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Paclitaxol predrug of biodegradable polymer and its synthesis method

A technology of biodegradation and synthesis method, which is applied in the field of paclitaxel prodrug and its synthesis, which can solve the problems of inability to release the parent drug rapidly, carcinogenicity in rodents, poor stability, etc.

Inactive Publication Date: 2005-06-22
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When the dissolved DEHP enters the human body, it will cause toxic and side effects, because animal experiments have shown that DEHP can cause liver cell toxicity in animals and cause cancer in rodents
[0015] Chinese patent application CN 1288890A discloses a class of water-soluble paclitaxel prodrugs containing thiosulfuric acid or its salts and 2′-(tert-butyldimethylsilyl) paclitaxel (ModifiedTaxols, 4.1 synthesis and biological activity of Taxol; Modified in the side chain, Journal of Natural Products 1998, 51, 28), although they all show cytotoxicity, they all have certain defects: some are too poor in stability, and will decompose and release paclitaxel very quickly, which cannot meet the requirements for Prodrug stability requirements; some are too stable in the body, insensitive to enzymes, cannot release the parent drug quickly, and cannot show the desired therapeutic effect
[0017] In the existing literature, it has been reported that an amino acid or a polypeptide is introduced between the polymer and paclitaxel as a linking arm, but there is no report of a paclitaxel prodrug with a low molecular weight polyester as a linking arm

Method used

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  • Paclitaxol predrug of biodegradable polymer and its synthesis method
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  • Paclitaxol predrug of biodegradable polymer and its synthesis method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] (1) 4 g of lactide (LA) monomer recrystallized three times with ethyl acetate and 10 g of polyethylene glycol monomethyl ether (MPEG) with a molecular weight of 4600 were added to a high-purity argon gas exchanged three times with In the dry ampoule of the water separator, reflux condenser and magnetic stirrer, add anhydrous toluene solvent with a total mass ratio of 2:1 to LA and MPEG to azeotropically remove water, then distill off half of the toluene, and add about 0.3 ml molarity is 2×10 -3 mol / l stannous octoate toluene solution. The reaction was stirred at 110°C for 24 hours, and then the product was dissolved in an appropriate amount of dichloromethane, and settled with ether to obtain a white product, which was dried under vacuum at 40°C. (10.2 g, 73% yield).

[0046] The NMR spectrum of gained block polymer MPEG-PLA is shown in Figure 4 .

[0047] (2) Ventilate a 100ml three-neck flask with a reflux condenser and a magnetic stirrer three times with high-pu...

Embodiment 2

[0055] (1) 5 g of the refined ε-caprolactone (CL) monomer and 10 g of MPEG with a molecular weight of 2000 are added to a high-purity argon gas exchanged three times with a water separator, a reflux condenser and a magnetic stirrer In the dry ampoule, add anhydrous toluene solvent with a total mass ratio of CL and MPEG of 2:1 to remove water azeotropically, then evaporate half of the toluene, add about 0.2ml molar concentration of 5×10 -4 mol / l stannous octoate toluene solution. The reaction was stirred at 110°C for 24h, then the product was dissolved in an appropriate amount of dichloromethane, and settled with ether to obtain a white product, which was dried under vacuum at 40°C (12.1 g, yield 81%).

[0056] (2) In a 100ml three-necked flask, dissolve 1g of MPEG-PCL diblock polymer and excess mono-tert-butyl diglycolate in 50ml of anhydrous dichloromethane, and add 70mg of DCC and 40mg of DMAP under ice-cooling , The reaction was stirred at 0°C for 24h. The precipitated di...

Embodiment 3

[0059] (1) Add the refined 8g lactide and 2g glycolide mixed monomer and 10g MPEG with a molecular weight of 1000 to a high-purity argon gas exchanged three times with water separator, reflux condenser and magnetic stirrer In a dry ampoule, add anhydrous toluene solvent with a total mass ratio of lactide, glycolide, and MPFG of 2:1 to azeotropically remove water, then distill off half of the toluene, and add about 0.5ml molar concentration of 2 ×10 3 mol / l stannous octoate toluene solution. The reaction was stirred at 110°C for 24 hours, and then the product was dissolved in an appropriate amount of dichloromethane, and settled with ether to obtain a white product, which was dried under vacuum at 40°C. (14.2 g, 71% yield).

[0060](2) In a 100ml there-necked flask, dissolve 1g of polyethylene glycol monomethyl ether-polylactide glycolide block polymer and excess mono-tert-butyl diglycolate in 50ml of anhydrous dichloromethane, and 70mg DCC and 40mg DMAP were added under ice...

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Abstract

The invention provides a paclitaxol predrug of biodegradable polymer and its synthesis method, which is bond from polyoxyalkylene-aliphatic polyester blocked copolymer and paclitaxol, the synthesizing process comprises, carrying out ring-opening polymerization of aliphatic cyclic esters at the presence of polyethylene glycol (PEG), solvent and catalyst, obtaining polyethylene glycol - aliphatic polyester blocked copolymer, then converting its end hydroxyl into end carboxyl, reacting with paclitaxol for esterification at the presence of condensing agent, the obtained paclitaxol predrug has amphiphilic, thus can be prepared into water based preparation.

Description

technical field [0001] The invention relates to a paclitaxel prodrug of a biodegradable polymer and a synthesis method thereof. Background technique [0002] Paclitaxel is a diterpene natural product, originally obtained from the Pacific yew tree, Taxus brevifolia, which has obvious anticancer effects and is used to treat various tumors, such as ovarian cancer, breast cancer, non-small cell lung cancer, head and neck cancer, etc. Its biological activity is related to its effect on cell division, during which it can promote the assembly of microtubule dimers into microtubules, and then inhibit the normal motility of microtubule network by preventing the multimerization process and enhancing the stability of microtubules The biological recombination affects the life cycle and division function of cells, thereby inhibiting the growth and reproduction of tumor cells. [0003] Although paclitaxel has a good clinical effect on many tumors, there are two problems that limit its w...

Claims

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Application Information

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IPC IPC(8): A61K31/337A61K47/34A61P35/00C07D305/14C08G81/00
Inventor 景遐斌张雪飞陈学思徐效义梁奇志杨立新边新超
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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