Adenosine A2B receptor antagonists
View Patent ↗The present invention provides compounds of the formula which are adenosine A 2B receptor antagonists and, thus, may be employed for the treatment of conditions and diseases mediated by the adenosine A 2B receptor activity. Such conditions include, but are not limited to, chronic and acute inflammatory diseases involving degranulation of mast cells, e.g., asthma, allergic rhinitis and allergic dermatitis; impaired sensitivity to insulin, e.g., type 2 diabetes, pre-diabetic state, and impaired glucose tolerance; diseases in which angiogenesis is a key component of pathogenesis, e.g., solid tumors and angiogenic retinopathies; apnea of preterm infants; myocardial reperfusion injury; inflammatory bowel disease; autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and lupus erythematosis; diseases involving microvascular abnormalities of the retina that are mediated by adenosine A 2B receptors, e.g., retinopathy of prematurity, macular degeneration, and diabetic retinopathy; and cardiac diseases including hyperplasia consequent to hypertension, arteriosclerosis, and heart attack.
1. A compound of the formula
wherein
R 1 and R 2 are, independently from each other, C 1 -C 6 alkyl optionally substituted by C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl or monocyclic aryl that may be optionally substituted by 1-3 substituents selected from the group consisting of C 1 -C 4 alkyl, trifluoromethyl, halo, hydroxy, C 1 -C 4 alkoxy, methylenedioxy, C 1 -C 4 alkylthio, cyano, carboxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylthiono or C 1 -C 4 alkylsulfonyl;
R 3 is hydrogen or halogen;
R 4 and R 5 are, independently from each other, hydrogen or C 1 -C 4 alkyl;
R 6 is aryl or heteroaryl each of which may be optionally substituted by 1-3 substituents selected from the group consisting of C 1 -C 6 alkyl, trifluoromethyl, C 3 -C 6 cycloalkyl, halo, hydroxy, C 1 -C 6 alkoxy, methylenedioxy, ethylenedioxy, C 1 -C 6 alkanoyl, C 1 -C 6 alkanoyloxy, C 6 -C 10 aryloxy, amino, C 1 -C 6 alkylamino, di(C 1 -C 6 alkyl)amino, C 1 -C 6 alkylthio, C 6 -C 10 arylthio, nitro, cyano, carboxy, C 1 -C 6 alkoxycarbonyl, carbamoyl, C 1 -C 6 alkylthiono, C 1 -C 6 alkylsulfonyl or C 6 -C 10 arylsulfonyl;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein
R 3 is hydrogen;
or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 2 , wherein
R 5 is hydrogen;
R 6 is monocyclic aryl which may be optionally substituted by 1-3 substituents selected from the group consisting of C 1 -C 6 alkyl, trifluoromethyl, C 3 -C 6 cycloalkyl, halo, hydroxy, C 1 -C 6 alkoxy, methylenedioxy, ethylenedioxy, C 1 -C 6 alkanoyl, C 1 -C 6 alkanoyloxy, C 6 -C 10 aryloxy, amino, C 1 -C 6 alkylamino, di(C 1 -C 6 alkyl)amino, C 1 -C 6 alkylthio, C 6 -C 10 arylthio, nitro, cyano, carboxy, C 1 -C 6 alkoxycarbonyl, carbamoyl, C 1 -C 6 alkylthiono, C 1 -C 6 alkylsulfonyl or C 6 -C 10 arylsulfonyl;
or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 3 , wherein
R 1 and R 2 are, independently from each other, C 1 -C 3 alkyl optionally substituted by cyclopropyl, —CH═CH 2 , —C≡CH or phenyl;
or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 4 , wherein
R 4 is methyl;
or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 1 selected from the group consisting of:
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-phenyl-acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-iodophenyl)-acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-bromophenyl)acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-chlorophenyl)-acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-fluoro-phenyl)-acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-methoxyphenyl)-acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(3,4-dimethylphenyl)-acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(3,4-dimethoxyphenyl)-acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-ethyl-pyrazol-1-yl]-N-(4-chlorophenyl)acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-pyrazol-1-yl]-N-(4-chloro-phenyl)-acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-dimethylaminophenyl)-acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-sec-butylphenyl)-acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(naphthalen-1-yl)-acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(3-methoxylphenyl)-acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(3-chlorophenyl)-acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(3,4-dichlorophenyl)-acetamide;
2-[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-p-tolyl-acetamide;
2-[4-Chloro-3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-chlorophenyl)-acetamide;
2-[4-Bromo-3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-chlorophenyl)-acetamide; and
2-[4-Iodo-3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl]-N-(4-chlorophenyl)-acetamide;
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutically acceptable carriers.