Phthalanilate compounds and methods of use
The invention provides antimicrobial compounds and compositions, and methods of using them. The compounds and compositions include, for example, a compound of any one of Formulas I-X. The invention further provides methods of preparing the compounds, and useful intermediates for their preparation. The compounds can possess highly specific and selective activity, such as antibacterial activity and/or enzymatic inhibitory activity. Accordingly, the compounds and compositions can be used to treat bacterial infections, or to inhibit or kill bacteria, either in vitro or in vivo.
1. A compound of Formula II:
wherein
X is absent or (C 1 -C 24 )alkyene;
Y is oxygen or sulfur;
Z is carbon or nitrogen, provided that when Z is nitrogen, R 8 is absent;
R 2 is hydrogen or halo;
R 3 is hydrogen, halo, or —CONH(C 6 -C 20 )alkyl;
R 4 and R 5 are each independently hydrogen, halo, or nitro;
R 6 , R 7 , and R 11 are each independently hydrogen or (C 1 -C 4 )alkyl;
R 8 is absent or hydrogen;
R 9 is hydrogen, (C 1 -C 4 )alkyl, trifluoromethyl, or trifluoromethoxy;
R 10 is hydrogen, halo, or —O(C 6 -C 20 )aryl;
any (C 1 -C 24 )alkylene or (C 6 -C 20 )aryl is optionally substituted on carbon with one or more oxo, hydroxyl, halo, (C 6 -C 20 )aryl, nitro, cyano, (C 1 -C 6 )alkoxy, or trifluoromethyl groups or any combination thereof, and optionally exchanged on carbon with one or more oxo, imino, or thio groups;
at least one of R 2 -R 11 is not hydrogen;
a is 0, 1, or 2; and
n is 0 or 1;
or a pharmaceutically acceptable salt, as prodrug, or to metabolite thereof.
2. The compound of claim 1 wherein R 2 , R 3 , R 4 , and R 5 are each halo.
3. The compound of claim 1 wherein R 2 , R 3 , R 4 , and R 5 are each flouro, chloro, or bromo.
4. The compound of claim 1 wherein R 3 is hydrogen or —CONH(C 6 )aryl wherein the (C 6 )aryl is optionally substituted with one or more hydroxyl, halo, (C 6 -C 20 )aryl, nitro, cyano, (C 1 -C 6 )alkoxy, or trifluoromethyl groups, or any combination thereof.
5. The compound of claim 1 wherein R 4 and R 5 are each independently hydrogen or nitro.
6. The compound of claim 1 wherein X is absent.
7. The compound of claim 1 wherein X is —CH 2 — or —CH(CH 3 )—.
8. The compound of claim 1 wherein Y is oxygen.
9. The compound of claim 1 wherein Y is sulfur.
10. The compound of claim 1 wherein R 9 is methyl, trifluoromethyl, or trifluoromethoxy, and a is 1 or 2.
11. The compound of claim 1 wherein R 10 is hydrogen or halo.
12. The compound of claim 1 wherein R 10 is chloro.
13. The compound of claim 1 wherein
X is absent, —CH 2 —, or —CH(CH 3 )—;
Y is oxygen or sulfur;
Z is carbon or nitrogen;
R 2 is hydrogen, fluorine, chlorine, or bromine;
R 3 is hydrogen, fluorine, chlorine, bromine, or —CONH(2-methoxy-4-nitro)phenyl;
R 4 and R 5 are each independently hydrogen, fluorine, chlorine, bromine, or nitro;
R 6 , R 7 , and R 11 are each hydrogen:
R 8 is absent or hydrogen;
R 9 is hydrogen, (C 1 -C 4 )alkyl, trifluoromethyl, or trifluoromethoxy;
R 10 is hydrogen, chlorine, or —O-phenyl;
a is 0, 1, or 2; and
n is 0 or 1.
14. The compound of claim 1 wherein the compound is:
15. The compound of claim 9 wherein the compound is:
16. The compound of claim 1 wherein the compound is:
17. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
18. A method of treating an animal afflicted with a bacterial infection comprising administering to an animal in need of such treatment an effective antibacterial amount of a compound of claim 1 .
19. A method of killing or inhibiting the growth of a bacteria comprising contacting the bacteria with an effective amount of a compound of claim 1 .
20. A pharmaceutical composition comprising an anti-vancomycin-resistant methicillin-resistant Staphylococcus aureus compound of claim 1 , and a pharmaceutically acceptable diluent or carrier.
21. The compound:
or a pharmaceutically acceptable salt thereof.