Purine nucleoside analogues for treating Flaviviridae including hepatitis C

a technology of flaviviridae and purine nucleosides, which is applied in the field of pharmaceutical chemistry, can solve the problems of significant economic losses worldwide, considerable pestivirus exposure, and the inability to predict the mutations that will be induced in the viral genome by a given drug

Inactive Publication Date: 2005-04-07
THE CENT NAT DEL LA RECH SCIQUE +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

In all embodiments, optional substituents are selected from the group consisting of one or more halogen, amino, hydroxy, carboxy and alkoxy groups or atoms, among others. It is to be understood that all stereoisomeric and tautomeric forms of the compounds shown are included herein.
The active compounds of the present invention can be administered in combination, alternation or sequential steps with another anti-HCV agent. In combination therapy, effective dosages of two or more agents are administered together, whereas in alternation or sequential-step therapy, an effective dosage o

Problems solved by technology

Pestivirus infections of domesticated livestock (cattle, pigs and sheep) cause significant economic losses worldwide.
However, serological surveys indicate considerable pestivirus exposure in humans.
One cannot predict, however, what mutations will be induced in the viral genome by a given drug, whether the mutation

Method used

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  • Purine nucleoside analogues for treating Flaviviridae including hepatitis C
  • Purine nucleoside analogues for treating Flaviviridae including hepatitis C
  • Purine nucleoside analogues for treating Flaviviridae including hepatitis C

Examples

Experimental program
Comparison scheme
Effect test

example 1

1′-C-Branched ribofuranosyl, -sulfonyl or cyclopentanyl-2-azapurine, Optionally Substituted

The title compound is prepared according to Schemes 1, 2, or 7. In a similar manner but using the appropriate sugar or cyclopentane ring and optionally substituted 2-azapurine base, the following nucleosides of Formulae (I) or (II) may be prepared:

wherein: base may be any of the Formulae (A)-(G) as described herein where R in each instance may exist in mono-, di- or triphosphate form.

Alternatively, the Dimroth rearrangement may be used for making 2-azapurines from the corresponding purine base. In this reaction, an N-alkylated or N-arylated imino heterocycle undergoes rearrangement to its corresponding alkylamino or arylamino heterocycle.

example 1a

1′-C-hydroxymethyl-2-azaadenosine

Step 1: 2-azaadenine, NaH, ACN, rt, 24 hrs; Step 2: MeONa / MeOH

The starting material 2-azaadenine may be prepared starting from malonitrile by the synthesis taught by D. W. Wooley, Journal of Biological Chemistry, (1951), 189:401.

example 2

2′-C-Branched ribofuranosyl, -sulfonyl or cyclopentanyl-2-azapurine, Optionally Substituted

The title compound is prepared according to Schemes 3, 4, or through protection of appropriately selected substituent groups in Schemes 7 or 8. In a similar manner but using the appropriate sugar or cyclopentane ring and optionally substituted 2-azapurine base, the following nucleosides of Formulae (I) or (II) may be prepared:

wherein: base may be any of the Formulae (A)-(G) as described herein where R in each instance may exist in mono-, di- or triphosphate form.

Alternatively, the Dimroth rearrangement may be used for making 2-azapurines from the corresponding purine base. In this reaction, an N-alkylated or N-arylated imino heterocycle undergoes rearrangement to its corresponding alkylamino or arylamino heterocycle.

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Abstract

This invention is directed to a method for treating a host, especially a human, infected with hepatitis C, flavivirus and/or pestivirus, comprising administering to that host an effective amount of an anti-HCV biologically active pentofuranonucleoside where the pentofuranonucleoside base is an optionally substituted 2-azapurine. The optionally substituted pentofuranonucleoside, or a salt or prodrug thereof, may be administered alone or in combination with one or more optionally substituted pentofuranonucleosides or other anti-viral agents.

Description

FIELD OF THE INVENTION This invention is in the area of pharmaceutical chemistry, and, in particular, in the area of purine nucleosides, their syntheses, and their use as anti-Flaviviridae agents in the treatment of hosts infected with Flaviviridae and especially with Hepatitis C. BACKGROUND OF THE INVENTION Flaviviridae Viruses The Flaviviridae family of viruses comprises at least three distinct genera: pestiviruses, which cause disease in cattle and pigs; flaviviruses, which are the primary cause of diseases such as dengue fever and yellow fever; and hepaciviruses such as hepatitis C (HCV). The flavivirus genus includes more than 68 members separated into groups on the basis of serological relatedness (Calisher et al., J. Gen. Virol, 1993, 70, 37-43). Clinical symptoms vary and include fever, encephalitis and hemorrhagic fever (Fields Virology, Editors: Fields, B. N., Knipe, D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia, Pa., 1996, Chapter 31, 931-959). Fl...

Claims

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Application Information

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IPC IPC(8): A61K31/00A61K31/706A61P31/14C07H19/044C07H19/052C07H19/056
CPCA61K31/00A61K31/706C07H19/044C07H19/04C07H19/056A61K45/06C07H19/052C07H19/23A61P31/14A61P43/00
Inventor STORER, RICHARDGOSSELIN, GILLESDUKHAN, DAVIDLEROY, FREDERIC
Owner THE CENT NAT DEL LA RECH SCIQUE
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