Prodrugs of 9-aminomethyl tetracycline compounds
The invention pertains to prodrugs of 9-aminomethyl substituted tetracycline compounds, methods of using the compounds, and pharmaceutical compositions containing them.
1 . A tetracycline compound of the formula (I):
wherein
E is oxygen, nitrogen, or a covalent bond;
G is alkyl; heterocyclicalkyl; aryl; alkylcarbonyloxyalkyl; arylcarbonyloxyalkyl; alkyloxycarbonyloxyalkyl; arylalkylcarbonyloxyalkyl; alkyloxyalkylcarbonyloxyalkyl; alkoxyalkoxycarbonyloxyalkyl, and pharmaceutically acceptable salts thereof.
2 . The tetracycline compound of claim 1 , wherein E is a covalent bond.
3 . The tetracycline compound of claim 2 , wherein G is alkyl.
4 . The tetracycline compound of claim 1 , wherein E is nitrogen.
5 . The tetracycline compound of claim 4 , wherein G is aryl.
6 . The tetracycline compound of claim 5 , wherein G is substituted phenyl.
7 . The tetracycline compound of claim 1 , wherein E is oxygen.
8 . The tetracycline compound of claim 7 , wherein G is alkylcarbonyloxyalkyl.
9 . The tetracycline compound of claim 8 , wherein G is of the formula —(CH 2 ) g —O—(C═O)—R 1 , wherein g is 1-5 and R 1 is alkyl.
10 . The tetracycline compound of claim 9 , wherein g is 1.
11 . The tetracycline compound of claim 10 , wherein R 1 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, —(CH 2 ) 10 —CH 3 , or —(CH 2 ) 11 CH 3 .
12 . The tetracycline compound of claim 10 , wherein R 1 is cycloalkyl.
13 . The tetracycline compound of claim 9 , wherein g is 2.
14 . The tetracycline compound of claim 13 , wherein R 1 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, —(CH 2 ) 10 —CH 3 , or —(CH 2 ) 11 CH 3 .
15 . The tetracycline compound of claim 7 , wherein G is alkyl.
16 . The tetracycline compound of claim 14 , wherein G is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, —(CH 2 ) 10 —CH 3 , or —(CH 2 ) 11 CH 3 .
17 . The tetracycline compound of claim 7 , wherein G is arylcarbonyloxyalkyl.
18 . The tetracycline compound of claim 17 , wherein G is of the formula: —(CH 2 ) f —O—(C═O)—R 2 , wherein f is 1-5 and R 2 is aryl.
19 . The tetracycline compound of claim 18 , wherein f is 1.
20 . The tetracycline compound of claim 19 , wherein R 2 is substituted or unsubstituted phenyl.
21 . The tetracycline compound of claim 20 , wherein said phenyl is substituted with one or more substituents selected from the group consisting of halogen, alkoxy, or alkyl.
22 . The tetracycline compound of claim 7 , wherein G is alkyloxycarbonyloxyalkyl.
23 . The tetracycline compound of claim 22 , where G is of the formula —(CH 2 )—O—(C═O)—O—R 3 , wherein R 3 is alkyl.
24 . The tetracycline compound of claim 23 , wherein R 3 is methyl, ethyl, propyl, butyl or pentyl.
25 . The tetracycline compound of claim 7 , wherein G is arylalkylcarbonyloxyalkyl.
26 . The tetracycline compound of claim 25 , wherein G is of the formula —(CH 2 )—O—(C═O)—(CH 2 ) h —R 4 , wherein h is 1-5, and R 4 is aryl.
27 . The tetracycline compound of claim 26 , wherein h is 1 or 2.
28 . The tetracycline compound of claim 27 , wherein R 4 is phenyl.
29 . The tetracycline compound of claim 7 , wherein G is alkyloxyalkylcarbonyloxyalkyl.
30 . The tetracycline compound of claim 29 , wherein G is of the formula —(CH 2 )—O—(C═O)—(CH 2 ) i —O—R 5 , wherein i is 1-5, and R 5 is alkyl.
31 . The tetracycline compound of claim 30 , wherein i is 1, 2, or 3.
32 . The tetracycline compound of claim 31 , wherein R 5 is methyl.
33 . The tetracycline compound of claim 7 , wherein G is alkoxyalkoxyalkylcarbonyloxyalkyl.
34 . The tetracycline compound of claim 33 , wherein G is of the formula of the formula —(CH 2 )—O—(C═O)—(CH 2 ) j —O—(CH 2 ) k —O—R 6 , wherein j and k are each 1-5, and R 6 is alkyl.
35 . The tetracycline compound of claim 34 , wherein j is 1 and k is 2.
36 . The tetracycline compound of claim 35 , wherein R 6 is methyl.
37 . The tetracycline compound of claim 7 , wherein G is heterocyclic alkyl.
38 . A tetracycline compound of the formula (II):
wherein
Q′ is a prodrug moiety and pharmaceutically acceptable salts thereof.
39 . The tetracycline compound of claim 38 , wherein Q′ is of the formula
—(C═O)-E 1 -G 1
wherein
E 1 is oxygen, nitrogen, or a covalent bond;
G 1 is alkyl; heterocyclicalkyl; aryl; alkylcarbonyloxyalkyl; arylcarbonyloxyalkyl; alkyloxycarbonyloxyalkyl; arylalkylcarbonyloxyalkyl; alkyloxyalkylcarbonyloxyalkyl; or alkoxyalkoxycarbonyloxyalkyl.
40 . The tetracycline compound of claim 39 , wherein E 1 is oxygen.
41 . The tetracycline compound of claim 40 , wherein G 1 is alkylcarbonyloxyalkyl.
42 . The tetracycline compound of claim 41 , wherein G 1 is of the formula —(CH 2 ) m —O—(C═O)—R 7 , wherein m is 1-5 and R 1 is alkyl.
43 . The tetracycline compound of claim 42 , wherein m is 1.
44 . The tetracycline compound of claim 43 , wherein R 7 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, —(CH 2 ) 10 —CH 3 , or —(CH 2 ) 11 CH 3 .
45 . A tetracycline compound of the formula (III):
wherein:
Q is a prodrug moiety, and pharmaceutically acceptable salts thereof.
46 . The tetracycline compound of claim 45 , wherein Q is —(C═O)-G 2 .
47 . The tetracycline compound of claim 45 , wherein G 2 is alkyloxycarbonylalkyl.
48 . A tetracycline compounds of the formula (IV):
wherein
Q″ is a prodrug moiety and pharmaceutically acceptable salts thereof.
49 . The tetracycline compound of claim 48 , wherein Q″ is of the formula
—(C═O)-E 3 -G 3
wherein
E 3 is oxygen, nitrogen, or a covalent bond;
G 3 is alkyl; heterocyclicalkyl; aryl; alkylcarbonyloxyalkyl; arylcarbonyloxyalkyl; alkyloxycarbonyloxyalkyl; arylalkylcarbonyloxyalkyl; alkyloxyalkylcarbonyloxyalkyl; or alkoxyalkoxycarbonyloxyalkyl.
50 . The tetracycline compound of claim 49 , wherein E 3 is oxygen.
51 . The tetracycline compound of claim 49 , wherein G 3 is substituted or unsubstituted alkyl.
52 . The tetracycline compound of claim 49 , wherein G 3 is substituted or unsubstituted aryl.
53 . A tetracycline compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
54 . A method for treating a tetracycline responsive state in a subject, comprising administering to said subject an effective amount of a tetracycline compound of any one of claims 1 , 38 , 45 , 48 , or 53 , such that said subject is treated.
55 . The method of claim 54 , wherein said tetracycline responsive state is a bacterial infection, a viral infection, or a parasitic infection.
56 . The method of claim 55 , wherein said bacterial infection is associated with E. coli.
57 . The method of claim 55 , wherein said bacterial infection is associated with S. aureus.
58 . The method of claim 55 , wherein said bacterial infection is associated with E. faecalis.
59 . The method of claim 54 , wherein said bacterial infection is resistant to other tetracycline antibiotics.
60 . The method of claim 55 , wherein said bacterial infection is a gram positive bacterial infection.
61 . The method of claim 55 , wherein said bacterial infection is a gram negative bacterial infection.
62 . The method of claim 54 , wherein said subject is a human.
63 . The method of claim 54 , wherein said tetracycline compound is administered with a pharmaceutically acceptable carrier.
64 . The method of claim 54 , wherein said tetracycline compound is metabolized in vivo.
65 . The method of claim 64 , wherein said tetracycline compound is metabolized in vivo to a compound of the formula:
66 . A pharmaceutical composition comprising a therapeutically effective amount of a tetracycline compound of any one of claims 1 , 38 , 45 , 48 , or 53 and a pharmaceutically acceptable carrier.