heparin and condensing agent in step 3), react for 48 hours, dialyze the solution for 72 hours through a dialysis bag with a molecular weight of 1000, and change the water every 4 hours , filter out the condensing agent and excess reactants, and fi...

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Abstract

The invention relates to a heparin alendronate sodium conjugate synthetic method and drugs in the field of medicine. The heparin alendronate sodium conjugate synthetic method comprises the steps: step1, firstly, dissolving 2-chloro-4,6-dimethoxy-1,3,5-triazine in tetrahydrofuran, adding 4-methylmorpholine, stirring for 1-2 h at room temperature, collecting by filtration and washing a precipitatefive times with THF, and thus then obtaining a DMT-MM condensation agent after 48 h of vacuum drying; and step 2, adding heparin and the condensation agent into ultra-pure water, stirring for 1 h, then adding an alendronate sodium solution into the mixed solution of heparin and the condensation agent, carrying out reaction for 24-48 h, pouring the solution into a dialysis bag, dialysing for 48-72h, changing water once every 4 h, finally, freeze-drying the product obtained from dialysis, and thus obtaining the heparin alendronate sodium conjugate drugs. In the method, alendronate sodium is modified by heparin, so the solubility of the drugs is increased, the bioavailability is improved, the cytotoxicity is reduced and the formation of osteoclasts is effectively inhibited.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a method for synthesizing heparin-alendronate sodium conjugates. Background technique [0002] Cancer is one of the important factors that threaten human health and life. According to the 2017 Cancer Statistics Annual Report of the American Cancer Society, in 2017, there were 1,688,780 new cases of cancer in the United States, and it is estimated that 600,920 people will die of cancer. Although the incidence of primary bone tumors is low, solid tumors are prone to metastasize to bone tissue due to the special environment of bone (especially cancers of the prostate, breast, lung, and kidney). For example, up to 70% of all patients diagnosed with breast cancer will develop bone metastases. In those patients with metastatic disease limited to the skeleton, decreased quality of life and eventual death were almost exclusively caused by complications such as bone pain, hypercalcemia, patholog...

Claims

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Application Information

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IPC IPC(8): A61K47/61A61K31/663A61K31/727A61P19/10A61P35/00A61P19/08A61P3/14C08B37/10
CPCA61K47/61A61K31/663A61K31/727A61P19/10A61P35/00A61P19/08A61P3/14C08B37/0075A61K2300/00
Inventor 朱沛志吴亚萍王进宇
Owner YANGZHOU UNIV
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