A1 adenosine receptor agonists

Abstract

Disclosed are novel compounds that are A 1 adenosine receptor agonists, useful for treating various disease states, in particular tachycardia and atrial flutter, angina, diseases related to release of nonesterified fatty acids, and myocardial infarction.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R is hydrogen or lower alkyl; 
 R 1  is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; 
 R 2  is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl; optionally substituted heteroaryl, or optionally substituted heterocyclyl; 
 R 3  is —CH 2 OR 6  or —C(O)NR 7 R 8 ; in which R 6  is hydrogen or acyl, and R 7  and R 8  are independently hydrogen or lower alkyl; 
 R 4  and R 5  are independently hydrogen or lower alkyl; and 
 Y is a covalent bond or optionally substituted alkylene; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , wherein:
 R is hydrogen;   R 1  is cycloalkyl of 3-6 carbon atoms;   R 2  is alkyl substituted by —SO 3 H, cycloalkyl substituted by —SO 3 H, aryl substituted by —SO 3 H; heteroaryl substituted by —SO 3 H, or heterocyclyl substituted by —SO 3 H; and   R 3  is —CH 2 OH.   
     
     
         3 . The compound of  claim 2 , wherein R 4  and R 5  are hydrogen; and Y is a covalent bond. 
     
     
         4 . The compound of  claim 3 , wherein R 2  is alkyl substituted by —SO 3 H or aryl substituted by —SO 3 H. 
     
     
         5 . The compound of  claim 4 , wherein R 2  is alkyl of 1-4 carbon atoms substituted by —SO 3 H. 
     
     
         6 . The compound of  claim 5 , wherein R 1  is cyclopentyl. 
     
     
         7 . The compound of  claim 6 , wherein R 2  is —CH 2 SO 3 H, namely N-({9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}methyl)carbamoylmethylsulfonic acid. 
     
     
         8 . The compound of  claim 4 , wherein R 2  is phenyl substituted by —SO 3 H. 
     
     
         9 . The compound of  claim 8 , wherein R 1  is cyclopentyl. 
     
     
         10 . The compound of  claim 9 , wherein R 2  is 4-benzenesulfonic acid, namely 4-[N-({9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}methyl)carbamoyl]benzenesulfonic acid. 
     
     
         11 . A method of treating a disease state in a mammal that is alleviable by treatment with an A 1  adenosine receptor agonist, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of  claim 1 . 
     
     
         12 . The method of  claim 11 , 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. 
     
     
         13 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of  claim 1 .