Details for Patent: 7,271,171

Title:	Adenosine A.sub.3 receptor modulators
Abstract:	The compounds of the following formula: ##STR00001## wherein R, R.sup.2, R.sup.3 and A have the meanings given in the specification, are endowed with selective A.sub.3 adenosine receptor antagonist activity. These compounds can be used in a pharmaceutical composition to treat disorders caused by excessive activation of the A.sub.3 receptor, or can be used in a diagnostic application to determine the relative binding of other compounds to the A.sub.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.sub.3 receptors.
Inventor(s):	Baraldi; Pier Giovanni (Ferrara, IT), Borea; Pier Andrea (Ferrara, IT)
Assignee:	King Pharmaceuticals Research and Development, Inc. (Cary, NC)
Filing Date:	Jun 27, 2005
Application Number:	11/169,311
Claims:	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: ##STR00024## wherein: A is imidazole, pyrazole, or triazole; R.sup.2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl; R.sup.3 is furan; R.sup.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.sup.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.sub.3 receptors, comprising administering to a patient in need of treatment thereof an effective amount of a compound of the following formula: ##STR00025## wherein: A is imidazole, pyrazole, or triazole; R.sup.2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl; R.sup.3 is furan; R.sup.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.sup.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)-pyrazol- o[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine, 5-[[(3-Chlorophenyl)amino]]carbonyl]amino-8-(2-isopentenyl)-2-(2-furyl)py- razolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine, 5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-(2-isopentenyl)-2-(2-furyl)-p- yrazolo[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-t- riazolo[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.sub.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)-pyrazol- o[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine, 5-[[(3-Chlorophenyl)amino]]carbonyl]amino-8-(2-isopentenyl)-2-(2-furyl)py- razolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine, 5-[[(4-Methoxyphenyl)amino]carbonyl]amino-8-(2-isopentenyl)-2-(2-furyl)-p- yrazolo[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-t- riazolo[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: ##STR00026## wherein: A is imidazole, pyrazole, or triazole; R.sup.2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl; R.sup.3 is furan; R.sup.6 is heteroaryl or substituted heteroaryl; or a pharmaceutically acceptable salt thereof. 12. The method of claim 11 wherein R.sup.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.sub.3 receptors, comprising administering to a patient in need of treatment thereof an effective amount of a compound of the following formula: ##STR00027## wherein: A is imidazole, pyrazole, or triazole; R.sup.2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl; R.sup.3 is furan; R.sup.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.sup.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.sup.2 is methyl, and R.sup.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: ##STR00028## wherein: A is imidazole, pyrazole, or triazole; R.sup.2 is hydrogen alkyl substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl; R.sup.3 is furan; R.sup.6 is heteroaryl or substituted heteroaryl; or a pharmaceutically acceptable salt thereof. 23. The method of claim 22 wherein R.sup.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: ##STR00029## wherein: A is imidazole, pyrazole, or triazole; R.sup.2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl; R.sup.3 is furan; R.sup.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.sup.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.