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A kind of doxorubicin polyethylene glycol epothilone b conjugate and preparation method thereof

A technology of epothilone and PEGylation, which is applied in the direction of drug combination, drug delivery, pharmaceutical formulation, etc., to achieve high selectivity and yield, enhance the efficacy of chemotherapy, and reduce the effects of side effects

Active Publication Date: 2021-06-18
长沙创新药物工业技术研究院有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since epothilone is an anti-tumor chemotherapy drug, it has certain cytotoxicity and can cause toxic side effects such as gastrointestinal reactions and bone marrow suppression.

Method used

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  • A kind of doxorubicin polyethylene glycol epothilone b conjugate and preparation method thereof
  • A kind of doxorubicin polyethylene glycol epothilone b conjugate and preparation method thereof
  • A kind of doxorubicin polyethylene glycol epothilone b conjugate and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0031] In a 50ml three-neck flask equipped with a mechanical stirrer, a thermometer, and a nitrogen bag, add Hz-PEG 22 - COOH (10 mmol), phosphoric acid (1 mmol) and 30 ml DMF. Under the protection of nitrogen, the system was stirred at a room temperature of 25° C. in the dark for 48 hours. Add 100 microliters of triethylamine (TEA), and then use a dialysis membrane to perform dialysis in a phosphate buffer solution of pH 8.0 until the dialysate no longer turns red, take out the dialysate and freeze-dry to obtain the intermediate compound DOX-PEG22 -COOH (90% yield). The synthesis of the product was confirmed by NMR and HPLC simultaneously.

[0032] Weigh Epothilone B (6mmol) and DOX-PEG22-COOH (6mmol) into a 25mL round bottom flask, stir to dissolve. Under nitrogen protection, 5 mL of dimethyl sulfoxide solution in which coupling agent DCC (6 mmol) and catalyst DMAP (12 mmol) were dissolved was slowly added. Ice bath, take it out after reacting for 2h, and continue to sti...

Embodiment 2

[0034] In a 50ml three-neck flask equipped with a mechanical stirrer, a thermometer, and a nitrogen bag, add Hz-PEG 72- COOH (10 mmol), phosphoric acid (1 mmol) and 30 ml DMF. Under the protection of nitrogen, the system was stirred at a room temperature of 25° C. in the dark for 48 hours. Add 100 microliters of triethylamine (TEA), and then use a dialysis membrane to perform dialysis in a phosphate buffer solution of pH 8.0 until the dialysate no longer turns red, take out the dialysate and freeze-dry to obtain the intermediate compound DOX-PEG22 -COOH (88% yield). The synthesis of the product was confirmed by NMR and HPLC simultaneously.

[0035] Weigh about Epothilone B (12mmol) and DOX-PEG72-COOH (6mmol) into a 25mL round bottom flask, stir to dissolve. Under nitrogen protection, 5 mL of dimethyl sulfoxide solution in which coupling agent DCC (6 mmol) and catalyst DMAP (6 mmol) were dissolved was slowly added. Ice bath, take it out after reacting for 2h, and continue t...

Embodiment 3

[0037] In a 50ml three-neck flask equipped with a mechanical stirrer, a thermometer, and a nitrogen bag, add Hz-PEG 120 - COOH (10 mmol), phosphoric acid (1 mmol) and 30 ml DMF. Under the protection of nitrogen, the system was stirred at a room temperature of 25° C. in the dark for 48 hours. Add 100 microliters of triethylamine (TEA), and then use a dialysis membrane to perform dialysis in a phosphate buffer solution of pH 8.0 until the dialysate no longer turns red, take out the dialysate and freeze-dry to obtain the intermediate compound DOX-PEG22 -COOH (90% yield). The synthesis of the product was confirmed by NMR and HPLC simultaneously.

[0038] Weigh about 12mmol of Epothilone B and 6mmol of DOX-PEG120-COOH into a 25mL round bottom flask, stir to dissolve. Under nitrogen protection, 5 mL of dimethyl sulfoxide solution in which coupling agent DCC (12 mmol) and catalyst DMAP (12 mmol) were dissolved was slowly added. Ice bath, take it out after reacting for 2h, and con...

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Abstract

The invention relates to a doxorubicin pegylated epothilone B and a preparation method thereof. The method mainly includes the following steps: 1) reacting doxorubicin and hydrazide polyethylene glycol carboxyl under the action of phosphoric acid to prepare Doxorubicin polyethylene glycol carboxyl intermediate, wherein the molar ratio of doxorubicin to phosphoric acid is 1:0.01-0.02; 2) under the action of the second coupling agent and catalyst, epothilone B and doxorubicin Polyethylene glycol carboxyl intermediate reacts to obtain doxorubicin pegylated epothilone B conjugate.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a doxorubicin pegylated epothilone B conjugate and a preparation method thereof. Background technique [0002] Doxorubicin is one of the most widely used small-molecule chemotherapy drugs. However, due to defects such as poor water solubility and non-selective drug distribution, doxorubicin has very serious side effects on normal tissues after entering the body. At the same time, if doxorubicin is used for a long time, it will also induce tumor cells to develop strong drug resistance, that is, the sensitivity of cancer cells to the same dose of doxorubicin will be reduced. The structural formula of doxorubicin is shown in formula 1. [0003] [0004] How to improve the specificity of doxorubicin distribution in vivo, enhance its chemotherapy efficacy, and minimize its toxic and side effects has become an urgent problem to be solved. As a medical material certified by ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/60A61K47/69A61K31/704A61K31/427A61P35/00C08G65/334
CPCA61K31/427A61K31/704A61K47/60A61K47/6935A61P35/00C08G65/3348A61K2300/00
Inventor 张安林邓泽平成佳李虎赵春晖
Owner 长沙创新药物工业技术研究院有限公司
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