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Novel polymer-bonded vascular blocker as well as preparation method and medical application thereof

A polymer and bonded drug technology, applied in the direction of pharmaceutical formulations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., to achieve the effects of improving cycle stability, improving distribution, and improving tumor inhibition effects

Inactive Publication Date: 2018-06-29
北京星昊嘉宇医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, polymer drugs bonded to DMXAA have not been reported

Method used

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  • Novel polymer-bonded vascular blocker as well as preparation method and medical application thereof
  • Novel polymer-bonded vascular blocker as well as preparation method and medical application thereof
  • Novel polymer-bonded vascular blocker as well as preparation method and medical application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0053] The present invention also provides a preparation method of amino acid block copolymer, comprising:

[0054] There is the monoaminopolyethylene glycol of formula (III) or formula (IV) structure and gamma-benzyl-L-aspartic acid ester-N-internal carboxylic anhydride monomer stirring reaction in organic solvent, obtains with A compound with a protecting group; reacting the compound with a protecting group with ethanolamine to obtain a block copolymer of formula (VII); or having a bisaminopolyethylene glycol of formula (V) or formula (VI) in combination with γ -Benzyl-L-aspartic acid-N-internal carboxylic acid anhydride monomer is stirred and reacted in an organic solvent to obtain a compound with a protecting group; the compound with a protecting group is reacted with ethanolamine to obtain a compound having the formula (VIII) block copolymers of structure;

[0055]

[0056] where R 1 Independently selected from C1~C40 alkyl groups or composed of sulfhydryl groups, su...

Embodiment 1

[0069] Add 5.00 g of polyethylene glycol monomethyl ether having a structure of formula (III) with a number average molecular weight of 5000 to the dry reaction bottle, and remove water with 80 mL of anhydrous toluene at 130° C. for 3 hours, then vacuum dry The remaining toluene; the obtained solid was dissolved in 50 mL of dry N,N-dimethylformamide to obtain the first solution; 3.50 g of γ-benzyl-L-aspartate-N-endocarboxylic anhydride Dissolve in 40mL of dry N,N-dimethylformamide to obtain the second solution; in a nitrogen atmosphere, mix the first solution and the second solution, stir and react at room temperature under nitrogen protection conditions for 48h; then increase the temperature At 35°C, 10 mL of acetic anhydride was added to continue the reaction for 24 h. After the reaction, most of the N,N-dimethylformamide and unreacted acetic anhydride were removed under reduced pressure, then settled with ether, filtered by suction, and dried to obtain a block copolymer wit...

Embodiment 2

[0075] Add 0.69 g of the block copolymer having the structure of formula (VII-a) prepared in Example 1, DMXAA (0.37 g) and DMAP (120 mg) into the dry reaction flask, and vacuumize for 12 h. Then 10 mL of dry N,N-dimethylformamide was added to dissolve; DIC (1.3 g) was added with a syringe, and the reaction was stirred at room temperature under nitrogen protection for 24 h. After the reaction, settle with excess diethyl ether, wash, suction filter, and dry, the obtained crude polymer bonded drug is dissolved in N,N-dimethylformamide, and then dialyzed in pure water for 72 hours. Water 10 times, the dialysate was purified by high-speed centrifugation, and then passed through a 220nm filter membrane. Finally, the polymer-bonded drug with the structure of formula (I) is obtained by freeze-drying.

[0076] Carry out nuclear magnetic resonance analysis to the block copolymer that obtains, the result sees image 3 , image 3 The H NMR spectrum of the polymer-bonded drug prepared i...

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Abstract

The invention provides a novel polymer-bonded tumor vascular blocker. The invention is characterized in that an ethanolamine modified amino acid block copolymer poly(ethylene glycol)-b-poly(L-asparticacid) and a small molecule vascular blocker DMXAA are bonded to obtain a novel polymer-bonded medicine. A polymer main body in the novel bonded medicine is polyamino acid with excellent biocompatibility and good degradability, and a poly(ethylene glycol)hydrophilic segment protects the stability of nanoparticles in blood circulation; the DMXAA group in the bonded medicine promotes spontaneous assembly of the polymer-bonded medicine into stable nanoparticles in an aqueous solution due to an own strong Pi-Pi stacking effect and an own strong hydrophobic action. The polymer-bonded medicine is simple in technology, is easily produced on a large scale, is good in biocompatibility and stability, has the characteristic of slow release, is accumulated and stays on a tumor site for a long time, and has the advantage of long-term destruction to tumor blood vessels. The invention further provides a preparation method of the polymer-bonded medicine. The polymer-bonded medicine has a very good application prospect in the field of tumor therapy.

Description

technical field [0001] The invention relates to the field of polymer bonded drugs, in particular to a polymer bonded drug based on polyamino acid block copolymer and small molecule blood vessel blocking agent DMXAA. Background technique [0002] DMXAA (also known as ASA404) is a new type of anti-tumor drug developed in recent years, its structural formula is as follows: [0003] [0004] Different from traditional cytotoxic anticancer drugs, such as paclitaxel, doxorubicin, cisplatin, etc. DMXAA has almost no ability to kill cancer cells and cannot directly kill tumor cells. Unlike these traditional anticancer drugs, it employs a new anticancer mechanism. DMXAA can selectively destroy the blood vessels of the tumor site, quickly cause irreversible damage to the blood vessels of the tumor site, cut off the blood supply of the tumor, cause severe hemorrhagic necrosis of the tumor, and basically have no effect on the blood supply of normal tissues. DMXAA first achieved ob...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/51A61K31/352A61K47/64A61K47/69A61P35/00C08G69/40
CPCA61K31/352C08G69/40
Inventor 不公告发明人
Owner 北京星昊嘉宇医药科技有限公司
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