Adenosine A3 receptor modulators
AssigneeKing Pharmaceuticals Research and Development, Inc.
InventorsPier Baraldi, Pier Borea
Life of this patent
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Abstract
The compounds of the following formula: wherein R, R2, R3 and A have the meanings given in the specification, are endowed with selective A3 adenosine receptor antagonist activity. These compounds can be used in a pharmaceutical composition to treat disorders caused by excessive activation of the A3 receptor, or can be used in a diagnostic application to determine the relative binding of other compounds to the A3 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 A3 receptors.
Claims76
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A method of treating diseases mediated by adenosine A3 receptors, wherein said diseases are selected from the group consisting of hypertension, inflammation, mast cell degranulation, and cardiac hypoxia, and protecting against 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:
- R2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl substituted heteroaryl or aryl;
- R3 is furan;
- and
- R4 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;
- and pharmaceutically acceptable salts thereof.
A method of treating cancer disease with high concentrations of adenosine A3 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:
- R2 is hydrogen alkyl, substituted alkyl alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;
- R3 is furan:
- and
- R4 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:
- and pharmaceutically acceptable salts thereof and
- wherein the cancer disease is selected from the group consisting of leukemia and lymphoma.
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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[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[1,5-c]pyrimidine,
- 5-[[(3-Chlorophenyl)amino]carbonyl]amino-8-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]-1,2,4-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-r[(4-Methoxyphenyl)amino]carbonyl]amino-8-(2-(phenyl)ethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[15-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)prolpyl)-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-1-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 allergic disease is selected from the group consisting of allergic rhinitis, allergic pollinosis, poison ivy induced responses, urticaria, scleroderma, arthritis, inflammatory bowel disease and asthma.
A method of treating cancer disease with high concentrations of adenosine A3 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[1,5-c]pyrimidine,
- 5-[[(3-Chlorophenyl)amino]carbonyl]amino-8-butyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-]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-[r(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-1-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.
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A method of treating cancer disease with high concentrations of adenosine A3 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;
- R2 is hydrogen alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;
- R3 is furan;
- and
- R6 is heteroaryl or substituted heteroaryl;
- and
- pharmaceutically acceptable salts thereof;
- and wherein the cancer disease is selected from the group consisting of leukemia and lymphoma.
Dependencies are inferred from the claim text.