Imidazoquinolinyl sulfonamides
View Patent ↗Imidazoquinolinyl, imidazopyridinyl, and imidazonaphthyridinyl sulfonamide compounds, pharmaceutical compositions containing the compounds, intermediates, and methods of making and methods of use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are disclosed.
1. A compound of the formula (Ia):
wherein:
X′ is selected from the group consisting of —CH(R 9 )—, —CH(R 9 )-alkylene, and —CH(R 9 )-alkenylene-;
R 1 and R 1 ′ are independently selected from the group consisting of:
hydrogen and
alkyl;
R 2 is selected from the group consisting of:
hydrogen,
alkyl,
hydroxyalkyl, and
alkyloxyalkyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R A and R B taken together form either a fused 6-membered aryl ring that is unsubstituted or substituted by one or more R a groups, or a fused 6-membered saturated ring that is unsubstituted or substituted by one or more R c groups;
R a is selected from the group consisting of:
fluoro,
alkyl,
haloalkyl,
alkoxy, and
—N(R 9 ) 2 ; and
R c is selected from the group consisting of:
halogen,
hydroxy,
alkyl,
alkenyl,
haloalkyl,
alkoxy,
alkylthio, and
—N(R 9 ) 2 ;
or a pharmaceutically acceptable salt thereof.
2. A compound of the formula (II):
wherein:
X′ is selected from the group consisting of —CH(R 9 )—, —CH(R 9 )-alkylene, and —CH(R 9 )-alkenylene-;
R 1 and R 1 ′ are independently selected from the group consisting of:
hydrogen and
alkyl;
R 2 is selected from the group consisting of:
hydrogen,
alkyl,
hydroxyalkyl; and
alkyloxyalkyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R a is selected from the group consisting of fluoro, alkyl, haloalkyl, alkoxy, and —N(R 9 ) 2 ; and
n is 0 to 4;
or a pharmaceutically acceptable salt thereof.
3. A compound of the formula (IIa):
wherein:
X′ is selected from the group consisting of —CH(R 9 )—, —CH(R 9 )-alkylene, and —CH(R 9 )-alkenylene-;
R 2 is selected from the group consisting of:
hydrogen,
alkyl,
hydroxyalkyl, and
alkyloxyalkyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R a is selected from the group consisting of fluoro, alkyl, haloalkyl, alkoxy, and —N(R 9 ) 2 ; and
n is 0 to 4;
or a pharmaceutically acceptable salt thereof.
4. A compound of the formula (III):
wherein:
X′ is selected from the group consisting of —CH(R 9 )—, —CH(R 9 )-alkylene, and —CH(R 9 )-alkenylene-;
R 1 and R 1 ′ are independently selected from the group consisting of:
hydrogen and
alkyl;
R 2 is selected from the group consisting of:
hydrogen,
alkyl,
hydroxyalkyl, and
alkyloxyalkyl;
R 9 is selected from the group consisting of hydrogen and alkyl;
R c is selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, and —N(R 9 ) 2 ; and
n is 0 to 4;
or a pharmaceutically acceptable salt thereof.
5. The compound or salt of claim 2 wherein n is 0.
6. The compound or salt of claim 1 wherein R 1 ′ is hydrogen or alkyl, and R 1 is hydrogen alkyl.
7. The compound or salt of claim 1 wherein R 1 ′ is hydrogen or methyl, and R 1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, and butyl.
8. The compound or salt of claim 7 wherein R 1 and R 1 ′ are both hydrogen.
9. The compound or salt of claim 1 wherein R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkyl-O—C 1-4 alkylenyl, and HO—C 1-3 alkylenyl.
10. The compound or salt of claim 9 wherein R 2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, hydroxymethyl, 2-hydroxyethyl, ethoxymethyl, and 2-methoxyethyl.
11. The compound or salt of claim 1 wherein X′ is —(CH 2 ) 1-7 —.
12. The compound or salt of claim 1 wherein X′ is —(CH 2 )—C(CH 3 ) 2 —.
13. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 in combination with a pharmaceutically acceptable carrier.
14. A method of cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of claim 1 to the animal, wherein the cytokine is a TNF alpha or IFN alpha.
15. The compound or salt of claim 2 wherein R 1 ′ is hydrogen or alkyl, and R 1 is hydrogen.
16. The compound or salt of claim 2 wherein R 1 ′ is hydrogen or methyl, and R 1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, and butyl.
17. The compound or salt of claim 2 wherein R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkyl-O—C 1-4 alkylenyl, and HO—C 1-3 alkylenyl.
18. The compound or salt of claim 17 wherein R 2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, hydroxymethyl, 2-hydroxyethyl, ethoxymethyl, and 2-methoxyethyl.
19. The compound or salt of claim 2 wherein X′ is —(CH 2 ) 1-7 —.
20. The compound or salt of claim 2 wherein X′ is —(CH 2 )—C(CH 3 ) 2 —.
21. The compound or salt of claim 3 wherein n is 0.
22. The compound or salt of claim 3 wherein R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkyl-O—C 1-4 alkylenyl, and HO—C 1-3 alkylenyl.
23. The compound or salt of claim 22 wherein R 2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, hydroxymethyl, 2-hydroxyethyl, ethoxymethyl, and 2-methoxyethyl.
24. The compound or salt of claim 3 wherein X′ is —(CH 2 ) 1-7 —.
25. The compound or salt of claim 3 wherein X′ is —(CH 2 )—C(CH 3 ) 2 —.
26. The compound or salt of claim 4 wherein n is 0.
27. The compound or salt of claim 4 wherein R 1 ′ is hydrogen or methyl, and R 1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, and butyl.
28. The compound or salt of claim 4 wherein R 1 and R 1 ′ are both hydrogen.
29. The compound or salt of claim 4 wherein R 2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, hydroxymethyl, 2-hydroxyethyl, ethoxymethyl, and 2-methoxyethyl.
30. The compound or salt of claim 4 wherein X′ is —(CH 2 ) 1-7 —.
31. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 2 in combination with a pharmaceutically acceptable carrier.
32. A method of cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of claim 2 to the animal, wherein the cytokine is a TNF alpha or IFN alpha.
33. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 3 in combination with a pharmaceutically acceptable carrier.
34. A method of cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of claim 3 to the animal, wherein the cytokine is a TNF alpha or IFN alpha.
35. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 4 in combination with a pharmaceutically acceptable carrier.
36. A method of cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of claim 4 to the animal, wherein the cytokine is a TNF alpha or IFN alpha.