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Paclitaxel phospholipid compound and drug combination and application thereof

A technology of phospholipid compounds and paclitaxel analogs, applied in the field of medicine, can solve the problems of slow drug speed, paclitaxel phospholipid prodrugs or liposome drug efficacy decline, etc.

Pending Publication Date: 2016-01-13
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Paclitaxel-based phospholipid prodrugs or liposomes are less effective because the drug release rate from the prodrug molecule is too slow

Method used

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  • Paclitaxel phospholipid compound and drug combination and application thereof
  • Paclitaxel phospholipid compound and drug combination and application thereof
  • Paclitaxel phospholipid compound and drug combination and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] Synthesis of bis(paclitaxel-7-dithioglycolic acid) phosphatidylcholine (route see figure 1 )

[0118] Dissolve paclitaxel 1.5g (1mmol) in 30mL chloroform, add 1mL triethylamine, add 1.5g tert-butyldimethylsilyl chloride (TBDMSCl), react at 0°C for 3h, add glacial ether, a white precipitate precipitates, centrifuge Separation, further separation by column chromatography (eluent, chloroform / methanol: 7 / 1, v / v) to obtain 2'-tert-butyldimethylsilyloxy-paclitaxel 1.24g , as a white powdery solid.

[0119] 0.20 g of 2'-tert-butyldimethylsilyloxy-paclitaxel was dissolved in 10 ml of chloroform, 0.12 g (1 mmol) of DMAP and 0.6 g of dithiodiethanol anhydride were added, and the reaction was stirred at room temperature for 24 h. Then, wash the above reaction solution with 2% HCl solution, remove DMAP, and separate by column chromatography (eluent, chloroform / methanol: 5 / 1, v / v) to obtain white powder 2'-tert-butyldi Methylsiloxy-paclitaxel-7-dithioglycolic acid monoester 0.13g...

Embodiment 2

[0122] Synthesis of Bis(docetaxel-2'-dithiodieglycolic acid) phosphatidylcholine (see the synthetic route figure 2 )

[0123] Docetaxel 0.6g was dissolved by adding 30ml of chloroform, DMAP0.3g and dithiodiethanol anhydride 0.64g (6mmol) were added, and the reaction was stirred at room temperature for 24h. Then, wash the above reaction solution with 2% HCl solution, remove DMAP, and separate by column chromatography (eluent, chloroform / methanol: 5 / 1, v / v) to obtain white powdery docetaxel-2'- Dithiodiglycolic acid monoester 0.43g.

[0124] Dissolve 0.20 g of docetaxel-2'-dithiodiethanol monoester in 20 ml of pyridine, add 0.4 g of tert-butyldimethylsilyl chloride, react at room temperature for 3 h, and add the reaction solution dropwise into 50 ml of ice ether, A white precipitate was precipitated, separated by centrifugation, and further separated by column chromatography (eluent, chloroform / methanol: 7 / 1, v / v) to obtain the end-capped product 7,10-bis(tert-butyldimethylsi...

Embodiment 3

[0128] Synthesis of bis(paclitaxel-7-diglycolic acid) phosphatidylcholine (route see image 3 )

[0129] Dissolve 0.20 g of paclitaxel 2'-blocked product 2'-tert-butyldimethylsiloxy-paclitaxel in Example 1 in 10 ml of chloroform, add 0.5 g of DMAP and 0.5 g of diglycolic anhydride, and stir the reaction at room temperature 24h. Then, the above reaction solution was washed with 2% HCl solution to remove DMAP and separated by column chromatography (eluent, chloroform / methanol: 5 / 1, v / v) to obtain white powder 2'-tert-butyl Dimethylsilyloxy-paclitaxel-7-diglycolic acid monoester. Dissolve 2'-tert-butyldimethylsilyloxy-paclitaxel-7-diglycolic acid monoester in 5 mL of chloroform, add CDI0.1g, activate for 1h, add GPC0.05g and DBU0.1g, react at room temperature for 24h , the reaction solution was treated with 0.5 g of tetrabutylammonium fluoride to remove TBDMS, and the reaction solution was purified by column chromatography to obtain 0.09 g of bis(paclitaxel-7-diglycolic acid) ...

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Abstract

The invention discloses a paclitaxel phospholipid compound and a drug combination and application thereof. The drug combination comprises the paclitaxel phospholipid compound or a medicinal combination of the paclitaxel phospholipid compound and a pharmacodynamically-acceptable carrier, and can be a liquid preparation, a solid preparation, a semisolid preparation, capsules, granules, gel and an injection. The drug combination is liposome nanoparticles prepared from the paclitaxel phospholipid compound or the paclitaxel phospholipid compound and an auxiliary, and grain diameter of the liposome nanoparticles is 10-1000 nanometers. The paclitaxel phospholipid compound and the liposome nanoparticles utilize quickly-breakable spacer arms in molecular structure to quickly release paclitaxel drug, can be used as liquid preparations, solid preparations, semisolid preparations, sterilizing preparations and sterile preparations, are low in toxicity and can be used for efficient treatment of various tumors.

Description

technical field [0001] The invention relates to a paclitaxel phospholipid compound with antitumor effect, its pharmaceutical composition and application, and relates to the technical field of medicine. Background technique [0002] Paclitaxel is an alkaloid that can be extracted from plants or chemically synthesized. Paclitaxel is a complex secondary metabolite in Taxus plants, and it is the only drug known to promote microtubule polymerization and stabilize the polymerized microtubules. Studies have shown that paclitaxel binds to polymerized microtubules and does not react with unpolymerized tubulin dimers. After the cells are exposed to paclitaxel, a large number of microtubules will accumulate in the cells. The accumulation of these microtubules interferes with various functions of the cells, especially stopping cell division at the mitotic stage and blocking the normal division of cells. Through Phase II-III clinical studies, paclitaxel is mainly applicable to ovarian ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/337A61K9/127C07F9/655A61P35/00A61K47/60
Inventor 李新松凌龙兵
Owner SOUTHEAST UNIV
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