N6 heterocyclic 8-modified adenosine derivatives

Abstract

N 6 heterocyclic 8 modified adenosine derivatives that are selective, partial or full 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.

What we claim is:  
     
         1 . A composition of matter having the formula:  
       
         
           
           
               
               
           
         
         wherein X 1 =O, S, NR 7 ;  
         R 1  is a monocyclic or polycyclic heterocyclic group containing from 3 to 15 carbon atoms wherein at least one carbon atom is substituted with an atom or a molecule selected from the group consisting of N, O, P and S-(O) 0-2  and 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 , R 4 , and R 5  are each individually selected from the group consisting of hydrogen, —(CO)—R′, —(CO)—R″, and —(CO)—R′″ wherein R′, R″, and R′″ are each individually 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 consisting of halo, NO 2 , alkyl, heterocyclyl, 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 , 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 each optional heteroaryl, aryl, alkyl, and heterocyclyl substituent is optionally further substituted with halo, NO 2 , alkyl, CF 3 , amino, mono- or di- alkylamino, alkyl amide, aryl amide, 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 6  and R 7  are each individually selected from the group consisting of hydrogen, C 1-15  alkyl, C 2-15  alkenyl, C 2-15  alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl substituents 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)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 , S(O) 3 R 2 , P(O)(OR 20 ) 2 , SO 2 NR 20 CON(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 optionally substituted with halo, NO 2 , alkyl, CF 3 , amino, mono- or di- alkylamino, alkyl amide, aryl amide, heteroaryl amide, NCOR 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) 3 R 20 , P(O)(OR 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 1-15  alkyl, C 2-15  alkenyl, C 2-15  alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl substituents 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, wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl substituents are optionally substituted with from 1 to 3 substituents independently selected from halo, alkyl, mono- or dialkylamino, alkyl amide, aryl amide, heteroaryl amide, CN, O-C 1-6  alkyl, CF 3 , aryl, and heteroaryl.  
       
     
     
         2 . The composition of  claim 1  wherein R 3 , R 4 , and R 5  are each individually selected from the group consisting of hydrogen, —(CO)-R′, —(CO)-R″, and —(CO)-R′″ wherein R′, R″, and R′″ are each individually selected from the group consisting of C 1-15  alkyl, heterocyclyl, aryl, and heteroaryl, which alkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with from 1 to 2 substituents independently selected from the group of halo, N0 2 , heterocyclyl, aryl, heteroaryl, CF 3 , CN, OR 20 , N(R 20 ) 2 , S(O)R 22 , SO 2 R 22 , SO 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  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 6  is selected from the group consisting of hydrogen, and C 1-15  alkyl optionally substituted with aryl;  
 R 7  is selected from the group consisting of hydrogen, C 1-15  alkyl, C 2-15  alkenyl, C 2-15  alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl substituents are optionally substituted with from 1 to 3 substituents independently selected from the group consisting 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 , P(O)(OR 20 ) 2 , 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 the optional heteroaryl, aryl, and heterocyclyl substituents are further optionally substituted with halo, alkyl, CF 3 , CO 2 R 20 , S(O) 3 R 20 , P(O)(OR 20 ) 2 , amino, mono- or di- alkylamino, 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 optionally substituted with from 1 to 2 substituents independently selected from the group consisting of 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 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 X 1 =NR 7 ; 
 R 2  is hydrogen;  
 R 3 , R 4 , and R 5  are each individually selected from the group consisting of hydrogen, —(CO)-R′, —CO)-R″, and —(CO)-R′″ wherein R′, R″, and R′″ are 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, and CF 3 ;  
 R 6  is selected from the group consisting of hydrogen, and C 1-3  alkyl that is optionally substituted with aryl;  
 R 7  is selected from the group consisting of hydrogen, C 1-8  alkyl, C 2-15  alkenyl, C 2-15  alkynyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl substituents 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 , CO 2 R 20 , S(O) 3 R 20 , SO 2 N(R 20 ) 2 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , COR 20 , and wherein the optional heteroaryl, and aryl substituents are each further optionally substituted with halo, alkyl, CF 3 , S(O) 3 R 20 , CO 2 R 20 , amino, mono- or di- alkylamino, 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, and 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, mono- or dialkylamino, alkyl or CN, O-C 1-6  alkyl, and CF 3 .  
 
     
     
         4 . The composition of  claim 1  wherein X 1 =NR 7 ; 
 R 2  is hydrogen;  
 R 3 , R 4 , and R 5  are each individually selected from the group consisting of hydrogen, —(CO)-R′, —(CO)-R″, and —(CO)-R′″ wherein R′, 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 each 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 each optional aryl substituent is further optionally substituted with halo, NO 2 , alkyl, and CF 3 ;  
 R 6  is selected from the group consisting of hydrogen, C 1-3  alkyl optionally substituted with aryl;  
 R 7  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-15  alkenyl, C 2-15  alkynyl, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, aryl, and heteroaryl substituents are optionally substituted with from 1 to 3 substituents independently selected from the group consisting of halo, alkyl, aryl, CF 3 , CN, OR 20 , SR 20 , S(O) 3 R 20 , CO 2 R 20 , NR 20 CO 2 R 22 , NR 20 CON(R 20 ) 2 , and wherein each optional aryl substituent is further optionally substituted with halo, alkyl, CF 3 , S(O) 3 R 20 , CO 2 R 20 , amino, mono- or di- alkylamino, 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, and 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 or CN, O-C 1-6  alkyl, and CF 3 .  
 
     
     
         5 . The composition of  claim 1  wherein X 1 =NR 7 ; 
 R 2  is hydrogen;  
 R 3  , R 4 , and R 5  are each individually selected from the group consisting of hydrogen, —(CO)-R′, —(CO)-R″, and —(CO)-R′″ wherein R′, R″, and R′″ are each independently selected from the group consisting of C 1-6  alkyl which alkyl is optionally substituted with 1 substituent selected from the group consisting of aryl, CF 3 , CN, OR 20 , N(R 20 ) 2 , and each optional aryl substituent is further optionally substituted with halo, NO 2 , alkyl, CF 3 ;  
 R 6  is selected from the group consisting of hydrogen, and C 1-3  alkyl;  
 R 7  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl, wherein the alkyl, alkenyl, and alkynyl substituents are optionally substituted with from 1 to 2 substituents independently selected from the group consisting of alkyl, aryl, CF 3 , OR 20 , SR 20 , CO 2 R 20 , S(O) 3 R 20 , and wherein each optional aryl substituent is further optionally substituted with halo, alkyl, CF 3 , S(O) 3 R 20 , CO 2 R 20 , amino, mono- or di- alkylamino, CN, or OR 20 ; and  
 R 20  is selected from the group consisting of H, and C 1-6  alkyl.  
 
     
     
         6 . The composition of  claim 1  wherein X 1 =NR 7 ; wherein R 2  is hydrogen; wherein R 3 , R 4 , and R 5  are independently selected from the group consisting of hydrogen, —(CO)-R′, —(CO)-R″, or —(CO)-R′″ wherein R′, R″, and R′″ are independently selected from the group consisting of C 1-6  alkyl; 
 wherein R 6  is independently selected from the group consisting of hydrogen, or C 1-3  alkyl;  
 wherein R 7  is independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl, wherein the alkyl, alkenyl, and alkynyl substituents are optionally substituted with from 1 substituent independently selected from the group consisting of alkyl, aryl, CF 3 , OR 20 , SR 20 , CO 2 R 20 , S(O) 3 R 20 , and wherein optional aryl substituent is optionally substituted with halo, alkyl, CF 3 ;  
 R 20  is a member selected from the group consisting of H, C 1-6  alkyl.  
 
     
     
         7 . The composition of  claim 1  wherein X 1 =NR 7 ; wherein R 2  is hydrogen; wherein R 3 , R 4 , and R 5  are independently selected from the group consisting of hydrogen, —(CO)-R′, —(CO)-R″, or —CO)-R′″ wherein R′, R″, and R′″= 0  are independently selected from the group consisting of C 1-3  alkyl; 
 wherein R 6  is hydrogen;  
 wherein R 7  is independently selected from the group consisting of hydrogen, , C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl, wherein the alkyl, alkenyl, and alkynyl substituents are optionally substituted with from 1 substituent independently selected from the group consisting of alkyl or aryl.  
 
     
     
         8 . The composition of  claim 1  wherein X 1 =NR 7 ; 
 R 2  is hydrogen;  
 R 3 , R 4 , and R 5  are each independently selected from the group consisting of hydrogen, —(CO)-R′, —(CO)-R″, and —(CO)-R′″ wherein R′, R″, and R′″ are each methyl;  
 R 6  is hydrogen;  
 R 7  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, and C 2-6  alkynyl, wherein the alkyl, alkenyl, and alkynyl substituents are optionally substituted with 1 substituent selected from the group consisting of alkyl or aryl.  
 
     
     
         9 . The composition of claim I wherein X 1 =NR 7 ; 
 R 2  is hydrogen;    R 3 , R 4 , and R 5  and R 6  are each hydrogen; and    R 7  is independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-4  alkenyl, and C 2-4  alkynyl, wherein the alkyl, alkenyl, and alkynyl substituents are optionally substituted with 1 substituent selected from the group consisting of alkyl or aryl.    
     
     
         10 . The composition of  claim 1  wherein X 1 =NR 7 ; 
 R 2  is hydrogen;  
 R 3 , R 4 , R 5  and R 6  are each hydrogen; and  
 R 7  is C 1-6  alkyl wherein the alkyl, is optionally substituted with 1 substituent selected from the group consisting of alkyl or aryl wherein the optional aryl substituent is further optionally substituted with halo, alkyl, CF 3 .  
 
     
     
         11 . The composition of  claim 1  wherein X 1 =NR 7 ; 
 R 2 , R 3 , R 4 , R 5  and R 6  are each hydrogen; and  
 R 7  is C 1-4  alkyl that is optionally substituted with phenyl.  
 
     
     
         12 . The composition of  claim 1  wherein X 1 =NR 7 ; 
 R 2 , R 3 , R 4 , R 5 , and R 6  are each hydrogen; and  
 R 7  is C 2-4  alkenyl that is optionally substituted with 1 substituent selected from the group consisting of alkyl and aryl.  
 
     
     
         13 . The composition of  claim 1  wherein=NR 7 ; 
 R 2 , R 3 , R 4 , R 5 , and R 6  are each hydrogen; and  
 R 7  is C 2-3  alkenyl.  
 
     
     
         14 . The composition of  claim 1  wherein X 1 =NR 7 ; 
 R 2 , R 3 , R 4 , R 5 , and R 6  are each hydrogen; and  
 R 7  is C 2-4  alkynyl that is optionally substituted with 1 substituent selected from the group consisting of alkyl or aryl.  
 
     
     
         15 . The composition of  claim 1  wherein X 1 =NRW; 
 R 2 , R 3 , R 4 , R 5 , and R 6  are each hydrogen; and  
 R 7  is C 2-3  alkynyl.  
 
     
     
         16 . 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.  
     
     
         17 . The composition of matter of  claim 1  wherein R 1  is a monocyclic, bicyclic, or tricyclic cycloalkyl group containing from 3 to 15 atoms wherein at least one carbon atom is substituted with an atom or molecule selected from the group consisting of 0 or S-(O) 0-2 .  
     
     
         18 . The composition of  claim 18  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  claim 1  wherein R 1  is:  
       
         
           
           
               
               
           
         
         wherein R 1 ′, R 1 ″, R 1 ′″, and R 1 ″″ are individually 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 0, or S (−O) 0-2 .  
       
     
     
         20 . The composition of  claim 19  wherein R 1 ′″ and R 1 ″″ can be a single oxygen atom.  
     
     
         21 . The composition of  claim 19  wherein R 1 ′, R 1 ″, R 1 ′″ and R 1 ″″ are individually selected from the group H, lower alkyl, substitute lower alkyl, alkoxy, aryl, and substituted aryl.  
     
     
         22 . The composition of  claim 19  wherein R 1 ′, R 1 ″, R 1 ′″, and R 1 ″″ are individually selected from the group H, lower alkyl, and substitute lower alkyl.  
     
     
         23 . The composition of  claim 1  wherein R 1  is selected from the group consisting of: wherein each may individually selected from the group consisting of H, lower alkyl, and substituted lower alkyl and wherein X is 0, or S (−O) 0-2 .  
     
     
         24 . 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  wherein R 1  is selected from the group consisting of 3-tetrahydrofuranyl, 3-tetrahydrothiofuranyl, 4-pyranyl, and 4 thiopyranyl.  
     
     
         25 . 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  wherein R 1  is 3-tetrahydrofuranyl.  
     
     
         26 . The composition of  claim 1  wherein the compound is selected from the group consisting of 2- {6-[((3 R)oxolan-3-yl)amino]-8-[(methylethyl)amino]purin-9-yl}(4 S,2 R,3 R,5 R) 5-(hydroxymethyl)oxolane-3,4-diol; 2- {6-[((3 R)oxolan-3-yl)amino]-8-(prop-2-enylamino)purin-9-yl}(4 S,2 R,3 R,5 R)-5-(hydroxymethyl)oxolane-3,4-diol; 2- {6-[((3 R)oxolan-3-yl)amino]-8-(prop-2-ynylamino)purin-9-yl}(4 S,2 R,3 R,5 R)-5-(hydroxymethyl)oxolane-3,4-diol; 2- {6-[((3 R)oxolan-3 -yl)amino]-8-(ethylamino)purin-9-yl}(4 S,2 R,3 R,5 R)-5-(hydroxymethyl)oxolane-3,4-diol; 2- {6-[((3 R)oxolan-3-yl)amino]-8-(propylamino)purin-9-yl}(4 S,2 R,3 R,5 R)-5-hydroxymethyl)oxolane-3 ,4-diol; 2- {6-[((3 R)oxolan-3-yl)amino]-8-(butylamino)purin-9-yl}(4 S,2 R,3 R,5 R)-5-(hydroxymethyl)oxolane-3,4-diol; 2- {6-[((3 R)oxolan-3-yl)amino]-8-[benzylamino]purin-9-yl}(4 S,2 R,3 R,5 R)-5-(hydroxymethyl)oxolane-3,4-diol; 2-{6-[((3 R)oxolan-3-yl)amino]-8-(methylamino)purin-9-yl}(4 S,2 R,3 R,5 R)-5-hydroxymethyl)oxolane-3,4-diol; and (5- {6-[((3 R)oxolan-3-yl)amino]-8-(ethylamino)purin-9-yl}(2 R,3 R,4 R,5 R)-3,4-diacetyloxyoxolan-2-yl)methyl acetate.  
     
     
         27 . 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.  
     
     
         28 . 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.  
     
     
         29 . 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.  
     
     
         30 . 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.  
     
     
         31 . 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.  
     
     
         32 . The method of  claim 27  or  28  or  29  or  30  or  31  wherein the therapeutically effective amount ranges from about 0.01 to about 100 mg/kg weight of the mammal.  
     
     
         33 . A pharmaceutical composition of matter comprising the composition of  claim 1  and one or more pharmaceutical excipients.  
     
     
         34 . The pharmaceutical composition of matter of  claim 33  wherein the pharmaceutical composition is in the form of a solution.  
     
     
         35 . The pharmaceutical composition of matter of  claim 33  wherein the pharmaceutical composition is in the form of a tablet.