Antibacterial agents: sidechainfluorinated myxopyronin derivatives
View Patent ↗The invention provides compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , and G are as described in the specification, as well as compositions comprising a compound of formula I, methods of making such compounds, and methods of using such compounds, e.g., as inhibitors of bacterial RNA polymerase and as antibacterial agents.
1. A compound of formula I:
or a salt thereof, wherein:
R 1 is one of CF 3 , CHF 2 , and CH 2 F;
R 2 is absent or is C 1 -C 8 alkyl, optionally substituted with halo;
R 3 , R 4 , and R 5 are independently H or methyl;
G is one of —CH═CH—NHC(O)—R 6 , —CH═CH—NHC(S)—R 6 , —CH 2 CH 2 NHC(O)—R 6 , —CH 2 CH 2 NHC(S)—R 6 , —CH 2 NHNHC(O)—R 6 , or —CH 2 NHNHC(S)—R 6 ;
R 6 is one of C 1 -C 6 alkyl, —O(C 1 -C 6 alkyl), —S(C 1 -C 6 alkyl), or —N(R 7 ) 2 ; and
each R 7 is independently H or —C 1 -C 6 alkyl.
2. The compound of claim 1 , or a salt thereof, wherein R 2 is C 1 -C 8 alkyl, optionally substituted with halo.
3. The compound of claim 1 , or a salt thereof, wherein R 1 is CF 3 .
4. The compound of claim 1 , or a salt thereof, wherein R 1 is CHF 2 .
5. The compound of claim 1 , or a salt thereof, wherein R 1 is CH 2 F.
6. The compound of claim 1 , or a salt thereof, wherein G is —CH═CH—NHC(O)—R 6 .
7. The compound of claim 1 , or a salt thereof, wherein G is —CH═CH—NHC(S)—R 6 .
8. The compound of claim 1 , or a salt thereof, wherein G is —CH 2 CH 2 NHC(O)—R 6 .
9. The compound of claim 1 , or a salt thereof, wherein G is —CH 2 CH 2 NHC(S)—R 6 .
10. The compound of claim 1 , or a salt thereof, wherein G is —CH 2 NHNHC(O)—R 6 .
11. The compound of claim 1 , or a salt thereof, wherein G is —CH 2 NHNHC(S)—R 6 .
12. A compound of formula 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16:
or a salt thereof.
13. The compound of claim 1 , or a salt thereof, wherein the salt is a pharmaceutically acceptable salt.
14. A pharmaceutical composition comprising a compound of claim 1 , or a salt thereof, and a pharmaceutically acceptable carrier.
15. A method of inhibiting a bacterial RNAP, comprising contacting a bacterial RNAP with a compound of claim 1 , or a salt thereof.
16. A method of treating a bacterial infection in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 , or a salt thereof.
17. The method of claim 15 , wherein the bacterium is Mycobacterium sp., Staphylococcus sp., Enterococcus sp., Bacillus sp., Escherichia sp., Francisella sp., Burkholderia sp., or Brucella sp.
18. A composition comprising:
(a) from about 0.1 mg/ml to about 10 mg/ml of a compound of claim 1 , or a pharmaceutically acceptable salt thereof;
(b) from about 0% to about 10% dimethylacetamide; and
(c) from about 0% to about 8% Cremophor EL;
and having a pH of at least about 6.
19. The composition of claim 18 that comprises from about 0.6 mg/ml to about 6 mg/ml of claim 1 , or a pharmaceutically acceptable salt thereof; about 0% to about 7.5% dimethylacetamide; and about 0% to about 6% Cremophor EL; and that has a pH of at least about 7.
20. The composition of claim 18 that comprises about 3 mg/ml of the compound of claim 1 , or a pharmaceutically acceptable salt thereof; about 5% dimethylacetamide; and about 4% Cremophor EL; and that has a pH of about 7.4.