Taxane prodrug, preparation method and application thereof

A taxane and drug technology, applied in the field of taxane drug precursors and their preparation, can solve the problems of poor drug stability, poor water solubility, low maximum tolerated dose and the like, and achieve the effect of increasing the application range

Pending Publication Date: 2021-01-22
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In order to solve the problems of poor water solubility of taxane drugs docetaxel and cabazitaxel, poor drug stability, and low maximum tolerated dose of drugs in vivo, the invention provides a taxane drug prodrug

Method used

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  • Taxane prodrug, preparation method and application thereof
  • Taxane prodrug, preparation method and application thereof
  • Taxane prodrug, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] The synthesis of embodiment 1 taxane prodrug 1

[0085] Such as figure 1 As shown, add bis(2-hydroxyethyl) disulfide (1.08g, 7.0mmol) and p-nitrophenyl chloroformate (3.10g, 15.4mmol) in a 100mL round bottom flask, and use anhydrous di Methane chloride (DCM, 8 mL) was dissolved, and N,N-diisopropylethylamine (DIEA) (2.26 g, 17.5 mmol) was added. The reaction mixture was stirred at 25°C for 5 hours, then washed with 5% aqueous citric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was collected and the solvent was removed under reduced pressure. The solid was separated and purified by column chromatography (hexane / ethyl acetate=4:1) to obtain an intermediate product (1.64 g, 48.4%).

[0086] intermediate product 1 The H NMR nuclear magnetic data is as follows:

[0087] 1 H NMR (400MHz; Chloroform-d): δ8.28(d, J=9.2Hz, 4H), 7.39(d, J=9.2Hz, 4H), 4.58(...

Embodiment 2

[0091] The synthesis of embodiment 2 taxane prodrug 2

[0092] Such as figure 2 As shown, add succinic acid (7.1mg, 0.06mmol), DTX (100mg, 0.12mmol) in a 100mL round bottom flask, add 4mL of anhydrous DCM (dichloromethane) to dissolve, then add EDC (118mg, 0.76mmol ) and DMAP (4-dimethylaminopyridine) (8 mg, 0.07 mmol). Stir and react at 25°C for 24 hours, then wash with 5% citric acid, saturated sodium bicarbonate, and saturated brine respectively; dry the organic phase with anhydrous sodium sulfate, filter, collect the filtrate and remove the solvent under reduced pressure; Product 2 (309 mg, yield 65.3%) was obtained after separation and purification (n-hexane:ethyl acetate=1:1).

Embodiment 3

[0093] The synthesis of embodiment 3 taxane prodrug 3

[0094] Such as image 3 As shown, add such as image 3 The indicated thioketal (50mg, 0.2mmol), DTX (355.5mg, 0.44mmol), after adding 3mL of anhydrous DCM (dichloromethane) to dissolve, then adding EDC (22.9mg, 0.14mmol) and DMAP (4- Dimethylaminopyridine) (12 mg, 0.1 mmol). Stir overnight at 45°C, then wash with 5% citric acid, saturated sodium bicarbonate, and saturated brine respectively; dry the organic phase with anhydrous sodium sulfate, filter, collect the filtrate and remove the solvent under reduced pressure; the solid is separated and purified by column chromatography (dichloromethane:methanol=1:1) to obtain product 3 (128.5 mg, yield 58.5%).

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Abstract

The invention discloses a taxane prodrug, which has a structure of Y1-R-Y2, wherein the Y1 and the Y2 are docetaxel or cabazitaxel, R comprises a specific connecting bond for environmental response intumor cells, and the taxane prodrug is generated by carrying out substitution or condensation reaction on a taxane drug and a tumor microenvironment-responsive connecting bond. According to the invention, the prodrug has good anti-tumor activity, can directly release active ingredients in vivo in a hydrolysis or oxidation mode, and can avoid in vivo toxicity caused by direct injection of taxane drugs; the prodrug disclosed by the invention not only has good solubility in water, but also can be self-emulsified in water to form nanoparticles; and the prodrug can be obtained through a single-step reaction method, the yield is high, the preparation cost is low, the stability is high, the safety is good, the requirements of clinical medication are met, the requirements of large-scale industrial production are met, and the prodrug has good market prospects and clinical application value.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and preparation, and specifically relates to a series of precursors of taxane drugs (docetaxel or cabazitaxel) and their preparation methods and applications. Background technique [0002] Docetaxel (DTX), also known as docetaxel and trade name taxotere, is a taxane antineoplastic drug semi-synthesized from 10-deacetylbaccatin III. The chemical name is benzoic acid {(2α,5β,7β,10β,13α)-4-acetyl-13-{(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3- Phenylpropionyloxy}-1-hydroxy-7,10-dihydroxy-9-oxo-5,20-epoxytaxane-11-en-2-yl}ester [0003] The structural formula is as follows: [0004] [0005] It stabilizes microtubules by inducing the polymerization and assembly of microtubule monomers and inhibiting depolymerization, thereby arresting the cell cycle, inhibiting cell mitosis, inhibiting the formation of spindles and spindle filaments, and preventing the proliferation of tumor cells. [...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14A61K47/55A61K31/337A61P35/00
CPCC07D305/14A61K47/55A61K31/337A61P35/00
Inventor 王杭祥周丽倩
Owner ZHEJIANG UNIV
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