Hydroxyalkyl substituted imidazonaphthyridines
Certain imidazonaphthyridines with a hydroxymethyl or hydroxyethyl substituent at the 2-position, pharmaceutical compositions containing the compounds, intermediates, methods of making and methods of use of these compounds as immunomodulators, for preferentially inducing IFN-α biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are disclosed.
1. A compound of Formula I:
wherein:
n is 1 or 2;
R 1 is selected from the group consisting of:
alkyl, aminoalkyl, dihydroxyalkyl, haloalkyl, hydroxyalkyl, heterocyclylalkylenyl that can be unsubstituted or substituted by one or more C 1-4 alkyl groups;
—X—Y—R 4 , and
—X—R 5 ;
X is straight chain or branched chain C 1-6 alkylene which can be optionally interrupted by one —O— group;
Y is
—N(R 8 )-Q-;
R 4 is selected from the group consisting of straight chain or branched chain alkyl, cycloalkyl, aryl, arylalkylenyl, and heteroaryl that is unsubstituted or substituted by methyl, wherein-the aryl and arylalkylenyl groups can be unsubstituted or substituted by a-substituent selected from the group consisting of alkyl halogen hydroxy and cyano;
R 5 is selected from the group consisting of
R 6 is ═O;
R 7 is propylene;
R 8 is selected from the group consisting of hydrogen and alkyl;
A is —O—;
Q is selected from the group consisting of —C(R 6 )—, —S(O) 2 , —C(R 6 )—N(R 8 )—, and —S(O) 2 —N(R 8 ); and
a and b are each 2;
or a pharmaceutically acceptable salt thereof.
2. The compound or salt of claim 1 wherein n is 1.
3. The compound or salt of claim 1 wherein n is 2.
4. The compound or salt of claim 1 wherein R 1 is selected from the group consisting of alkyl, aminoalkyl, dihydroxyalkyl, haloalkyl, and hydroxyalkyl.
5. The compound or salt of claim 4 wherein R 1 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, 2-methylpropyl, 2-amino-2-methylpropyl, 3-amino-2,2-dimethylpropyl, 2,3-dihydroxypropyl, 2-fluoro-2-methylpropyl, and 2-hydroxy-2-methylpropyl.
6. The compound or salt of claim 1 wherein R 1 is heterocyclylalkylenyl which can be unsubstituted or substituted by one or more C 1-4 alkyl groups.
7. The compound or salt of claim 6 wherein heterocyclyl is selected from the group consisting of 1,3-dioxolanyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, and morpholinyl, and alkylenyl is C 1-4 alkylenyl.
8. The compound or salt of claim 6 wherein R 1 is selected from the group consisting of tetrahydro-2H-pyran-4-ylmethyl and (2,2-dimethyl-1,3-dioxolan-4-yl)methyl.
9. The compound or salt of claim 1 wherein R 1 is —X—Y—R 4 wherein X is straight chain or branched chain C 1-6 alkylene which may be interrupted by one —O— group; Y is selected from the group consisting of —N(R 8 )—C(O)—, —N(R 8 )—S(O) 2 —, and —N(R 8 )—C(O)—N(R 8 )—,
wherein R 8 is selected from hydrogen and methyl; and R 4 is selected from the group consisting of C 1-6 alkyl, isoquinolinyl, N-methylimidazolyl, pyridinyl, quinolinyl, phenyl, and phenyl substituted by a substituent selected from the group consisting of chloro, cyano, fluoro, hydroxy, and methyl.
10. The compound or salt of claim 1 wherein R 1 is selected from the group consisting of 2-[(cyclopropylcarbonyl)amino]ethyl, 4-[(cyclopropylcarbonyl)amino]butyl, 2-[(cyclohexylcarbonyl)amino]-2-methylpropyl, 2-{[(1-methylethyl)carbonyl]amino}ethyl, 4-{[(1-methylethyl)carbonyl]amino}butyl, 2-methyl-2-{[(1-methylethyl)carbonyl]amino}propyl, 2-[(methylsulfonyl)amino]ethyl, 4-[(methylsulfonyl)amino]butyl, 2-methyl-2-[(methylsulfonyl)amino]propyl, and 2-methyl-2-({[(1-methylethyl)amino]carbonyl}amino)propyl.
11. The compound or salt of claim 1 wherein R 1 is —X—Y—R 4 wherein X is straight chain or branched chain C 1-6 alkylene which may be interrupted by one —O— group; Y is selected from the group consisting of —N(R 8 )—C(O)—, —N(R 8 )—S(O) 2 —, —N(R 8 )—C(O)—N(R 8 )—, and —N(R 8 )—S(O) 2 —N(R 8 )—, wherein R 8 is selected from hydrogen and methyl; and R 4 is selected from the group consisting of C 1-6 alkyl, aryl, arylalkylenyl, and heteroaryl which is unsubstituted or substituted by methyl, wherein aryl and arylalkyleneyl are unsubstituted or substituted by a substituent selected from the group consisting of chloro, cyano, fluoro, hydroxy, and methyl.
12. The compound or salt of claim 1 wherein R 1 is selected from the group consisting of 4-(1,1-dioxidoisothiazolidin-2-yl)butyl, 4-[(4-morpholinecarbonyl)amino]butyl, and 2-[(4-morpholinecarbonyl)amino]ethyl.
13. 2-Hydroxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine or a pharmaceutically acceptable salt thereof.
14. A compound selected from the group consisting of 1-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c][1,5]naphthyrin-1-yl)-2-methylpropan-2-ol and 1-[4-amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c][1,5]naphthyrin-1-yl]-2-methylpropan-2-ol, or a pharmaceutically acceptable salt thereof.
15. A compound selected from the group consisting of N-[4-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c][1,5]naphthyrin-1-yl)butyl]methanesulfonamide and N-{4-[4-amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c][1,5]naphthyrin-1-yl]butyl]}methane sulfonamide, or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 and a pharmaceutically acceptable carrier.
17. A method of preferentially inducing the biosynthesis of IFN-α in an animal comprising administering an effective amount of a compound or salt of claim 1 to the animal.
18. The method of claim 17 wherein the compound or salt is administered systemically.