7-N-substituted phenyl tetracycline compounds

Abstract

7-substituted tetracycline compounds, methods of treating tetracycline responsive states, and pharmaceutical compositions containing the 7-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 an N-substituted phenyl; and pharmaceutically acceptable salts thereof, 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 2-N-substituted phenyl.  
   
   
       4 . The compound of  claim 3 , wherein said 2-N-substituted phenyl is substituted with a nitro group.  
   
   
       5 . The compound of  claim 4 , wherein said compound is 7-(2-nitrophenyl)sancycline.  
   
   
       6 . The compound of  claim 3 , wherein said 2-N-substituted phenyl is 2-amino substituted.  
   
   
       7 . The compound of  claim 5 , wherein said 2-amino substituent is dialkylamino.  
   
   
       8 . The compound of  claim 3 , wherein said compound is selected from the group consisting of 7-(2-aminophenyl)sancycline, 7-(2-nitrophenyl)sancycline, 7-(2-N,N,-dimethylaminophenyl)sancycline, 7-(2-N,N,-diethylaminophenyl)sancycline, 7-(2-N,N,-dipropylaminophenyl)sancycline, and 7-(2-N,N,-dibutylaminophenyl)sancycline.  
   
   
       9 . The compound of  claim 7 , wherein said dialkyl amino group is dimethylamino.  
   
   
       10 . The compound of  claim 9 , wherein said compound is 7-(4-N,N,-dimethylaminophenyl)sancycline.  
   
   
       11 . The compound of  claim 1 , wherein R 7  is 3-N-substituted phenyl.  
   
   
       12 . The compound of  claim 10 , wherein said 3-N-substituted phenyl is substituted with a nitro group.  
   
   
       13 . The compound of  claim 12 , wherein said compound is 7-(3-nitrophenyl)sancycline.  
   
   
       14 . The compound of  claim 11 , wherein said 3-N-substituted phenyl is 3-amino substituted.  
   
   
       15 . The compound of  claim 14 , wherein said 3-amino substituent is dialkylamino.  
   
   
       16 . The method of  claim 14 , wherein said compound is selected from the group consisting of 7-(3-aminophenyl)sancycline, 7-(3-N,N,-dimethylaminophenyl)sancycline, 7-(3-N,N,-diethylaminophenyl)sancycline, 7-(3-N,N,-dipropylaminophenyl)sancycline, and 7-(3-N,N,-dibutylaminophenyl)sancycline.  
   
   
       17 . The compound of  claim 15 , wherein said dialkyl amino group is dimethylamino.  
   
   
       18 . The compound of  claim 17 , wherein said compound is 7-(4-N,N,-dimethylaminophenyl)sancycline.  
   
   
       19 . The compound of  claim 1 , wherein R 7  is 4-N-substituted phenyl.  
   
   
       20 . The compound of  claim 19 , wherein said 4-N-substituted phenyl is substituted with a nitro group.  
   
   
       21 . The compound of  claim 20 , wherein said compound is 7-(4-nitrophenyl)sancycline.  
   
   
       22 . The compound of  claim 19 , wherein said 4-substituted phenyl is 4-amino substituted.  
   
   
       23 . The compound of  claim 22 , wherein said 4-amino substituent is dialkyl.  
   
   
       24 . The method of  claim 23 , wherein said compound is 7-(4-aminophenyl)sancycline, 7-(4-N,N,-diethylaminophenyl) sancycline, 7-(4-N,N,-dipropylaminophenyl)sancycline, or 7-(4-N,N,-dibutylaminophenyl)sancycline.  
   
   
       25 . The compound of  claim 23 , wherein said dialkyl amino group is dimethyl.  
   
   
       26 . The compound of  claim 25 , wherein said compound is 7-(4-N,N,-dimethylaminophenyl)sancycline.  
   
   
       27 . 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 an N-substituted phenyl; and pharmaceutically acceptable salts thereof, such that the tetracycline responsive state is treated.  
     
   
   
       28 . The method of  claim 27 , wherein R 5 , R 6  and R 6′  are each hydrogen and R 4  and R 4′  are each methyl.  
   
   
       29 . The method of  claim 27 , wherein R 7  is 2-N-substituted phenyl.  
   
   
       30 . The method of  claim 29 , wherein said 2-N-substituted phenyl is substituted with a nitro group.  
   
   
       31 . The method of  claim 29 , wherein said 2-N-substituted phenyl is 2-amino substituted.  
   
   
       32 . The method of  claim 29 , wherein said compound is selected from the group consisting of 7-(2-aminophenyl)sancycline, 7-(2-nitrophenyl)sancycline, 7-(2-N,N,-dimethylaminophenyl)sancycline, 7-(2-N,N,-diethylaminophenyl)sancycline, 7-(2-N,N,-dipropylaminophenyl)sancycline, and 7-(2-N,N,-dibutylaminophenyl)sancycline.  
   
   
       33 . The method of  claim 27 , wherein R 7  is 3-N-substituted phenyl.  
   
   
       34 . The method of  claim 33 , wherein said 3-N-substituted phenyl is substituted with a nitro group.  
   
   
       35 . The method of  claim 33 , wherein said 3-N-substituted phenyl is 3-amino substituted.  
   
   
       36 . The method of  claim 33 , wherein said compound is selected from the group consisting of 7-(3-aminophenyl)sancycline, 7-(3-nitrophenyl)sancycline, 7-(3-N,N,-dimethylaminophenyl)sancycline, 7-(3-N,N,-diethylaminophenyl)sancycline, 7-(3-N,N,-dipropylaminophenyl)sancycline, and 7-(3-N,N,-dibutylaminophenyl)sancycline.  
   
   
       37 . The method of  claim 27 , wherein R 7  is 4-N-substituted phenyl.  
   
   
       38 . The method of  claim 37 , wherein said 4-N-substituted phenyl is substituted with a nitro group.  
   
   
       39 . The method of  claim 37 , wherein said 4-substituted phenyl is 4-amino substituted.  
   
   
       40 . The method of  claim 39 , wherein said compound is 7-(4-aminophenyl)sancycline, 7-(4-nitrophenyl)sancycline, 7-(4-N,N,-dimethylaminophenyl)sancycline, 7-(4-N,N,-diethylaminophenyl)sancycline, 7-(4-N,N,-dipropylaminophenyl)sancycline, or 7-(4-N,N,-dibutylaminophenyl)sancycline.  
   
   
       41 . The method of  claim 27 , wherein said tetracycline responsive state is a bacterial infection.  
   
   
       42 . The method of  claim 41 , wherein said bacterial infection is associated with  E. coli.    
   
   
       43 . The method of  claim 41 , wherein said bacterial infection is associated with  S. aureus.    
   
   
       44 . The method of  claim 41 , wherein said bacterial infection is associated with  E. faecalis.    
   
   
       45 . The method of  claim 41 , wherein said bacterial infection is resistant to other tetracycline antibiotics.  
   
   
       46 . The method of  claim 27 , wherein said compound is administered with a pharmaceutically acceptable carrier.  
   
   
       47 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.  
   
   
       48 . The pharmaceutical composition of  claim 47 , wherein said compound is selected from the group consisting of 7-(2-aminophenyl)sancycline, 7-(2-nitrophenyl)sancycline, 7-(2-N,N,-dimethylaminophenyl)sancycline, 7-(2-N,N,-diethylaminophenyl)sancycline, 7-(2-N,N,-dipropylaminophenyl)sancycline, 7-(2-N,N,-dibutylaminophenyl)sancycline, 7-(3-aminophenyl)sancycline, 7-(3-nitrophenyl)sancycline, 7-(3-N,N,-dimethylaminophenyl)sancycline, 7-(3-N,N,-diethylaminophenyl)sancycline, 7-(3-N,N,-dipropylaminophenyl)sancycline, 7-(3-N,N,-dibutylaminophenyl)sancycline, 7-(4-aminophenyl)sancycline, 7-(4-nitrophenyl)sancycline, 7-(4-N,N,-dimethylaminophenyl)sancycline, 7-(4-N,N,-diethylaminophenyl)sancycline, 7-(4-N,N,-dipropylaminophenyl)sancycline, and 7-(4-N,N,-dibutylaminophenyl)sancycline.