2′-branched nucleosides and Flaviviridae mutation

• US 7,824,851 B2
• Filed: 11/17/2003
• Issued: 11/02/2010
• Est. Priority Date: 11/15/2002
• Status: Active Grant

• Current Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Original Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.), Universita' Degli Studi Di Bari (Repubblica Italiana)
• Inventors: Sommadossi, Jean-Pierre, Standring, David, Qu, Lin, LaColla, Paolo, Bichko, Vadim
• Primary Examiner(s): Lucas; Zachariah
• Assistant Examiner(s): HUMPHREY, LOUISE WANG ZHIYING
• Application Number:
  US10/715,729
• Publication Number:
  US 20050031588A1
• Time in Patent Office: 2,542 Days
• Field of Search: None
• US Class Current: 435/5
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/215 IFN-beta
• CPC Class Codes: A61K 38/217 IFN-gamma
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C12N 2770/24022 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 2770/24122 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 2770/24222 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12Q 1/04 Determining presence or kind of microorganism; Use of selective media for testing antibiotics or bacteriocides; Compositions containing a chemical indicator therefor C12Q1/6897 takes precedence
• CPC Class Codes: C12Q 1/18 : Testing for antimicrobial activity of a material
• CPC Class Codes: C12Q 1/701 : Specific hybridization probes
• CPC Class Codes: C12Q 1/707 : non-A, non-B Hepatitis, excluding hepatitis D
• CPC Class Codes: C12Q 2600/156 : Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 : Expression markers
• CPC Class Codes: G01N 2333/186 : Hepatitis C; Hepatitis NANB
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention discloses a method for the treatment of Flaviviridae infection that includes the administration of a 2′-branched nucleoside, or a pharmaceutically acceptable prodrug and/or salt thereof, to a human in need of therapy in combination or alternation with a drug that directly or indirectly induces a mutation in the viral genome at a location other than a mutation of a nucleotide that results in a change from seine to a different amino acid in the highly conserved consensus sequence, XRXSGXXXT (Sequence ID No. 63), of domain B of the RNA polymerase region, or is associated with such a mutation. The invention also includes a method to detect a mutant strain of Flaviviridae and a method for its treatment.

Claims

1. A method for treating a hepatitis C virus infection in a host, comprising (a) administering an effective amount of a 2′

-branched nucleoside of the formula;

2. The method of claim 1, wherein the 2′

-branched nucleoside is β

-D-2′

-CH₃-riboC, or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof.

3. The method of claim 1, wherein the 2′

-branched nucleoside is a 3′

-amino acid prodrug of β

-D-2′

-CH₃-riboC.

4. The method of claim 3, wherein the 2′

-branched nucleoside is a 3′

-L-valinyl prodrug of β

-D-2′

-CH₃-riboC.

5. The method of claim 1, wherein R¹ is a mono, di or triphosphate.

6. The method of claim 1, wherein R² is an amino acid ester.

7. The method of claim 1, wherein R⁴ is methyl.

8. The method of claim 1, wherein R² is an ester of a naturally occurring or synthetic α

, β

, γ

, or δ

amino acid.

9. The method of claim 1, wherein R² is an ester of valine.

10. The method of claim 1, wherein

R⁴ methyl;

R² is acyl or an amino acid ester;

R³ is H; and

R¹ is H.

11. The method of claim 10, wherein R² is an amino acid ester.

12. The method of claim 10, wherein R² is an ester of valine.

13. The method of claim 1 wherein the host is human.

14. The method of claim 1, wherein the 2′

-branched nucleoside is in a pharmaceutically acceptable carrier or diluent.

15. The method of claim 1, wherein the drug in step (c) is interferon.

16. The method of claim 1, wherein identifying viral resistance in step (b) comprises assaying the blood of the host to test for seroconversion from wildtype to mutant hepatitis C virus.

17. The method of claim 1, wherein identifying viral resistance in step (b) comprises phenotypic analysis of viral plaque growth from a viral culture sample from the host.

18. The method of claim 17, wherein the phenotypic analysis of step (b) comprises

(i) obtaining a viral culture sample from the host;

(ii) culturing the sample and comparing the plaque growth between the sample and wild type virus; and

(iii) determining whether the plaque growth of the sample is smaller than the plaque growth of the wildtype virus.

19. The method of claim 1, wherein identifying viral resistance in step (b) comprises determination of the replication fitness of the virus.

20. The method of claim 19, wherein determination of the replication fitness of the virus in step (b) comprises

(i) obtaining a viral culture sample from the host;

(ii) determining the replication fitness of the sample virus; and

(iii) determining whether the replication fitness of the sample virus is less than the replication fitness of the wildtype virus.

21. The method of claim 1, wherein identifying viral resistance in step (b) comprises detecting the presence of cytidine at nucleotide 8443 of the RNA polymerase region of the hepatitis C virus.

22. The method of claim 1, wherein identifying viral resistance in step (b) comprises:

(i) contacting a sample containing a hepatitis C virus nucleic acid sequence with a detectable oligonucleotide probe having a sequence complementary to a codon that encodes a serine in the highly conserved consensus sequence, XRXSGXXXT, or SEQ ID NO;

63, of domain B of the RNA polymerase region of the hepatitis C virus;

(ii) allowing the probe to hybridize to the sequence; and

(iii) detecting the hybridization of the probe to the sequence.

26. The method of claim 1, wherein the compound according to the formula is administered.

23. A method of treating a hepatitis C virus infection in a host infected with a hepatitis C virus that contains a mutation at nucleotide 8443 (G to C) of the HCV genome or amino acid 282 Ser to Thr of the RNA polymerase region of HCV, comprising administering to the host infected with said virus an effective amount of one or more drugs that directly or indirectly induce a mutation in a hepatitis C virus at a location other than nucleotide 8443 (G to C) of the HCV genome or amino acid 282 Ser to Thr of the RNA polymerase region of HCV.

24. The method of claim 23, wherein the drug is interferon.

25. A method for treating a hepatitis C virus infection in a host, comprising (a) administering an effective amount of a 2′

-branched nucleoside of formula IV;

27. The method of claim 25, wherein the compound according to Formula IV is administered.