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Polyethylene glycol (PEG)-amino acid oligopeptide-irinotecan combo and its medicinal composition

A technology of polyethylene glycol and conjugates, which can be used in drug combinations, anti-tumor drugs, pharmaceutical formulations, etc., and can solve problems such as drug loading rate limitations

Active Publication Date: 2013-05-08
JENKEM TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in this structure, each polyethylene glycol end group can only have one inotecan connected to it, and the loading rate of the drug is limited.

Method used

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  • Polyethylene glycol (PEG)-amino acid oligopeptide-irinotecan combo and its medicinal composition
  • Polyethylene glycol (PEG)-amino acid oligopeptide-irinotecan combo and its medicinal composition
  • Polyethylene glycol (PEG)-amino acid oligopeptide-irinotecan combo and its medicinal composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Example 1: Preparation of linear polyethylene glycol (20k)-amino acid pentapeptide-Inotecan conjugate (CPT-1)

[0070] 29.4 g of L(+)-glutamic acid, 40 g of p-toluenesulfonic acid, and 80 mL of benzyl alcohol were dissolved in 500 mL of toluene, and 11 mL of water was separated under reflux under nitrogen protection. The reflux was continued for 3 hours, and 150 mL was evaporated. After cooling to 50°C, the reaction solution was poured into a beaker containing 600 mL petroleum ether, stirred for 1 hour, and the precipitate was collected by filtration. After the filter cake was heated and dissolved with 280 mL of 95% ethanol, the heating was stopped and the cake was cooled overnight. The precipitate was collected by filtration and dried under vacuum to obtain 61 g of L(+)-glutamic acid dibenzyl ester p-toluenesulfonate.

[0071] 30g of dibenzyl glutamate p-toluenesulfonate was dissolved in 500mL of dichloromethane, 20.86g of tert-butoxycarbonyl-L-glutamate-5-benzyl ester was...

Embodiment 2

[0076] Example 2: Preparation of linear polyethylene glycol acetic acid (20k)-amino acid hepeptide-Inotecan conjugate

[0077] 29.4 g of L(+)-glutamic acid, 40 g of p-toluenesulfonic acid, and 80 mL of benzyl alcohol were dissolved in 500 mL of toluene, and 11 mL of water was separated under reflux under nitrogen protection. The reflux was continued for 3 hours, and 150 mL was evaporated. After cooling to 50°C, the reaction solution was poured into a beaker containing 600 mL petroleum ether, stirred for 1 hour, and the precipitate was collected by filtration. After the filter cake was heated and dissolved with 280 mL of 95% ethanol, the heating was stopped and the cake was cooled overnight. The precipitate was collected by filtration and dried under vacuum to obtain 61 g of L(+)-glutamic acid dibenzyl ester p-toluenesulfonate.

[0078] 30g of dibenzyl glutamate p-toluenesulfonate was dissolved in 500mL of dichloromethane, 20.86g of tert-butoxycarbonyl-L-glutamate-5-benzyl ester wa...

Embodiment 3

[0082] Example 3: Preparation of Y-type polyethylene glycol (40k)-amino acid pentapeptide-Inotecan conjugate

[0083] N-tert-butoxycarbonyl glutamate benzyl ester dipeptide (Boc-Glu(obzl)-Glu(obzl)-obzl) 0.776g (Example 1) was dissolved in 7mL dichloromethane, and 3mL trifluoroacetic acid was added at room temperature Reaction for 2h. Remove the solvent, add 100 mL of dichloromethane, use 5% sodium bicarbonate solution (NaHCO 3 ) Adjust pH=7-8. Extract and separate the liquids, and use 5% sodium bicarbonate solution (NaHCO 3 ) Wash twice and dry with anhydrous sodium sulfate. Filter, add the filtrate directly to the reaction flask, under the protection of nitrogen, add Y-type polyethylene glycol carboxylic acid (molecular weight is 40,000, structure such as (V)) 40.0g, 4-dimethylaminopyridine (DMAP) 245mg, 1 -Hydroxybenzotriazole (HOBT) 135mg. After all was dissolved, 412 mg of dicyclohexylcarbodiimide (DCC) was added. The reaction was stirred overnight at room temperature. ...

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Abstract

The invention relates to a PEG-amino acid oligopeptide-irinotecan combo having a structure represented by general formula (I), and a medicinal composition containing the combo. In the combo, PEG represents polyethylene glycol, and the molecular weight of PEG is 300-60,000Dalton; (AA)i represents oligopeptides, and AA represents same or different amino acids in the oligopeptides; i is an integer between 2 and 12 and represents the quantity of the amino acids in the oligopeptides; and j is an integer between 2 and 12 and represents the quantity of irinotecans connected with the oligopeptides. In the combo, each PEG end group can be connected with a plurality of irinotecans through the amino acid oligopeptides, so the medicine loading rate is substantially improved. The modification of a hydrophilic polymer can protect irinotecan, improve the medicine absorption, prolong the action time, enhance the curative effects, reduce the administration dosage and avoid toxic and side effects.

Description

Technical field [0001] The present invention relates to polyethylene glycol conjugates, especially polyethylene glycol, amino acid oligopeptide and drug inotecan conjugates and pharmaceutical compositions thereof. Background technique [0002] Irinotecan (CPT-11) is a camptothecin derivative with good anti-cancer activity and a unique mechanism of action. It is one of the best-selling anti-tumor drugs so far. In 2003, its worldwide sales exceeded US$1 billion, and with an annual sales growth rate of 20%, it became one of the best anticancer drugs in the world. Inotecan has a broad anti-tumor spectrum. Phase I and Phase II clinical studies show that the drug has a positive effect on chemotherapy-resistant tumors, such as metastatic colorectal cancer, non-small cell lung cancer, ovarian cancer and cervical cancer. It also has a certain effect on gastric cancer, malignant lymphoma, non-Hodgkin's lymphoma, breast cancer, small cell lung cancer, skin cancer, and pancreatic cancer. I...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/4745A61P35/00
CPCA61K47/48A61K47/48215A61K31/4745A61K47/65A61K47/60A61P35/00
Inventor 徐立华黄文哲赵宣
Owner JENKEM TECH
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