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High polymer CA4 bonding medicine and preparation method thereof

A technology of bonded drugs and polymers, which is applied in the direction of pharmaceutical formulations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve problems affecting the tumor blood vessel inhibitory effect, and achieve short action time, Realize the effect of mass production and simple preparation method

Inactive Publication Date: 2016-09-28
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the rapid clearance of CA4P in the body and insufficient tumor site residence have seriously affected its long-term tumor vascular inhibition effect; therefore, it is currently necessary to obtain CA4-type angioblocker anti-tumor drugs that can act on tumor sites for a long time. solved problem

Method used

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  • High polymer CA4 bonding medicine and preparation method thereof
  • High polymer CA4 bonding medicine and preparation method thereof
  • High polymer CA4 bonding medicine and preparation method thereof

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preparation example Construction

[0064] The present invention also provides a preparation method of polymer CA4 bonded drug, comprising:

[0065] The copolymer having the structure of formula (II) is reacted with CA4 under the action of a condensing agent to obtain the polymer CA4 bonded drug of the structure of formula (I).

[0066]

[0067]

[0068] in,

[0069] R 1 Selected from C2-C10 straight-chain alkyl, C3-C10 branched-chain alkyl or C6-C20 aryl;

[0070] R 2 selected from a hydrogen atom or a cation;

[0071] R 3 Be selected from unsubstituted C1-C20 alkyl or substituted C1-C20 alkyl;

[0072] R 4 Alkylacyl group selected from hydrogen atom or C1-C6;

[0073] L 1 , L 2 , L 3 Independently selected from -CH 2 -or-CH 2 CH 2 -;

[0074] x, y, z are degree of aggregation, 10≤x+y+z≤5000, y>0, z>0;

[0075] n is the degree of polymerization, 10≤n≤500.

[0076] According to the present invention, the present invention reacts the copolymer with formula (II) structure and CA4 under the ef...

Embodiment 1

[0080] Dissolve 42.1 g (160.0 mmol) of γ-benzyl-L-glutamate-N-endocarboxylic anhydride monomer (BLG-NCA) in 270 mL of anhydrous N,N-dimethylformamide (DMF) After stirring and dissolving, 1.0 mL (1.0 mmol / L DMF solution) of n-hexylamine (n-HA) was added, sealed, and stirred and reacted for 72 h at a temperature of 25° C. After the reaction was finished, the obtained reaction solution was settled into 2.0L of diethyl ether, filtered and washed with diethyl ether successively, and vacuum-dried at room temperature for 24h to obtain the intermediate product poly(γ-benzyl-L-glutamate) ( PBLG).

[0081] 10.0 g of the above-prepared poly(γ-benzyl-L-glutamate) was dissolved in 100 mL of dichloroacetic acid, and under stirring conditions, 30 mL of hydrogen bromide / glacial acetic acid solution with a mass content of 33% was added, The reaction was stirred for 1 h at a temperature of 30 °C. Afterwards, the obtained reaction solution was settled into 1.0L of ether, centrifuged, and the r...

Embodiment 2

[0084] Dissolve 42.1 g (160.0 mmol) of γ-benzyl-L-glutamate-N-endocarboxylic anhydride monomer (BLG-NCA) in 270 mL of anhydrous N,N-dimethylformamide (DMF) After stirring and dissolving, 1.0 mL (1.0 mmol / L DMF solution) of n-hexylamine (n-HA) was added, sealed, and stirred and reacted for 72 h at a temperature of 25° C. Afterwards, 2.0 g (20.0 mmol) of acetic anhydride was added to the above reaction system, and the reaction was continued for 6 h. After the reaction was finished, the obtained reaction solution was settled into 2.0L of diethyl ether, filtered and washed with diethyl ether successively, and vacuum-dried at room temperature for 24h to obtain the intermediate product poly(γ-benzyl-L-glutamate) ( PBLG).

[0085] 10.0 g of the above-prepared poly(γ-benzyl-L-glutamate) was dissolved in 100 mL of dichloroacetic acid, and under stirring conditions, 30 mL of hydrogen bromide / glacial acetic acid solution with a mass content of 33% was added, The reaction was stirred fo...

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Abstract

The invention provides high polymer CA4 bonding medicine and a preparation method thereof. The bonding medicine has a structure shown in the formula (I). By grafting CA4 to a specific polymer carrier, the obtained bonding medicine can be enriched on tumor vessels and slowly released, the function of breaking tumor vessels is achieved for a long time at tumor parts, and an outstanding tumor restraining effect is achieved. The problems that CA4P acting time is short and treatment effect is not good enough are effectively solved, and the medicine has wide development prospects in the tumor treatment field. In addition, the preparation method is simple, raw materials are wide in source, mass production can be achieved, and industrialization can be achieved.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a polymer CA4 bonded drug and a preparation method thereof. Background technique [0002] Compretastatin (combretastatin, (Z)-3,4,5,4',-tetramethoxy-3'-hydroxystilbene, Combretastatin A4, CA4) is a new type of anti- Tumor active compound, its structural formula is as follows: [0003] [0004] Unlike traditional cytotoxic anticancer drugs, CA4 does not directly kill tumor cells. CA4 adopts a new anti-cancer mechanism: by combining with the tubulin of tumor vascular endothelial cells, it destroys the blood vessels inside the tumor, cuts off the blood and nutrient supply to the tumor, and causes severe necrosis inside the tumor. Due to the structural differences between tumor blood vessels and normal tissue blood vessels, CA4 selectively destroys tumor blood vessels, but basically has no effect on the blood supply of normal tissues. Therefore, this class of drugs has h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/167A61P35/00C08G69/48
CPCA61K31/167C08G69/48A61K35/00A61P35/00A61K31/09C08G69/10A61K47/60A61K47/595C08G65/33324C08G81/00
Inventor 汤朝晖宋万通于海洋牛月伟张大为马胜张瑜陈学思
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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