Imidazo[4,5-c] ring compounds containing guanidine substituted benzamide groups
View Patent ↗Imidazo[4,5-c] ring compounds of formula I, (particularly imidazo4,5-c]quinolines, 6,7,8,9-tetrahydroimidazo[4,5-c]quinolines, imidazo[4,5-c]naphthyridines, and 6,7,8,9-tetrahydroimidazo[4,5-c]naphthyridine compounds) having a guanidine substituted benzamide that is attached at the N−1 position by a linking group, pharmaceutical compositions containing the compounds, and methods of making the compounds are disclosed. Methods of use of the compounds as immune response modifiers, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are also disclosed.
1. A compound of the Formula (I):
wherein:
R 3 and R 4 are taken together to form a fused benzene ring, a fused pyridine ring, a fused cyclohexene ring, or a fused tetrahydropyridine ring; wherein the fused benzene ring, fused pyridine ring, fused cyclohexene ring, or fused tetrahydropyridine ring is either unsubstituted or substituted by one or more R groups;
R is selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, haloalkyl, —C(O)—O-alkyl, —C(O)—O—CH 2 Ph, —C(O)—O-aryl, amino, alkylamino, and dialkylamino aryl, arylalkylenyl, aryloxyalkylenyl, arylalkyleneoxy, aryloxy, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkyenyl, heteroarylalkyleneoxy, and heteroaryloxy, wherein the alkyl, aryl, arylalkylenyl, aryloxyalkylenyl, arylalkyleneoxy, aryloxy, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkyenyl, heteroaryalkyleneoxy, and heteroaryloxy groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkyleneoxy, and nitrile;
W is selected from the group consisting of a covalent bond, —O—, and NH—;
X is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein any of the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene or heteroarylene and optionally interrupted by one or more —O— groups;
R 9 is -Q-N(R 7 )—C(═N—R 5 )—N(H)R 6 ;
Q is selected from the group consisting of a covalent bond and alkylene;
R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, —O-alkyl, hydroxyalkylenyl, alkoxyalkylenyl, alkylaminoalkylenyl, hydroxyl, —CH 2 —NH—O-alkyl, and —CH 2 NHC(O)-alkyl;
R 8 is selected from the group consisting of hydrogen, alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and cycloalkylalkylenyl; wherein any of the alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and cycloalkylalkylenyl groups can be either unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, haloalkyl, and nitrile;
R 7 is selected from the group consisting of hydrogen, alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and cycloalkylalkylenyl; wherein any of the alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and cycloalkylalkylenyl groups can be either unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, haloalkyl, and nitrile;
R 5 and R 6 are independently selected from the group consisting of hydrogen, —C(O)—O— alkyl, alkyl, cycloalkyl, aryl, arylalkylenyl, aryloxyalkylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, cycloalkylalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and benzyloxyalkylenyl; wherein any of the alkyl, cycloalkyl, aryl, arylalkylenyl, aryloxyalkylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, cycloalkylalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and benzyloxyalkylenyl groups can be either unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkoxy, alkyl, haloalkyl, cycloalkyl, nitrile, aryl, heteroaryl, and dialkylamino; or a pharmaceutically acceptable salt thereof.
2. The compound or salt of claim 1 , wherein R 3 and R 4 are taken together to form a fused benzene ring, a fused pyridine ring, or a fused cyclohexene ring, and the fused benzene ring, fused pyridine ring, or fused cyclohexene ring is either unsubstituted or substituted by one and only one R group.
3. The compound or salt of claim 1 , wherein R 7 is hydrogen and R 8 is hydrogen.
4. The compound or salt of claim 1 , wherein W is a covalent bond or —O—.
5. The compound or salt of claim 1 , wherein X is alkylene optionally interrupted by one or more —O— groups.
6. The compound or salt of claim 1 , wherein X is selected from the group consisting of —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 C(CH 3 ) 2 —, —CH 2 C(CH 3 ) 2 CH 2 —, —CH 2 CH 2 —O—CH 2 CH 2 —, —CH 2 CH 2 —O—CH 2 CH 2 CH 2 —, —CH 2 CH 2 —O—CH 2 CH 2 —O—CH 2 CH 2 —, —(CH 2 ) 2-4 —O—(CH 2 ) 2-4 —, —(CH 2 ) 2-4 —(OCH 2 CH 2 -) 1-5 , and —(CH 2 ) 2-6 —(OCH 2 CH 2 -) 1-4 .
7. The compound or salt of claim 1 , wherein X is —C 1-5 alkylene-arylene-C 1-5 alkylene- or —C 1-5 alkylene-heteroarylene-C 1-5 alkylene-.
8. The compound or salt of claim 1 , wherein X is —CH 2 -phenylene-CH 2 —.
9. The compound or salt of claim 1 , wherein R 2 is selected from the group consisting hydrogen, alkyl, alkoxyalkylenyl.
10. The compound or salt of claim 1 , wherein R 2 is selected from the group consisting of hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 CH 2 OCH 3 .
11. The compound or salt of claim 1 , wherein R 5 and R 6 are independently selected from the group consisting of hydrogen, alkyl, phenyl, and phenylalkylenyl.
12. The compound or salt of claim 1 , wherein R 5 is hydrogen and R 6 is hydrogen.
13. A compound of the Formula XIV:
wherein:
W B is selected from the group consisting of a covalent bond, —O—, and —NH—;
X B is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein any of the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene or heteroarylene and optionally interrupted by one or more —O— groups;
R 9B is -Q B -N(R 7B )—C(═N—R 5B )—N(H)R 6B ;
Q B is selected from the group consisting of a covalent bond and alkylene;
R 2B is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, —O-alkyl, hydroxyalkylenyl, alkoxyalkylenyl, alkylaminoalkylenyl, hydroxyl, —CH 2 —NH—O-alkyl, and —CH 2 NHC(O)-alkyl;
R 8B is selected from the group consisting of hydrogen, alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and cycloalkylalkylenyl; wherein any of the alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and cycloalkylalkylenyl groups can be either unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, haloalkyl, and nitrile;
R 7B is selected from the group consisting of hydrogen, alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and cycloalkylalkylenyl; wherein any of the alkyl, arylalkylenyl, alkoxyalkylenyl, aryloxyalkylenyl, benzyloxyalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and cycloalkylalkylenyl groups can be either unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, alkyl, alkoxy, haloalkyl, and nitrile;
R 5B and R 6B are independently selected from the group consisting of hydrogen, —C(O)—O-alkyl, alkyl, cycloalkyl, aryl, arylalkylenyl, aryloxyalkylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, cycloalkylalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and benzyloxyalkylenyl;
wherein any of the, cycloalkyl, aryl, arylalkylenyl, aryloxyalkylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, cycloalkylalkylenyl, aryl-(CH 2 ) 2-6 —O-alkylenyl, and benzyloxyalkylenyl groups can be either unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, alkoxy, alkyl, haloalkyl, cycloalkyl, nitrile, aryl, heteroaryl, and dialkylamino;
or a pharmaceutically acceptable salt thereof.
14. The compound or salt of claim 13 , wherein R 7B is hydrogen and R 8B is hydrogen.
15. The compound or salt of claim 13 , wherein R 2B is selected from the group consisting hydrogen, alkyl, alkoxyalkylenyl.
16. The compound or salt of claim 13 , wherein R 2B is selected from the group consisting of hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , and —CH 2 CH 2 OCH 3 .
17. The compound or salt of claim 13 , wherein R 5B and R 6B are independently selected from the group consisting of hydrogen, alkyl, phenyl, phenylalkylenyl.
18. The compound or salt of claim 13 , wherein R 5B is hydrogen and R 6B is hydrogen.
19. The compound or salt of claim 13 , wherein X B is alkylene optionally interrupted by one or more —O— groups.
20. The compound or salt of claim 13 , wherein X B is selected from the group consisting of —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, —CH 2 C(CH 3 ) 2 —, —CH 2 C(CH 3 ) 2 CH 2 —, —CH 2 CH 2 —O—CH 2 CH 2 —, —CH 2 CH 2 —O—CH 2 CH 2 CH 2 —, —CH 2 CH 2 —O—CH 2 CH 2 —O—CH 2 CH 2 —, —(CH 2 ) 2-4 —O—(CH 2 ) 2-4 —, —(CH 2 ) 2-4 —(OCH 2 CH 2 -) 1-5 , and —(CH 2 ) 2-6 —(OCH 2 CH 2 -) 1-4 .
21. The compound or salt of claim 13 , wherein X B is —C 1-5 alkylene-arylene-C 1-5 alkylene- or —C 1-5 alkylene-heteroarylene-C 1-5 alkylene-.
22. The compound or salt of claim 13 , wherein X B is —CH 2 -phenylene-CH 2 —.
23. A method of inducing biosynthesis of IFN-alpha in an animal comprising administering an effective amount of a compound or salt of claim 1 to the animal.
24. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 in combination with a pharmaceutically acceptable carrier.