Macrocyclic inhibitors of hepatitis C virus
Inhibitors of HCV replication of formula (I) and the N-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond; X is N, CH and where X bears a double bond it is C; R 1 is —OR 7 , —NH—SO 2 R 8 ; R 2 is hydrogen, and where X is C or CH, R 2 may also be C 1-6 alkyl; R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, C 3-7 cycloalkyl; R 4 is aryl or Het; n is 3, 4, 5, or 6; R 5 is halo, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, phenyl, or Het; R 6 is C 1-6 alkoxy, or dimethylamino; R 7 is hydrogen; aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; R 8 is aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.
1. A method of treating a hepatitis C virus (HCV) infection in a patient comprising administering to the patient a compound having the formula
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the compound is a sodium salt of
3. The method of claim 1 , wherein the patient is infected with HCV genotype 1.
4. The method of claim 3 , wherein the compound is administered with another anti-HCV agent.
5. The method of claim 4 , wherein the other anti-HCV agent is an HCV polymerase inhibitor, an HCV protease inhibitor, an inhibitor of another target in the HCV life cycle, and immunomodulatory agent, an antiviral agent, or a combination thereof.
6. The method of claim 4 , wherein the other anti-HCV agent is an HCV polymerase inhibitor, an HCV protease inhibitor, an antiviral agent, or a combination thereof.
7. The method of claim 4 , wherein the other anti-HCV agent is an HCV polymerase inhibitor.
8. The method of claim 4 , wherein the other anti-HCV agent is an HCV protease inhibitor.
9. The method of claim 4 , wherein the other anti-HCV agent is an antiviral agent.
10. The method of claim 4 , wherein the other anti-HCV agent is ribavirin.
11. The method of claim 4 , wherein the other anti-HCV agent is pegylated interferon-α.
12. The method of claim 4 , wherein the other anti-HCV agent is ribavirin and pegylated interferon-α.
13. The method of claim 4 , wherein the compound is a sodium salt of
and the other anti-HCV agent is ribavirin and pegylated interferon-a.
14. The method of claim 4 , wherein the compound and the other anti-HCV agent are administered simultaneously.
15. The method of claim 4 , wherein the compound and the other anti-HCV agent are administered separately.
16. The method of claim 4 , wherein the compound and the other anti-HCV agent are administered sequentially.