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

A technology for synthesizing ilulustat and derivatives, which is applied in the field of multi-arm PEGylated ilulustat derivatives and their preparation, can solve problems such as limited loading, achieve good water solubility, improve curative effect, and increase the existence time. Effect

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

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preparation of 4arm-PEG24-Ebrustat (III)

[0026] Dissolve 10mmol of 4-Arm-PEG24-GA-I in 50ml of N,N-dimethylformamide, add 10mmol of EDCI and 10mmol of NHS, and stir at 25°C for 2h. 2 mmol of 4arm-PEG24-NH2 was added to the reaction, and the reaction was carried out at 30°C for 12 hours. After the complete reaction of ebrustat was detected by TLC tracking, 9.4 mmol of 4arm-PEG24-elukastat (I) was obtained by recrystallization and column chromatography. Yield: 94%. NMR data are as follows: HNMR(CDCl3)δ6.72-6.88(m,3H),5.80(d,1H),4.88(d,1H),4.24-4.21(m,6H),4.14-4.21(m,1H) ,3.63(s, 96H),2.72-2.83(m,4H),2.53-2.70(m,6H),2.07(t,2H),2.04(s,2H),1.85-1.74(m,4H),1.44 -1.57(m,2H),1.14-1.31(m,8H),0.87(t,3H).

Embodiment 2

[0028] Preparation of 4arm-PEG124-Ebrustat (III)

[0029] Dissolve 10mmol of 4-Arm-PEG124-GA-I in 50ml of N,N-dimethylformamide, add 10mmol of DCC and 6mmol of DMAP, and stir at 25°C for 2h. 2 mmol of 4arm-PEG124-NH2 was added to the reaction, and the reaction was carried out at 25°C for 16 hours. After the completion of the reaction of ebrustat by TLC tracking detection, the pure 4arm-PEG124-elukastat (III) was obtained by recrystallization and chromatography column purification. Yield: 90%. NMR data are as follows: HNMR(CDCl3)δ6.72-6.88(m, 3H), 5.80(d,1H), 4.88(d,1H), 4.24-4.21(m,6H), 4.14-4.21(m,1H) ,3.63(s, 496H),2.72-2.83(m,4H),2.53-2.70(m,6H),2.07(t,2H),2.04(s,2H),1.85-1.74(m,4H),1.44 -1.57(m,2H),1.14-1.31(m,8H),0.87(t,3H).

Embodiment 3

[0031] Preparation of 4arm-PEG240-Ebrustat (III)

[0032] Dissolve 10mmol of 4-Arm-PEG240-GA-I in 50ml of dichloromethane, add 10mmol of HOBT and 8mmol of DIC, and stir at 25°C for 2h. 2 mmol of 4arm-PEG240-NH2 was added to the reaction, and the reaction was carried out at 30°C for 20 hours. After the completion of the reaction of ebrustat through TLC tracking detection, the pure 4arm-PEG240-elukastat (III) was obtained by recrystallization and chromatographic column purification. Yield: 86.9%. NMR data are as follows: HNMR(CDCl3)δ6.72-6.88(m, 3H), 5.80(d,1H), 4.88(d,1H), 4.24-4.21(m,6H), 4.14-4.21(m,1H) ,3.63(s, 960H),2.72-2.83(m,4H),2.53-2.70(m,6H),2.07(t,2H),2.04(s,2H),1.85-1.74(m,4H),1.44 -1.57(m,2H),1.14-1.31(m,8H),0.87(t,3H).

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Abstract

The invention relates to a multi-arm PEGylated (Polyethylene Glycolylated) eliglustat derivative and preparation thereof. By utilizing the characteristic that the multi-arm PEG is non-toxic and easy to bind, four-arm PEG, six-arm PEG and multi-arm PEG are all connected with eliglustat. The multi-arm PEG supported eliglustat prodrug has excellent water solubility. The most important characteristicsare that one multi-arm PEG chain can be connected with multiple eliglustat 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, the stable blood concentration is maintained, the toxic and side effects are greatly decreased; therefore, the curative effects are improved. ThePEGylated eliglustat prepared by the method disclosed by the invention is high in yield, simple in after-treatment process and extremely high in purity.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a multi-armed PEGylated ebrustat derivative and a preparation method thereof. Background technique [0002] Eliglustat is a glucosylceramide synthetase inhibitor developed by Genzyme, a subsidiary of Sanofi. The U.S. Food and Drug Administration granted the drug orphan drug status on September 17, 2008, and officially approved its marketing (trade name Cerdelga) on August 19, 2014, as the only treatment for adult patients with specific type I Gaucher disease. First-line oral therapy. Gaucher disease is a glucocerebrosidosis caused by autosomal recessive inheritance. It is mainly due to the mutation of the structural gene encoding GIUcocerebrosidase, which leads to the lack of the enzyme, resulting in the loss of glucocerebrosidase in macrophages. Glucocerebroside cannot be further hydrolyzed and accumulates in lysosomes, causing cells to lose their original functions and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60A61K31/4025A61P3/00C08G65/333
CPCA61K47/60A61K31/4025A61P3/00C08G65/33327C08G65/33396
Inventor 张安林邓泽平成佳
Owner 湖南华腾制药有限公司
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