2-(N-pyrazolo)adenosines with application as adenosine A2A receptor agonists

Abstract

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.

What we claim is: 
     
       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 .