Imidazotriazinone derivatives as PDE 7 (phosphodiesterase 7) inhibitors
The present invention provides the compounds inhibiting PDE 7 selectively, and therefore, enhances cellular cAMP level. Consequently, the compound is useful for treating various kinds of disease such as allergic disease, inflammatory disease or immunologic disease. The compound is imidazotriazinone compound represented by the following formula (IA) or (IB): especially, R1 is cyclohexyl group, R2 is methyl group; R3 is a hydrogen atom; nitro group; cyano group; a halogen atom; heteroaryl group; substituted or unsubstituted C1-C6 alkyl group; substituted or unsubstituted C2-C6 alkenyl group; saturated or unsaturated heterocycloalkyl group which is substituted or unsubstituted; a group: —NR5R6, —C(O)R7, —SO2R7, —OR8, —NR8COR7, —NR8S02R7; A is CR4; and B is CH.
1. A compound represented by the following formula (IA):
wherein
A is N or CR 4 ;
B is N or CH;
R 1 is substituted or unsubstituted cycloalkyl group or tert-butyl group;
R 2 is a hydrogen atom or C 1 -C 6 alkyl group;
R 3 is a hydrogen atom; intro group; cyano group; a halogen atom; heteroaryl group, wherein the heteroaryl group is pyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, tetrazolyl, pyridinyl, pyrazolyl, pyridazinyl, or pyrimidinyl; substituted or unsubstituted C 1 -C 6 alkyl group; substituted or unsubstituted C 2 -C 6 alkenyl group; saturated or unsaturated heterocycloalkyl group which is substituted or unsubstituted; a group: —NR 5 R 6 , —C(O)R 7 , —SO 2 R 7 , —OR 8 , —NR 8 COR 7 , —NR 8 SO 2 R 7 ;
R 4 is a hydrogen atom or C 1 -C 3 alkoxy group which is unsubstituted or substituted by one or more fluorine atom(s);
R 5 and R 6 are, same or different from each other, a hydrogen atom; substituted or unsubstituted C 1 -C 6 alkyl group; substituted or unsubstituted acyl group; or substituted or unsubstituted heterocycloalkyl group;
R 7 is a hydrogen atom; substituted or unsubstituted C 1 -C 6 alkyl group; substituted or unsubstituted heterocycloalkyl group; OH; —OR 8 or —NR 5 R 6 ;
R 8 is a hydrogen atom, substituted or unsubstituted C 1 -C 6 alkyl group; or substituted or unsubstituted heterocycloalkyl group; or pharmaceutically acceptable salts thereof.
2. The compound according to claim 1 , in which R 1 is substituted or unsubstituted C 3 -C 8 cycloalkyl group.
3. The compound according to claim 2 , in which R 1 is cyclopentyl, cyclohexyl or cycloheptyl.
4. The compound according to claim 1 , in which A is CR 4 wherein R 4 is methoxy or ethoxy group.
5. The compound according to claim 1 , in which B is CH.
6. The compound according to claim 1 , in which R 2 is methyl group.
7. The compound according to claim 1 , in which R 3 is a hydrogen atom; a halogen atom; saturated or unsaturated heterocycloalkyl group; an —NR 5 R 6 , —C(O)R 7 , or —SO 2 R 7 group, wherein R 7 is OH, —OR 8 , —NR 5 R 6 or a substituted or unsubstituted heterocycloalkyl group.
8. A pharmaceutical composition comprising a compound according to claim 1 , or pharmaceutically acceptable salts thereof as an active ingredient.
9. The compound of claim 1 , wherein the compound is 6-cyclohexyl-2-(2-methoxyphenyl)-8-methylimidazo-[1,5-a][1,3,5]-triazin-4(3H)-one; or 6-cyclohexyl-2-(4-bromo-2-methoxyphenyl)-8-methylimidazo-[1,5-a][1,3,5]triazin-4(3H)-one.
10. The compound of claim 1 , wherein the compound is 6-cyclohexyl-2-[2-methoxy-4-(1-piperazinyl)phenyl]-8-methylimidazo-[1,5-a][1,3,5]triazin-4(3H)-one; or 6-cyclohexyl-2-[2-methoxy-4-(4-methyl-1-piperazinyl)phenyl]-8-methylimidazo-[1,5-a][1,3,5]triazin-4(3H)-one.
11. The compound of claim 1 , wherein the compound is 2-[4-(4-amino-1-piperidinyl)-2-methoxyphenyl]-6-cyclohexyl-8-methylimidazo[1,5-a][1,3,5]-triazin-4(3H)-one; 6-cyclohexyl-2-{2-methoxy-4-[4-(methylamino)-1-piperidinyl]phenyl}-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; 6-cyclohexyl-2-{4-[4-(dimethylamino)-1-piperidinyl]-2-methoxy-phenyl}-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; or 6-cyclohexyl-2-[4-(4-hydroxy-1-piperidinyl)-2-methoxyphenyl]-8-methylimidazo[1,5-a])[1,3,5]triazin-4(3H)-one.
12. The compound of claim 1 , wherein the compound is 6-cyclohexyl-2-[4-(1,4-diazepan-1-yl)-2-methoxyphenyl]-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; or 6-cyclohexyl-2-[2-methoxy-4-(4-methyl-1,4-diazepan-1-yl)phenyl]-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one.
13. The compound of claim 1 , wherein the compound is 6-cyclohexyl-2-{4-[(4-hydroxy-1-piperidinyl)sulfonyl]-2-methoxyphenyl}-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; 6-cyclohexyl-2-[2-methoxy-4-(1-piperazinylsulfonyl)phenyl]-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; 6-cyclohexyl-2-{2-methoxy-4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; 6-cyclohexyl-2-[4-(1,4-diazepan-1-ylsulfonyl)-2-methoxyphenyl]-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; or 6-cyclohexyl-2-{2-methoxy-4-[(4-methyl-1,4-diazepam-1-yl)sulfonyl]phenyl}-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one.
14. The compound of claim 13 , wherein the compound is 6-cyclohexyl 2-{4-[(4-hydroxy-1-piperidinyl)sulfonyl]-2-methoxyphenyl}-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one.
15. The compound of claim 13 , wherein the compound is 6-cyclohexyl-2-[2-methoxy-4-(1-piperazinylsulfonyl)phenyl]-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; or 6-cyclohexyl-2-{2-methoxy-4-[(4-methyl-1-piperazinyl)sulfonyl]-phenyl}-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one.
16. The compound of claim 13 , wherein the compound is 6-cyclohexyl-2-[4-(1,4-diazepan-1-ylsulfonyl)-2-methoxyphenyl]-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; or 6-cyclohexyl-2-{2-methoxy-4-[(4-methyl-1,4-diazepam-1-yl)sulfonyl]-phenyl}-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one.
17. The compound of claim 1 , wherein the compound is 6-cyclohexyl-2-(2-ethoxyphenyl)-8-methylimidazo[1,5-a][1,3,5]-triazin-4(3H)-one.
18. The compound of claim 1 , wherein the compound is 6-cyclohexyl-2-[2-ethoxy-4-(1-piperazinyl)phenyl]-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; or 6-cyclohexyl-2-[2-ethoxy-4-(4-methyl-1-piperazinyl)phenyl]-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one.
19. The compound of claim 1 , wherein the compound is 2-[4-(4-amino-1-piperidinyl)-2-ethoxyphenyl]-6-cyclohexyl-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; 6-cyclohexyl-2-{2-ethoxy[4-(methylamino)-1-piperidinyl]phenyl}-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; 6-cyclohexyl-2-{4-[4-(dimethylamino)-1-piperidinyl]-2-ethoxy-phenyl}-8-methylimidazo[1,5-a]([1,3,5]triazin-4(3H)-one; or 6-cyclohexyl-2-[4-(4-hydroxy-1-piperidinyl)-2-ethoxyphenyl]-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one.
20. The compound of claim 1 , wherein the compound is 6-cyclohexyl-2-[4-(1,4-diazepan-1-yl)-2-ethoxyphenyl]-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; or 6-cyclohexyl-2-[2-ethoxy-4-(4-methyl-1,4-diazepan-1-yl)phenyl]-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one.
21. The compound of claim 1 , wherein the compound is 6-cyclohexyl-2-{4-[(4-hydroxy-1-piperidinyl)sulfonyl]-2-ethoxy-phenyl}-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; 6-cyclohexyl-2-[2-ethoxy-4-(1-piperazinylsulfonyl)phenyl]-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; 6-cyclohexyl-2-{2-ethoxy-4-[(4-methyl-1-piperazinyl)sulfonyl]-phenyl}-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; 6-cyclohexyl-2-[4-(1,4-diazepan-1-ylsulfonyl)-2-ethoxyphenyl]-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; or 6-cyclohexyl-2-{2-ethoxy-4-[(4-methyl-1,4-diazepan-1-yl)sulfonyl]-phenyl}-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one.
22. The compound of claim 21 , wherein the compound is 6-cyclohexyl-2-{4-[(4-hydroxy-1-piperidinyl)sulfonyl]-2-ethoxy-phenyl}-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one.
23. The compound of claim 21 , wherein the compound is 6-cyclohexyl-2-[2-ethoxy-4-(1-piperazinylsulfonyl)phenyl]-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; or 6-cyclohexyl-2-{2-ethoxyl-4-[(4-methyl-1-piperazinyl)sulfonyl]-phenyl}-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one.
24. The compound of claim 21 , wherein the compound is 6-cyclohexyl-2-[4-(1,4-diazepan-1-ylsulfonyl)-2-ethoxyphenyl]-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one; or 6-cyclohexyl-2-{2-ethoxy-4-[(4-methyl-1,4-diazepan-1-yl)sulfonyl]-phenyl}-8-methylimidazo[1,5-a][1,3,5]triazin-4(3H)-one.