Water-soluble taxol polymer with tumor actively-targeted property

A technology of compounds and taxanes, applied in the field of medicine, can solve the problems of undisclosed preparation methods and characterization data, and achieve the effect of improving active selectivity, high curative effect, and high curative effect

Active Publication Date: 2013-04-03
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At the same time, the pharmacological activity data of a paclitaxel-PG (polyglutamic ac...

Method used

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  • Water-soluble taxol polymer with tumor actively-targeted property
  • Water-soluble taxol polymer with tumor actively-targeted property
  • Water-soluble taxol polymer with tumor actively-targeted property

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1 prepares polyglutamic acid

[0058] Dissolve 54.0g of triphosgene in 300mL of anhydrous tetrahydrofuran, add 50.0g of L-glutamic acid-γ benzyl ester in three batches at room temperature, exothermic heat rises in the system, add ice water bath to cool if necessary, after the reaction is stable, oil The temperature of the bath was raised to 50°C, and after all the solids were dissolved, the temperature was kept for half an hour. The solvent was removed by rotary evaporation under reduced pressure to obtain an off-white or light yellow solid, which was recrystallized by adding a mixed solvent of 150mL tetrahydrofuran and 200mL petroleum ether hot at 50°C, recrystallized again according to the above solvent ratio, filtered by suction, and dried under reduced pressure at room temperature for 12 Hours, 22.7g white solid was obtained, yield: 40.9%, mp: 91.4-92.7°C. 1 HNMR (500MHz, CDCl 3 ): δ7.25~7.38(m, 5H, Ar-H), 6.71(s, 1H, -NH), 5.13(s, 2H, -CH 2 ), 4.37(t,...

Embodiment 2

[0061] Embodiment 2: Preparation of polyglutamic acid paclitaxel sodium salt

[0062] Dissolve 0.3g polyglutamic acid in 7.5mL N,N-dimethylformamide, add 0.1g paclitaxel, 0.1g EDC and a small amount of DMAP, keep away from light, stir at room temperature for 6 hours, detect by thin layer chromatography, develop The agent was dichloromethane:methanol=95:5 (v / v), and paclitaxel disappeared completely. The reaction solution was poured into 500 mL of dichloromethane for eluting, suction filtered, rinsed, and vacuum-dried in the dark at room temperature for 6 hours. 0.33 g of off-white poly-paclitaxel was obtained. Yield 82.5%. By changing the weight ratio of paclitaxel and polyglutamic acid in the starting material, polyglutamic acid paclitaxel containing different concentrations of paclitaxel can be synthesized.

[0063] Polyglutamic acid paclitaxel was dissolved in 0.5 mol / L sodium bicarbonate solution to obtain polyglutamic acid paclitaxel sodium salt. The aqueous solution ...

Embodiment 3

[0072] The preparation of embodiment 3 folic acid-butylene diamine

[0073]

[0074] Dissolve 5 g of folic acid in 20 mL of dimethyl sulfoxide, add 1.66 g of NHS, 4.4 g of EDC, and 0.5 g of DMAP and stir for half an hour. Under vigorous stirring, the solution was slowly added dropwise to a solution of 40 g of butanediamine dissolved in 5 mL of dimethyl sulfoxide, and reacted at room temperature for 12 hours. The reaction solution was rinsed with 1000 mL of dichloromethane, quickly filtered and rinsed under nitrogen protection, and vacuum-dried at 30°C to obtain 5.1 g of a light yellow solid, which was sealed in water-proof form for future use. Yield 87.2%.

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Abstract

The invention discloses a water-soluble polymer containing taxol and taxol ester and actively targeting a tumor and a preparation method of the polymer. The water-soluble polymer is prepared by conjugating a polymer containing taxol or docetaxel with polyglutamic acid, and tumor actively-targeted molecular folic acid is modified on the structure basis of polyglutamic acid-taxane compounds. The water-soluble polymer disclosed by the invention can be used for treatment of tumors.

Description

technical field [0001] The invention belongs to the field of medicine, and more specifically relates to a water-soluble paclitaxel polymer actively targeting tumors, in particular to a polyglutamic acid paclitaxel polymer using folic acid as a tumor active targeting ligand. Background technique [0002] Paclitaxel (PTX) is an anti-tumor drug widely used clinically. It is a natural tricyclic diterpenoid extracted from yew, which works by disrupting the microtubule protein-microtubule system. It can bind to microtubule polymers and inhibit microtubule depolymerization to form stable microtubule bundles, thereby destroying the mitosis of tumor cells. Paclitaxel was officially approved by the FDA for clinical use in 1992, and has been approved for the treatment of ovarian cancer, breast cancer, non-small cell lung cancer, esophageal cancer, head and neck tumors, and gastric cancer. Paclitaxel has a broad anti-tumor spectrum and good curative effect. However, the main difficul...

Claims

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Application Information

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IPC IPC(8): C08G69/48A61K47/48A61K31/337A61P35/00
Inventor 赵俊吉同琴孙敏于春江马俊杰
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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