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Camptothecine and non-linear polyethyleneglycol prodrug of derivative thereof

A polyethylene glycol, non-linear technology, used in anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve problems such as oversize, metabolic clearance and biodegradation, and large proportion of ineffective molecules

Inactive Publication Date: 2009-03-18
AMERICAN CAOYAOQUAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the previously disclosed related inventions did not give careful and adequate consideration to these factors, nor did they recognize the possible impact of the polyethylene glycol configuration on the distribution of the prodrug
For example, the polyethylene glycol molecules selected by previous designers are often either small or large, and it is difficult to achieve the goal of passive targeting; while in the configuration selection of polyethylene glycol, single-functional or bifunctional linear structures are often used. Molecule
In fact, this type of traditional linear polyethylene glycol is only suitable for the modification of protein and polypeptide drugs, and when used for the modification of small molecule drugs, the obvious disadvantage is that the effective drug loading is small (each molecule can only carry at most two small molecule drugs), the proportion of ineffective molecules is too large
Extensive and unreasonable use of polymer carriers in the human body may lead to problems in metabolism, clearance and biodegradation

Method used

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  • Camptothecine and non-linear polyethyleneglycol prodrug of derivative thereof
  • Camptothecine and non-linear polyethyleneglycol prodrug of derivative thereof
  • Camptothecine and non-linear polyethyleneglycol prodrug of derivative thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Embodiment 1. Compound 1 (polyethylene glycol tetracarboxylic acid, 20k 4arm-PEG-OCH 2 -COOH)

[0055] Four-arm polyethylene glycol ( 20k 4arm-PEG-OH, 8.0g, 0.4mmol) was dissolved in toluene (80ml), and the toluene / water azeotrope (20ml) was distilled off under reduced pressure. The solution was cooled to 30-35°C, and potassium tert-butoxide (0.538 g, 4.8 mmol) was added. After the mixture was refluxed for 1 hour, it was cooled to 40°C, ethyl bromoacetate (1.18 g, 6.4 mmol) was added, and stirred overnight at 40°C. After the reactant was cooled to room temperature, diethyl ether was slowly added to precipitate the product. The suspension was filtered with suction, the precipitate was washed twice with ether, the solid was dissolved in 1N sodium hydroxide (50 ml), and stirred at room temperature for 2 hours to obtain a hydrolyzate. After the hydrolyzate was acidified with hydrochloric acid, it was extracted three times with dichloromethane (DCM) (25mlX3). The combi...

Embodiment 2

[0056] Embodiment 2. Compound 2 (polyethylene glycol octacarboxylic acid, 20k 8arm-PEG-OCH 2 -COOH)

[0057] The preparation process of Compound 2 is basically the same as that of Compound 1 in Example 1 above, except that the molecular ratio of potassium tert-butoxide and ethyl bromoacetate to polyethylene glycol is doubled.

Embodiment 3

[0058] Embodiment 3. Compound 3 (20- 20k 4arm-PEG-OCH 2 -C(O)CPT)

[0059] Compound 1 (500mg, 0.025mmol) was dissolved in toluene (15ml), evaporated under reduced pressure to remove the toluene / water azeotrope (10ml), cooled, added dichloromethane (15ml), camptothecin (CPT, 52.2mg, 0.15mmol ). The mixture was cooled to 0°C, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 28.7mg, 0.15mmol) and dimethylaminopyridine (DMAP, 18.3 mg, 0.15 mmol), the ice-water bath was removed, the reaction mixture was gradually warmed to room temperature, and stirring was continued overnight. The reaction solution was washed with dilute hydrochloric acid, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, the residue was dissolved in methanol, and subjected to silica gel column chromatography. The eluates were combined and concentrated by evaporation. The concentrated solution was precipitated with diethyl ether, the precipitate was s...

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Abstract

The invention discloses a pro-drug as shown in general formula (I), which is formed by coupling camptothecin or a derivative of the camptothecin with non-linear configuration glycol polyethylene, wherein, the definition for varied groups is available in the specification. A physiological disposition research on nude mice discloses that: the pro-drug has a time-delay plasma concentration - time curve, and the plasma concentration can still be maintained at over 100ng / ml 72 hours after intravenous medication. Evaluation on physiological drug effect shows that the pro-drug has strong growth inhibiting effect against the LOVO HCT116 cell line transplantable tumor inoculated into the nude mice and also has obvious growth inhibitory activity against human lung carcinoma H460 cell line transportable tumor inoculated into the nude mice. The inhibition of the pro-drug is better than that of Irinotecan, a positive control drug and has no obvious systemic toxicity.

Description

technical field [0001] The present invention relates to prodrugs of antineoplastic drugs, more specifically, non-linear polyethylene glycol prodrugs of camptothecin and its derivatives, their preparation methods and their application in tumor treatment. Background technique [0002] Camptothecin (CPT), a pentacyclic alkaloid isolated from Camptotheca acuminata, is the only anti-cancer plant that selectively inhibits DNA topoisomerase I (Topo I) medicine. Although camptothecin and its derivatives have significant antitumor activity, their clinical application is greatly limited due to the characteristics of the drug itself. First of all, camptothecin has poor water solubility and fat solubility. Therefore, in the 1970s, it was made into a water-soluble sodium salt for clinical trial, but failed due to low curative effect and high toxicity. Secondly, the study found that the lactone ring of camptothecin drugs is very unstable, and it is very easy to hydrolyze and open the ri...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/4745A61P35/00A61K47/60
Inventor 肖俊方柏育文徐明旭李书宽
Owner AMERICAN CAOYAOQUAN
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