2-(N-pyrazolo)adenosines with application as adenosine A
View Patent ↗N-pyrazole substituted 2-adenosine compounds and methods for using the compounds as A 2 A-adenosine receptor agonists useful to stimulate mammalian coronary vasodilation for therapeutic purposes and as adjuncts in cardiological imaging.
1. A compound having the formula:
wherein R 1 =CH 2 OH;
R 3 is selected from the group consisting of CO 2 R 20 , —CONR 7 R 8 , and aryl, wherein the aryl substituent is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, alkyl, and OR 20 ;
R 7 is selected from the group consisting of hydrogen, straight or branched C 1-15 alkyl and C 3-8 cycloalkyl, wherein the alkyl substituent is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of aryl and CO 2 R 20 , and wherein the optional aryl substituent is optionally substituted with halo;
R 8 is selected from the group consisting of hydrogen, straight or branched C 1-15 alkyl and C 3-8 cycloalkyl;
R 20 is selected from the group consisting of hydrogen and C 1-15 alkyl;
and wherein R 2 and R 4 are hydrogen.
2. The compound of claim 1 wherein R 3 is CO 2 R 20 ; and R 20 is selected from the group consisting of hydrogen and C 1-4 alkyl.
3. The compound of claim 1 wherein R 3 is CONR 7 R 8 ;
R 7 is selected from the group consisting of hydrogen, straight or branched C 1-10 alkyl and C 3-5 cycloalkyl, wherein the alkyl substituent is optionally substituted with from 1 to 2 substituents independently selected from the group consisting of aryl and CO 2 R 20 ;
R 8 is selected from the group consisting of hydrogen, straight and branched C 1-3 alkyl and C 3-5 cycloalkyl; and
R 20 is selected from the group consisting of C 1-4 alkyl.
4. The compound of claim 1 wherein R 3 is aryl, wherein the aryl substituent is optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, alkyl and OR 20 ; and
R 20 is selected from and the group consisting of C 1-4 alkyl.
5. The compound of claim 2 wherein R 3 is CO 2 R 20 ; and
R 20 is selected from the group consisting of hydrogen and C 1-4 alkyl.
6. The compound of claim 3 wherein R 7 is selected from the group consisting of hydrogen, C 1-3 alkyl and cyclopentyl, wherein the alkyl substituent is optionally substituted with from 1 to 2 substituents, independently selected from the group consisting of phenyl and CO 2 R 20 and wherein each optional phenyl substituent is optionally substituted with halo;
R 8 is selected from hydrogen and methyl; and
R 20 is selected from hydrogen and ethyl.
7. The compound of claim 4 wherein
R 3 is aryl, wherein the aryl substituent is phenyl optionally substituted with from 1 to 2 substituents independently selected from the group consisting of chloro, methyl and OR 20 ;
and R 20 is methyl.
8. The compound of claim 1 selected from the group consisting of ethyl 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4- carboxylate;
(4S,2R,3R,5R)-2-{6-amino-2-[4-(4-chlorophenyl)-pyrazolyl]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol;
(4S,2R,3R,5R)-2-{6-amino-2-[4-(4-methoxyphenyl)pyrazolyl]purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol;
(4S,2R,3R,5R)-2-{6-amino-2-[4-(4-methylphenyl)pyrazolyl]purin-9-yl}-5-(hydroxymethyl)-oxolane-3,4-diol;
(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N- methylcarboxamide;
1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxylic acid;
(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N,N- dimethylcarboxamide;
(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N- ethylcarboxamide;
1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazole-4-carboxamide;
1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N- (cyclopentyl)carboxamide;
(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N-[(4-chlorophenyl)methyl]carboxamide, and
ethyl 2-[(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4- yl)carbonylamino]acetate.
9. A method for stimulating coronary vasodilation in a mammal comprising administering by intravenous bolus injection an amount of a compound of claim 1 that is sufficient to stress the heart and induce a coronary steal situation for the purpose of imaging the heart.
10. The method of claim 9 wherein the mammal is a human.
11. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutical excipients.
12. The pharmaceutical composition of claim 11 wherein the pharmaceutical composition is in the form of a solution.
13. The compound of claim 8 wherein the compound is (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N- methylcarboxamide.
14. The compound of claim 8 wherein the compound is 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N- (cyclopentyl)carboxamide.
15. The compound of claim 8 wherein the compound is (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5(hydroxymethyl)oxolan-2-yl]-6-aminopurin-2-yl}pyrazol-4-yl)-N- ethylcarboxamide.
16. A method of dilating the coronary vessels of a mammal, as an adjunct to angioplasty, with the pharmaceutical composition of claim 11 .
17. A method for adjunctive therapy in conjunction with angioplasty in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 .
18. A method for inhibition of platelet aggregation in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 .