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Antitumor prodrug and preparation method thereof

An anti-tumor drug and anti-tumor technology, applied in the direction of anti-tumor drugs, preparation of sugar derivatives, chemical instruments and methods, etc., can solve the problems of limited application, short cycle time, poor biocompatibility, etc.

Active Publication Date: 2011-12-14
CHANGZHOU INST OF ENERGY STORAGE MATERIALS &DEVICES
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  • Abstract
  • Description
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Problems solved by technology

For example, Ulbrich et al. disclosed in European Journal of Pharmaceutical Sciences (Vol.37, p405-412, 2009) that poly(N-2 hydroxypropyl methacrylamide) (HPMA) was used as a carrier to bond doxorubicin to Combined with the anti-tumor prodrug obtained on its side chain, cell and animal experiments show that the pro-drug can reduce the toxic and side effects of anti-tumor drugs and has good anti-tumor efficacy, but HPMA is not biodegradable and has poor biocompatibility
In 2010, Young-IL Jeong et al. disclosed in Macromolecular Research (Vol.18, p1115-1120, 2010) that poly(L-lactide-co-glycolide) (PLGA) was used as a carrier, and A Mycin is connected to the PLGA chain to obtain an anti-tumor prodrug. Cell experiments show that the prodrug can reduce the side effects of anti-tumor drugs and improve the anti-tumor effect. However, the poor water solubility of PLGA and the short circulation time in the body limit its in vivo and clinical applications

Method used

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  • Antitumor prodrug and preparation method thereof
  • Antitumor prodrug and preparation method thereof
  • Antitumor prodrug and preparation method thereof

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preparation example Construction

[0095] The present invention also provides a preparation method of the antitumor prodrug described in the above technical scheme, comprising the following steps:

[0096] Anthracycline antineoplastic drugs, fluorenyl methaneoxycarbonyl succinimide and triethylamine are stirred and reacted in N, N-dimethylformamide to obtain amino-protected anthracycline antineoplastic drugs, and the anthracycline Antineoplastic drugs are doxorubicin, epirubicin or pirarubicin;

[0097] Stirring and reacting the amino-protected anthracycline antitumor drug, dicyclohexylcarbodiimide, 4-dimethylaminopyridine and polyethylene glycol derivatives in N,N-dimethylformamide to obtain The first intermediate product, the polyethylene glycol derivative has a structure shown in formula (III) or a structure shown in formula (IV):

[0098]

[0099] Among them, m is the degree of polymerization, 10≤m≤1500;

[0100] Piperidine is added to the first intermediate product to obtain an antitumor prodrug after...

Embodiment 6～10

[0157] Embodiment 6~10 have the preparation of the polyethylene glycol derivative of formula (IV) structure

[0158] Weigh 10 g of polyethylene glycol with a number average molecular weight of 1000 (0.01mol), 5000 (0.002mol), 10000 (0.001mol), 20000 (0.0005mol) and 40000 (0.00025mol) respectively, and put them into 5 dry In a reaction flask with a branch, add 100mL of toluene to azeotropically remove water, dissolve the obtained product in 100mL of anhydrous dichloromethane, cool to 0°C, add 10.12g, 2.02g, 1.01g, 0.51g and 0.25g of triethylamine, then add 36.20g, 7.24g, 3.62g, 1.81g and 0.91g of acryloyl chloride dropwise respectively. After the addition of acryloyl chloride, react at 0°C for 2h, return to 25°C, and continue to After the reaction was completed for 24 hours, the resulting precipitate was filtered off, and the filtrate was settled with ether, filtered, washed, and vacuum-dried at 25°C for 24 hours to obtain polyethylene glycol acrylate. Carry out nuclear magnet...

Embodiment 11

[0164] The preparation of the doxorubicin of embodiment 11 amino protection

[0165] Dissolve 200 mg of doxorubicin hydrochloride in 5 mL of N,N-dimethylformamide, add 139.6 mg of fluorenylmethoxycarbonyl succinimide and 3.5 mg of triethylamine, stir at room temperature for 3 h, and remove the solvent under reduced pressure , the residue was recrystallized with an aqueous solution of trifluoroacetic acid with a mass concentration of 0.1%, and the obtained crystals were rinsed and filtered with cold ether to remove traces of fluorenylmethoxycarbonyl succinimide, and amino-protected doxorubicin was obtained after drying.

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Abstract

The invention provides antineoplastic prodrugs with structures represented by formulas (I), (II), (V), (VI), (VII), or (VIII), and a preparation method thereof. According to the invention, polyethylene glycol or polyethylene glycol monomethyl ether is adopted as a carrier, and anthracycline antineoplastic drugs are bonded on the carriers through ester bonds, amide bonds or hydrazone bonds, such that the antineoplastic prodrugs are obtained. According to the antineoplastic prodrugs provided by the invention, polyethylene glycol or polyethylene glycol monomethyl ether is adopted as a carrier, such that the drug-loading of the anthracycline antineoplastic drugs is improved, toxic and side-effects are reduced, and the bioavailability is improved. Polyethylene glycol or polyethylene glycol monomethyl ether has good biocompatibility and biodegradation property. When polyethylene glycol or polyethylene glycol monomethyl ether is used as an antineoplastic prodrug carrier, no harm is brought to human bodies. With polyethylene glycol or polyethylene glycol monomethyl ether, anthracycline antineoplastic drug dissolvability and circulation period in human bodies can be improved. Therefore, the method assists in improving the performances of anthracycline antineoplastic drugs.

Description

technical field [0001] The invention belongs to the technical field of drug controlled release, and in particular relates to an antitumor prodrug and a preparation method thereof. Background technique [0002] Prodrugs refer to some compounds with little or no activity in vitro, which release active substances through enzymatic catalysis or non-enzymatic action in vivo to exert their pharmacological effects. A new chemical entity formed by a non-toxic compound linked by a covalent bond is also called a prodrug. Prodrugs can improve the physical and chemical properties of the original drug, improve the selectivity of the drug on the target site, improve the pharmacokinetic process of the drug in the body, such as absorption, distribution, transport and metabolism, prolong the action time, and increase the bioavailability. The advantages of eliminating bad smell and reducing the toxic and side effects of drugs, especially the anti-tumor prodrugs designed by combining prodrugs...

Claims

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Application Information

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IPC IPC(8): C08G65/48C07H15/252C07H1/00A61P35/00
Inventor 汤朝晖栗迪丁建勋孙海庄秀丽陈学思
Owner CHANGZHOU INST OF ENERGY STORAGE MATERIALS &DEVICES
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