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A paclitaxel phospholipid compound, its pharmaceutical composition and application

A technology of phospholipid compounds and paclitaxel analogues, which is applied in the field of medicine, can solve the problems that drugs are difficult to exert their efficacy and drugs leak out.

Inactive Publication Date: 2017-02-01
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the fluidity of the liposome membrane, the drug is easy to leak out, making it difficult for the encapsulated drug to exert a good drug effect

Method used

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  • A paclitaxel phospholipid compound, its pharmaceutical composition and application
  • A paclitaxel phospholipid compound, its pharmaceutical composition and application
  • A paclitaxel phospholipid compound, its pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] Synthesis of paclitaxel-2'-phospholipid compound (route see figure 1 )

[0112] Paclitaxel (Paclitaxel) 0.3g, tert-butyl malonate 0.3g, DCC 0.3g, DMAP 0.1.5g, add dichloromethane or chloroform as reaction solvent, react at 40°C for 12h; wash with dilute hydrochloric acid three times, filter dilute For the hydrochloric acid layer, take the filter cake; add methanol to dissolve, place at 4°C for 12 hours, filter, take the filter cake, and dry to obtain the intermediate product paclitaxel-2'-tert-butyl malonate, add acetic acid and dichloromethane, and react at room temperature for 12 hours , Remove the tert-butyl group to obtain paclitaxel-2'-malonic acid monoester.

[0113] Take 0.22g of the intermediate paclitaxel-2'-malonate monoester, add 0.3g of CDI, add dichloromethane, chloroform or DMSO as the reaction solvent, add 0.15g of GPC and 0.2g of DBU to react at room temperature, and the obtained reaction solution passes through Purified by column chromatography to obt...

Embodiment 2

[0116] Synthesis of paclitaxel-7-phospholipid compound (synthetic route sees figure 2 )

[0117] Baccatin III (baccatin III) 0.5g, DCC 0.5g and DMAP 0.3g, tert-butyl malonate 1g, dichloromethane or chloroform as the reaction solvent, react at room temperature for 24h. Further, in the presence of DCC 1g and DMAP 0.2g, react with 1g N-benzoyl-3-phenylisoserine; add acetic acid, dichloromethane, and react at room temperature for 12 hours to remove the tert-butyl group to obtain paclitaxel-7' - malonate monoester.

[0118] Take 0.43g of the intermediate paclitaxel-7-malonate monoester, add 0.4g of CDI, add dichloromethane, chloroform or DMSO as the reaction solvent, add 0.3g of GPC and 0.6g of DBU to react at room temperature, and the resulting reaction solution passes through the column Purified by chromatography to obtain 0.35 g of the product paclitaxel-7-phospholipid compound.

[0119] 1 H NMR (500MHz, CD3OD:CDCl 31:1): δ7.96-7.58(20H,m), 7.25-6.93(10H,m), 5.68(2H,d), 5....

Embodiment 3

[0122] Synthesis of docetaxel-10-phospholipid compound (synthetic route sees image 3 )

[0123] Docetaxel 0.3g, acetic acid 1g, DCC 1g, DMAP 0.1g, add dichloromethane or chloroform as the reaction solvent, react at room temperature for 12h; wash with dilute hydrochloric acid three times, filter the dilute hydrochloric acid layer, and take the filter cake; Add methanol to dissolve, place at 4°C for 12h, filter, take the filter cake, and dry to obtain the intermediate product docetaxel-2',7-diacetate. Intermediate product 0.22g, succinic anhydride 1g, DMAP 0.1g, triethylamine 1g, add dichloromethane or chloroform as reaction solvent, reflux reaction for 12h; wash with dilute hydrochloric acid three times, filter the dilute hydrochloric acid layer, and take the filter cake; Add methanol to dissolve, place at 4°C for 12h, filter, take the filter cake, and dry to obtain the intermediate product docetaxel-2',7-diacetate-10-butanedioic acid monoester.

[0124] Docetaxel-2',7-diace...

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Abstract

Disclosed are a taxol phospholipid compound, a pharmaceutical composition and a use thereof. In the invention, the pharmaceutical composition comprises a composition of the taxol phospholipid compound and a pharmacodynamically acceptable carrier, and is a liquid preparation, a solid preparation, a semi-solid preparation, a capsule, a granule, a gel or an injection. The pharmaceutical composition is a liposome nanoparticle prepared by using the taxol phospholipid compound and an adjuvant, and the particle size of the nanoparticle is 10-1000 nm.

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 the genus Taxus, 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 ovari...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/48A61K9/127A61K31/337C07F9/655A61P35/00
CPCA61K9/127A61K31/337A61K47/50C07F9/655
Inventor 李新松方硕
Owner SOUTHEAST UNIV
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