Purine monophosphate prodrugs for treatment of viral infections

A prodrug and chiral technology, applied in antiviral agents, pharmaceutical formulations, organic active ingredients, etc., can solve problems such as limiting the diversity of 6-substituted purine nucleoside triphosphates

Inactive Publication Date: 2014-03-26
RFS PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This conversion severely limits the diversity of 6-substituted purine nucleoside triphosphates that can be formed in vivo as potential antiviral agents

Method used

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  • Purine monophosphate prodrugs for treatment of viral infections
  • Purine monophosphate prodrugs for treatment of viral infections
  • Purine monophosphate prodrugs for treatment of viral infections

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0203]The preparation of the compound of formula A and B adopts (a) Rajagopalan, P.; Boudinot, F.D; Chu, C.K.; Tennant, B.C.; Baldwin, B.H.; .b)Recent Advances in Nucleosides:Chemistry and Chemotherapy:Chu,C.K.;Eds.Elsevier:2002.c)Frontiers in Nucleosides&Nucleic Acids,2004,Eds.R.F.Schinazi&D.C.Liotta,IHL Press,Tucker,GA,USA,pp : 319-37d) Handbook of Nucleoside Synthesis: Vorbruggen H. & Ruh-Pohlenz C. John Wiley & sons 2001) and using the general scheme 1-2 by first preparing nucleoside 1 to complete, the preparation of nucleoside 1 can be done by ordinary people in the art Technicians complete. Specifically, nucleoside 1 can be prepared by coupling sugar 2 with a protected silylated or free purine base in the presence of a Lewis acid such as TMSOTf. Deprotection of the 3' and 5' hydroxyls affords nucleoside 1.

[0204]

[0205] Scheme 1 Synthetic method of nucleoside 1. (The base is 2,6-diaminopurine or can be converted to 2,6-diaminopurine (such as 2-NH 2 , 6-Cl puri...

specific Embodiment

[0246] Specific compounds representative of the invention are prepared according to the following examples and reaction sequences; the examples and diagrams describing the reaction sequences are provided by way of illustration to aid in the understanding of the invention and should not be construed as limiting in any way the hereinafter appended The invention described in the claims. The present compounds can also be used as intermediates in subsequent examples to generate additional compounds of the invention. did not try Figure 1 Determine the yields obtained by optimizing any reaction. Those skilled in the art will know how to increase this yield through routine changes in reaction times, temperatures, solvents and / or reagents.

[0247] Anhydrous solvents were purchased from Aldrich Chemical Company, Inc. (Milwaukee). Reagents were purchased from commercial sources. Unless otherwise indicated, materials used in the examples were obtained from readily available commerci...

Embodiment 1

[0248] Example 1: Synthesis of 2,6-diamino 2'-C-methyl monophosphate prodrugs 8a and 8b

[0249]

[0250] (2R,3R,4R,5R)-5-((benzoyl)methyl)-2-(2,6-diamino-9H-purin-9-yl)-3-methyltetrahydrofuran-3,4 -Diyldiphenyl potassium ester 3

[0251] To (3R,4S,5R)-5-((benzoyl)methyl)-3-methyltetrahydrofuran-2,3,4-triyltriphenyl potassium ester 1 (2.9g, 5mmol) at -78°C To a stirred suspension of 2,6-diaminopurine 2 (830 mg, 5.5 mmol) in anhydrous acetonitrile was added DBU (2.3 mL, 15.0 mmol) followed by slow addition of TMSOTf (3.8 mL, 20.0 mmol). The reaction mixture was stirred at -78°C for 20 minutes and then warmed to 0°C. After stirring at 0 °C for 30 min, the reaction mixture was gradually heated to 65 °C and stirred overnight. The reaction mixture was washed with CH 2 Cl 2 (200mL) and dilute with saturated NaHCO 3 washing. The layers were separated and the resulting aqueous layer was washed with CH 2 Cl 2 (2x20 mL) extraction. The combined organic layers were washed wi...

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Abstract

The present invention is directed to compounds, compositions and methods for treating or preventing viral infections using nucleoside analog monophosphate prodrugs. More specifically, HCV, Norovirus, Saporovirus, Dengue virus, Chikungunya virus and Yellow fever in human patients or other animal hosts. The compounds are certain 2,6-diamino 2-C-methyl purine nucleoside monophosphate prodrugs and modified prodrug analogs, and pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof. In particular, the compounds show potent antiviral activity against HCV, Norovirus, Saporovirus, Dengue virus, Chikungunya virus and Yellow fever. This invention teaches how to modify the metabolic pathway of 2,6-diamino 2'-C-methyl purine and deliver nucleotide triphosphate(s) to polymerases at heretofore unobtainable therapeutically-relevant concentrations.

Description

technical field [0001] The present invention relates to compounds, methods and compositions for treating or preventing viral infections using nucleotide analogs. More specifically, the present invention describes 2,6-diamino 2'-C-methylpurine nucleoside monophosphate prodrugs and modified prodrug analogs, pharmaceutically acceptable salts or other derivatives thereof, and its role in viral infections, especially 1) Flaviviridae viruses including hepatitis C (HCV), West Nile virus, dengue virus, Chikungunya virus and yellow fever and 2) use in the treatment of calicivirus infections including Norovirus and Sapovirus. The present invention teaches how to modify the metabolic pathway of 2,6-diamino 2'-C-methylpurine and how to deliver nucleotide triphosphates to polymerases at heretofore unavailable therapeutically relevant concentrations. Background technique [0002] Nucleoside analogs as a class have a well-established regulatory history, with more than 10 currently a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/20C07H19/173C07H19/10C07D405/04C07D487/04A61K31/7076A61K31/7072A61K31/7028A61P31/12
CPCC07H19/207C07D473/16C07H19/213C07H19/20A61P31/12C07H19/16A61K31/7076A61K45/06C07F9/65586C07F9/65742
Inventor 雷蒙德·F·斯基那兹赵忠贤周龙胡张宏旺于戈·普拉代尔斯蒂文·J·科阿斯
Owner RFS PHARMA
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