Partial and full agonists of a1 adenosine receptors

Abstract

Disclosed are novel compounds that are partial and full A 1 adenosine receptor agonists, useful for treating various disease states, in particular tachycardia and atrial flutter, angina, myocardial infarction and hyperlipidemia.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is cycloalkyl or heterocyclyl; 
 R 2  is hydrogen; 
 R 3  is phenyl optionally substituted by halo, lower alkyl of 1-4 carbon atoms, or lower alkoxy of 1-4 carbon atoms, or R 3  is heteroaryl optionally substituted by halo, lower alkyl of 1-4 carbon atoms, lower alkoxy of 1-4 carbon atoms, or phenyl optionally substituted by halo, lower alkyl of 1-4 carbon atoms, or lower alkoxy of 1-4 carbon atoms; 
 R 4  and R 5  are independently hydrogen or acyl; 
 T and X are independently a covalent bond or alkylene of 1-3 carbon atoms; 
 Y is —S—; and 
 Z is alkylene of 1-3 carbon atoms. 
 
     
     
         2 . The compound of  claim 1 , wherein R 4  and R 5  are hydrogen. 
     
     
         3 . The compound of  claim 2 , wherein R 1  is cycloalkyl and X and T are both covalent bonds. 
     
     
         4 . The compound of  claim 3 , wherein R 1  is cyclopentyl and Z is methylene. 
     
     
         5 . The compound of  claim 4 , wherein R 3  is phenyl optionally substituted by halo, lower alkyl of 1-4 carbon atoms, or lower alkoxy of 1-4 carbon atoms. 
     
     
         6 . The compound of  claim 5 , wherein R 3  is heteroaryl optionally substituted by halo, lower alkyl of 1-4 carbon atoms, lower alkoxy of 1-4 carbon atoms, or phenyl optionally substituted by halo, lower alkyl of 1-4 carbon atoms, or lower alkoxy of 1-4 carbon atoms. 
     
     
         7 . The compound of  claim 6 , wherein R 3  is 3-(2-chlorophenyl)isoxazol-5-yl, namely (4S,2R,3R,5R)-2-[(3-(2-chlorophenyl)isoxazol-5-ylthio)methyl]-2-[6-(cyclopentylamino)-purin-9-yl]tetrahydrofuran-3,4-diol. 
     
     
         8 . The compound of  claim 6 , wherein R 3  is 3-(4-chlorophenyl)isoxazol-5-yl, namely (4S,2R,3R,5R)-2-[(3-(4-chlorophenyl)isoxazol-5-ylthiomethyl]-2-[6-(cyclopentylamino)-purin-9-yl]tetrahydrofuran-3,4-diol. 
     
     
         9 . The compound of  claim 6 , wherein R 3  is 3-(4-methoxyphenyl)isoxazol-5-yl, namely (4S,2R,3R,5R)-2-[(3-(4-methoxyphenyl)isoxazol-5-ylthio)methyl]-2-[6-(cyclopentylamino)-purin-9-yl]tetrahydrofuran-3,4-diol. 
     
     
         10 . The compound of  claim 6 , wherein R 3  is 5-methylisoxazol-5-yl, namely (4S,2R,3R,5R)-2-[(5-methylisoxazol-3-ylthio)methyl]-2-[6-cyclopentylamino)purin-9-yl]tetrahydrofuran-3,4-diol. 
     
     
         11 . The compound of  claim 6 , wherein R 3  is 3-phenylisoxazol-3-yl, namely (4S,2R,3R,5R)-2-[(3-phenylisoxazol-5-ylthio)methyl]-2-[6-cyclopentylamino)purin-9-yl]tetrahydrofuran-3,4-diol. 
     
     
         12 . The compound of  claim 6 , wherein R 3  is 1,2,4-oxadiazol-3-yl, namely (4S,2R,3R,5R)-2-[1,2,4-oxadiazol-3-ylthio)methyl]-5-[6-(cyclopentylamino)-purin-9-yl]tetrahydrofuran-3,4-diol. 
     
     
         13 . The compound of  claim 6 , wherein R 3  is 5-t-butyl-1,2,4-oxadiazol-3-yl, namely (4S,2R,3R,5R)-2-[5-t-butyl-1,2,4-oxadiazol-3-ylthio)methyl]-5-[6-(cyclopentylamino)-purin-9-yl]tetrahydrofuran-3,4-diol 
     
     
         14 . The compound of  claim 3 , wherein R 1  is tetrahydrofuran-3-yl and Z is methylene. 
     
     
         15 . The compound of  claim 14 , wherein R 3  is 3,5-dimethylisoxazol-4-yl, namely (4S,2R,3R,5R)-2-[(3,5-dimethylisoxazol-4-ylthio)methyl]-2-[6-(tetrahydrofuran-3-ylamino)purin-9-yl]tetrahydrofuran-3,4-diol. 
     
     
         16 . The compound of  claim 14 , wherein R 3  is 5-methylisoxazol-3-yl, namely (4S,2R,3R,5R)-2-[(5-methylisoxazol-3-ylthiomethyl]-2-[6-(tetrahydrofuran-3-ylamino)purin-9-yl]tetrahydrofuran-3,4-diol. 
     
     
         17 . The compound of  claim 14 , wherein R 3  is 3-phenylisoxazol-5-yl, namely (4S,2R,3R,5R)-2-[(3-phenylisoxazol-5-ylthio)methyl]-2-[6-(tetrahydrofuran-3-ylamino)purin-9-yl]tetrahydrofuran-3,4-diol. 
     
     
         18 . The compound of  claim 14 , wherein R 3  is 3-(4-methoxyphenyl)isoxazol-5-yl, namely (4S,2R,3R,5R)-2-[(3-(4-methoxyphenyl)isoxazol-5-ylthio)methyl]-2-[6-(tetrahydrofuran-3-ylamino)-purin-9-yl]tetrahydrofuran-3,4-diol. 
     
     
         19 . The compound of  claim 14 , wherein R 3  is 3-(4-chlorophenyl)isoxazol-5-yl, namely (4S,2R,3R,5R)-2-[(3-(4-chlorophenyl)isoxazol-5-ylthio)methyl]-2-[6-(tetrahydrofuran-3-ylamino)-purin-9-yl]tetrahydrofuran-3,4-diol. 
     
     
         20 . The compound of  claim 14 , wherein R 3  is 5-t-butyl-1,2,4-oxadiazol-3-yl, namely (4S,2R,3R,5R)-2-[(5-t-butyl-1,2,4-oxadiazol-3-ylmethylthio)methyl]-5-[6-((tetrahydrofuran-3-yl amino)purin-9-yl]tetrahydrofuran-3,4-diol. 
     
     
         21 . The compound of  claim 14 , wherein R 3  is 2-methylthiazol-4-yl, namely (4S,2R,3R,5R)-2-[(2-methylthiazol-4-ylmethylthio)methyl]-5-[6-((tetrahydrofuran-3-yl amino)purin-9-yl]tetrahydrofuran-3,4-diol. 
     
     
         22 . A pharmaceutical composition consisting of from 1-6 pharmaceutically acceptable excipients and a therapeutically effective amount of a compound of  claim 1 . 
     
     
         23 . A method of treating a disease state in a mammal that is alleviable by treatment with a partial or full A 1  adenosine receptor agonist, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of  claim 1 . 
     
     
         24 . The method of  claim 23 , wherein the disease state is chosen from atrial fibrillation, supraventricular tachycardia and atrial flutter, congestive heart failure, epilepsy, stroke, diabetes, obesity, ischemia, stable angina, unstable angina, cardiac transplant, and myocardial infarction. 
     
     
         25 . The method of  claim 24 , wherein the disease state is hyperlipidemia. 
     
     
         26 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of  claim 1 .