Isomorphs of remdesivir and methods for synthesis of same

a technology of isomorphs and remdesivir, which is applied in the field of new isomorphs of 2ethylbutyl (), can solve the problems of viral infections caused by, arenaviridae, coronaviridae, filoviridae, etc., and achieve the effect of improving the aqueous solubility

Inactive Publication Date: 2021-07-29
ANZALP PHARMASOLUTIONS PVT LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The treatment of viral infections caused by Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, and / or Paramyxoviridae presents challenges due to a lack of vaccine or post-exposure treatment modality for preventing or managing infections caused by viruses from these families.
This results in the termination of RNA transcription and decreases viral RNA production in the body.
Remdesivir, however, is relatively insoluble in water and chemically unstable in aqueous media.
Such solubilizers, however, may have certain undesirable effects described in Stella, et. al.
For example, a formulation including polysorbate 80 may have potential hemodynamic effects, tubing limitations, extractables and leachables from tubing, limitations on stoppers, potential for precipitation upon dilution, or issues with adaptability for pediatric use.

Method used

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  • Isomorphs of remdesivir and methods for synthesis of same
  • Isomorphs of remdesivir and methods for synthesis of same
  • Isomorphs of remdesivir and methods for synthesis of same

Examples

Experimental program
Comparison scheme
Effect test

example 1

on of 2-ethylbutyl (chloro(phenoxy)phosphoryl)-L-alaninate

[0082]2-ethylbutyl (chloro(phenoxy)phosphoryl)-L-alaninate was prepared by the process reported in US′360. Accordingly, Phenyl dichlorophosphate was 20 reacted with 2-ethylbutyl alanine ester in presence of trimethylamine and methylene dichloride solvent to obtain 2-ethylbutyl (chloro(phenoxy)phosphoryl)-L-alaninate.

example 2

on of (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy) methyl) dihydrofuran-2(3H)-one

[0083](3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one was prepared by the process reported in US′360. Accordingly, (3R,4R,5R)-3,4-bis (benzyloxy)-5-((benzyloxy)methyl) tetrahydrofuran 2-ol was reacted with acetic anhydride in DMSO to obtain (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one.

example 3

on of (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-carbonitrile

[0084]To the compound of example 2 (50 gm) was charged MDC and the reaction mass was cooled to −75±5° C. followed by addition of trifluoromethane sulfonic acid (15 ml) at same temperature, stirred to get the thick mass. To the mass was added TMSOTf (12.5 ml), stirred at same temperature, added TMSCN (50 ml), stirred reaction mass for 2 hrs. After completion of reaction, was added TEA (40 ml) at −75±5° C., raised the temperature to 30±5° C., charged NaHCO3 (50 gm), water (300 ml) and allowed to settle the mass at room temperature. The reaction mass was extracted with MDC, washed the organic layer with 10% NaCl solution, distilled the organic layer under vacuum below 45° C., cooled, dried to obtain the product. Yield: 60-65 gm; HPLC purity: NLT 98.0%

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PUM

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Abstract

A new isoform of 2-ethylbutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate (Remdesivir) having increased water solubility is disclosed, along with methods for making the same. Also disclosed are solid and liquid pharmaceutical compositions suitable for treating viral infections such as Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, or Paramyxoviridae viral infections which contain an effective amount of Remdesivir prepared according to the inventive method and the use of those compositions for treating such viral infections.

Description

FIELD OF INVENTION[0001]The present invention relates to a new isomorph of 2-ethylbutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate, which is more commonly known as Remdesivir, and methods of making the same. The present invention also relates to solid and liquid pharmaceutical compositions suitable for treating viral infections such as Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, or Paramyxoviridae viral infections which contain an effective amount of the new isomorph of Remdesivir and the use of those compositions for treating such viral infections.BACKGROUND OF THE INVENTION[0002]The treatment of viral infections caused by Arenaviridae, Coronaviridae, Filoviridae, Flaviviridae, and / or Paramyxoviridae presents challenges due to a lack of vaccine or post-exposure treatment modality for preventing or managing infections caused by viruses from these families. In some cases,...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/706A61K9/00
CPCA61K31/706A61K9/0019C07F9/26C07F9/6561Y02A50/30
Inventor TRIPATHI, VINAY SHANKARPATEL, AKSHAY NIKHIL
Owner ANZALP PHARMASOLUTIONS PVT LTD
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