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 6 , 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-amino)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 11 , 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 11 , wherein said compound is selected from the group consisting of 7-(3-amino)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. 
     
     
         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 22 , wherein said compound is 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 30 , wherein said compound is 7-(2-nitrophenyl)sancycline. 
     
     
         32 . The method of  claim 29 , wherein said 2-N-substituted phenyl is 2-amino substituted. 
     
     
         33 . The method of  claim 32 , wherein said 2-amino substituent is dialkylamino. 
     
     
         34 . The method of  claim 29 , wherein said compound is selected from the group consisting of 7-(2-amino)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. 
     
     
         35 . The method of  claim 33 , wherein said dialkyl amino group is dimethylamino. 
     
     
         36 . The method of  claim 35 , wherein said compound is 7-(4-N,N,-dimethylaminophenyl)sancycline. 
     
     
         37 . The method of  claim 27 , wherein R 7  is 3-N-substituted phenyl. 
     
     
         38 . The method of  claim 37 , wherein said 3-N-substituted phenyl is substituted with a nitro group. 
     
     
         39 . The method of  claim 38 , wherein said compound is 7-(3-nitrophenyl)sancycline. 
     
     
         40 . The method of  claim 37 , wherein said 3-N-substituted phenyl is 3-amino substituted. 
     
     
         41 . The method of  claim 40 , wherein said 3-amino substituent is dialkylamino. 
     
     
         42 . The method of  claim 37 , wherein said compound is selected from the group consisting of 7-(3-amino)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. 
     
     
         43 . The method of  claim 41 , wherein said dialkyl amino group is dimethylamino. 
     
     
         44 . The method of  claim 43 , wherein said compound is 7-(4-N,N,-dimethylaminophenyl)sancycline. 
     
     
         45 . The method of  claim 27 , wherein R 7  is 4-N-substituted phenyl. 
     
     
         46 . The method of  claim 45 , wherein said 4-N-substituted phenyl is substituted with a nitro group. 
     
     
         47 . The method of  claim 46 , wherein said compound is 7-(4-nitrophenyl)sancycline. 
     
     
         48 . The method of  claim 45 , wherein said 4-substituted phenyl is 4-amino substituted. 
     
     
         49 . The method of  claim 48 , wherein said 4-amino substituent is dialkyl. 
     
     
         50 . The method of  claim 48 , wherein said compound is 7-(4-N,N,-diethylaminophenyl)sancycline, 7-(4-N,N,-dipropylaminophenyl)sancycline, or 7-(4-N,N,-dibutylaminophenyl)sancycline. 
     
     
         51 . The method of  claim 49 , wherein said dialkyl amino group is dimethyl. 
     
     
         52 . The method of  claim 51 , wherein said compound is 7-(4-N,N,-dimethylaminophenyl)sancycline. 
     
     
         53 . The method of  claim 27 , wherein said tetracycline responsive state is a bacterial infection. 
     
     
         54 . The method of  claim 53 , wherein said bacterial infection is associated with  E. coli.    
     
     
         55 . The method of  claim 53 , wherein said bacterial infection is associated with  S. aureus.    
     
     
         56 . The method of  claim 53 , wherein said bacterial infection is associated with  E. faecalis.    
     
     
         57 . The method of  claim 53 , wherein said bacterial infection is resistant to other tetracycline antibiotics. 
     
     
         58 . The method of  claim 27 , wherein said compound is administered with a pharmaceutically acceptable carrier. 
     
     
         59 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         60 . The pharmaceutical composition of  claim 59 , wherein said compound is selected from the group consisting of 7-(2-amino)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-amino)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-amino)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.