7-Phenyl-Substituted Tetracycline Compounds

Abstract

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

1 . A 7-substituted tetracycline compound which is substantially free of positional isomers, said compound having 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, N-substituted or unsubstituted phenyl, and pharmaceutically acceptable salts thereof, wherein said tetracycline compound is substantially free of positional isomers. 
 
     
     
         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 1 , wherein R 7  is 2-substituted phenyl. 
     
     
         5 . The compound of  claim 4 , 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. 
     
     
         6 . The compound of  claim 1 , wherein R 7  is 3-substituted phenyl. 
     
     
         7 . The compound of  claim 6 , 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. 
     
     
         8 . The compound of  claim 1 , wherein R 7  is 4-substituted phenyl. 
     
     
         9 . The compound of  claim 8 , 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. 
     
     
         10 . The compound of  claim 1 , wherein R 7  is 2-N-substituted phenyl. 
     
     
         11 . The compound of  claim 10 , wherein said 2-N-substituted phenyl is substituted with a nitro group. 
     
     
         12 . The compound of  claim 11 , wherein said compound is 7-(2-nitrophenyl) sancycline. 
     
     
         13 . The compound of  claim 10 , wherein said 2-N-substituted phenyl is 2-amino substituted. 
     
     
         14 . The compound of  claim 13 , wherein said 2-amino substituent is dialkylamino. 
     
     
         15 . The compound of  claim 14 , wherein said dialkyl amino group is dimethylamino. 
     
     
         16 . The compound of  claim 13 , wherein said compound is selected from the group consisting of 7-(2-aminophenyl) 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. 
     
     
         17 . The compound of  claim 1 , wherein R 7  is 3-N-substituted phenyl. 
     
     
         18 . The compound of  claim 17 , wherein said 3-N-substituted phenyl is substituted with a nitro group. 
     
     
         19 . The compound of  claim 18 , wherein said compound is 7-(3-nitrophenyl) sancycline. 
     
     
         20 . The compound of  claim 17 , wherein said 3-N-substituted phenyl is 3-amino substituted. 
     
     
         21 . The compound of  claim 20 , wherein said 3-amino substituent is dialkylamino. 
     
     
         22 . The compound of  claim 21 , wherein said dialkyl amino group is dimethylamino. 
     
     
         23 . The compound of  claim 20 , 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. 
     
     
         24 . The compound of  claim 1 , wherein R 7  is 4-N-substituted phenyl. 
     
     
         25 . The compound of  claim 24 , wherein said 4-N-substituted phenyl is substituted with a nitro group. 
     
     
         26 . The compound of  claim 25 , wherein said compound is 7-(4-nitrophenyl) sancycline. 
     
     
         27 . The compound of  claim 24 , wherein said 4-substituted phenyl is 4-amino substituted. 
     
     
         28 . The compound of  claim 27 , wherein said 4-amino substituent is dialkyl. 
     
     
         29 . The compound of  claim 28 , wherein said dialkyl amino group is dimethyl. 
     
     
         30 . The compound of  claim 29 , wherein said compound is 7-(4-aminophenyl) 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. 
     
     
         31 . A tetracycline compound which is substantially free of positional isomers, wherein said tetracycline compound is 7,9-diphenyl sancycline, and pharmaceutically acceptable salts thereof, wherein said tetracycline compound is substantially free of positional isomers. 
     
     
         32 . The compound of any one of  claims 1  or  31 , wherein said compound is at least 75% free of positional isomers. 
     
     
         33 . The compounds of  claim 32 , wherein said compound is at least 80% free of positional isomers. 
     
     
         34 . The compounds of  claim 33 , wherein said compound is at least 85% free of positional isomers. 
     
     
         35 . The compound of  claim 34 , wherein said compound is at least 90% free of positional isomers. 
     
     
         36 . The compound of  claim 35 , wherein said compound is at least 95% free of positional isomers. 
     
     
         37 . A method for treating a tetracycline responsive state in a mammal, comprising administering to said mammal a 7-substituted tetracycline compound, which is substantially free of positional isomers, 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, N-substituted or unsubstituted phenyl; and pharmaceutically acceptable salts thereof, such that the tetracycline responsive state is treated, wherein said tetracycline compound is substantially free of positional isomers. 
 
     
     
         38 . The method of  claim 37 , wherein R 5 , R 6  and R 6′  are each hydrogen and R 4  and R 4′  are each methyl. 
     
     
         39 . The method of  claim 38 , wherein R 7  is unsubstituted phenyl. 
     
     
         40 . The method of  claim 38 , wherein R 7  is 2-substituted phenyl. 
     
     
         41 . The method of  claim 40 , wherein said compound is selected from the group consisting of 7-(2-fluorophenyl) sancycline, 7-(2-chlorophenyl) sancycline, 7-(2-bromophenyl) sancycline, 7-(2-iodophenyl) sancycline, 7-(2-nitrophenyl) sancycline, 7-(2-aminophenyl) 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. 
     
     
         42 . The method of  claim 38 , wherein R 7  is 3-substituted phenyl. 
     
     
         43 . The method of  claim 42 , wherein said compound is selected from the group consisting of 7-(3-fluorophenyl) sancycline, 7-(3-chlorophenyl) sancycline, 7-(3-bromophenyl) sancycline, 7-(3-iodophenyl) sancycline, 7-(3-nitrophenyl) sancycline, 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. 
     
     
         44 . The method of  claim 38 , wherein R 7  is 4-substituted phenyl. 
     
     
         45 . The method of  claim 44 , 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, 7-(4-triiodomethylphenyl) sancycline, 7-(4-nitrophenyl) sancycline, 7-(4-aminophenyl) 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. 
     
     
         46 . A method for treating a tetracycline responsive state in a mammal, comprising administering to said mammal 7,9-diphenyl sancycline and pharmaceutically acceptable salts thereof, which is substantially free of positional isomers, such that the tetracycline responsive state is treated, wherein said 7,9-diphenyl sancycline is substantially free of positional isomers. 
     
     
         47 . The method of  claim 37  or  46 , wherein said tetracycline responsive state is a bacterial infection. 
     
     
         48 . The method of  claim 47 , wherein said bacterial infection is associated with  E. coli.    
     
     
         49 . The method of  claim 47 , wherein said bacterial infection is associated with  S. aureus.    
     
     
         50 . The method of  claim 47 , wherein said bacterial infection is associated with  E. faecalis.    
     
     
         51 . The method of  claim 47 , wherein said bacterial infection is resistant to other tetracycline antibiotics. 
     
     
         52 . The method of  claim 37  or  46 , wherein said compound is administered with a pharmaceutically acceptable carrier. 
     
     
         53 . The method of any one of  claims 37  or  46 , wherein said compound is at least 75% free of positional isomers. 
     
     
         54 . The method of  claim 53 , wherein said compound is at least 80% free of positional isomers. 
     
     
         55 . The method of  claim 54 , wherein said compound is at least 85% free of positional isomers. 
     
     
         56 . The method of  claim 55 , wherein said compound is at least 90% free of positional isomers. 
     
     
         57 . The method of  claim 56 , wherein said compound is at least 95% free of positional isomers. 
     
     
         58 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  or  31 , and a pharmaceutically acceptable carrier. 
     
     
         59 . The pharmaceutical composition of  claim 58 , wherein said compound is selected from the group consisting of 7-phenyl sancycline, 7,9 diphenylsancycline, 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, 7-(4-triiodomethylphenyl) sancycline, 7-(2-nitrophenyl) sancycline, 7-(2-aminophenyl) 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-nitrophenyl) sancycline, 7-(3-aminophenyl) 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-nitrophenyl) sancycline, 7-(4-aminophenyl) 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. 
     
     
         60 . The pharmaceutical composition of  claim 58  wherein said compound is at least 75% free of positional isomers. 
     
     
         61 . The pharmaceutical composition of  claim 60 , wherein said compound is at least 80% free of positional isomers. 
     
     
         62 . The pharmaceutical composition of  claim 61 , wherein said compound is at least 85% free of positional isomers. 
     
     
         63 . The pharmaceutical composition of  claim 62 , wherein said compound is at least 90% free of positional isomers. 
     
     
         64 . The pharmaceutical composition of  claim 63 , wherein said compound is at least 95% free of positional isomers.