Partial or full A1 agonists - N6 heterocyclic 5' thio substituted adenosine derivatives

Abstract

N 6 heterocyclic 5′ modified adenosine derivatives that are adenosine A 1 receptor partial or full agonists, and as such, are useful for modifying cardiac activity, modifying adipocyte function, treating central nervous system disorders, and treating diabetic disorders and obesity in mammals, and especially in humans.

1 . A composition of matter having the formula:  
       
         
           
           
               
               
           
         
         wherein X 1 ═S, S(O), S(O) 2 ;  
         R 1  is a monocyclic or polycyclic heterocyclic group containing from 3 to 15 carbon atoms wherein at least one carbon atom is substituted p ith an atom or molecule selected from the group consisting of N, O, P and S—(O) 0-2  wherein R 1  does not contain an epoxide group;  
         R 2  is selected from the group consisting of hydrogen, halo, CF 3 , and cyano;  
         R 3  and R 4  are each independently selected from the group consisting of hydrogen, —(CO)—R′, and —(CO)—R″ wherein R′ and R″ are each independently selected from the group consisting of C 1-15  alkyl, C 2-15  alkenyl, C 2-15  alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with from 1 to 3 substituents independently selected from the group of halo, NO 2 , heterocyclyl, aryl, heteroaryl, CF 3 , CN, OR 20 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CO 2 R 22 , SO 2 NR 20 CON(R 20 ) 2 , N(R 20 ) 2 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 20 C(NR 20 )NHR 23 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , CONR 20 SO 2 R 22 , NR 20 SO 2 R 22 , SO 2 NR 20 CO 2 R 22 , OCONR 20 SO 2 R 22 , OC(O)R 20 , C(O)OCH 2 OC(O)R 20 , and OCON(R 20 ) 2  and wherein each optional heteroaryl, aryl, and heterocyclyl substituent is further optionally substituted with halo, NO 2 , alkyl, CF 3 , amino, mono- or di-alkylamino, alkyl or aryl or heteroaryl amide, NR 20 COR 22 , NR 20 SO 2 R 22 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 CON(R 20 ) 2 , OC(O)R 20 , OC(O)N(R 20 ) 2 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, or OR 20 ;  
         R 5  is selected from the group consisting of C 1-15  alkyl, C 2-15  alkenyl, C 2-15  alkynyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl alkynyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, alkyl, NO 2 , heterocyclyl, aryl, heteroaryl, CF 3 , CN, OR 20 , SR 20 , S(O) 3 R 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , SO 2 NR 20 COR 22 , SO 2 NR 20 CO 2 R 22 , SO 2 NR 20 CON(R 20 ) 2 , P(O)(OR 20 ) 2 , N(R 20 ) 2 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , NR 20 C(NR 20 )NHR 23 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , CONR 20 SO 2 R 22 , NR 20 SO 2 R 22 , SO 2 NR 20 CO 2 R 22 , OCONR 20 SO 2 R 22 , OC(O)R 20 , C(O)OCH 2 OC(O)R 20 , and OCON(R 20 ) 2  and wherein the optional heteroaryl, aryl, and heterocyclyl substituent are each further optionally substituted x-ith halo, NO 2 , alkyl, CF 3 , amino, mono- or di-alkylamino, alkyl or aryl or heteroaryl amide, NR 20 COR 22 , NR 20 SO 2 R 22 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 CON(R 20 ) 2 , OC(O)R 20 , OC(O)N(R 20 ) 2 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, or OR 20 ;  
         R 20  is selected from the group consisting of H, C 1-15  alkyl, C 2-15  alkenyl, C 2-15  alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O—C 1-6  alkyl, CF 3 , aryl, and heteroaryl: and  
         R 22  is selected from the group consisting of C 1-15  alkyl, C 2-15  alkenyl, C 2-15  alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, CN, O—C 1-6  alkyl, CF 3 , and heteroaryl.  
       
     
     
         2 . The composition of  claim 1  wherein R 2  is selected from the group consisting of hydrogen, and halo; 
 R 3  and R 4  are each independently selected from the group consisting of hydrogen, —(CO)—R′, and —(CO)—R″ wherein R′ and R″ are each independently selected from the group consisting of C 1-15  alkyl, heterocyclyl, aryl, and heteroaryl, which alkyl, aryl, heterocyclyl, and heteroaryl are each optionally substituted with from 1 to 2 substituents independently selected from the group of halo, NO 2 , heterocyclyl, aryl, heteroaryl, CF 3 , CN, OR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , N(R 20 ) 2 , NR 20 COR 22 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 . NR 20 C(NR 20 )NHR 20 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , CONR 20 SO 2 R 22 , NR 20 SO 2 R 22  and wherein each optional heteroaryl, aryl, and heterocyclyl substituent is further optionally substituted with halo, NO 2 , alkyl, CF 3 , amino, mono- or di-alkylamino, CN, or OR 20 ;    R 5  is selected from the group consisting of C 1-15  alkyl, C 1-15  alkenyl, C 2-15  alkynyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with from 1 to 3 substituents independently selected from the group of halo, alkyl, heterocyclyl, aryl, heteroaryl, CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , S(O) 3 R 20 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , and wherein each optional heteroaryl, and aryl substituent is optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 CON(R 20 ) 2 , SR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, or OR 20 ;    R 20  is selected from the group consisting of H, C 1-15  alkyl, aryl, and heteroaryl, which alkyl, aryl, and heteroaryl are each optionally substituted with from 1 to 2 substituents independently selected from halo, alkyl, mono- or dialkylamino, CN, O—C 1-6  alkyl, CF 3 ; and    R 22  is selected from the group consisting of C 1-15  alkyl, aryl, and heteroaryl, which alkyl, aryl, and heteroaryl are each optionally substituted with from 1 to 2 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl or CN, O—C 1-6  alkyl, and CF 3 .    
     
     
         3 . The composition of  claim 1  wherein R 2  is a hydrogen: 
 R 3  and R 4  are each independently selected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″ wherein R′ and R″ are each independently selected from the group consisting of C 1-10  alkyl, aryl, and heteroaryl, which alkyl, aryl, and heteroaryl are optionally substituted with from 1 to 2 substituents independently selected from the group of halo, NO 2 , aryl, heteroaryl, CF 3 , CN, OR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , NR 20 COR 22 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , NR 20 SO 2 R 22 , and wherein each optional heteroaryl, aryl, and heterocyclyl substituent is further optionally substituted with halo, NO 2 , alkyl, CF 3 ;    R 5  is selected from the group consisting of C 1-15 , alkyl. C 2-15  alkenyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with from 1 to 3 substituents independently selected from the group consisting of hallo, alkyl, aryl, heteroaryl, CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , COR 20 , CO 2 R 20 , CON(R 20 ) 2 , and wherein each optional heteroaryl, and aryl substituent is further optionally substituted with halo, alkyl, CF 3 , CO 2 R 21 , CON(R 20 ) 2 , NR 21 CON(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, and OR 20 ;    R 20  is selected from the group consisting of H, C 1-6  alkyl, and aryl, which alkyl, and aryl, are optionally substituted with 1 substituent selected from halo, alkyl, mono- or dialkylamino, CN, O—C 1-6  alkyl, CF 3 ; and    R 22  is selected from the group consisting of C 1-6  alkyl and aryl, which alkyl and aryl are optionally substituted with 1 substituent independently selected from halo, alkyl, mono- or dialkylamino, alkyl or CN, O—C 1-6  alkyl, and CF 3 .    
     
     
         4 . The composition of  claim 1  wherein R 2  is a hydrogen: 
 R 3  and R 4  are each independently selected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″ wherein R′ and R″ are each independently selected from the group consisting of C 1-6  alkyl, and aryl, which alkyl and aryl are optionally substituted with from 1 to 2 substituents independently selected from the group of halo, NO 2 , aryl, CF 3 , CN, OR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , N(R 20 ) 2 , and wherein each optional aryl substituent is optionally substituted with halo, NO 2 , alkyl, CF 3 ;    R 5  is selected from the group consisting of C 1-15  alkyl, C 2-15  alkenyl, aryl, and heteroaryl, wherein alkyl, alkenyl, aryl, and heteroaryl are optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, alkyl, aryl, heteroaryl, CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , CO 2 R 20 , CON(R 20 ) 2 , and wherein each optional heteroaryl, and aryl substituent is further optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 , CON(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, or OR 20 ;    R 20  is selected from the group consisting of H, C 1-6  alkyl, and aryl, which alkyl and aryl are optionally substituted with 1 substituent selected from halo, alkyl, mono- or dialkylamino, CN, O—C 1-6  alkyl, CF 3 ; and    R 22  is selected from the group consisting of C 1-6  alkyl and aryl, which alkyl and aryl are optionally substituted with 1 substituent selected from halo, alkyl or CN, O—C 1-6  alkyl, and CF 3 .    
     
     
         5 . The composition of  claim 1  wherein R 2  is a hydrogen: 
 R 3  and R 4  are each independently selected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″ wherein each R′ and R″ are independently selected from the group consisting of C 1-6  (alkyl which alkyl are optionally substituted with 1 substituent selected from the group of aryl, CF 3 , CN, OR 20 , N(R 20 ) 2 , and wherein each optional aryl substituent is further optionally substituted with halo, NO 2 , alkyl, CF 3 ;    R 5  is selected from the group consisting of C 1-8  alkyl, C 2-8  alkenyl, and aryl wherein alkyl, alkenyl, and aryl are optionally substituted with from 1 to 2 substituents independently selected from the group consisting of halo, alkyl, aryl, heteroaryl, CF 3 , CN, OR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 . NR 20 CON(R 20 ) 2 , CO 2 R 20 , CON(R 20 ) 2 , and wherein each optional heteroaryl, and aryl substituent is further optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 , CN, and OR 20 ;    R 20  is selected from the group consisting of H C 1-6  alkyl; and    R 22  is selected from the group consisting of C 1-6 .    
     
     
         6 . The composition of  claim 1  wherein X 1 ═S or SO 2 ; 
 R 2  is a hydrogen;    R 3  and R 4  are each independently selected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″ wherein R′ and R″ are each independently selected from the group consisting of C 1-6  alkyl;    R 5  is selected from the group consisting of C 1-8  alkyl, and aryl wherein alkyl, and aryl are optionally substituted with from 1 to 2 substituents independently selected from the group consisting of halo, alkyl, aryl, heteroaryl, CF 3 , CN, OR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CON(R 20 ) 2 , CO 2 R 20 , CON(R 20 ) 2 , and wherein each optional heteroaryl, and aryl substituent is further optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 , CN, and OR 20 ;    R 20  is selected from the group consisting of H, C 1-6  alkyl; and    R 22  is selected from the group consisting of C 1-6 .    
     
     
         7 . The composition of  claim 1  wherein X 1 ═S or SO 2 ; 
 R 2  is a hydrogen;    R 3  and R 4  are hydrogen;    R 5  is selected from the group consisting of C 1-8  alkyl, and aryl wherein alkyl, and aryl are optionally substituted with from 1 to 2 substituents independently selected from the group consisting of halo, alkyl, CF 3 , CN, OR 20 , CO 2 R 20 ; and    R 20  is selected from the group consisting of H, C 1-6  alkyl.    
     
     
         8 . The composition of  claim 1  wherein X 1 ═S or SO 2 : 
 R 2  is a hydrogen;    R 3  and R 4  are hydrogen;    R 5  is selected from the group consisting of C 1-8  alkyl, and aryl wherein alkyl, and aryl are optionally substituted with from 1 to 2 substituents independently selected from the group consisting of halo, alkyl, CF 3 , OR 20 ; and    R 20  is selected from the group consisting of H, C 1-6  alkyl.    
     
     
         9 . The composition of  claim 1  wherein X 1 ═S or SO 2 ; 
 R 2  is a hydrogen;    R 3  and R 4  are independently selected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″ wherein R′ and R″ are each independently selected from the group consisting of C 1-6  alkyl which alkyl are optionally substituted with 1 substituent selected from the group consisting of aryl, CF 3 , CN, OR 20 , N(R 20 ) 2 , and wherein each optional aryl substituent is further optionally substituted with halo, NO 2 , alkyl, CF 3 ;    R 5  is C 1-8  alkyl, wherein alkyl, is optionally substituted with from 1 to 2 substituents independently selected from the group consisting of halo, alkyl, aryl, heteroaryl, CF 3 , CN, OR 20 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CON(R 20 ) 2 , CO 2 R 20 , CON(R 20 ) 2 , wherein each optional heteroaryl, and aryl substituent is further optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 , CN, and OR 20 ;    R 20  is selected from the group consisting of H, C 1-6  alkyl; and    R 22  is selected from the group consisting of C 1-6 .    
     
     
         10 . The composition of  claim 1  wherein X 1 ═S or SO 2 ; 
 R 2  is a hydrogen;    R 3  and R 4  are independently selected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″ wherein R′ and R″ are each independently selected from the group consisting of C 1-6  alkyl:    R 5  is C 1-8  alkyl that is optionally substituted with from 1 to 2 substituents independently selected from the group consisting of aryl, heteroaryl, OR 20 , S(O)R 22 , CO 2 R 20 , CON(R 20 ) 2 , and wherein each optional heteroaryl, and aryl substituent is further optionally substituted with halo, alkyl, CF 3 , COR 2 R 20 , CN, and OR 20 ;    R 20  is selected from the group consisting of H, C 1-6  alkyl; and    R 22  is selected from the group consisting of C 1-6 .    
     
     
         11 . The composition of  claim 1  wherein ═S or SO 2 : 
 R 2  is a hydrogen;    R 3  and R 4  are hydrogen;    R 5  is C 1-8  alkyl that is optionally substituted with 1 substituent selected from the group consisting of CO 2 R 20 , and CON(R 20 ) 2 ; and    R 20  is selected from the group consisting of H, and methyl.    
     
     
         12 . The composition of  claim 11  wherein R 5  is C 1-6  alkyl.  
     
     
         13 . The composition of  claim 1  wherein R 5  is selected from the group consisting of methyl and ethyl and isopropyl.  
     
     
         14 . The composition of  claim 1  wherein R 2  is a hydrogen; 
 R 3  and R 4  are each independently selected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″ wherein each R′ and R″ are independently selected from the group consisting of C 1-6  alkyl, and aryl, which alkyl and aryl are optionally substituted with from 1 to 2 substituents independently selected from the group of halo, NO 2 , aryl. CF 3 , CN, OR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , N(R 20 ) 2 , and wherein each optional aryl substituent is further optionally substituted with halo, NO 2 , alkyl, CF 3 ;    R 5  is selected from the group consisting of, aryl, and heteroaryl, wherein aryl, and heteroaryl are optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, alkyl, aryl, heteroaryl, CF 3 , CN, OR 20 , SR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ), CO 2 R 20 , CON(R 20 ) 2 , and wherein each optional heteroaryl, and aryl substituent is further optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 , CON(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 2 N(R 20 ) 2 , CN, or OR 20 ;    R 20  is selected from the group consisting of H, C 1-6  alkyl, and aryl, which alkyl and aryl are optionally substituted with 1 substituent selected from halo, alkyl, mono- or dialkylamino, CN, O—C 1-6  alkyl, CF 3 ; and    R 22  is selected from the group consisting of C 1-6  alkyl and alkyl and aryl, which alkyl and aryl are optionally substituted with 1 substituent selected from halo, alkyl or CN, O—C 1-6  alkyl, and CF 3 .    
     
     
         15 . The composition of  claim 1  wherein X 1 ═S; 
 R 2  is a hydrogen;    R 3  and R 4  are each independently selected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″ wherein R′ and R″ are each independently selected from the group consisting of C 1-6  alkyl;    R 5  is selected from the group consisting of, aryl, and heteroaryl, wherein aryl, and heteroaryl are optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, alkyl, CF 3 , CN, OR 20 , SR 20 , CO 2 R 20 , CON(R 20 ) 2 ; and    R 20  is selected from the group consisting of H, C 1-3  alkyl.    
     
     
         16 . The composition of  claim 1  wherein X 1 ═S; 
 R 2  is a hydrogen;    R 3  and R 4  are hydrogen;    R 5  is aryl that is optionally substituted with from 1 to 2 substituents independently selected from the group consisting of halo, alkyl, CF 3 , OR 20 , CO 2 R 20 , CON(R 20 );    R 20  is selected from the group consisting of H, and methyl; and    R 22  is selected from the group consisting of C 1-6  alkyl.    
     
     
         17 . The composition of  claim 16  wherein R 5  is phenyl that is optionally substituted with a substituent selected from the group consisting of methoxy, chloro, fluoro, methyl, and trifluoromethyl.  
     
     
         18 . The composition of  claim 1  wherein R 1  is mono or polysubstituted with one or more compounds selected from the group consisting of halogen, oxo, hydroxyl, lower alkyl, substituted lower alkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro, cyano and mixtures thereof.  
     
     
         19 . The composition of matter of  claim 1  wherein R 1  is a monocyclic, bicyclic, or tricyclic cycloalkyl group containing from 3 to 15 carbon atoms wherein at least one carbon atom is substituted with an atom or molecule selected from the group consisting of O or S—(O) 0-2 .  
     
     
         20 . The composition of  claim 19  wherein R 1  is mono or polysubstituted with one or more compounds selected from the group consisting of halogen, oxo, hydroxyl, lower alkyl, substituted lower alkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro, cyano and mixtures thereof.  
     
     
         21 . The composition of  claim 1  wherein R 1  is:  
       
         
           
           
               
               
           
         
       
       wherein R 1 ′, R 1 ″, R 1 ′″, and R 1 ″″ are each independently selected from the group halogen, hydroxyl, lower alkyl, substituted lower alkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl, heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, nitro, cyano and mixtures thereof and X is O, or S(—O)O 0-2 .  
     
     
         22 . The composition of  claim 21  wherein R 1 ′″ and R 1 ″″ can together be a single oxygen atom.  
     
     
         23 . The composition of  claim 21  wherein R 1 ′, R 1 ″, R 1 ′″, and R 1 ″″ are each individually selected from the group H, lower alkyl, substitute lower alkyl, alkoxy, aryl, and substituted aryl.  
     
     
         24 . The composition of  claim 21  wherein R 1 ′, R 1 ″, R 1 ′″, and R 1 ″″ are each individually selected from the group H, lower alkyl, and substitute lower alkyl.  
     
     
         25 . The composition of  claim 1  wherein R 1  is selected from the group consisting  
       
         
           
           
               
               
           
         
       
       wherein each R may be independently selected from the group consisting of H, lower alkyl, and substituted lower alkyl and wherein X is O, or S(—O) 0-2 .  
     
     
         26 . The composition of claims  1  or  2  or  3  or  4  or  5  or  6  or  7  or  8  or  9  or  10  or  11  or  12  or  13  or  14  or  15  or  16  wherein R 1  is selected from the group consisting of 3-tetrahydrofuranyl, 3-tetrahydrothiofuranyl, 4-pyranyl, and 4 thiopyranyl.  
     
     
         27 . The composition of claims  1  or  2  or  3  or  4  or  5  or  6  or  7  or  8  or  9  or  10  or  11  or  12  or  13  or  14  or  15  or  16  wherein R 1  is 3-tetrahydrofuranyl.  
     
     
         28 . The composition of  claim 1  wherein the compound is selected from the group of compounds consisting of 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(methylthiomethyl)oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(Ethylthio)methyl]oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(Methylethylthio)methyl]oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(phenylthiomethyl)oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-Methoxyphenylthio)methyl]oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-chlorophenylthio)methyl]oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-fluorophenylthio)methyl]oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-methylphenylthio)methyl]oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-(trifluoromethyl)phenylthio)methyl]oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2-Methoxyphenylthio)methyl]oxolane-3,4-diol; (5-{6-[((3R)oxolan-3-yl)amino]purinyl-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)(ethylsulfonyl)methane 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2,4-difluorophenylthio)methyl]oxolane-3,4-diol; 2-{6-[((R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(3-fluorophenylthio)methyl]oxolane-3,4-diol; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol; 5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3R,4R,5R)-4-acetyloxy-2-[(fluorophenylthio)methyl]oxolan-3-yl acetate; Methyl 2[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)methylthio]benzoate; {2[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)methylthio]phenyl}-N-methylcarboxamidebenzoate; 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(benzoxazol-2-ylthiomethyl)oxolane-3,4-diol; 2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(1-methylimidazol-2-yl-thio)methyl]oxolane-3,4-diol; 2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(pyrimidine-2-ylthiomethyl)oxolane-3,4-diol: 2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(2-pyridylthiomethyl)oxolane-3,4-diol; 2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(4-pyridylthiomethyl)oxolane-3,4-diol; and 5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3R,4R,5R)-4-acetyloxy-2-[(4-fluorophenylthio)methyl]oxolan-3-yl]acetate.  
     
     
         29 . A method for modifying cardiac activity in a mammal experiencing a heart electrical disorder that can be treated by stimulating an A 1  adenosine receptor comprising the administration of a therapeutically effective amount of the composition of  claim 1  to the mammal.  
     
     
         30 . A method for modifying mammalian adipocyte function by stimulating an A 1  adenosine receptor comprising administering a therapeutically effective amount of the composition of  claim 1  to the mammal.  
     
     
         31 . A method to restore sensitivity and efficacy of insulin in a mammal by stimulating an A 1  adenosine receptor comprising the administration of a therapeutically effective amount of a composition of  claim 1  to the mammal.  
     
     
         32 . A method for providing a mammal with central nervous system neuroprotection by stimulating an A 1  adenosine receptor comprising administering a therapeutically effective amount of the composition of  claim 1  to the mammal.  
     
     
         33 . A method for providing a mammal with cardiomyocyte protection from ischemia by stimulating an A 1  adenosine receptor comprising administering a therapeutically effective amount of the composition of  claim 1  to the mammal.  
     
     
         34 . The method of  claim 29  or  30  or  31  or  32  or  33  wherein the therapeutically effective amount ranges from about 0.01 to about 100 mg/kg weight of the mammal.  
     
     
         35 . The method of  claim 29  wherein the composition is administered to the mammal experiencing a heart electrical disorder selected from the group consisting of supraventricular tachycardias, atrial fibrillation, atrial flutter, and AV nodal re-entrant tachycardia.  
     
     
         36 . The method of  claim 30  or  31  wherein the composition is administered to a mammal experiencing a disorder selected from the group consisting of diabetes and obesity.  
     
     
         37 . The method of  claim 32  wherein the composition is administered to a mammal experiencing an central nervous system disorder selected from the group consisting of epilepsy, and stroke.  
     
     
         38 . The method of  claim 33  wherein the composition is administered to a mammal experiencing an ischemic event in the heart selected from the group consisting of stable angina, unstable angina, cardiac transplant, and myocardial infarction.  
     
     
         39 . The method of;  claim 29  or  30  or  31  or  32  or  33  wherein the mammal is a human.  
     
     
         40 . A pharmaceutical composition of matter comprising the composition of  claim 1  and one or more pharmaceutical excipients.  
     
     
         41 . The pharmaceutical composition of matter of  claim 40  wherein the pharmaceutical composition is in the form of a solution.  
     
     
         42 . The pharmaceutical composition of matter of  claim 40  wherein the pharmaceutical composition is in the form of a tablet.