7-Phenyl-Substituted Tetracycline Compounds
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.