Hepatitis C virus inhibitors

• US 20070099825A1
• Filed: 11/01/2006
• Published: 05/03/2007
• Est. Priority Date: 11/03/2005
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Campbell, Jeffrey, D'Andrea, Stanley, McPhee, Fiona, Scola, Paul, Zheng, Zhizhen, Good, Andrew
• Granted Patent: US 7,741,281 B2
• Time in Patent Office: Days
• US Class Current: 424/85.4
• 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 38/2013 IL-2
• CPC Class Codes: A61K 38/204 IL-6
• CPC Class Codes: A61K 38/208 IL-12
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07K 5/06139 with the first amino acid being heterocyclic
• CPC Class Codes: C07K 5/0804 and aliphatic

Abstract

Macrocyclic peptides are disclosed having the general formula:

• • wherein R′, R³, R^3′, R⁴, R⁶, X, Q, and W are described. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.

Claims

1. A compound of formula (I)

2. A compound of claim 1 wherein X is O.

3. A compound of claim 2 wherein R′

is other than quinoline or isoquinoline.

4. A compound of claim 1 wherein X is selected from S, SO, SO₂, OCH₂, CH₂O and NH.

11. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

12. The composition of claim 11 further comprising one or two additional compounds having anti-HCV activity.

13. The composition of claim 12 wherein at least one of the additional compounds is an interferon or ribavirin.

14. The composition of claim 13 wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.

15. The composition of claim 12 wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′

-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

16. The composition of claim 12 wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH.

17. A method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of the compound of claim 1.

18. The method of claim 17 wherein the method further comprises administering one or two additional compounds prior to, after, or simultaneously with the compound of claim 1.

19. The method of claim 18 wherein at least one of the additional compounds is an interferon or ribavirin.

20. The method of claim 19 wherein the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, lymphoblastiod interferon tau.

21. The method of claim 18 wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5′

-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

22. The method of claim 18 wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH.

5. A compound of formula (II)

6. A compound of claim 5 wherein X is O.

7. A compound of claim 6 wherein R′

is other than quinoline or isoquinoline.

8. A compound of claim 5 wherein R⁴ is C(O)—

OR⁵;

wherein R⁵ is C_1-9 alkyl.

9. A compound of claim 5 wherein Q is a C_5-7 saturated or unsaturated chain optionally containing one oxygen atom.

10. A compound of claim 5 wherein W is NH—

SO₂—

R²;

wherein R2 is unsubstituted C_3-7 cycloalkyl.