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 sodium salt of
2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a sodium salt of
3. A combination comprising:
(a) a sodium salt of
and
(b) another anti-HCV compound.
4. The combination according to claim 3 , wherein the other anti-HCV compound is an HCV polymerase inhibitor, an HCV protease inhibitor, an inhibitor of another target in the HCV life cycle, an immunomodulatory agent, an antiviral agent, or combinations thereof.
5. The combination according to claim 4 , wherein the other anti-HCV compound is an HCV polymerase inhibitor.
6. The combination according to claim 4 , for simultaneous, separate, or sequential use in the treatment of HCV infections.
7. The combination according to claim 5 , for simultaneous, separate, or sequential use in the treatment of HCV infections.
8. The combination according to claim 3 comprising the sodium salt of
ribavirin, and pegylated interferon-α.
9. A method of inhibiting HCV replication comprising administering to a patient in need thereof, a sodium salt of
10. A method of inhibiting HCV replication comprising administering to a patient in need thereof, a sodium salt of
in combination with another compound.
11. The method according to claim 10 , wherein the other compound is another anti-HCV compound.
12. The method according to claim 11 , wherein the other anti-HCV compound is an HCV polymerase inhibitor, an HCV protease inhibitor, an inhibitor of another target in the HCV life cycle, an immunomodulatory agent, an antiviral agent, or combinations thereof.
13. The method according to claim 11 , wherein the other anti-HCV compound is an HCV polymerase inhibitor.
14. The method according to claim 12 , wherein the combination is administered simultaneously, separately, or sequentially in the treatment of the HCV replication inhibition.
15. The method according to claim 13 , wherein the combination is administered simultaneously, separately, or sequentially in the treatment of the HCV replication inhibition.
16. The method according to claim 10 , wherein the combination comprises the sodium salt of
ribavirin; and pegylated interferon-α.