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Multi-arm PEGylated (Polyethylene Glycolylated) azithromycin derivative and preparation thereof

A derivative and integer technology, used in the preparation of antitumor drugs, multi-arm PEGylated DOX derivatives and their preparation and preparation fields, can solve the toxicity and side effects of tissues and organs, limited drug immobilization rate, and drug The slow release effect is not obvious and other problems, so as to reduce the toxic and side effects, increase the existence time, and reduce the toxic and side effects.

Inactive Publication Date: 2018-11-02
湖南华腾制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

First of all, ordinary linear PEG has only one or two modified ends, and the drug immobilization rate is very limited.
Secondly, although monodisperse PEG can improve the water solubility of the drug, it does not have a significant effect on the sustained release of the drug.
And the linear monodisperse PEGylated doxorubicin can not achieve targeted release for lesions, and has toxic and side effects on normal tissues and organs

Method used

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  • Multi-arm PEGylated (Polyethylene Glycolylated) azithromycin derivative and preparation thereof
  • Multi-arm PEGylated (Polyethylene Glycolylated) azithromycin derivative and preparation thereof
  • Multi-arm PEGylated (Polyethylene Glycolylated) azithromycin derivative and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Preparation of 4arm-PEG24-DOX(III)

[0029] 10 mmol equivalent of 4-arm-PEGm-Hz-I and 6 mmol of doxorubicin hydrochloride were dissolved in anhydrous DMF solvent, and 1 mmol% catalytic equivalent of phosphoric acid was added to the organic solvent. The reaction was carried out in the dark for 48 hours at a reaction temperature of 10°C, and the target product was obtained by recrystallization through column chromatography after the completion of the detection reaction. Yield: 83%. The NMR data are as follows: 1 H NMR (400MHz,DMSO)δ,9.05(s,1H),8.89–8.86(m,1H),8.55–8.52(m,2H),7.87–7.85(m,1H),7.76–7.73(m,1H ),7.40(s,1H),6.51(s,1H), 4.75-4.74(m,2H),4.22-4.19(t,2H),3.58-3.52(m,108H),2.82(t,2H), 2.50-2.47 (m, 2H), 2.04-1.98 (m, 2H), 0.94–0.90 (m, 3H).

Embodiment 2

[0031] Preparation of 4arm-PEG124-DOX(III)

[0032] 10 mmol equivalent of 4-arm-PEGm-Hz-I and 8 mmol of doxorubicin hydrochloride were dissolved in anhydrous DMSO solvent, and 5 mmol% catalytic equivalent of phosphoric acid was added to the organic solvent. React at a reaction temperature of 25° C. in the dark for 54 hours, check that the reaction is complete, and recrystallize through column chromatography to obtain the target product. Yield: 81.2%. The NMR data are as follows: 1 H NMR (400MHz,DMSO)δ,9.05(s,1H),8.89–8.86(m,1H), 8.55–8.52(m,2H),7.87–7.85(m,1H),7.76–7.73(m,1H ),7.40(s,1H),6.51(s,1H),4.75-4.74(m,2H),4.22-4.19(t,2H),3.58-3.52(m,508H),2.82(t,2H), 2.50-2.47(m,2H),2.04-1.98(m,2H),0.94–0.90(m,3H).

Embodiment 3

[0034] Preparation of 4arm-PEG240-DOX(III)

[0035] 10 mmol equivalent of 4-arm-PEG240-Hz-I and 10 mmol of doxorubicin hydrochloride were dissolved in anhydrous chloroform solvent, and 10 mmol% catalytic equivalent of phosphoric acid was added to the organic solvent. React at a reaction temperature of 30° C. in the dark for 60 hours, check that the reaction is complete, and recrystallize through column chromatography to obtain the target product. Yield: 85.4%. The NMR data are as follows: 1 H NMR (400MHz,DMSO)δ,9.05(s,1H),8.89–8.86(m,1H), 8.55–8.52(m,2H),7.87–7.85(m,1H),7.76–7.73(m,1H ),7.40(s,1H),6.51(s,1H),4.75-4.74(m,2H),4.22-4.19(t,2H),3.58-3.52(m,972H),2.82(t,2H), 2.50-2.47(m,2H), 2.04-1.98(m,2H),0.94–0.90(m,3H).

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Abstract

The invention relates to a multi-arm PEGylated (Polyethylene Glycolylated) azithromycin derivative and the preparation thereof. By utilizing the characteristic that the multi-arm PEG is non-toxic andeasy to bind, four-arm PEG, six-arm PEG and multi-arm PEG are all connected with DOX. The multi-arm PEG supported DOX prodrug has excellent water solubility. The most important characteristic is thatone multi-arm PEG chain can be connected with multiple DOX residues, and the drug loading rate is greatly improved. Moreover, the half-life of the drug is greatly prolonged, so that lifetime of the drug in plasma is obviously increased, and the curative effects are improved.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a multi-armed PEGylated DOX derivative, its preparation, its preparation method and its application in the preparation of antitumor drugs. Background technique [0002] Adriamycin (Doxorubicin, Dox), also known as doxorubicin, is an allanine antibiotic and is one of the most commonly used antineoplastic drugs in clinical practice. Its mechanism of action is that DOX acts on DNA molecules, directly intercalates between nucleobase pairs, prevents the formation of mRNA, interferes with the transcription process and produces anti-tumor effects, and belongs to the periodic non-specific anticancer drug. It is mainly used for the treatment of malignant lymphoma, breast cancer, lung cancer, bladder cancer and other solid tumors. DOX is highly lethal to tumors, but DOX has poor selectivity and can cause toxic and side effects on normal tissues and organs such as the liver, kidney,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60A61K31/704A61P35/00C08G65/333
CPCA61K47/60A61K31/704A61P35/00C08G65/33396
Inventor 张安林邓泽平成佳
Owner 湖南华腾制药有限公司
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