7-Substituted fused ring tetracycline compounds

Abstract

7-substituted fused ring tetracycline compounds, methods of treating tetracycline responsive states, and pharmaceutical compositions containing the 7-substituted fused ring tetracycline compounds are described.

1 . A 7-substituted fused ring tetracycline compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is CR 6 R 6′ ;  
 R 4  and R 4′  are each alkyl;  
 R 5  is hydrogen, hydroxyl, or a prodrug moiety;  
 R 6  and R 6′  are each independently hydrogen, hydroxyl, alkyl, or taken together, alkenyl;  
 Y and Y′ are each independently optionally substituted C, N, O, or S;  
 m is 1 or 2; and pharmaceutically acceptable salts thereof.  
 
     
     
         2 . The compound of  claim 1 , wherein R 5 , R 6  and R 6′  are each hydrogen and R 4  and R 4′  are each methyl.  
     
     
         3 . The compound of  claim 1 , wherein Y and Y′ are each oxygen.  
     
     
         4 . The compound of  claim 1 , wherein m is 1.  
     
     
         5 . The compound of  claim 1 , wherein said compound is 7-(3′,4′-methylene dioxyphenyl)sancycline.  
     
     
         6 . A method for treating a tetracycline responsive state in a mammal, comprising administering to said mammal a 7-substituted fused ring tetracycline compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is CR 6 R 6′ ;  
 R 4  and R 4′  are each alkyl;  
 R 5  is hydrogen, hydroxyl, or a prodrug moiety;  
 R 6  and R 6′  are each independently hydrogen, hydroxyl, alkyl, or taken together, alkenyl;  
 Y and Y′ are each independently optionally substituted C, N, O, or S;  
 m is 1 or 2; and pharmaceutically acceptable salts thereof, such that the tetracycline responsive state is treated.  
 
     
     
         7 . The method of  claim 6  wherein R 5 , R 6  and R 6′  are each hydrogen and R 4  and R 4′  are each methyl.  
     
     
         8 . The method of  claim 6 , wherein Y and Y′ are each oxygen.  
     
     
         9 . The method of  claim 6 , wherein m is 1.  
     
     
         10 . The method of  claim 7 , wherein said compound is 7-(3′,4′-methylene dioxyphenyl)sancycline.  
     
     
         11 . The method of  claim 7 , wherein said tetracycline responsive state is a bacterial infection.  
     
     
         12 . The method of  claim 11 , wherein said bacterial infection is associated with  E. coli.    
     
     
         13 . The method of  claim 11 , wherein said bacterial infection is associated with  S. aureus.    
     
     
         14 . The method of  claim 11 , wherein said bacterial infection is associated with  E. faecalis.    
     
     
         15 . The method of  claim 11 , wherein said bacterial infection is resistant to other tetracycline antibiotics.  
     
     
         16 . The method of  claim 11 , wherein said compound is administered with a pharmaceutically acceptable carrier.  
     
     
         17 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         18 . The pharmaceutical composition of  claim 16 , wherein said compound is 7-(3′,4′-methylene dioxyphenyl)sancycline.