The compounds of the following formula: wherein R, R 2 , R 3 and A have the meanings given in the specification, are endowed with selective A 3 adenosine receptor antagonist activity. These compounds can be used in a pharmaceutical composition to treat disorders caused by excessive activation of the A 3 receptor, or can be used in a diagnostic application to determine the relative binding of other compounds to the A 3 receptor. The compounds can be labeled, for example with fluorescent or radiolabels, and the labels used in vivo or in vitro to determine the presence of tumor cells which possess a high concentration of adenosine A 3 receptors.
1. A method of inhibiting mast cell degranulation, comprising administering to a patient in need thereof an effective amount of a compound of the following formula:
wherein:
A is imidazole, pyrazole, or triazole;
R 2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;
R 3 is furan;
R 4 is hydrogen, alkyl, amino, substituted alkyl, alkyl substituted amino, alkyl di-substituted amino, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heterocycle, aryl, substituted aryl, sulfonyl or substituted sulfonyl;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 wherein R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl.
3. The method of claim 1 wherein A is a pyrazolo ring.
4. The method of claim 1 wherein A is a triazolo ring.
5. A method of treating cancer disease expressing adenosine A 3 receptors, comprising administering to a patient in need of treatment thereof an effective amount of a compound of the following formula:
wherein:
A is imidazole, pyrazole, or triazole;
R 2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;
R 3 is furan;
R 4 is hydrogen, alkyl, amino, substituted alkyl, alkyl substituted amino, alkyl di-substituted amino, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heterocycle, aryl, substituted aryl, sulfonyl or substituted sulfonyl;
or a pharmaceutically acceptable salt thereof; and
wherein the cancer disease is selected from the group consisting of leukemia and lymphoma.
6. The method of claim 5 wherein R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl.
7. The method of claim 5 wherein A is a pyrazolo ring.
8. The method of claim 5 wherein A is a triazolo ring.
9. A method of treating allergic disease, comprising administering to a patient in need of treatment thereof an effective amount of a compound selected from the group of compounds consisting of:
5-[[(3-Chlorophenyl)amino] carbonyl]amino-8-methyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(3-Chlorophenyl)amino]carbonyl]amino-8-ethyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-ethyl-2-(2-furyl)-pyrazolo[4,3-e]- 1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(3-Chlorophenyl)amino]carbonyl]amino-8-propyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-propyl-2-(2-furyl)-pyrazole[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(3-Chlorophenyl)amino]carbonyl]amino-3-butyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-butyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(3-Chlorophenyl)amino]carbonyl]amino-8-isopentyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-isopentyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(3-Chlorophenyl)amino]]carbonyl]amino-8-(2-isopentenyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-(2-isopentenyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(3-Chlorophenyl)amino]carbonyl]amino-8-(2-(phenyl)ethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-(2-(phenyl)ethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(3-Chlorophenyl)amino]carbonyl]amino-8-(3-(phenyl)propyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-(3-(phenyl)propyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[(Benzyl)carbonyl]amino-8-isopentyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[(Benzyl)carbonyl]amino-8-(3-(phenyl)propyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
N-[4-(diethylamino)phenyl]-N-[2-(2-furyl)-8-methyl-8H-pyrazolo [4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]urea,
N-[8-methyl-2-(2-furyl)-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]-N-′[4-(dimethylamino)phenyl]urea hydrochloride,
N-[8-methyl-2-(2-furyl)-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl[-N′-[4-(dimethylamino)phenyl]urea hydrochloride,
N-(2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-N′-[4-(morpholin-4-ylsulfonyl)phenyl]urea,
N-[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]-N′-{4-[(4-methylpiperazin-l-yl)sulfonyl]-phenyl}urea,
N-[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4triazolo[1,5-c]pyrimidin-5-yl]-N′-pyridin-4-yl urea,
N-[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]-N′-pyridin-4-ylurea hydrochloride,
5-[[(4-methoxyphenyl)amino]carbonyl]amino-8-propyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine, and
5-[[(4-methoxyphenyl)amino]carbonyl]amino-8-ethyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine; and
wherein the allergic disease is asthma.
10. A method of treating cancer disease expressing adenosine A 3 receptors, comprising administering to a patient in need of treatment thereof an effective amount of a compound selected from the group of compounds consisting of:
5-[[(3-Chlorophenyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(3-Chlorophenyl)amino]carbonyl]amino-8-ethyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-ethyl-2-(2-furyl)-pyrazolo[[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(3-Chlorophenyl)amino]carbonyl]amino-8-propyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-propyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[5-c]pyrimidine,
5-[[(3-Chlorophenyl)amino]carbonyl]amino-8-butyl-2-(2-fury9-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-butyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(3-Chlorophenyl)amino]carbonyl]amino-8-isopentyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-isopentyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(3-Chlorophenyl)amino]]carbonyl]amino-8-(2-isopentenyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-(2-isopentenyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(3-Chlorophenyl)amino]carbonyl]amino-8-(2-(phenyl)ethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-(2-(phenyl)ethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(3-Chlorophenyl)amino]carbonyl]amino-8-(3-(phenyl)propyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-(3-(phenyl)propyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[(Benzyl)carbonyl]amino-8-isopentyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
5-[(Benzyl)carbonyl]amino-8-(3-(phenyl)propyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine,
N-4-[(diethylamino)phenyl-N′-[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]urea,
N-[8-methyl-2-(2-furyl)-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]-N′-[4-(dimethylamino)phenyl]urea hydrochloride,
N-[8-methyl-2-(2-furyl)-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl-N′-4-(dimethylamino)phenyl]urea hydrochloride,
N-(2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl)-N′-[4-(morpholin-4-ylsulfonyl)phenyl]urea,
N-[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]-N′-{4-[(4-methylpiperazin-l-yl)sulfonyl]-phenyl}urea,
N-[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]-N′-pyridin-4-yl urea,
N[-2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]-N′-pyridin-4-ylurea hydrochloride,
5-[[(4-methoxyphenyl)amino]carbonyl]amino-8-propyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine, and
5-[[(4-methoxyphenyl)amino]carbonyl]amino-8-ethyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine; and
wherein the cancer disease is selected from the group consisting of leukemia and lymphoma.
11. A method of inhibiting mast cell degranulation, comprising administering to a patient in need thereof an effective amount of a compound of the following formula:
wherein:
A is imidazole, pyrazole, or triazole;
R 2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;
R 3 is furan;
R 6 is heteroaryl or substituted heteroaryl;
or a pharmaceutically acceptable salt thereof.
12. The method of claim 11 wherein R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl.
13. The method of claim 11 wherein A is a pyrazolo ring.
14. The method of claim 11 wherein A is a triazolo ring.
15. A method of treating cancer disease expressing adenosine A 3 receptors, comprising administering to a patient in need of treatment thereof an effective amount of a compound of the following formula:
wherein:
A is imidazole, pyrazole, or triazole;
R 2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;
R 3 is furan;
R 6 is heteroaryl or substituted heteroaryl;
or a pharmaceutically acceptable salt thereof; and
wherein the cancer disease is selected from the group consisting of leukemia and lymphoma.
16. The method of claim 15 wherein R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl.
17. The method of claim 15 wherein A is a pyrazolo ring.
18. The method of claim 15 wherein A is a triazolo ring.
19. The method of claim 5 wherein A is a pyrazolo ring, R 2 is methyl, and R 4 is dimethylamino or diethylamino.
20. The method of claim 15 , wherein the compound is N-[2-(2-furyl)-8-methyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-yl]N′-pyridin-4-yl urea; or a pharmaceutically acceptable salt thereof.
21. The method of claim 20 , wherein the pharmaceutically acceptable salt is the hydrochloride salt.
22. A method of treating hypertension, cardiac hypoxia and cerebral ischemia, comprising administering to a patient in need of treatment thereof an effective amount of a compound of the following formula:
wherein:
A is imidazole, pyrazole, or triazole;
R 2 is hydrogen alkyl substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;
R 3 is furan;
R 6 is heteroaryl or substituted heteroaryl;
or a pharmaceutically acceptable salt thereof.
23. The method of claim 22 wherein R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl.
24. The method of claim 22 wherein A is a pyrazolo ring.
25. The method of claim 22 wherein A is a triazolo ring.
26. A method of treating hypertension, cardiac hypoxia and cerebral ischemia, comprising administering to a patient in need of treatment thereof an effective amount of a compound of the following formula:
wherein:
A is imidazole, pyrazole, or triazole;
R 2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;
R 3 is furan;
R 4 is hydrogen, alkyl, amino, substituted alkyl, alkyl substituted amino, alkyl di-substituted amino, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heterocycle, aryl, substituted aryl, sulfonyl or substituted sulfonyl;
or a pharmaceutically acceptable salt thereof.
27. The method of claim 26 wherein R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl.
28. The method of claim 26 wherein A is a pyrazolo ring.
29. The method of claim 26 wherein A is a triazolo ring.