Nucleoside compounds for treating viral infections

• US 7,244,713 B2
• Filed: 10/21/2004
• Issued: 07/17/2007
• Est. Priority Date: 10/27/2003
• Status: Expired due to Fees

• Current Assignee: Smithkline Beecham Corporation (GSK plc)
• Original Assignee: Genelabs Technologies, Inc. (GSK plc)
• Inventors: Roberts, Christopher D., Dyatkina, Natalia B., Keicher, Jesse D.
• Primary Examiner(s): CRANE, LAWRENCE E
• Application Number:
  US10/971,477
• Publication Number:
  US 20050215511A1
• Time in Patent Office: 999 Days
• Field of Search: 514/43, 536/26.23, 536/26.26, 536/26.7, 536/27.2
• US Class Current: 514/43
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07H 19/14 Pyrrolo-pyrimidine radicals

Abstract

Disclosed are compounds, compositions and methods for treating viral infections caused by a flaviviridae family virus, such as hepatitis C virus. Such compounds are represented by Formula I as follows:

wherein, T, Y, W, W¹ and W² are as defined herein.

Claims

1. A compound of Formula I:

2. The compound according to claim 1, wherein W is H.

3. The compound according to claim 1, wherein W¹ is H.

4. The compound according to claim 1, wherein W² is H.

5. The compound according to claim 1, wherein W and W¹ are H.

6. The compound according to claim 1, wherein W and W² are H.

7. The compound according to claim 1, wherein W¹ and W² are H.

8. The compound according to claim 1, wherein W, W¹ and W² are H.

9. The compound of claim 1, wherein W¹ and W² are hydrogen and W is represented by the formula:

10. The compound of claim 1, wherein W and W² are hydrogen and W¹is represented by the formula:

11. A compound according to any one of claims 1 and 2 to 10 wherein T is —

C≡

C—

R and R is selected from the group consisting of tri(C₁-C₄)alkylsilyl, —

C(O)NR¹R², alkoxyalkyl, heteroaryl, substituted heteroaryl, phenyl and phenyl substituted with 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, aminoacyl, amidino, amino, substituted amino, carboxyl, carboxyl ester, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, guanidino, halo, heteroaryl, substituted heteroaryl, hydrazino, hydroxyl, nitro, thiol, and —

S(O)_mR³;

where R¹ and R² are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl provided that only one of R¹ and R² is amino or substituted amino, and further wherein R¹ and R², together with the nitrogen atom pendant thereto, form a heterocyclyl or substituted heterocyclyl;

R³ is selected from the group consisting of alkyl, substituted alkyl, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl; and

m is an integer equal to 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 11 wherein R is selected from the group consisting of —

C(O)NH₂, —

Si(CH₃)₃, pyrid-2-yl, 4-methoxyphenyl, and —

CH(OCH₂CH₃)₂.

13. A compound according to any one of claims 1 and 2 to 10 wherein T is —

C(═

O)H.

14. A compound according to any one of claims 1 and 2 to 10 wherein T is —

CH═

NNHR¹⁵ where R¹⁵ is independently selected from the group consisting of hydrogen and alkyl.

15. A compound according to any one of claims 1 and 2 to 10 wherein T is —

CH═

N(OR¹⁵) where R¹⁵ is independently selected from the group consisting of hydrogen and alkyl.

16. A compound according to any one of claims 1 and 2 to 10 wherein T is —

CH(OR¹⁶)₂ where R¹⁶ is independently (C₃-C₆)alkyl.

17. A compound according to any one of claims 1 and 2 to 10 wherein T is —

B(OR¹⁵)₂, where R¹⁵ is independently selected from the group consisting of hydrogen and alkyl.

32. A pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of any one of claims 1, or 2 to 10, or 18 to 26, or 27 to 31.

33. A method for treating a viral infection in a mammal in need thereof mediated at least in part by hepatitis C virus which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a pharmaceutical composition according to claim 32.

18. A compound selected from the group consisting of:

7-(2′

-methyl-β

-D-ribofuranosyl)-4-amino-5-(2′

-trimethylsilylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methy-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-2-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-4-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(2-(4-methoxyphenyl)-ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(2-carboxamidoethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-[(3,3-diethoxy)proparg-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-[(N,N-dimethyl-2-carboxamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-[(N-amino-2-carboxamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(2′

-trimethylsilylethyl-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-2-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-4-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(2-(4-methoxyphenyl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(2-carboxamidoethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-[(3,3-diethoxy)proparg-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-[2-(N,N -dimethylcarboxamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-[2-(N-aminocarboxamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(2′

-trimethylsilylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-2-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-4-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(2-(4-methoxyphenyl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(2-carboxamidoethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-[(3,3-diethoxy)proparg-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-[(N,N-dimethyl-2-carboxamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-[(N-amino-2-carboxamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(2′

-trimethylsilylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-2-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-4-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(2-(4-methoxyphenyl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(2-carboxamidoethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-[(3,3-diethoxy)proparg-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-[(N,N-dimethylcarboxylamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine; and

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-[(N-aminocarboxylamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-D-ribofuranosyl)-4-amino-5-(2-carboxyethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(2-carboxyethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(2-carboxyethyn-1-yl)-pyrrolo[2,3-d]pyrimidine; and

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(2-carboxyethyn-1-yl) -pyrrolo[2,3]-dipyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-[(ethyl2-carboxyl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-[(methyl2-carboxyl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-[(ethyl2-carboxyl)ethyn-1yl]-pyrrolo[2,3]-dipyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-[(methyl2-carboxyl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-[(ethyl2-carboxyl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-[(methyl2-carboxyl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-[(ethyl2-carboxyl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-[(methyl2-carboxyl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(2-phenylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(2-(4-fluorophenyl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(2-(4-methylphenyl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(2-phenylethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(2-(4-fluorophenyl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(2-(4-methylphenyl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(2-phenylethyn-1-yl) -pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(2-(4-fluorophenyl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(2-(4-methylphenyl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(2-(4-fluorophenyl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine; and

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(2-(4-methylphenyl)ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(ethen-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(2-cis-methoxy-ethen-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-monophospho-β

-D-ribofuranosyl)-4-amino-5-(ethen-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-monophospho-β

-D-ribofuranosyl)-4-amino-5-(2-cis-methoxy-ethen-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(ethen-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(2-cis-methoxy-ethen-1-yl) -pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(ethen-1-yl)-pyrrolo[2,3-d]dipyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(2-cis-methoxy-ethen-1-yl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(formyl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(formyl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(formyl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(formyl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-methyl-β

-D-ribofuranosyl)-4-amino-5-(hydrazono)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(hydrazono)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(hydrazono)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(hydrazono)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(carbaldehyde oxime)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(carbaldehyde oxime)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(carbaldehyde oxime)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(carbaldehyde oxime)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(diisopropoxymethyl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(diisopropoxymethyl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(diisopropoxymethyl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(diisopropoxymethyl)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(boronic acid)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-phospho-β

-D-ribofuranosyl)-4-amino-5-(boronic acid)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-diphospho-β

-D-ribofuranosyl)-4-amino-5-(boronic acid)-pyrrolo[2,3-d]pyrimidine;

7-(2′

-C-methyl-5′

-triphospho-β

-D-ribofuranosyl)-4-amino-5-(boronic acid)-pyrrolo[2,3-d]pyrimidine;

and pharmaceutically acceptable salts or partial salts thereof.

19. 7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-[2-(trimethylsilyl)-ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.

20. 7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-[(2-pyrid-2-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.

21. 7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-[2-(pyrid-4-yl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.

22. 7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-[2-(4-methoxyphenyl)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.

23. 7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(2-carboxamido ethyn-1-yl)-pyrrolo[2,3-d]pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.

24. 7 (2′

-C-methyl β

-D-ribofuranosyl)-4-amino-5-[(3,3diethoxy)proparg-1-yl]-pyrrolo[2,3-d]pyrimidine.

25. 7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-[(N,N-dimethyl-2-carboxylamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.

26. 7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-[(N-amino-2-carboxylamido)ethyn-1-yl]-pyrrolo[2,3-d]pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.

27. 7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(formyl)-pyrrolo[2,3-d]pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.

28. 7-(2′

-methyl-β

-D-ribofuranosyl)-4-amino-5-(hydrazono)-pyrrolo[2,3-d]pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.

29. 7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(carbaldehyde oxime)-pyrrolo[2,3-d]pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.

30. 7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(diisopropoxymethyl)-pyrrolo[2,3-d]pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.

31. 7-(2′

-C-methyl-β

-D-ribofuranosyl)-4-amino-5-(boronic acid)-pyrrolo[2,3-d]pyrimidine or a pharmaceutically acceptable salt or partial salt thereof.