US 2006/0142309 A1Published application

8-Heteroaryl xanthine adenosine A2B receptor antagonists

AssigneeKing Pharmaceuticals Research and Development, Inc.

InventorsPier Baraldi, Pier Borea

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Abstract

The present invention relates generally to compounds of formula (I): wherein X is a five or six-membered heteroaromatic ring, containing one to four heteroatoms, selected from nitrogen, oxygen, or sulfur, provided that at least one heteroatom is nitrogen; and G1 and G2 are independently CH or N. The present invention also relates to the preparation of the compounds, pharmaceutical formulations thereof, and their use in medicine as potent or selective A2B adenosine receptor antagonists and their uses for treating asthma, autoimmune diseases and retinal vascular diseases.

Claims40

Dependent claims

A method of treating diseases mediated by adenosine A2B receptors comprising administering to a patient in need of treatment thereof an effective amount of a compound of formula (I):

wherein
R1and R2 are independently hydrogen, (C1 to C8)alkyl, (C2 to C8)alkenyl, (C2 to C8)alkynyl, (C7 to C14)aralkyl, (C8 to C14)aralkenyl, or (C8 to C14)aralkynyl;
R3 is hydrogen, (C1 to C4)alkyl, (C2 to C5)alkenyl, or (C2 to C5)alkynyl;
A is a carbon-carbon bond, alkyl chain of one to four carbons, alkenyl chain of two to four carbons, or alkynyl chain of two to four carbons;
X is an optionally substituted five or six-membered heteroaromatic ring, containing one to four heteroatoms, selected from nitrogen, oxygen, or sulfur, provided that at least one heteroatom is nitrogen;
M is a (C1 to C8)alkylene, (C2 to C8)alkenylene, or (C2 to C8)alkynylene, wherein at least one of the carbon atoms of the alkylene, alkenylene, or alkynylene group is present as a carbonyl, and one or more of the remaining carbon atoms of the alkylene, alkenylene, or alkynylene group may be replaced by —O—, —N(R7)—, —S—, —S(O)—, or —S(O)2—;
G1 and G2 are independently CH or N;
R4, R5 and R6 are independently hydrogen, (C1 to C4)alkyl, (C2 to C5)alkenyl, (C2 to C5)alkynyl, optionally substituted (C6 to C10)aryl, (C7 to C14)aralkyl, (C8 to C14)aralkenyl, or (C8 to C14)aralkynyl, acyl, optionally substituted alkoxy, aralkoxyalkylthio, amino, substituted amino, disubstituted amino, fluoro, chloro, bromo, iodo, nitro, cyano, azido, hydroxy, sulflhydryl, S(O)alkyl, S(O)2alkyl, CO2H, SO3H;
or
taken together with the carbon atoms to which they are attached either R4 and R5 or R5 and R6 form a five or six-membered heterocyclic or heteroaromatic ring containing one to four hetereoatoms selected from nitrogen, oxygen, or sulfur;
or
taken together with the carbon atoms to which they are attached either R4 and R5 or R5 and R6 form a carbocyclic or heterocyclic fused ring selected from the group of fused rings comprising —OCH2O—, —OCH(R7)O—, —OC(R7)2O—, —OCH2CH2O—, —OCH2CH2—, —CH2CH2O—, —OCH2CH2CH2—, —CH2CH2CH2O—, —OCH═CH—, —CH═CH—O—, —O—CH═CH—O—, —CH═CH—CH═CH—, —CH2CH2CH2— and —CH2CH2CH2CH2—;
R7 is hydrogen, (C1 to C4)alkyl, (C2 to C5)alkenyl, or (C2 to C5)alkynyl;
or a pharmaceutically acceptable salt thereof.

11 more elements

A method of treating diseases mediated by adenosine A2B receptors comprising administering to a patient in need of treatment thereof an effective amount of a compound selected from the group consisting of:

8-(3-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione;
[3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)isoxazol-5-yl]methyl-benzoate;
8-(1-methyl-4-nitro-1H-pyrrol-2-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione;
4-{[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]amino}-4-oxobutanoic acid;
tert-butyl 4-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]amino}-4-oxobutylcarbamate;
4-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]amino}-4-oxobutan-1-aminium chloride;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylacetamide;
2-(2,4-dichlorophenoxy)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
2-(3-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-isobutylphenyl)acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-nitrophenyl)acetamide;
2-[4-benzyloxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
2-[4-hydroxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
(2S)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylpropanamide;
(2R)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylpropanamide;
{3-[(E)-2-( 1,3-dipropyl-7-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)vinyl]isoxazol-5-yl}methyl benzoate;
2-(4-chlorophenoxy)-N-[5-( 1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-fluorophenyl)acetamide;
2-(4-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3-chlorophenyl)acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3-fluorophenyl)acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-[4-(N,N-dimethylamino)phenyl]acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-chlorophenyl)acetamide;
2-(3,4-dimethoxyphenyl-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{[2-(trifluoromethyl)benzyl]oxy}phenyl)acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{4-nitro-benzyloxy}phenyl)acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-[4-(trifluoromethyl)phenyl]acetamide;
phenyl 4-[(E)-2-(7-methyl-1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)vinyl]-1-methyl-1H-pyrrole-2-carboxylate;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]-2-phenylacetamide;
8-(5-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione;
8-(3-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;
N-[5-(2,6-dioxo-1,3-dimethyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylacetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3,4-difluorophenyl)acetamide;
2-(2,3,4-trimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
N-[4-(dimethylamino)phenyl]-N′-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea;
N-(3-chlorophenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-N′-(3-methoxyphenyl)urea;
2-[4-(benzyloxy)-3-methoxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
2-(1,3-benzodioxol-5-yl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-methyl-1H-pyrazol-3-yl]acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-hydroxy-3-methoxyphenyl)acetamide;
N-(4-methylphenyl)-2-{[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide;
N-(4-bromophenyl)-2-{[3-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}acetamide;
N-(4-fluorophenyl)-2-{[3-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}acetamide;
2-{[3-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-yl]oxy}-N-(4-fluorophenyl)acetamide;
2-{[3-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}-N-(4-bromophenyl)acetamide;
2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-fluorophenyl)acetamide;
2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide;
2-{[5-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-fluorophenyl)acetamide;
2-{[5-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide;
N-1,3-benzodioxol-5-yl-2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide;
2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-methoxyphenyl)acetamide;
1-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-3-(4-methoxyphenyl)-urea;
1,3-di-n-propyl-8-{5-[(4-sec-butyl-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;
1,3-di-n-propyl-8-{5-[(4-methyl-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;
1,3-di-n-propyl-8-{5-[(4-(morpholine-4-yl)-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;
1,3-di-n-propyl-8-{5-[(4-carboxy-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;
1,3-di-n-propyl-8-{5-[(3,4-dimethyl-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3yl}-xanthine;
1,3-di-n-propyl-8-{5-[(3,4-dimethoxy-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;
1,3-di-n-propyl-8-{5-[(pyridin-4-yl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;
1,3-di-n-propyl-8-{5-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;
8-(5-{2-[4-(4-fluorophenyl)-piperazin-1-yl]-2-oxo-ethoxy}-2-methyl-2H-pyrazol-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione;
1,3-di-n-propyl-8-{5-[2-oxo-2-(4-methyl-piperazin-1-yl)-ethoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;
8-(5-{2-[4-(4-benzyl-phenyl)-piperazin-1-yl]-2-oxo-ethoxy}-2-methyl-2H-pyrazol-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione;
1,3-di-allyl-8-{5-[2-oxo-2-(4-phenyl-piperazin-1-yl)-ethoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;
1,3-di-n-propyl-8-{3-[(3,4-methylendioxy-phenylcarbamoyl)-methoxy]-isoxazol-5-yl}-xanthine;
1,3-di-n-propyl-8-{3-[(3,4-dimethoxy-phenylcarbamoyl)-methoxy]-isoxazol-5-yl}-xanthine;
1,3-di-n-propyl-8-{3-[(4-fluoro-phenylcarbamoyl)-methoxy]-isoxazol-5-yl }-xanthine;
1,3-di-n-propyl-8-{3-[(4-methoxy-phenylcarbamoyl)-methoxy]-isoxazol-5-yl}-xanthine;
1,3-di-n-propyl-8-{6-[(4-iodo-phenylcarbamoyl)-methoxy]-pyridin-3-yl}-xanthine;
1,3-di-n-propyl-8-{6-[(4-iodo-phenylcarbamoyl)-methoxy]-pyridazin-3-yl}-xanthine;
N-1,3-benzodioxol-5-yl-2-{[5-(2,6-dioxo-1,3-diallyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide;
1,3-di-n-propyl-8-{5-[(4-(ethoxycarbonyl)-phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;
1,3-di-n-propyl-8-(2-hydroxypyridin-5-yl)-xanthine;
and
1,3-di-n-propyl-8-{5-[(4-(aminosulfonyl)phenylcarbamoyl)-methoxy]-2-methyl-2H-pyrazole-3-yl}-xanthine;
or a pharmaceutically acceptable salt thereof.

74 more elements

N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylacetamide;
2-(3-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-nitrophenyl)acetamide;
2-[4-benzyloxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
2-[4-hydroxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-fluorophenyl)acetamide;
2-(4-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3-chlorophenyl)acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3-fluorophenyl)acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-[4-(N,N-dimethylamino)phenyl]acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-chiorophenyl)acetamide;
2-(3,4-dimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{[2-(trifluoromethyl)benzyl]oxy}phenyi)acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-{4-nitro-benzyloxy}phenyl)acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]-2-phenylacetamide;
8-(5-amino-1-methyl-1H-pyrazol-3-yl)-1,3-dipropyl-3,7-dihydro-1H-purine-2,6-dione;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(3,4-difluorophenyl)acetamide;
N-[4-(dimethylamino)phenyl]-N′-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea;
N-(3-chlorophenyl)-N′-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]urea;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-N′-(3-methoxyphenyl)urea;
2-[4-(benzyloxy)-3-methoxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
2-(1,3-benzodioxol-5-yl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-methyl-1H-pyrazol-3-yl]acetamide;
N-(4-bromophenyl)-2-{[3-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}acetamide;
2-{[3-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-5-yl]oxy}-N-(4-bromophenyl)acetamide;
2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-fluorophenyl)acetamide;
2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide;
2-{[5-(1,3-diisobutyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-bromophenyl)acetamide;
N-1,3-benzodioxol-5-yl-2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide;
and
2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-methoxyphenyl)acetamide;
or a pharmaceutically acceptable salt thereof.

29 more elements

2-(3-methoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-(4-nitrophenyl)acetamide;
2-[4-benzyloxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
2-[4-hydroxyphenyl]-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-[4-(N,N-dimethylamino)phenyl]acetamide;
2-(3,4-dimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide;
8-(3-amino-1-methyl-1H-pyrazol-5-yl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;
N-[5-(2,6-dioxo-1,3-dimethyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]-2-phenylacetamide;
N-(4-methylphenyl)-2-{[5-(1,3-dipropyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}acetamide;
and
2-{[5-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-N-(4-methoxyphenyl)acetamide;
or a pharmaceutically acceptable salt thereof.

9 more elements

A method of treating diseases mediated by adenosine A2B receptors comprising administering to a patient in need of treatment thereof an effective amount of a compound of formula (IA):

wherein
R1 and R2 are independently (C1 to C3)alkyl or allyl;
A is a carbon-carbon bond;
X is selected from the group consisting of
M is selected from the group consisting of —NHC(O)CH2—, —NHC(O)CH2O—, —NHC(O)CH(CH3)—, and —NHC(O)NH—;
R4, R5 and R6 are independently hydrogen, (C1 to C4)alkyl, (C2 to C5)alkenyl, (C2 to C5)alkynyl, optionally substituted (C6 to C10)aryl, (C7 to C14)aralkyl, (C8 to C14)aralkenyl, or (C8 to C14)aralkynyl, acyl, optionally substituted alkoxy, aralkoxy, amino, substituted amino, disubstituted amino, fluoro, chloro, bromo, nitro, hydroxy, CO2H;
or
taken together with the carbon atoms to which they are attached either R4 and R5 or R5 and R6 form a five or six-membered heterocyclic or heteroaromatic ring containing one to four hetereoatoms selected from nitrogen, oxygen, or sulfur;
or
taken together with the carbon atoms to which they are attached either R4 and R5 or R5 and R6 form a heterocyclic fused ring in which either R4 and R5 or R5 and R6 combined are —OCH2O—;
or a pharmaceutically acceptable salt thereof.

8 more elements

A method of treating diseases mediated by adenosine A2B receptors comprising administering to a patient in need of treatment thereof an effective amount of a compound of formula (IB):

wherein
R1 and R2 are independently (C1 to C4)alkyl;
A is a carbon-carbon bond;
X is selected from the group consisting of
M is —OCH2C(O)NH—;
G1 and G2 are independently CH or N;
R4, R5 and R6 are independently hydrogen, (C1 to C4)alkyl, (C2 to C5)alkenyl, (C2 to C5)alkynyl, optionally substituted (C6 to C10)aryl, (C7 to C14)aralkyl, (C8 to C14)aralkenyl, or (C8 to C14)aralkynyl, acyl, optionally substituted alkoxy, aralkoxy, amino, substituted amino, disubstituted amino, fluoro, chloro, bromo, nitro, hydroxy, CO2H;
or
taken together with the carbon atoms to which they are attached either R4 and R5 or R5 and R6 form a five or six-membered heterocyclic or heteroaromatic ring containing one to four hetereoatoms selected from nitrogen, oxygen, or sulfur;
or
taken together with the carbon atoms to which they are attached either R4 and R5 or R5 and R6 form a heterocyclic fused ring comprising —OCH2O—;
or a pharmaceutically acceptable salt thereof.

9 more elements

A method of treating diseases mediated by adenosine A2B receptors comprising administering to a patient in need of treatment thereof an effective amount of a compound of formula (IC):

wherein
R1 and R2 are independently (C1 to C3)alkyl;
R3 is hydrogen or methyl;
A is selected from the group consisting of a carbon-carbon bond and —CH═CH—;
X is
M is —CH2OC(O)—;
R4, R5 and R6 are independently hydrogen, (C1 to C4)alkyl, (C2 to C5)alkenyl, (C2 to C5)alkynyl, optionally substituted (C6 to C10)aryl, (C7 to C14)aralkyl, (C8 to C14)aralkenyl, or (C8 to C14)aralkynyl, acyl, optionally substituted alkoxy, aralkoxy, amino, substituted amino, disubstituted amino, fluoro, chloro, bromo, nitro, hydroxy, CO2H;
or
taken together with the carbon atoms to which they are attached either R4 and R5 or R5 and R6 form a five or six-membered heterocyclic or heteroaromatic ring containing one to four hetereoatoms selected from nitrogen, oxygen, or sulfur;
or a pharmaceutically acceptable salt thereof.

7 more elements

A method of treating diseases mediated by adenosine A2B receptors comprising administering to a patient in need of treatment thereof an effective amount of a compound of formula (I):

wherein
R1 and R2 are independently hydrogen, (C1 to C8)alkyl, (C2 to C8)alkenyl, (C2 to C8)alkynyl, (C7 to C14)aralkyl, (C8 to C14)aralkenyl, or (C8 to C14)aralkynyl;
R3 is hydrogen, (C1 to C4) alkyl, (C2 to C5)alkenyl, or (C2 to C5)alkynyl;
A is a carbon-carbon bond, alkyl chain of one to four carbons, alkenyl chain of two to four carbons, or alkynyl chain of two to four carbons;
X is a five or six-membered heteroaromatic ring, containing one to four heteroatoms, selected from nitrogen, oxygen, or sulfur, provided that at least one heteroatom is nitrogen, optionally substituted by one or two substituents selected from the group consisting of lower alkyl, amino, hydroxy, alkyloxy, acyloxy and acylamino;
M is a (C1 to C8)alkylene, (C2 to C8)alkenylene, or (C2 to C8)alkynylene, wherein at least one of the carbon atoms of the alkylene, alkenylene, or alkynylene group is present as a carbonyl, and one or more of the remaining carbon atoms of the alkylene, alkenylene, or alkynylene group may be replaced by —O—, —N(R7)—, —S—, —S(O)—, or —S(O)2—;
or a carbon substituted with a lower alkyl group;
G1 and G2 are independently CH or N;
R4, R5 and R6 are independently hydrogen, (C1 to C4)alkyl, (C2 to C5)alkenyl, (C2 to C5)alkynyl, optionally substituted (C6 to C1)aryl, (C7 to C14)aralkyl, (C8 to C14)aralkenyl, or (C8 to C14)aralkynyl, acyl, optionally substituted alkoxy, aralkoxyalkylthio, amino, substituted amino, disubstituted amino, fluoro, chloro, bromo, iodo, nitro, cyano, azido, hydroxy, sulflhydryl, S(O)alkyl, S(O)2alkyl, CO2H, SO3H;
or
taken together with the carbon atoms to which they are attached either R4 and R5 or R5 and R6 form a five or six-membered heterocyclic or heteroaromatic ring containing one to four hetereoatoms selected from nitrogen, oxygen, or sulfur;
or
taken together with the carbon atoms to which they are attached either R4 and R5 or R5 and R6 form a carbocyclic or heterocyclic fused ring selected from the group of fused rings comprising —OCH2O—, —OCH(R7)O—, —OC(R7)2O—, —OCH2CH2O—, —OCH2CH2—, —CH2CH2O—, —OCH2CH2CH2—, —CH2CH2CH2O—, —OCH═CH—, —CH═CH—O—, —O—CH═CH—O—, —CH═CH—CH═CH—, —CH2CH2CH2— and —CH2CH2CH2CH2—;
R7 is hydrogen, (C1 to C4)alkyl, (C2 to C5)alkenyl, or (C2 to C5)alkynyl;
or a pharmaceutically acceptable salt thereof.

12 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/359,661Filed 22 Feb 2006
Priority: 1 Feb 2002
Published: 29 Jun 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification25 codes

C07D 473/08
With radicals containing only hydrogen and carbon atoms, attached in position 1 or 3: with methyl radicals in positions 1 and 3, e.g. theophylline
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 5/50
Of the pancreatic hormones: for increasing or potentiating the activity of insulin

Family

Application60/353,317Us provisional application · filed 1 Feb 2002
Application10/357,865Division · filed 3 Feb 2003
Application11/359,661Division · filed 22 Feb 2006
US 2003/0207879 A1Published application
US 7,205,403 B2Related patent
US 7,335,655 B2Related patent
US 2006/0142309 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A method of treating diseases mediated by adenosine A2B receptors comprising administering to a patient in need of treatment thereof an effective amount of a compound of formula (I):

wherein
R1and R2 are independently hydrogen, (C1 to C8)alkyl, (C2 to C8)alkenyl, (C2 to C8)alkynyl, (C7 to C14)aralkyl, (C8 to C14)aralkenyl, or (C8 to C14)aralkynyl;
R3 is hydrogen, (C1 to C4)alkyl, (C2 to C5)alkenyl, or (C2 to C5)alkynyl;
A is a carbon-carbon bond, alkyl chain of one to four carbons, alkenyl chain of two to four carbons, or alkynyl chain of two to four carbons;
X is an optionally substituted five or six-membered heteroaromatic ring, containing one to four heteroatoms, selected from nitrogen, oxygen, or sulfur, provided that at least one heteroatom is nitrogen;
M is a (C1 to C8)alkylene, (C2 to C8)alkenylene, or (C2 to C8)alkynylene, wherein at least one of the carbon atoms of the alkylene, alkenylene, or alkynylene group is present as a carbonyl, and one or more of the remaining carbon atoms of the alkylene, alkenylene, or alkynylene group may be replaced by —O—, —N(R7)—, —S—, —S(O)—, or —S(O)2—;
G1 and G2 are independently CH or N;
R4, R5 and R6 are independently hydrogen, (C1 to C4)alkyl, (C2 to C5)alkenyl, (C2 to C5)alkynyl, optionally substituted (C6 to C10)aryl, (C7 to C14)aralkyl, (C8 to C14)aralkenyl, or (C8 to C14)aralkynyl, acyl, optionally substituted alkoxy, aralkoxyalkylthio, amino, substituted amino, disubstituted amino, fluoro, chloro, bromo, iodo, nitro, cyano, azido, hydroxy, sulflhydryl, S(O)alkyl, S(O)2alkyl, CO2H, SO3H;
or
taken together with the carbon atoms to which they are attached either R4 and R5 or R5 and R6 form a five or six-membered heterocyclic or heteroaromatic ring containing one to four hetereoatoms selected from nitrogen, oxygen, or sulfur;
or
taken together with the carbon atoms to which they are attached either R4 and R5 or R5 and R6 form a carbocyclic or heterocyclic fused ring selected from the group of fused rings comprising —OCH2O—, —OCH(R7)O—, —OC(R7)2O—, —OCH2CH2O—, —OCH2CH2—, —CH2CH2O—, —OCH2CH2CH2—, —CH2CH2CH2O—, —OCH═CH—, —CH═CH—O—, —O—CH═CH—O—, —CH═CH—CH═CH—, —CH2CH2CH2— and —CH2CH2CH2CH2—;
R7 is hydrogen, (C1 to C4)alkyl, (C2 to C5)alkenyl, or (C2 to C5)alkynyl;
or a pharmaceutically acceptable salt thereof.

11 more elements

Facts

Application

11/359,661Filed 22 Feb 2006

Priority

1 Feb 2002

Published

29 Jun 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification25 codes

C07D 473/08
With radicals containing only hydrogen and carbon atoms, attached in position 1 or 3: with methyl radicals in positions 1 and 3, e.g. theophylline
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 5/50
Of the pancreatic hormones: for increasing or potentiating the activity of insulin

Family

Application60/353,317Us provisional application · filed 1 Feb 2002

Application10/357,865Division · filed 3 Feb 2003

Application11/359,661Division · filed 22 Feb 2006

US 2003/0207879 A1Published application

US 7,205,403 B2Related patent

US 7,335,655 B2Related patent

US 2006/0142309 A1This patent

From the US filing history. Foreign family members aren’t listed.