7-phenyl-substituted tetracycline compounds

Abstract

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

1 . A 7-substituted tetracycline compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 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;  
 R 7  is halo substituted or unsubstituted phenyl; 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 R 7  is unsubstituted phenyl.  
     
     
         4 . The compound of  claim 3 , wherein said compound is 7-phenylsancycline.  
     
     
         5 . The compound of  claim 1 , wherein R 7  is 2-substituted phenyl.  
     
     
         6 . The compound of  claim 5 , wherein said compound is selected from the group consisting of 7-(2-fluorophenyl) sancycline, 7-(2-chlorophenyl) sancycline, 7-(2-bromophenyl) sancycline, and 7-(2-iodophenyl) sancycline.  
     
     
         7 . The compound of  claim 1 , wherein R 7  is 3-substituted phenyl.  
     
     
         8 . The compound of  claim 7 , wherein said compound is selected from the group consisting of 7-(3-fluorophenyl) sancycline, 7-(3-chlorophenyl) sancycline, 7-(3-bromophenyl) sancycline, and 7-(3-iodophenyl) sancycline.  
     
     
         9 . The compound of  claim 1 , wherein R 7  is 4-substituted phenyl.  
     
     
         10 . The compound of  claim 9 , wherein said compound is selected from the group consisting of 7-(4-fluorophenyl) sancycline, 7-(4-chlorophenyl) sancycline, 7-(4-bromophenyl) sancycline, 7-(4-iodophenyl) sancycline, 7-(4-trichloromethylphenyl) sancycline, 7-(4-trifluoromethylphenyl) sancycline, 7-(4-tribromomethylphenyl) sancycline, and 7-(4-triiodomethylphenyl) sancycline.  
     
     
         11 . A method for treating a tetracycline responsive state in a mammal, comprising administering to said mammal a 7-substituted tetracycline compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 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;  
 R 7  is halo substituted or unsubstituted phenyl; and pharmaceutically acceptable salts thereof, such that the tetracycline responsive state is treated.  
 
     
     
         12 . The method of  claim 11 , wherein R 5 , R 6  and R 6′0  are each hydrogen and R 4  and R 4 ′ are each methyl.  
     
     
         13 . The method of  claim 11 , wherein R 7  is unsubstituted phenyl.  
     
     
         14 . The method of  claim 13 , wherein said compound is 7-phenylsancycline.  
     
     
         15 . The method of  claim 1 , wherein R 7  is 2-substituted phenyl.  
     
     
         16 . The method of  claim 15 , wherein said compound is selected from the group consisting of 7-(2-fluorophenyl) sancycline, 7-(2-chlorophenyl) sancycline, 7-(2-bromophenyl) sancycline, and 7-(2-iodophenyl) sancycline.  
     
     
         17 . The method of  claim 11 , wherein R 7  is 3-substituted phenyl.  
     
     
         18 . The method of  claim 17 , wherein said compound is selected from the group consisting of 7-(3-fluorophenyl) sancycline, 7-(3-chlorophenyl) sancycline, 7-(3-bromophenyl) sancycline, and 7-(3-iodophenyl) sancycline.  
     
     
         19 . The method of  claim 11 , wherein R 7  is 4-substituted phenyl.  
     
     
         20 . The method of  claim 19 , wherein said compound is selected from the group consisting of 7-(4-fluorophenyl) sancycline, 7-(4-chlorophenyl) sancycline, 7-(4-bromophenyl) sancycline, 7-(4-iodophenyl) sancycline, 7-(4-trichloromethylphenyl) sancycline, 7-(4-trifluoromethylphenyl) sancycline, 7-(4-tribromomethylphenyl) sancycline, and 7-(4-triiodomethylphenyl) sancycline.  
     
     
         21 . The method of  claim 11 , wherein said tetracycline responsive state is a bacterial infection.  
     
     
         22 . The method of  claim 21 , wherein said bacterial infection is associated with  E. coli.    
     
     
         23 . The method of  claim 21 , wherein said bacterial infection is associated with  S. aureus.    
     
     
         24 . The method of  claim 21 , wherein said bacterial infection is associated with  E. faecalis.    
     
     
         25 . The method of  claim 21 , wherein said bacterial infection is resistant to other tetracycline antibiotics.  
     
     
         26 . The method of  claim 11 , wherein said compound is administered with a pharmaceutically acceptable carrier.  
     
     
         27 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein said compound is selected from the group consisting of 7-phenyl sancycline, 7-(2-fluorophenyl) sancycline, 7-(2-chlorophenyl) sancycline, 7-(2-bromophenyl) sancycline, 7-(2-iodophenyl) sancycline, 7-(3 -fluorophenyl) sancycline, 7-(3-chlorophenyl) sancycline, 7-(3 -bromophenyl) sancycline, 7-(3-iodophenyl) sancycline, 7-(4-fluorophenyl) sancycline, 7-(4-chlorophenyl) sancycline, 7-(4-bromophenyl) sancycline, 7-(4-iodophenyl) sancycline, 7-(4-trichloromethylphenyl) sancycline, 7-(4-trifluoromethylphenyl) sancycline, 7-(4-tribromomethylphenyl) sancycline, and 7-(4-triiodomethylphenyl) sancycline.  
     
     
         29 . A tetracycline compound, wherein said compound is 7,9-diphenyl sancycline or a pharmaceutically acceptable salt thereof.  
     
     
         30 . A method for treating a tetracycline responsive state in a mammal, comprising administering to said mammal an effective amount of 7,9-diphenyl sancycline or a pharmaceutically acceptable salt thereof, such that said mammal is treated.  
     
     
         31 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 29  and a pharmaceutically acceptable carrier.