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Cabazitaxel-oligo/polylactic acid coupled prodrug, preparation thereof, preparation method and application of preparation

A technology of cabazitaxel and polylactic acid, which is used in pharmaceutical formulations, anti-tumor drugs, drug combinations, etc., can solve problems such as affecting application and poor water solubility, and achieve the effects of good anti-tumor, reduced damage, and good anti-tumor activity.

Active Publication Date: 2019-02-01
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Although cabazitaxel has a low probability of drug tolerance and strong antitumor effect, its water solubility is poor, and it needs to be treated by adding surfactants (hydrogenated castor oil, Tween 80) and ethanol.
However, surfactants show certain physiological toxicity in clinical application, and cabazitaxel itself has strong myelosuppressive toxicity, both of which greatly affect its clinical application.

Method used

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  • Cabazitaxel-oligo/polylactic acid coupled prodrug, preparation thereof, preparation method and application of preparation
  • Cabazitaxel-oligo/polylactic acid coupled prodrug, preparation thereof, preparation method and application of preparation
  • Cabazitaxel-oligo/polylactic acid coupled prodrug, preparation thereof, preparation method and application of preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1o (LA) 8 - Synthesis of CTX-coupled prodrug 1, as figure 1 Shown:

[0053] Add CTX (cabazitaxel, 100mg, 0.1196mmol), mPLA600·SA (129.2mg, 0.1794mmol) and DMAP (21.9mg, 0.1794mmol) successively into a 100ml round bottom flask equipped with a spherical condenser, dissolve in 4ml water, dichloromethane, and EDC (27.9 mg, 0.1794 mmol) was added rapidly dropwise. Stir at 43°C overnight, and observe the reaction by thin-layer chromatography (developing solvent: DCM:MeOH=20:1). When the reaction was basically completed, the reaction liquid was cooled, and then washed with 5% citric acid, saturated sodium bicarbonate, and saturated saline respectively. The organic layer was dried over anhydrous sodium sulfate, and filtered after complete drying. The filtrate was rotary evaporated to remove the solvent. The final product 1 (corresponding to the structure of n=8 in formula I, 168.3 mg, yield 91.5%) was isolated and purified by column chromatography (DCM:MeOH=80:1). ...

Embodiment 2

[0056] Example 2o(LA) 18 - Synthesis of CTX-coupled prodrug 2, as figure 2 Shown:

[0057] Add CTX (200mg, 0.2393mmol), mPLA1200·SA (560mg, 0.3590mmol) and DMAP (43.9mg, 0.3590mmol) successively in a 100ml round bottom flask equipped with a spherical condenser, dissolve in 7ml of anhydrous dichloromethane, EDC (55.7mg, 0.3590mmol) was added rapidly dropwise. Stir at 43°C overnight, and observe the reaction by thin-layer chromatography (developing solvent: DCM:MeOH=20:1). When the reaction was basically completed, the reaction liquid was cooled, and then washed with 5% citric acid, saturated sodium bicarbonate, and saturated saline respectively. The organic layer was dried over anhydrous sodium sulfate, and filtered after complete drying. The filtrate was rotary evaporated to remove the solvent. The final product 2 (corresponding to the structure of n=18 in formula I, 475.7 mg, yield 83.6%) was obtained by separation and purification by column chromatography (DCM:MeOH=80:...

Embodiment 3

[0060] Example 3o (LA) 36 - Synthesis of CTX-coupled prodrug 3, as image 3 Shown:

[0061] Add CTX (80mg, 0.09570mmol), mPLA2600·SA (403.9mg, 0.1436mmol) and DMAP (17.5mg, 0.1436mmol) sequentially into a 100ml round bottom flask equipped with a spherical condenser, dissolve in 6ml of anhydrous dichloromethane , and EDC (22.3 mg, 0.1436 mmol) was added rapidly dropwise. Stir at 43°C overnight, and observe the reaction by thin-layer chromatography (developing solvent: DCM:MeOH=20:1). When the reaction was basically completed, the reaction liquid was cooled, and then washed with 5% citric acid, saturated sodium bicarbonate, and saturated saline respectively. The organic layer was dried over anhydrous sodium sulfate, and filtered after complete drying. The filtrate was rotary evaporated to remove the solvent. The final product 2 (corresponding to the structure of n=36 in formula I, 246.4 mg, yield 70.9%) was separated and purified by column chromatography (DCM:MeOH=80:1).

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Abstract

The invention discloses a cabazitaxel oligo / polylactic acid coupled prodrug and a preparation method thereof. The preparation method is characterized in that cabazitaxel and oligo / polylactic acid undergo an esterification reaction under the action of a condensing agent and a catalyst to obtain the cabazitaxel oligo / polylactic acid coupled prodrug. The invention also discloses a cabazitaxel-oligo / polylactic acid coupled prodrug preparation, and a preparation method and an application thereof. The oligo / polylactic acid is covalently coupled with cabazitaxel, so the in vivo release rate of cabazitaxel is can be regulated, the precipitation of cabazitaxel, caused by strong release, is prevented, the in vivo cycle period of the cabazitaxel is prolonged, and the maximum tolerable dose is increased. The oligo / polylactic acid is approved for use by the US FDA and has an excellent application prospect. The cabazitaxel oligo / polylactic acid prodrug and an amphiphilic polymer PEG5k-PLA8k are assembled to form nanoparticles, and the nanoparticles have a passive targeting effect, and are easily retained in the tumor site by the EPR effect in order to greatly reduce the toxic and side effects ofthe drug on normal tissues.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a cabazitaxel-oligo / polylactic acid coupled prodrug, preparation, preparation method and application thereof. Background technique [0002] Cabazitaxel, a taxane derivative, was approved by the US FDA in June 2010 for the treatment of hormone-refractory metastatic prostate cancer. Compared with paclitaxel and docetaxel, cabazitaxel has stronger tumor growth inhibitory activity, and the affinity between cabazitaxel and P-glycoprotein (P-glycoprotein) is lower, and the probability of drug resistance is low. It can be used to treat multidrug resistant tumors. It mainly binds to tubulin in tumor cells to make microtubules more stable, inhibit microtubule depolymerization, and affect the progress of mitosis, thereby inhibiting tumor cell proliferation. [0003] Although cabazitaxel has a low probability of drug tolerance and strong antitumor effect, its water solu...

Claims

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Application Information

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IPC IPC(8): A61K47/59A61K9/51A61K47/34A61K31/337A61P35/00
CPCA61K9/5153A61K31/337A61K47/593A61P35/00
Inventor 王杭祥万建钦
Owner ZHEJIANG UNIV
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