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Multi-arm PEGylated oritavancin derivative and preparation method thereof

A technology of oritavancin and derivatives, applied in the preparation and treatment of acute bacterial skin and skin structure infections, multi-arm PEGylated oritavancin derivatives and their preparation and preparation fields, can solve the problem of loading limited quantity and other problems, to achieve the effect of easy quality control, good in vitro and in vivo activity of the drug, and reduced cost

Active Publication Date: 2020-01-03
湖南华腾医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ordinary straight-chain PEG has only two terminal modification groups. When connecting with small molecule drugs, the loading capacity is very limited, while multi-armed PEG has more than 2 modifiable terminals.

Method used

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  • Multi-arm PEGylated oritavancin derivative and preparation method thereof
  • Multi-arm PEGylated oritavancin derivative and preparation method thereof
  • Multi-arm PEGylated oritavancin derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] (1) Preparation of 4-Arm-PEG24-GA-II

[0029] Dissolve 10mmol of 4-Arm-PEG24-OH-I in 100ml of DMF, add 11mmol of adipic anhydride and 10mmol of DMAP at room temperature, and then stir at 100°C for 10h. After the reaction was completed, the solution was distilled off under reduced pressure to obtain a crude product. The crude product was purified by chromatography to obtain 4-Arm-PEG24-GA-II. Yield: 90%. NMR data are as follows: 1H NMR (400MHz, CDCl3) δ4.26(s,2H),3.66(m,96H),2.86(s,2H),2.74(s,2H),2.52(s,2H), 2.09( s,2H).

[0030] (2) Preparation of 4Arm-PEG24-oritavancin-II

[0031] Dissolve 10mmol of 4-Arm-PEGm-GA-II in 50ml of N,N-dimethylformamide, add 10mmol of DIC and 10mmol of 4-PPY, and stir at 25°C for 2h. 80 mmol of oritavancin was added to the reaction, and the reaction was carried out at 30°C for 12 hours. After the completion of the oritavancin reaction as detected by TLC tracking, 4Arm-PEG24-oritavancin-II was obtained by recrystallization and chromato...

Embodiment 2

[0033] (1) Preparation of 4-Arm-PEG124-GA-II

[0034] Dissolve 10mmol of 4-Arm-PEG124-OH-I in 100ml of DMF, add 11mmol of adipic anhydride and 10mmol of DMAP at room temperature, and then stir at 100°C for 8h. After the reaction was completed, the solution was distilled off under reduced pressure to obtain a crude product. The crude product was purified by chromatography to obtain (4or 6or 8)-Arm-PEGm-GA-II. Yield: 90%. NMR data are as follows: 1H NMR (400MHz, CDCl3) δ4.26(s,2H),3.66(m,496H),2.86(s,2H),2.74(s,2H),2.52(s,2H),2.09( s,2H).

[0035] (2) Preparation of 4Arm-PEG124-oritavancin-II

[0036] Dissolve 10mmol of 4-Arm-PEG24-GA-II in 50ml of N,N-dimethylformamide, add 10mmol of DIC and 10mmol of 4-PPY, and stir at 25°C for 2h. 80 mmol of oritavancin was added to the reaction, and the reaction was carried out at 30°C for 12 hours. After TLC tracking detection oritavancin reaction was complete, 4Arm-PEG124-oritavancin-II was obtained by recrystallization and chromatog...

Embodiment 3

[0038] (1) Preparation of 4-Arm-PEG240-GA-II

[0039] Dissolve 10mmol of 4-Arm-PEG240-OH-I in 100ml of DMF, add 11mmol of adipic anhydride and 10mmol of DMAP at room temperature, and then stir at 120°C for 10h. After the reaction was completed, the solution was distilled off under reduced pressure to obtain a crude product. The crude product was purified by chromatography to obtain 4-Arm-PEG240-GA-II. Yield: 90%. NMR data are as follows: 1H NMR (400MHz, CDCl3) δ4.26(s, 2H), 3.66(m, 960H), 2.86(s, 2H), 2.74(s, 2H), 2.52(s, 2H), 2.09( s,2H).

[0040] (2) Preparation of 4Arm-PEG240-oritavancin-II

[0041] Dissolve 10mmol of 4-Arm-PEG240-GA-II in 50ml of N,N-dimethylformamide, add 10mmol of DIC and 10mmol of 4-PPY, and stir at 25°C for 2h. 80 mmol of oritavancin was added to the reaction, and the reaction was carried out at 30°C for 12 hours. After TLC tracking detection oritavancin reaction was complete, 4Arm-PEG240-oritavancin-II was obtained by recrystallization and chromat...

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Abstract

According to the invention, four-arm PEG (polyethylene glycol), six-arm PEG and multi-arm PEG are respectively connected with oritavancin by utilizing the characteristics that the multi-arm PEG is non-toxic and easy to combine. A multi-arm PEG loaded oritavancin prodrug not only has good water solubility, but also is most importantly characterized in that one multi-arm PEG chain can be connected with a plurality of oritavancin residues, so that the loading rate of the drug is greatly increased, the half-life period of the drug is greatly prolonged, the existence time of the drug in plasma is remarkably prolonged, and the curative effect is improved.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a multi-armed PEGylated oritavancin derivative and its preparation method and its application in the preparation and treatment of acute bacterial skin and skin structure infections. Background technique [0002] In recent years, with the increasing use of antibacterial drugs, the problem of bacterial resistance has become increasingly serious, and the proportion of MRSA in skin infections has increased year by year. Clinically, vancomycin and teicoplanin are usually used to treat serious infections caused by MRSA. However, the rapid emergence of vancomycin-resistant strains makes it urgent to find new anti-MRSA antibacterial drugs. [0003] Oritavancin is a second-generation glycopeptide antibacterial drug developed on the basis of vancomycin. It is the first and only single-agent antibacterial drug approved by the FDA for the treatment of ABSSSIs. The approval of oritav...

Claims

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Application Information

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IPC IPC(8): C08G65/337A61P31/02A61P31/04A61P17/00
CPCC08G65/337A61P31/02A61P31/04A61P17/00C08G2650/04
Inventor 张安林邓泽平成佳
Owner 湖南华腾医药有限公司
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