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Taxol phospholipids compound, medicine composition and application thereof

A technology of phospholipid compounds and paclitaxel analogs, applied in the field of medicine, can solve the problems of difficulty in exerting drug efficacy, leakage of drugs and the like

Inactive Publication Date: 2014-12-24
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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  • Taxol phospholipids compound, medicine composition and application thereof
  • Taxol phospholipids compound, medicine composition and application thereof
  • Taxol phospholipids compound, medicine composition and application thereof

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 DCC1g and DMAP0.2g, react with 1g N-benzoyl-3-phenylisoserine; add acetic acid, dichloromethane, react at room temperature for 12 hours, remove the tert-butyl group, and 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 a 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), 5.27(2H,d),...

Embodiment 3

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

[0123] Docetaxel (Docetaxel) 0.3g, acetic acid 1g, DCC1g, DMAP0.1g, 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, take the filter cake; Dissolve in methanol, place at 4°C for 12 hours, 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 trichloromethane as reaction solvent, reflux reaction for 12h; wash with dilute hydrochloric acid three times, filter dilute hydrochloric acid layer, take 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-diac...

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Abstract

The invention discloses a taxol phospholipids compound, a medicine composition and application thereof. The medicine composition comprises the taxol phospholipids compound or a combined medicine composition which is combined by the taxol phospholipids compound and a carrier which can be accepted in pharmacology, namely a liquid preparation, a solid preparation, a semi-solid preparation, a capsule, a granule, a gel and an injection. The medicine composition is the taxol phospholipids compound or a liposomal nano particle which is prepared by the taxol phospholipids compound and an assistant, and the diameter of the particle is 10 to 1000 nanometer. The taxol phospholipids compound and the liposomal nano particle can be used as liquid preparations, solid preparations, semi-solid preparations, sterilization preparations and sterile preparations, the toxicity is low, so that the taxol phospholipids compound and the liposomal nano particle can be applied to the 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 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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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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