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US 2003/0144266 A1Published application
Adenosine A3 receptor modulators
AssigneeKing Pharmaceuticuals Research & Development, Inc.
InventorsPier Giovanni Baraldi, Pier Andrea Borea
Life of this patent
Estimating the term…
Abstract
The compounds of the following formula: 1 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.
Claims74
A compound of the following formula:
- 24
- wherein:
- A is imidazole, pyrazole, or triazole;
- R is —C(X)R1, —C(X)—N(R1)2, —C(X)OR1, —C(X)SR1, —SOnR1, —SOnSR1, or —SOn—N(R1)2;
- R1 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, heterocyclic, lower alkenyl, lower alkanoyl, or, if linked to a nitrogen atom, then taken together with the nitrogen atom, forms an azetidine ring or a 5-6 membered heterocyclic ring containing one or more heteroatoms;
- R2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;
- R3 is furan, pyrrole, thiophene, benzofuran, benzypyrrole, benzothiophene, optionally substituted with one or more substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acyloxy, acylamino, alkaryl, aryl, substituted aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, thioalkoxy, substituted thioalkoxy, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl, —SO2-heteroaryl, and trihalomethyl;
- X is O, S, or NR1;
- and
- pharmaceutically acceptable salts thereof.
7 more elements
A compound of the following formula:
- 25
- 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.
6 more elements
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-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-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.
24 more elements
A radiolabeled compound of the following formula:
- 26
- wherein:
- A is imidazole, pyrazole, or triazole;
- R is —C(X)R1, —C(X)—N(R1)2, —C(X)O R1, —C(X)S R1, —SOnR1, —SOnSR1, or SOn—N(R1)2;
- R1 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, heterocyclic, lower alkenyl, lower alkanoyl, or, if linked to a nitrogen atom, then taken together with the nitrogen atom, forms an azetidine ring or a 5-6 membered heterocyclic ring containing one or more heteroatoms;
- R2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, aryl or substituted aryl;
- R3 is furan, pyrrole, thiophene, benzofuran, benzypyrrole, benzothiophene, optionally substituted with one or more substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acyloxy, acylamino, alkaryl, aryl, substituted aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, thioalkoxy, substituted thioalkoxy, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl, —SO2-heteroaryl, and trihalomethyl;
- X is O, S, or NR1;
- pharmaceutically acceptable salts thereof;
- wherein one of more of the hydrogen atoms is a radioisotope.
7 more elements
A radiolabeled compound of the following formula:
- 27
- wherein:
- A is imidazole, pyrazole, or triazole;
- R is —C(X)R1, —C(X)—N(R1)2, —C(X)OR1, —C(X)SR1, —SOnR1, —SOnSR1, or —SOn—N(R1)2,
- R1 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, heterocyclic, lower alkenyl, lower alkanoyl, or, if linked to a nitrogen atom, then taken together with the nitrogen atom, forms an azetidine ring or a 5-6 membered heterocyclic ring containing one or more heteroatoms;
- R2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, aryl or substituted aryl;
- R3 is furan, pyrrole, thiophene, benzofuran, benzypyrrole, benzothiophene, optionally substituted with one or more substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acyloxy, acylamino, alkaryl, aryl, substituted aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, thioalkoxy, substituted thioalkoxy, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl, —SO2-heteroaryl, and trihalomethyl;
- X is O, S, or NR;
- pharmaceutically acceptable salts thereof;
- wherein 14C is a carbon radioisotope.
7 more elements
A fluorescent labeled compound of the following formula:
- 28
- wherein:
- A is imidazole, pyrazole, or triazole;
- R is —C(X)R1, —C(X)—N(R1)2, —C(X)OR1, —C(X)SR1, —SOnR1—SOnSR1 or —SOn—N(R1)2;
- R1 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, heterocyclic, lower alkenyl, lower alkanoyl, or, if linked to a nitrogen atom, then taken together with the nitrogen atom, forms an azetidine ring or a 5-6 membered heterocyclic ring containing one or more heteroatoms;
- R2 is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl;
- R3 is furan, pyrrole, thiophene, benzofuran, benzypyrrole, benzothiophene, optionally substituted with one or more substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acyloxy, acylamino, alkaryl, aryl, substituted aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, thioalkoxy, substituted thioalkoxy, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO2-alkyl, —SO2-substituted alkyl, —SO2-aryl, —SO2-heteroaryl, and trihalomethyl;
- X is O, S, or NR1;
- pharmaceutically acceptable salts thereof;
- further comprising one or more fluorescent labels;
- wherein the fluorescent label is selected from the group of fluorescent labels consisting of fluorescein, 5,6-carboxymethyl fluorescein, Texas red, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose, coumarin, dansyl chloride and rhodamine.
8 more elements
A compound of the following formula:
- 29
- 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.
6 more elements
Dependencies are inferred from the claim text.