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Preparation method and application of cabazitaxel prodrug

A technology of cabazitaxel and medicine, which is applied in the field of cabazitaxel drug precursor and its preparation, can solve the problems of low maximum tolerated dose, poor drug stability, and poor water solubility of cabazitaxel, and achieve high in vivo and in vitro stability, The effect of increasing the tolerance dose and avoiding the use of preparation excipients

Active Publication Date: 2019-12-31
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In order to solve the problems of poor water solubility of cabazitaxel, poor drug stability, and low maximum tolerated dose of the drug in vivo, the invention provides a prodrug of cabazitaxel (CTX), the structural formula of the prodrug of CTX is shown in formula (I) :

Method used

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  • Preparation method and application of cabazitaxel prodrug
  • Preparation method and application of cabazitaxel prodrug
  • Preparation method and application of cabazitaxel prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041]Embodiment 1 contains the synthesis of the CTX prodrug 1 of unsaturated alkane chain compound

[0042] Add CTX (100mg, 0.12mmol) and cis-4,7,10,13,16,19-docosahexaenoic acid (DHA, 39mg, 0.12mmol) into a 100mL round bottom flask, dissolve in 5mL anhydrous In DCM (dichloromethane), add EDC·HCl (25 mg, 0.13 mmol), DMAP (4-dimethylaminopyridine) (16 mg, 0.13 mmol) and DIEA (N,N-diisopropylethylamine) ( 21 μL, 0.13 mmol). Stir overnight at 25°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 (DCM:MeOH=200:1) yielded product 1 (80 mg, yield 58%).

[0043] product 1 1 H NMR nuclear magnetic data and mass spectrometry data are as follows:

[0044] 1 H NMR (400MHz, CDCl3): δ0.86-0.90(t, 3H), 1.20-1.22(d, 6H, J=6.4), 1.25(s, 3H), 1.35(s, 9H)...

Embodiment 2

[0046] Embodiment 2 contains the synthesis of the CTX prodrug 2 of unsaturated alkane chain compound

[0047] Add CTX (100mg, 0.12mmol) and linolenic acid (34mg, 0.12mmol) to a 100mL round bottom flask, dissolve in 5mL of anhydrous dichloromethane, then add EDC·HCl (25mg, 0.13mmol), 4-dimethyl Aminopyridine (16 mg, 0.13 mmol) and N,N-diisopropylethylamine (21 μL, 0.13 mmol). Stir overnight at 25°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 (DCM:MeOH=200:1) to obtain product 2 (115 mg, yield 87%).

[0048] product 2 1 H NMR nuclear magnetic data and mass spectrometry data are as follows:

[0049] 1 H NMR (400MHz, CDCl3): δ0.86-0.90(t,3H),1.22(s,9H),1.26(s,8H),1.35(s,9H),1.51-1.55(t,2H),1.62 -1.67(m,2H),1.76-1.82(m,2H),2.00(s,3H),2.04...

Embodiment 3

[0051] Embodiment 3 contains the synthesis of the CTX prodrug 3 of unsaturated alkane chain compound

[0052] Add CTX (100mg, 0.12mmol) and linoleic acid (34mg, 0.12mmol) into a 100mL round bottom flask, dissolve in 5mL of anhydrous dichloromethane, then add EDC·HCl (25mg, 0.13mmol), 4-di Aminopyridine (16 mg, 0.13 mmol) and N,N-diisopropylethylamine (21 μL, 0.13 mmol). Stir overnight at 25°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 (DCM:MeOH=200:1) to obtain product 3 (120 mg, yield 91%).

[0053] product 3 1 H NMR nuclear magnetic data and mass spectrometry data are as follows:

[0054] 1 H NMR (400MHz, CDCl 3 ):δ0.86-0.90(t,3H),1.22(s,9H),1.26(s,14H),1.35(s,9H),1.51-1.55(t,2H),1.62-1.67(m,2H ),1.76-1.82(m,2H),2.00(s,3H),2.04-2...

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Abstract

The invention discloses a cabazitaxel prodrug as well as a preparation method and an application thereof. A structural formula of the prodrug is represented as a formula (I) and the prodrug is prepared from cabazitaxel and hydrophobic molecules through an esterification reaction. The prodrug has better antitumor activity, can directly release active components in a hydrolytic manner in vivo, and can prevent in-vivo toxicity caused by direct injection of cabazitaxel. The prodrug has better solubility in water and can form nanoparticles in water through self-emulsification; the prodrug can be obtained with a single-step esterification method, is high in yield, low in preparation cost, high in stability and good in safety, meets requirements of clinical medication and large-scale industrial production, and has good market prospect and clinical application value.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and preparations, and in particular relates to a series of cabazitaxel drug precursors and their preparation methods and applications. Background technique [0002] Cabazitaxel (CTX) is a semi-synthetic taxane compound (C.J.Paller andE.S.Antonarakis.Cabazitaxel: a novel second-line treatment for metastaticcastration-resistant prostate cancer,Drug Des.Dev.Ther., 2011, 5, 117-124). Its precursor is extracted from the needles of the yew tree, and its chemical name is benzoic acid {(2α,5β,7β,10β,13α)-4-acetyl-13-{(2R,3S)-3-[(t Butoxycarbonyl)amino]-2-hydroxy-3-phenylpropionyloxy}-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytaxane-11 -en-2-yl} ester, the structural formula is as follows: [0003] [0004] CTX is a broad-spectrum anti-cancer small molecule drug. Its mechanism of inhibiting tumor cells is similar to that of paclitaxel and docetaxel. It mainly promotes microtubule polymerization and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D305/14A61P35/00
CPCC07D305/14
Inventor 王杭祥
Owner ZHEJIANG UNIV
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