Methods and compositions for treating flaviviruses and pestiviruses

• US 9,968,628 B2
• Filed: 11/13/2012
• Issued: 05/15/2018
• Est. Priority Date: 05/26/2000
• Status: Expired due to Fees

• 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, LaColla, Paolo
• Primary Examiner(s): McIntosh, III, Traviss C
• Application Number:
  US13/675,937
• Publication Number:
  US 20130310336A1
• Time in Patent Office: 2,009 Days
• Field of Search: None
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7064 containing condensed or non-condensed pyrimidines
• 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 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 19/073 with 2-deoxyribosyl as the saccharide radical
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/23 Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
• 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

A method and composition for treating a host infected with flavivirus or pestivirus comprising administering an effective flavivirus or pestivirus treatment amount of a described 1′, 2′ or 3′-modified nucleoside or a pharmaceutically acceptable salt or prodrug thereof, is provided.

Claims

1. A method for the treatment of a flavivirus or pestivirus infection in a host, comprising administering to a host infected with a flavivirus or a pestivirus an anti-virally effective amount of a compound of Formula XI:

2. The method of claim 1, wherein R¹ and R² are independently H;

phosphate;

monophosphate;

diphosphate;

triphosphate;

or a stabilized phosphate prodrug.

3. The method of claim 1, wherein R¹ and R² are each hydrogen.

4. The method of claim 1, wherein X is O.

5. The method of claim 1, wherein R⁶ is methyl.

6. The method of claim 1, wherein Base is a purine or pyrimidine base selected from adenine, N6-alkyl purine, N6-acyl purine, N6-benzylpurine, N6-halopurine, N6-vinylpurine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-thioalkyl purine, N2-alkyl purine, N2-alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil, 5-halouracil, 5-fluorouracil, C5-alkylpyrimidine, C5-benzyl pyrimidine, C5-halopyrimidine, C5-vinyl pyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl purine, C5-amidopyrimidine, C5-cyanopyrimidine, C5-nitropyrimidine, C5-aminopyrimidine, N2-alkyl purine, N2-alkyl-6-thiopurine, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, guanine, hypoxanthine, 2,6-diaminopurine, or 6-chloropurine.

7. The method of claim 1, wherein Base is a purine or pyrimidine base selected from adenine, thymine, cytosine, uracil or guanine.

8. The method of claim 1, wherein Base is cytosine or uracil.

9. The method of claim 1, wherein the flavivirus or pestivirus is selected from dengue hemorrhagic fever virus, yellow fever virus, shock syndrome or Japanese encephalitis virus.

10. A method for the treatment of a flavivirus or pestivirus infection in a host, comprising contacting a cell infected with a flavivirus or a pestivirus with an anti-virally effective amount of a compound of Formula XI:

11. The method of claim 10, wherein R¹ and R² are independently H;

phosphate;

monophosphate;

diphosphate;

triphosphate;

or a stabilized phosphate prodrug.

12. The method of claim 10, wherein R¹ and R² are each hydrogen.

13. The method of claim 10, wherein X is O.

14. The method of claim 10, wherein R⁶ is methyl.

15. The method of claim 10, wherein Base is a purine or pyrimidine base selected from adenine, N6-alkyl purine, N6-acyl purine, N6-benzyl purine, N6-halopurine, N6-vinyl purine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-thioalkyl purine, N2-alkyl purine, N2-alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil, 5-halouracil, 5-fluorouracil, C5-alkylpyrimidine, C5-benzyl pyrimidine, C5-halopyrimidine, C5-vinyl pyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl purine, C5-amidopyrimidine, C5-cyanopyrimidine, C5-nitropyrimidine, C5-aminopyrimidine, N2-alkylpurine, N2-alkyl-6-thiopurine, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, guanine, hypoxanthine, 2,6-diaminopurine, or 6-chloropurine.

16. The method of claim 10, wherein Base is a purine or pyrimidine base selected from adenine, thymine, cytosine, uracil or guanine.

17. The method of claim 10, wherein Base is cytosine or uracil.

18. The method of claim 10, wherein the flavivirus or pestivirus is selected from dengue hemorrhagic fever virus, yellow fever virus, shock syndrome or Japanese encephalitis virus.

19. A method for the treatment of a flavivirus or pestivirus infection in a host, comprising contacting a flavivirus or pestivirus polymerase with an anti-virally effective amount of a compound of Formula XI:

20. The method of claim 19, wherein R¹ and R² are independently H;

phosphate;

monophosphate;

diphosphate;

triphosphate;

or a stabilized phosphate prodrug.

21. The method of claim 19, wherein R¹ is triphosphate and R² is hydrogen.

22. The method of claim 19, wherein X is O.

23. The method of claim 19, wherein R⁶ is methyl.

24. The method of claim 19, wherein Base is a purine or pyrimidine base selected from adenine, N6-alkyl purine, N6-acyl purine, N6-benzyl purine, N6-halopurine, N6-vinyl purine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-thioalkyl purine, N2-alkyl purine, N2-alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil 5-halouracil, 5-fluorouracil C5-alkyl pyrimidine, C5-benzylpyrimidine, C5-halopyrimidine, C5-vinyl pyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl purine, C5-amidopyrimidine, C5-cyanopyrimidine, C5-nitropyrimidine, C5-aminopyrimidine, N2-alkylpurine, N2-alkyl-6-thiopurine, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, guanine, hypoxanthine, 2,6-diaminopurine, or 6-chloropurine.

25. The method of claim 19, wherein Base is a purine or pyrimidine base selected from adenine, thymine, cytosine, uracil or guanine.

26. The method of claim 19, wherein Base is cytosine or uracil.

27. The method of claim 19, wherein the flavivirus or pestivirus is selected from dengue hemorrhagic fever virus, yellow fever virus, shock syndrome or Japanese encephalitis virus.