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 the supraventricular tachycardias, emesis, angina, myocardial infarction and hyperlipidemia.

1 . A compound of the formula:  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;  
         R 2  is hydrogen, halo, trifluoromethyl, or cyano;  
         R 3  is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl,  
         R 4  and R 5  are independently hydrogen or optionally substituted acyl;  
         X is a covalent bond or lower alkylene optionally substituted by cycloalkyl;  
         X 1  is a covalent bond or alkylene.  
         Y is a covalent bond or lower alkylene optionally substituted by hydroxy or cycloalkyl; and  
         Z is —C≡C—, —R 6 C═CR 7 —, or —CHR 6 CHR 7 —, in which R 6  and R 7  at each occurrence are hydrogen or lower alkyl.  
       
     
     
         2 . The compound of  claim 1 , wherein Z is —C≡C—.  
     
     
         3 . The compound of  claim 2 , wherein X, X 1  and Y are covalent bonds.  
     
     
         4 . The compound of  claim 3 , wherein R 1  is optionally substituted cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.  
     
     
         5 . The compound of  claim 4 , wherein R 2 , R 4  and R 5  are hydrogen.  
     
     
         6 . The compound of  claim 5 , wherein R 3  is hydrogen or optionally substituted aryl.  
     
     
         7 . The compound of  claim 6 , wherein R 1  is optionally substituted cyclopentyl or optionally substituted tetrahydrofuranyl and R 3  is hydrogen or optionally substituted phenyl.  
     
     
         8 . The compound of  claim 7 , wherein R 1  is cyclopentyl and R 3  is hydrogen, namely (4S,2R,3R,5R)-2-[6-(cyclopentylamino)purin-9-yl]-5-ethynyloxolane-3,4-diol.  
     
     
         9 . The compound of  claim 7 , wherein R 1  is 2-hydroxycyclopentyl and R 3  is hydrogen, namely (4S,2R,3R,5R)-5-ethynyl-2-{6-[(2-hydroxycyclopentyl)amino]purin-9-yl}oxolane-3,4-diol.  
     
     
         10 . The compound of  claim 7 , wherein R 1  is tetrahydrofuran-3-yl and R 3  is hydrogen, namely (4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purin-9-yl]-5-ethynyloxolane-3,4-diol.  
     
     
         11 . The compound of  claim 7 , wherein R 1  is cyclopentyl and R 3  is 2-fluorophenyl, namely (4S,2R,3R,5R)-2-[6-(cyclopentylamino)purin-9-yl]-5-[2-(2-fluorophenyl)ethynyl]oxolane-3,4-diol.  
     
     
         12 . The compound of  claim 7 , wherein R 1  is cyclopentyl and R 3  is 2-trifluoromethylphenyl, namely (4S,2R,3R,5R)-2-[6-(cyclopentylamino)purin-9-yl]-5-{2-[2-(trifluoromethyl)-phenyl]ethynyl}oxolane-3,4-diol.  
     
     
         13 . The compound of  claim 7 , wherein R 1  is tetrahydrofuran-3-yl and R 3  is 2-fluorophenyl, namely (4S,2R,3R,5R)-2-[6-(oxalan-3-ylamino)purin-9-yl]-5-{2-[2-fluorophenyl]ethynyl}-oxolane-3,4-diol.  
     
     
         14 . The compound of  claim 7 , wherein R 1  is tetrahydrofuran-3-yl and R 3  is 2-trifluoromethylphenyl, namely (4S,2R,3R,5R)-2-[6-(oxalan-3-ylamino)purin-9-yl]-5-{2-[2-(trifluoromethyl)phenyl]-ethynyl}oxolane-3,4-diol.  
     
     
         15 . The compound of  claim 5 , wherein R 3  is optionally substituted heteroaryl.  
     
     
         16 . The compound of  claim 15 , wherein R 1  is optionally substituted cyclopentyl or optionally substituted tetrahydrofuranyl and R 3  is optionally substituted thienyl.  
     
     
         17 . The compound of  claim 16 , wherein R 1  is cyclopentyl or tetrahydrofuran-3-yl and R 3  is thien-2-yl.  
     
     
         18 . The compound of  claim 1 , wherein Z is —R 6 C═CR 7 —, in which R 6  and R 7  are both hydrogen.  
     
     
         19 . The compound of  claim 18 , wherein X, X 1  and Y are covalent bonds.  
     
     
         20 . The compound of  claim 19 , wherein R 1  is optionally substituted cycloalkyl.  
     
     
         21 . The compound of  claim 20 , wherein R 2 , R 4  and R 5  are hydrogen.  
     
     
         22 . The compound of  claim 21 , wherein R 3  is optionally substituted aryl or optionally substituted heteroaryl.  
     
     
         23 . The compound of  claim 22 , wherein R 1  is cyclopentyl and R 3  is 5-chlorothien-2-yl, 4-methylisoxazol-3-yl or 3,5-dimethylisoxazol-4-yl.  
     
     
         24 . The compound of  claim 22 , wherein R 1  is cyclopentyl and R 3  is 2-methyphenyl, namely 5-[2-(2-methylphenyl)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamino)purin-9-yl]oxolane-3,4-diol.  
     
     
         25 . The compound of  claim 22 , wherein R 1  is cyclopentyl and R 3  is phenyl, namely 5-[2-(phenyl)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamino)purin-9-yl ]oxolane-3,4-diol.  
     
     
         26 . A method of treating a disease state in a mammal by administration of an A 1  adenosine receptor agonist, comprising administering to a mammal in need thereof a therapeutically effective dose of a compound of  claim 1 .  
     
     
         27 . The method of  claim 26 , 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.  
     
     
         28 . The method of  claim 27 , wherein the disease state is chosen from atrial fibrillation, supraventricular tachycardia and atrial flutter.  
     
     
         29 . The method of  claim 26 , wherein the A 1  adenosine receptor agonist of  claim 1  has an antilipolytic effect.  
     
     
         30 . The method of  claim 29 , wherein said antilipolytic effect treats disease states related to metabolic disorders  
     
     
         31 . The method of  claim 30 , wherein the metabolic disorder is hyperlipidemia, non-insulin-dependent diabetes mellitus, or obesity.  
     
     
         32 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Formula I.  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;  
         R 2  is hydrogen, halo, trifluoromethyl, or cyano;  
         R 3  is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl,  
         R 4  and R 5  are independently hydrogen or optionally substituted acyl;  
         X is a covalent bond or lower alkylene optionally substituted by cycloalkyl;  
         X 1  is a covalent bond or alkylene;  
         Y is a covalent bond or lower alkylene optionally substituted by hydroxy or cycloalkyl; and  
         Z is —C≡C—, —R 6 C═CR 7 —, or —CHR 6 CHR 7 —, in which R 6  and R 7  at each occurrence are hydrogen or lower alkyl.  
       
     
     
         34 . The method of claim  33 , wherein the disease state is selected from atrial fibrillation, supraventricular tachycardia and atrial flutter.  
     
     
         35 . The method of claim  33 , wherein the disease state is chosen from diabetes and obesity.