A1 adenosine receptor antagonists

Abstract

A compound useful as an A 1 adenosine receptor antagonist has formula (I), wherein R 1 is selected from the group consisting of C 1 -C 8 alkyl; R 2 is of formula (II), wherein n is an integer ranging from 1 to 8; R 5 is H or CH 3 (CH 2 ) p , wherein p is an integer ranging from 1 to 7; and R 6 is H; (CH 2 ) m H; or (CH 2 ) m OH, wherein m is an integer ranging from 1 to 8; R 3 is selected from the group consisting of: (a), (b), (c) and (d), wherein q is an integer ranging from 1 to 8; D is selected from the group consisting of NH, S, and O; wherein R 7 is selected from the group consisting of H, OH, NH 2 , R 9 COOH, wherein R 9 is an alkylene or alkenylene group having 1 to 8 carbon atoms, and (CH 2 ) t OH, wherein t is an integer ranging from 1 to 8; R 11 is selected from the group consisting of —CH 2 COOH and —CH 2 —CONH(CH 2 ) w NHZ, wherein w is an integer ranging from 1 to 2 and Z is selected from the group consisting of hydrogen and acetate; and R 4 is of formula (III), wherein R 8 is selected from the group consisting of H; OH; (CH 2 ) f NH 2 wherein f is selected from the group consisting of 0 and an integer ranging from 1 to 8; (CH 2 ) 5 OH, wherein s is an integer ranging from 1 to 8; and R 10 COOH, wherein R 10 is an alkylene or alkenylene group having 1 to 8 carbon atoms; and r is an integer ranging from 1 to 8.

That which is claimed is:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is selected from the group consisting of C 1 -C 8  alkyl;  
 R 2  is of the formula:  
                     wherein n is an integer ranging from 1 to 8; R 5  is H or CH 3  (CH 2 ) p , wherein p is an integer ranging from 1 to 7; and R 6  is H; (CH 2 ) m H; or (CH 2 ) m OH, wherein m is an integer ranging from 1 to 8;    
 R 3  is selected from the group consisting of: 
 —(CH 2 ) q C 6 H 4 —R 7   
                     wherein q is an integer ranging from 1 to 8; D is selected from the group consisting of NH, S, and O; wherein R 7  is selected from the group consisting of H, OH, NH 2 , R 9 COOH, wherein R 9  is an alkylene or alklenylene group having  1  to 8 carbon atoms, and (CH 2 ) t OH, wherein t is an integer ranging from 1 to 8; R 11  is selected from the group consisting of, —CH 2 COOH and —CH 2 —CONH(CH 2 ) w NHZ, wherein w is an integer ranging from 1 to 2 and Z is selected from the group consisting of hydrogen and acetate; and    
 R 4  is of the formula:  
                     wherein R 8  is selected from the group consisting of H; OH; (CH 2 ) f NH 2  wherein f is selected from the group consisting of 0 and an integer ranging from 1 to 8; (CH 2 ) s OH, wherein s is an integer ranging from 1 to 8; and R 10 COOH, wherein R 10  is an alkylene or alkenylene group having 1 to 8 carbon atoms; and r is an integer ranging from 1 to 8.    
 
     
     
         2 . The compound according to  claim 1 , wherein R 1  is C 3  alkyl; R 3  is: 
       —(CH 2 ) q C 6 H 4 —R 7   
       R 5  is CH 3  (CH 2 ) p  wherein p is 1; R 6  is (CH 2 ) m OH wherein m is 2; R 7  is H; R 8  is NH 2 ; f is 0; n is 2; m is 2; q is 1; and r is 2.  
     
     
         3 . The compound according to  claim 1 , wherein R 1  is C 3  alkyl; R 3  is: 
       —(CH 2 ) q C 6 H 4 —R 7   
       R 5  is CH 3  (CH 2 ) p  wherein p is 1; R 6  is H; R 7  is NH 2 ; R 8  is NH 2 ; f is 0; n is 2; q is 1; and r is 2.  
     
     
         4 . The compound according to  claim 1 , wherein R 1  is C 3  alkyl; R 3  is: 
       —(CH 2 ) q C 6 H 4 —R 7   
       R 5  is CH 3  (CH 2 ) p  wherein p is 1; R 6  is H; R 7  is H; R 8  is NH 2 ; f is 0; n is 2; q is 1; and r is 2.  
     
     
         5 . The compound according to  claim 1 , wherein R 1  is C 3  alkyl; R 3  is: 
       —(CH 2 ) q C 6 H 4 —R 7   
       R 5  is CH 3  (CH 2 ) p  wherein p is 1; R 6  is H; R 7  is H; R 8  is selected from the group consisting of (CH 2 ) s OH wherein s is 2 and R 10 COOH, wherein R 10  is CH═CH; n is 2; q is 1; and r is 2.  
     
     
         6 . The compound according to  claim 1 , wherein R 1  is C 3  alkyl; R 3  is: 
       —(CH 2 ) q C 6 H 4 —R 7   
       R 5  is CH 3  (CH 2 ) p  wherein p is 1; R 6  is H; R 7  is selected from the group consisting of (CH 2 ) t OH wherein t is 2 and R 9 COOH, wherein R 9  is CH═CH; R 8  is NH 2  ; f is 0; n is 2; q is 1; and r is 2.  
     
     
         7 . An assay-type probe of the compound defined in  claim 1 , wherein said assay-type probe is labeled with non-radioactive material.  
     
     
         8 . The assay-type probe: according to  claim 7 , wherein said non-radioactive material is a fluorescent dye.  
     
     
         9 . The assay-type probe according to  claim 7 , wherein said non-radioactive material is biotin.  
     
     
         10 . The assay-type probe according to  claim 7 , wherein R 1  is C 3  alkyl; R 3  is: 
       —(CH 2 ) q C 6 H 4 —R 7   R 5  is CH 3  (CH 2 ) p  wherein p is 1; R 7  is H; R 8 is NH 2 ; f is 0; n is 2; q is 1; r is 2; and R 6  is (CH 2 ) m OH wherein m is 2;    wherein said non-radioactive material is biotin bonded to the hydroxyl group present on R 6 .    
     
     
         11 . The assay-type probe according to  claim 7 , wherein R 1  is C 3  alkyl; R 3  is: 
       —(CH 2 ) q C 6 H 4 —R 7   R 5  is CH 3  (CH 2 ) p  wherein p is 1; R 6  is H; R 7  is NH 2 ; n is 2; q is 1; r is 2; and R 8  is NH 2 ; f is 0;    wherein said non-radioactive material is biotin bonded to the amino group present on R 8 .    
     
     
         12 . The assay-type probe according to  claim 7 , wherein R 1  is C 3  alkyl; R 3  is: 
       —(CH 2 ) q C 6 H 4 —R 7   R 5  is CH 3  (CH 2 ) p  wherein p is 1; R 6  is H; R 7 is H; n is 2; q is 1; r is 2; and R 8  is R 10 COOH, wherein R 10  is an alkylene or alkenylene group having 1 to 8 carbon atoms;    wherein said non-radioactive,e material is biotin bonded to the carboxyl group present on R 8 .    
     
     
         13 . An assay-type probe of the compound defined in  claim 1 , wherein said assay-type probe is labeled with radioactive material.  
     
     
         14 . The assay-type probe according to  claim 13 , wherein said radioactive material is a radioactive isotope selected from the group consisting of  18 F,  19 F, tritium, and  125 I.  
     
     
         15 . A pharmaceutically,y acceptable salt of compound defined by the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is selected from the group consisting of C 1 -C 8  alkyl;  
 R 2  is of the formula:  
                     wherein n is an integer ranging from 1 to 8; R 5  is H or CH 3  (CH 2 ) p , wherein p is an integer ranging from 1 to 7; and R 6  is H; (CH 2 ) m H; or (CH 2 ) m OH, wherein m is an integer ranging from 1 to 8;    
 R 3  is selected from the group consisting of: 
 —(CH 2 ) q C 6 H 4 —R 7   
                     wherein q is an integer ranging from 1 to 8; D is selected from the group consisting of NH, S, and O; wherein R 7  is selected from the group consisting of H, OH, NH 2 , R 9 COOH, wherein R 9  is an alkylene or alkenylene group having 1 to 8 carbon atoms, and (CH 2 ) t OH, wherein t is an integer ranging from 1 to 8; R 11  is selected from the group consisting of —CH 2 COOH and —CH 2 —CONH(CH 2 ) w MHZ, wherein w is an integer ranging from 1 to 2 and Z is selected from the group consisting of hydrogen and acetate; and    
 R 4  is of the formula:  
                     wherein R 8  is selected from the group consisting of H; OH; (CH 2 ) f NH 2  wherein f is selected from the group consisting of 0 and an integer ranging from 1 to 8; (CH 2 ) s OH, wherein s is an integer ranging from 1 to 8; and R 10 COOH, wherein R 10  is an alkylene or alkenylene group having 1 to 8 carbon atoms; and r is an integer ranging from 1 to 8.    
 
     
     
         16 . The compound according to  claim 15 , wherein R 1  is C 3  alkyl; R 3  is: 
       —(CH 2 ) q C 6 H 4 —R 7   
       R 5  is CH 3  (CH 2 ) p  wherein p is 1; R 6  is (CH 2 ) m OH wherein m is 2; R 7  is H; R 8  is NH 2 ; f is 0; n is 2; m is 2; q is 1; and r is 2.  
     
     
         17 . The compound according to  claim 15 , wherein R 1  is C 3  alkyl; R 3  is: 
       —(CH 2 ) q  C 6 H 4 —R 7   
       R 5  is CH 3  (CH 2 ) p  wherein p is 1; R 6  is H; R 7  is NH 2 ; R 8  is NH 2 ; f is 0; n is 2; q is 1; and r is 2.  
     
     
         18 . The compound according to  claim 15 , wherein R 1  is C 3  alkyl; R 3  is: 
       —(CH 2 ) q C 6 H 4 —R 7   
       R 5  is CH 3  (CH 2 ) p  wherein p is 1; R 6  is H; R 7  is H; R 8  is NH 2 ; f is 0; n is 2; q is 1; and r is 2.  
     
     
         19 . The compound according to  claim 15 , wherein R 1  is C 3  alkyl; R 3  is: 
       —(CH 2 ) q C 6 H 4 —R 7   
       R 5  is CH 3  (CH 2 ) p  wherein p is 1; R 6  is H; R 7  is H; R 8  is selected from the group consisting of (CH 2 ) s OH wherein s is 2 and R 10 COOH, wherein R 10  is CH═CH; n is 2; q is 1; and r is 2.  
     
     
         20 . The compound according to  claim 15 , wherein R 1  is C 3  alkyl; R 3  is: 
       —(CH 2 ) q C 6 H 4 —R 7   
       R 5  is CH 3  (CH 2 ) p  wherein p is 1; R 6  is H; R 7  is selected from the group consisting of (CH 2 ) t OH wherein t is 2 and R 9 COOH, wherein R 9  is CH═CH; R 8  is NH 2 ; f is 0; n is 2; q is 1; and r is 2.  
     
     
         21 . A pharmaceutical composition which comprises a compound of  claim 1  and a pharmaceutically acceptable carrier.