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Amphiphilic polymer prodrug of reduced response Combastine and preparation method and application thereof

A technology of amphiphilic polymers and polymers, applied in the direction of drug combinations, pharmaceutical formulations, medical preparations of non-active ingredients, etc., can solve the problem of not being able to release the original drug, and achieve mass production, yield and product purity High and mild reaction conditions

Pending Publication Date: 2019-07-19
烟台药物研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The present invention aims at the disadvantage that the polymer drug formed by connecting the hydrophilic polymer and the hydrophobic drug through the disulfide bond cannot release the original drug when the disulfide bond is broken, and provides a reduction-responsive combustine. Amphiphilic polymer prodrug and its preparation method

Method used

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  • Amphiphilic polymer prodrug of reduced response Combastine and preparation method and application thereof
  • Amphiphilic polymer prodrug of reduced response Combastine and preparation method and application thereof
  • Amphiphilic polymer prodrug of reduced response Combastine and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] A reduction-responsive amphiphilic polymer prodrug of combustin has the following molecular structure:

[0040]

[0041] where 5

[0042]The preparation method of above-mentioned amphiphilic polymer prodrug is as follows:

[0043] 1) Preparation of 2-(2-pyridyldithio)ethanol:

[0044] 2-Mercaptoethanol (1.0 g, 12.8 mmol) and 2,2'-dithiobipyridine (Py-SS-Py, 8.46 g, 38.4 mmol) were added into 100 mL of methanol, and stirred at room temperature for 12 hours. Methanol was distilled off under reduced pressure, purified by silica gel column, concentrated and dried in vacuo to obtain 2.2 g of light yellow solid product with a yield of 84%.

[0045] (2) Preparation of 4-nitrophenyl-2-(2-pyridyldithio)ethyl carbonate:

[0046] 2-(2-pyridyldithio)ethanol (2.2g, 10.8mmol) and triethylamine (2.2g, 21.6mmol) were dissolved in 100mL of dichloromethane, and phenyl p-nitrochloroformate ( 6.5g, 32.4mmol) was slowly added dropwise to the solution, after the drop was comple...

Embodiment 2

[0055] A nanomicelle containing the amphiphilic polymer prodrug obtained in Example 1 is prepared by the following method: 20 mg of the polymer prodrug and 10 μL of medium-chain fatty acid triglyceride are placed in water, then ultrasonicated for 1 min, and filtered Add mannitol to the membrane and freeze-dry it to obtain the reduction-responsive polymer nanomicelle freeze-dried powder. The particle size and distribution ( Figure 4 ).

Embodiment 3

[0057] A reduction-responsive amphiphilic polymer prodrug of combustin has the following molecular structure:

[0058]

[0059] where 100

[0060] The preparation method of above-mentioned amphiphilic polymer prodrug is as follows:

[0061] 1) Preparation of pyridyl dithioethylamine hydrochloride:

[0062] Add mercaptopropylamine hydrochloride (1.0 g, 7.9 mmol) and 2,2'-dithiobipyridine (Py-SS-Py, 2.3 g, 9.4 mmol) into 60 mL of methanol, and stir at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure, the target product was precipitated with ether, suction filtered, and vacuum-dried to obtain 1.39 g of a light yellow oily liquid product shown in formula e, with a yield of 74.4%.

[0063] 2) Preparation of 4-nitrophenyl-(2-pyridyldithio)aminocarbonate:

[0064] Pyridyldithioethylamine hydrochloride (1.39g, 5.9mmol) and triethylamine (0.72g, 7.1mmol) were dissolved in 50mL of dichloromethane, and phenyl p-nitrochloroformate ...

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Abstract

The invention relates to an amphiphilic polymer prodrug of reduced response Combastine and a preparation method and an application thereof. The prodrug has a molecular structure, wherein the degree ofpolymerization n is from 5 to 1,000, m is 1 or 2, and X is O or NH. The prodrug provided by the invention can achieve targeted administration, which not only retains the advantages of a nano drug-loading system, but also exhibits the characteristic of specific degradation of a disulfide bond at the tumor site. Compared with conventional 2,2'-disulfanediyldiacetic acid, 3,3'-dithiodipropionic acidand other connecting arms, the prodrug and the preparation method thereof have the advantage that an anticancer drug with an original drug molecular form can be obtained without further hydrolysis.

Description

technical field [0001] The invention relates to an amphiphilic polymer prodrug and its preparation method and application, in particular to an amphiphilic polymer prodrug of combustine, its preparation method and application. Background technique [0002] Combretastatin A-4 (CA-4) (abbreviation: Combustin) is a natural and powerful small molecule anti-mitotic agent isolated from the bark of the South African shrub willow. It is a polyhydroxy stilbene natural compound with a chemical name It is cis-1-(3,4,5-trimethoxyphenyl)-2-(3′-hydroxy-4′-methoxyphenyl)ethylene, and its action site is the same as that of colchicine, which can inhibit microbes Tubulin polymerization, while inhibiting tubulin depolymerization and mitotic accumulation in cells. CA-4 can specifically target and destroy the tumor blood vessels that have been formed, so that the tumor cannot receive oxygen and nutrients until the tumor is "starved to death", thereby achieving the effect of killing tumor cells. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K47/60A61K31/122A61P35/00
CPCA61K31/122
Inventor 任春光李亚平栾委静孔德旭李泽民李暖暖李艺张丽徐梅霞
Owner 烟台药物研究所
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