7-N-substituted phenyl tetracycline compounds
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.