Morpholinyl containing benzimidazoles as inhibitors of respiratory syncytial virus replication
View Patent ↗The present invention concerns morpholinyl containing benzimidazoles having inhibitory activity on the replication of the respiratory syncytial virus and having the formula a prodrug, N-oxide, addition salt, quaternary amine, metal complex or stereochemically isomeric form thereof wherein G is a direct bond or optionally substituted C 1-10 alkanediyl; R 1 is Ar 1 or a monocyclic or bicyclic heterocycle Q is R 7 , pyrrolidinyl substituted with R 7 , piperidinyl substituted with R 7 or homopiperidinyl substituted with R 7 ; one of R 2a and R 3a is selected from halo, optionally mono- or polysubstituted C 1-6 alkyl, optionally mono- or polysubstituted C 2-6 alkenyl, nitro, hydroxy, Ar 2 , N(R 4a R 4b ), N(R 4a R 4b )sulfonyl, N(R 4a R 4b )carbonyl, C 1-6 alkyloxy, Ar 2 oxy, Ar 2 C 1-6 alkyloxy, carboxyl, C 1-6 alkyloxycarbonyl, or —C(=Z)Ar 2 ; and the other one of R 2a and R 3a is hydrogen; in case R 2a is different from hydrogen then R 2b is hydrogen, C 1-6 alkyl or halogen and R 3b is hydrogen; in case R 3a is different from hydrogen then R 3b is hydrogen, C 1-6 alkyl or halogen and R 2b is hydrogen. It further concerns the preparation thereof and compositions comprising these compounds, as well as the use thereof as a medicine.
1. A compound which is 2-[6-{[2-(3-hydroxy-propyl)-5-methyl-phenylamino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol, or an, N-oxide, pharmaceutically acceptable salt, quaternary amine, or metal complex thereof.
2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a compound as described in claim 1 .
3. A method for treating a respiratory syncytial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the compound of claim 1 .
4. A method for treating a respiratory syncytial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the composition of claim 3 .
5. A pharmaceutical composition made by mixing the compound of claim 1 and a pharmaceutically acceptable carrier.
6. A process for making a pharmaceutical composition comprising mixing the compound of claim 1 and a pharmaceutically acceptable carrier.
7. The pharmaceutical composition of claim 2 , further comprising an additional antiviral agent.
8. The pharmaceutical composition of claim 2 , further comprising an antiviral agent selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
9. A method of treating a warm-blooded animal infected by a respiratory syncytial virus, or being at risk of infection by a respiratory syncytial virus, comprising administering to the warm-blooded animal an anti-virally effective amount of the compound of claim 1 .
10. A method for treating a respiratory synctial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the compound of claim 1 and an additional antiviral agent.
11. The method of claim 10 , wherein the additional antiviral agent is selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
12. A method of treating a warm-blooded animal infected by a respiratory syncytial virus, or being at risk of infection by a respiratory syncytial virus, comprising administering to the warm-blooded animal an anti-virally effective amount of the compound of claim 1 and an additional antiviral agent.
13. The method of claim 12 , wherein the additional antiviral agent is selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
14. A compound which is 2-[6-{[2-(3-hydroxy-propyl)-5-methyl-phenylamino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol and pharmaceutically acceptable salts thereof.
15. A pharmaceutical composition comprising the compound of claim 14 and a pharmaceutically acceptable carrier.
16. A method for treating a respiratory syncytial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the compound of claim 14 .
17. A method for treating a respiratory syncytial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the composition of claim 15 .
18. A pharmaceutical composition made by mixing the compound of claim 14 and a pharmaceutically acceptable carrier.
19. A process for making a pharmaceutical composition comprising mixing the compound of claim 14 and a pharmaceutically acceptable carrier.
20. The pharmaceutical composition of claim 15 , further comprising an additional antiviral agent.
21. The pharmaceutical composition of claim 15 , further comprising an additional antiviral agent selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
22. A method of treating a warm-blooded animal infected by a respiratory syncytial virus, or being at risk of infection by a respiratory syncytial virus, comprising administering to the warm-blooded animal an anti-virally effective amount of the compound of claim 14 .
23. A method for treating a respiratory synctial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the compound of claim 14 , and an additional antiviral agent.
24. The method of claim 23 , wherein the additional antiviral agent is selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
25. A method of treating a warm-blooded animal infected by a respiratory syncytial virus, or being at risk of infection by a respiratory syncytial virus, comprising administering to the warm-blooded animal an anti-virally effective amount of the compound of claim 14 and an additional antiviral agent.
26. The method of claim 25 , wherein the additional antiviral agent is selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
27. A compound which is 2-[6-{[2-(3-hydroxy-propyl)-5-methyl-phenylamino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol.
28. A pharmaceutical composition comprising the compound of claim 27 and a pharmaceutically acceptable carrier.
29. A method for treating a respiratory syncytial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the compound of claim 27 .
30. The pharmaceutical composition of claim 28 , further comprising an additional antiviral agent.
31. The pharmaceutical composition of claim 28 , further comprising an additional antiviral agent selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
32. A method of treating a warm-blooded animal infected by a respiratory syncytial virus, or being at risk of infection by a respiratory syncytial virus, comprising administering to the warm-blooded animal an anti-virally effective amount of the compound of claim 27 .
33. A method for treating a respiratory synctial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the compound of claim 27 and an additional antiviral agent.
34. The method of claim 33 , wherein the additional antiviral agent is selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
35. A method of treating a warm-blooded animal infected by a respiratory syncytial virus, or being at risk of infection by a respiratory syncytial virus, comprising administering to the warm-blooded animal an anti-virally effective amount of the compound of claim 27 and an additional antiviral agent.
36. The method of claim 35 , wherein the additional antiviral agent is selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.