Azolopyrimidines as inhibitors of cannabinoid 1 activity
View Patent ↗The invention provides compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of Cannabinoid Receptor 1 (CB1). The compounds are of the Formulae Ia, Ic, Ig and Ik:
1. A compound selected from Formula Ia:
in which:
R 2 is selected from halo, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, pyridinyl-N-oxide and phenyl; wherein said pyrimidinyl, pyridinyl, pyridinyl-N-oxide, pyrazinyl and phenyl of R 2 is optionally substituted with a group selected from amino;
R 3 is selected from hydrogen, methyl-sulfonyl, methyl-sulfoxide and dimethyl-amino-carbonyl; and
R 4 is selected from, amino-carbonyl, and methyl-sulfonyl.
2. The compound of claim 1 selected from:
6-[4-(6-amino-pyridazin-3-yl)-phenyl]-5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;
3-[6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzamide;
3-[6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzamide;
6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;
6-[4-(5-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;
6-[4-(5-amino-pyrazin-2-yl)-phenyl]-5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;
6-[4-(2-amino-pyrimidin-5-yl)-phenyl]-5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;
3-[5-(4-chloro-phenyl)-4-oxo-6-(4-pyrazin-2-yl-phenyl)-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl1-benzamide;
5-(4-chlorophenyl)-1-(3-(methylsulfonyl)phenyl)-6-(4-(pyrazin-2-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;
5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-6-(4-pyrimidin-5-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one; and
5-(4-chloro-phenyl)-1-(3-methanesulfonyl-phenyl)-6-(4-pyrimidin-2-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one.
3. A method of treating a disease mediated by the Cannabinoid-1 wherein said disease is an eating disorder associated with excessive food intake, comprising administration of to a patient in need of such treatment of a therapeutically effective amount of a compound of claim 1 .
4. The method according to claim 3 wherein the eating disorder associated with excessive food intake is selected from obesity, bulimia nervosa, and compulsive eating disorders.
5. The method according to claim 4 wherein the eating disorder associated with excessive food intake is obesity.
6. A method of preventing obesity in a person at risk for obesity comprising administration to said person of about 0.001 mg to about 100 mg per kg of a compound selected from a compound of claim 1 .
7. A composition comprising a pharmaceutically acceptable carrier and a compound selected from a compound of claim 1 .
8. A compound selected from Formula Ia:
in which:
R 2 is selected from halo, pyrazinyl, pyridazinyl, pyrimidinyl, pyridinyl, pyridinyl-N-oxide and phenyl; wherein said pyrimidinyl, pyridinyl, pyridinyl-N-oxide, pyrazinyl and phenyl of R 2 is optionally substituted with a radical selected from amino, halo, amino-sulfonyl and phenyl;
R 3 is selected from hydrogen, methyl-sulfonyl, methyl-sulfoxide and dimethyl-amino-carbonyl; and
R 4 is selected from carbamimidoyl, tetrazolyl, amino-sulfonyl, and methyl-sulfonyl-amino.
9. The compound of claim 8 selected from:
3-(6-(4-bromophenyl)-5-(4-chlorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzenesulfonamide;
3-[6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzamidine;
3-[6-[4-(5-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzamidine;
6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-1-[3-(1H-tetrazol-5-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;
6-[4-(5-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-1-[3-(1H-tetrazol-5-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one;
N-(3-(6-(4-(6-aminopyridin-3-yl)phenyl)-5-(4-chlorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)methanesulfonamide;
N-(3-(6-(4-(5-aminopyridin-2-yl)phenyl)-5-(4-chlorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)methanesulfonamide;
N-(3-(5-(4-chlorophenyl)-4-oxo-6-(4-(pyrimidin-2-yl)phenyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)methanesulfonamide;
N-{3-[5-(4-chloro-phenyl)-4-oxo-6-(4-pyrimidin-5-yl-phenyl)-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-phenyl}-methane sulfonamide;
3-[5-(4-chloro-phenyl)-4-oxo-6-(4-pyrazin-2-yl-phenyl)-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzamidine;
N-(3-(5-(4-chlorophenyl)-4-oxo-6-(4-(pyridazin-3-yl)phenyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)methanesulfonamide;
N-(3-(5-(4-chlorophenyl)-4-oxo-6-(4-(pyrazin-2-yl)phenyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)methanesulfonamide;
3-(5-(4-chlorophenyl)-4-oxo-6-(4-(pyrazin-2-yl)phenyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzenesulfonamide; and
3-[6-[4-(5-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzene sulfonamide.