METHODS AND COMPOSITIONS FOR TREATING FLAVIVIRUSES AND PESTIVIRUSES

• US 20130310336A1
• Filed: 11/13/2012
• Published: 11/21/2013
• Est. Priority Date: 05/26/2000
• 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, LACOLLA, Paolo
• Granted Patent: US 9,968,628 B2
• Time in Patent Office: Days
• US Class Current: 514/51
• 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 the group consisting of adenine, N⁶-alkylpurine, N⁶-acylpurine, N⁶-benzylpurine, N⁶-halopurine, N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkyl purine, N⁶-thioalkyl purine, N²-alkylpurine, 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-benzylpyrimidine, C⁵-halopyrimidine, C⁵-vinylpyrimidine, 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, and 6-chloropurine.

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

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

9. The method of claim 1, wherein R⁷ is chlorine.

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

11. 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:

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

phosphate;

monophosphate;

diphosphate;

triphosphate;

or a stabilized phosphate prodrug.

13. The method of claim 11, wherein R¹ and R² are each hydrogen.

14. The method of claim 11, wherein X is O.

15. The method of claim 11, wherein R⁶ is methyl.

16. The method of claim 11, wherein Base is a purine or pyrimidine base selected from the group consisting of adenine, N⁶-alkylpurine, N⁶-acylpurine, N⁶-benzylpurine, N⁶-halopurine, N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkyl purine, N⁶-thioalkyl purine, N²-alkylpurine, N²-alkyl-6-thiopurine, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil, 5-halouracil, 5-fluorouracil, C-alkylpyrimidine, C⁵-benzylpyrimidine, C⁵-halopyrimidine, C⁵-vinylpyrimidine, 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, and 6-chloropurine.

17. The method of claim 11, wherein Base is a purine or pyrimidine base selected from the group consisting of adenine, thymine, cytosine, uracil and guanine.

18. The method of claim 11, wherein Base is cytosine or uracil.

19. The method of claim 11, wherein R⁷ is chlorine.

20. The method of claim 11, wherein the flavivirus or pestivirus is selected from the group consisting of dengue hemorrhagic fever virus, yellow fever virus, shock syndrome and Japanese encephalitis virus.

21. 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:

22. The method of claim 21, wherein R¹ and R² are independently H;

phosphate;

monophosphate;

diphosphate;

triphosphate;

or a stabilized phosphate prodrug.

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

24. The method of claim 21, wherein X is O.

25. The method of claim 21, wherein R⁶ is methyl.

26. The method of claim 21, wherein Base is a purine or pyrimidine base selected from the group consisting of adenine, N⁶-alkylpurine, N⁶-acylpurine, N⁶-benzylpurine, N⁶-halopurine, N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkyl purine, N⁶-thioalkyl purine, N²-alkylpurine, 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-benzylpyrimidine, C⁵-halopyrimidine, C⁵-vinylpyrimidine, 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, and 6-chloropurine.

27. The method of claim 21, wherein Base is a purine or pyrimidine base selected from the group consisting of adenine, thymine, cytosine, uracil and guanine.

28. The method of claim 21, wherein Base is cytosine or uracil.

29. The method of claim 21, wherein R⁷ is chlorine.

30. The method of claim 21, wherein the flavivirus or pestivirus is selected from the group consisting of dengue hemorrhagic fever virus, yellow fever virus, shock syndrome and Japanese encephalitis virus.