Adenosine receptor antagonists and methods of making and using the same

Abstract

The invention is based on the discovery that compounds of Formula I are unexpectedly highly potent and selective inhibitors of the adenosine A 1 receptor. Adenosine A 1 antagonists can be useful in the prevention and/or treatment of numerous diseases, including cardiac and circulatory disorders, degenerative disorders of the central nervous system, respiratory disorders, and many diseases for which diuretic treatment is suitable. In one embodiment, the invention features a compound of formula I:

What is claimed is:  
     
         1 . A compound comprising the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2 , independently, are selected from the group consisting of: 
 a) hydrogen;  
 b) alkyl, alkenyl of not less than 3 carbons, and alkynyl of not less than 3 carbons;  
 wherein the alkyl, alkenyl, or alkynyl is either unsubstituted or functionalized with one or two substituents selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl, acylamino, alkylsulfonylamino, and heterocyclylcarbonylamino; and  
 c) aryl and substituted aryl;  
 R 3  is a bicyclic or tricyclic group selected from the group consisting of:  
                     
 wherein the bicyclic or tricyclic group is either unsubstituted or functionalized with one or more substituents selected from the group consisting of:  
 (a) alkyl, alkenyl, and alkynyl; wherein the alkyl, alkenyl, and alkynyl are either unsubstituted or functionalized with one or more substituents selected from the group consisting of alkoxy, alkoxycarbonyl, alkoxycarbonylaminoalkylamino, aralkoxycarbonyl, —R5, dialkylamino, heterocyclylalkylamino, hydroxy, substituted arylsulfonylaminoalkylamino, and substituted heterocyclylaminoalkylamino;  
 (b) acylaminoalkylamino, alkenylamino, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkylamino, alkoxycarbonylaminoacyloxy, alkoxycarbonylaminoalkylamino, alkylamino, amino, aminoacyloxy, carbonyl, —R 5 , R 5 -alkoxy, R 5 -alkylamino, dialkylaminoalkylamino, heterocyclyl, heterocyclylalkylamino, hydroxy, phosphate, substituted arylsulfonylaminoalkylamino, substituted heterocyclyl, and substituted heterocyclylaminoalkylamino;  
 R 4  is selected from the group consisting of —H, —C 1-4 -alkyl, —C 1-4 -alkyl-CO 2 H, and phenyl; and is either unsubstituted or functionalized with one or more substituents selected from the group consisting of halogen, —OH, —OMe, —NH 2 , NO 2  or benzyl, optionally substituted with one to three groups selected from halogen, —OH, —OMe, —NH 2 , and —NO 2 ;  
 R 5  is selected from the group consisting of —CH 2 COOH, —C(CF 3 ) 2 OH, —CONHNHSO 2 CF 3 , —CONHOR 4 , —CONHSO 2 R 4 , —CONHSO 2 NHR 4 , —C(OH)R 4 PO 3 H 2 , —NHCOCF 3 , —NHCONHSO 2 R 4 , —NHPO 3 H 2 , —NHSO 2 R 4 , —NHSO 2 NHCOR 4 , —OPO 3 H 2 , —OSO 3 H, —PO(OH)R 4 , —PO 3 H 2 , —SO 3 H, —SO 2 NHR 4 , —SO 3 NHCOR 4 , —SO 3 NHCONHCO 2 R 4 , and:  
                     
 X 1  and X 2  are independently selected from O and S;  
 Z is selected from the group consisting of a single bond, —O—, —(CH 2 ) 1-3 —, —O(CH 2 ) 1-2 —, —CH 2 OCH 2 —, —(CH 2 ) 1-2 O—, —CH═CHCH 2 —, —CH═CH—, and —CH 2 CH═CH—; and  
 R 6  is selected from the group consisting of hydrogen, alkyl, acyl, alkylsufonyl, aralkyl, substituted aralkyl, substituted alkyl, and heterocyclyl. The compound of  claim 1 , wherein the compound is in a form selected from the group consisting of an achiral compound, a racemate, an optically active compound, a pure diastereomer, a mixture of diastereomers, and a pharmacologically acceptable addition salt.  
 
     
     
         2 . The compound of  claim 1 , wherein R 1  and R 2  are each alkyl groups.  
     
     
         3 . The compound of  claim 1 , wherein R 1  and R 2  are each n-propyl.  
     
     
         4 . The compound of  claim 3 , wherein Z is a single bond.  
     
     
         5 . The compound of  claim 1 , wherein R 3  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and is functionalized with one or more substituents selected from carbonyl, hydroxy, alkenyl, alkenyloxy, hydroxyalkyl, carboxy, carboxyalkenyl, carboxyalkyl, aminoacyloxy, carboxyalkoxy, dialkylaminoalkenyl, and dialkylaminoalkyl.  
     
     
         6 . The compound of  claim 1 , wherein R 3  is:  
       
         
           
           
               
               
           
         
       
       and is functionalized with one or more substituents selected from carbonyl, hydroxy, alkenyl, carboxyalkenyl, hydroxyalkyl, dialkylaminoalkenyl, and dialkylaminoalkyl.  
     
     
         7 . The compound of  claim 6 , wherein R 3  is substituted with a substituent selected from the group consisting of hydroxy, hydroxyalkyl, dialkylaminoalkenyl, and dialkylaminoalkyl.  
     
     
         8 . The compound of  claim 1 , wherein the compound is 8-(5-Hydroxy-tricyclo[2.2.1.0 2,6 ]hept-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.  
     
     
         9 . The compound of  claim 1 , wherein the compound is 8-(5-Hydroxymethyl-tricyclo[2.2.1.0 2,6 ]hept-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.  
     
     
         11 . The compound of  claim 1 , wherein the compound is 8-[5-(3-Dimethylaminopropylidene)-tricyclo[2.2.1.0 2,6 ]hept-3-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.  
     
     
         12 . The compound of  claim 1 , wherein the compound is 8-[5-(3-Dimethylaminopropyl)-tricyclo[2.2.1.0 2,6 ]hept-3-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.  
     
     
         13 . The compound of  claim 1 , wherein R 3  is selected from  
       
         
           
           
               
               
           
         
       
       and is functionalized with one or more substituents selected from the group consisting of hydroxy, carbonyl, alkyl, —R 5 , R 5 -alkyl, dialkylaminoalkylamino, alkoxycarbonylalkylamino, R 5 -alkylamino, heterocyclyl, alkenylamino, amino, alkylamino, heterocyclylalkylamino, acylaminoalkylamino, phosphate, heterocyclylaminoalkylamino, and heterocyclylaminoalkylaminoalkyl.  
     
     
         14 . The compound of  claim 1 , wherein R 3  is  
       
         
           
           
               
               
           
         
       
       and is functionalized with one or more substituents selected from the group consisting of hydroxy, —R 5 , R 5 -alkyl, and hydroxyalkyl.  
     
     
         15 . The compound of  claim 1 , wherein the compound is 4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purine-8-yl)-bicyclo[3.2.1]octane-1 -carboxylic acid.  
     
     
         16 . The compound of  claim 1 , wherein R 3  is:  
       
         
           
           
               
               
           
         
       
       and is functionalized with one or more substituents selected from the group consisting of alkyl, hydroxy, carbonyl, —R 5 , and R 5 -alkyl.  
     
     
         17 . The compound of  claim 1 , wherein the compound is 8-(4-Hydroxy-bicyclo[3.2.1]oct-6-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.  
     
     
         18 . The compound of  claim 1 , wherein the compound is 8-(4-Oxo-bicyclo[3.2.1]oct-6-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.  
     
     
         19 . The compound of  claim 1 , wherein R 3  is:  
       
         
           
           
               
               
           
         
       
       and is functionalized with one or more substituents selected from the group consisting of carbonyl, hydroxy, dialkylaminoalkylamino, —R 5 , and substituted heterocyclylaminoalkylaminoalkyl.  
     
     
         20 . The compound of  claim 1 , wherein the compound is 8-[8-(2-Dimethylaminoethylamino)-bicyclo[3.2.1]oct-3-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.  
     
     
         21 . The compound of  claim 1 , wherein the compound is 8-(8-Hydroxy-bicyclo[3.2.1]oct-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.  
     
     
         22 . The compound of  claim 1 , wherein R 3  is:  
       
         
           
           
               
               
           
         
       
       and is functionalized with one or more substituents selected from the group consisting of carbonyl, hydroxy, and —R 5 .  
     
     
         23 . The compound of  claim 1 , wherein the compound is 8-(3-Hydroxy-bicyclo[3.2.1]oct-8-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.  
     
     
         24 . The compound of  claim 5 , wherein R 3  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and is functionalized with one or more substituents selected from the group consisting of hydroxyalkyl, hydroxy, and alkoxycarbonyl.  
     
     
         25 . The compound of  claim 1 , wherein the compound is 8-(8-Oxa-bicyclo[3.2.1]oct-6-en-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.  
     
     
         26 . The compound of  claim 1 , wherein R 3  is:  
       
         
           
           
               
               
           
         
       
       and is functionalized with one or more substituents selected from the group consisting of carbonyl, aralkyloxycarbonylalkyl, and alkoxycarbonylalkyl.  
     
     
         27 . The compound of  claim 1 , wherein the compound is 8-(2-Oxo-3-aza-bicyclo[3.2.1]oct-8-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione.  
     
     
         28 . A medicament composition comprising a compound of  claim 1  together with a suitable excipient.  
     
     
         29 . A method of treating a subject suffering from a condition characterized by an elevated adenosine concentration and/or increased sensitivity to adenosine; the method comprising administering to the subject an effective adenosine antagonizing amount of a compound of  claim 1 .  
     
     
         30 . The method of  claim 29 , wherein the condition is selected from the group consisting of cardiac and circulatory disorders, degenerative disorders of the central nervous system, respiratory disorders, diseases for which diuretic treatment is indicated, Parkinson's disease, depression, traumatic brain damage, post-stroke neurological deficit, respiratory depression, neonatal brain trauma, dyslexia, hyperactivity, cystic fibrosis, cirrhotic ascites, neonatal apnea, renal failure, diabetes, asthma, and edematous conditions.  
     
     
         31 . The method of  claim 29 , wherein the condition is selected from the group consisting of congestive heart failure and renal dysfunction.  
     
     
         32 . A method of making 8-substituted xanthines comprising the steps of: 
 a) obtaining a N7, C8-dihydroxanthine;    b) protecting the N7 position of the xanthine;    c) deprotonating the C8 position with strong base to generate an anion;    d) trapping the anion with a carboxyl, carbonyl, aldehyde, or ketone compound; and    e) deprotecting the protected N7 position to obtain an 8-substituted xanthine.