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Multi-arm pegylated adempas derivative and preparation

A technology of riociguat and its derivatives, which is applied in the application field of multi-arm PEGylated riociguat derivatives and its preparation and preparation, and preparation of anti-pulmonary hypertension drugs, which can solve the problems of limited loading and achieve the existence of The effect of increasing time, reducing toxic and side effects, and simple preparation process

Inactive Publication Date: 2018-11-30
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 linear PEG has only two terminal modification groups, so when it is connected 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 adempas derivative and preparation
  • Multi-arm pegylated adempas derivative and preparation
  • Multi-arm pegylated adempas derivative and preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] (1) Preparation of intermediate 4-arm-PEG24-SG-II

[0027] Dissolve 10mmol of 4-arm-PEG24-OH-I in 100ml of toluene, add 42mmol of glutaric anhydride and 5mmol of DMAP at room temperature, and then stir at 100°C for 12h. After the reaction was completed, the reaction system was cooled to 25°C. 45 mmol of DSC was added, and the reaction continued for 12 hours. After the reaction, the solvent was evaporated under reduced pressure, and the crude product was recrystallized to obtain 4-arm-PEG24-SG-II. Yield: 92%. The NMR data are as follows: 1 HNMR (400MHz, CDCl 3 )δ4.18(s,2H),3.59(s,48H),2.80(s,4H),2.65(s,2H),2.43(s,2H),2.01(s,2H).

[0028] (2) Preparation of 4arm-PEG24-riociguat (III)

[0029] Dissolve 10mmol of the intermediate 4-arm-PEG24-SG-II in 50ml of DMF, add 5mmol% triethylamine, and stir until completely dissolved. 40 mmol of riociguat and 0.1 mmol of silver oxide were added to the reaction system, and the reaction was carried out at 25° C. for 8 hours. TLC...

Embodiment 2

[0031] (1) Preparation of intermediate 4-arm-PEG124-SG-II

[0032] Dissolve 10mmol of 4-arm-PEG124-OH-I in 100ml of toluene, add 42mmol of glutaric anhydride and 5mmol of DMAP at room temperature, and then stir at 100°C for 12h. After the reaction was completed, the reaction system was cooled to 25°C. 45 mmol of DSC was added, and the reaction continued for 12 hours. After the reaction, the solvent was evaporated under reduced pressure, and the crude product was recrystallized to obtain 4-arm-PEG124-SG-II. Yield: 92%. The NMR data are as follows: 1 HNMR (400MHz, CDCl 3 )δ4.18(s,2H),3.59(s,48H),2.80(s,4H),2.65(s,2H),2.43(s,2H),2.01(s,2H).

[0033] (2) Preparation of 4arm-PEG124-riociguat (III)

[0034]Dissolve 10mmol intermediate 4-arm-PEG124-SG-II in 50ml toluene, add 5mmol% pyridine, and stir until completely dissolved. 40 mmol of riociguat and 0.2 mmol of silver oxide were added to the reaction system, and the reaction was carried out at 35° C. for 12 hours. After TLC...

Embodiment 3

[0036] (1) Preparation of intermediate 4-arm-PEG240-SG-II

[0037] Dissolve 10mmol of 4-arm-PEG240-OH-I in 100ml of toluene, add 42mmol of glutaric anhydride and 5mmol of DMAP at room temperature, and then stir at 100°C for 12h. After the reaction was completed, the reaction system was cooled to 25°C. 45 mmol of DSC was added, and the reaction continued for 12 hours. After the reaction, the solvent was evaporated under reduced pressure, and the crude product was recrystallized to obtain 4-arm-PEG240-SG-II. Yield: 86%. The NMR data are as follows: 1 HNMR (400MHz, CDCl 3 )δ4.18(s,2H),3.59(s,48H),2.80(s,4H),2.65(s,2H),2.43(s,2H),2.01(s,2H).

[0038] (2) Preparation of 4arm-PEG240-riociguat (III)

[0039] Dissolve 10mmol of intermediate 4-arm-PEG240-SG-II in 50ml of acetonitrile, add 4mmol% potassium carbonate, and stir until completely dissolved. 40 mmol of riociguat and 0.4 mmol of silver oxide were added to the reaction system, and the reaction was carried out at 25° C. f...

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Abstract

The invention discloses a multi-arm pegylated adempas derivative and preparation. By connecting the adempas on the multi-PEG through a chemical reaction , the solubility of the drugh is improved, theabsorption rate of the drug is greatly improved and the bioavailability of the drug is obviously improved. At the same time, the multi-arm pegylated adempas is simple in preparation process, low in cost and suitable for commercialized production.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a multi-armed PEGylated riociguat derivative, its preparation, its preparation method and its application in the preparation of anti-pulmonary hypertension drugs. Background technique [0002] Pulmonary arterial hypertension (PAH) is a common clinical disease with complex etiology and can be caused by a variety of heart, lung or pulmonary vascular diseases. When it occurs, pulmonary artery pressure increases, resulting in vascular remodeling, increased right heart load and heart failure. In 1973, the World Health Organization (WHO) divided PAH into two categories: primary and secondary. After discussions and revisions at several meetings, PAH was still divided into 5 categories at the 5th World Forum on Pulmonary Hypertension held in 2013: ① idiopathic and hereditary PAH. ② PAH associated with left heart disease. ③Respiratory system disease or hypoxia-related PAH. ④ ch...

Claims

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Application Information

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IPC IPC(8): C08G65/337A61K31/506A61P11/00A61P9/12A61K47/60
CPCC08G65/337A61K31/506A61K47/60A61P9/12A61P11/00C08G2650/04
Inventor 张安林邓泽平成佳
Owner 湖南华腾制药有限公司
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