Difluorothioacetamides of oxazolidinones as antibacterial agents
The present invention describes difluororthioacetamide oxazolidinones of formula I: R is —CH 2 — or —CH 2 CH 2 —; R 2 and R 3 are independently —H or —F; X is —CH—; Y is —SO—, —SO 2 —, or —SONR 4 —; and R 4 is —H or —C 1-4 alkyl. These compounds are useful to treat infectives diseases caused by gram-positive and gram-negative bacteria.
1. A compound of formula I
or pharmaceutically acceptable salt wherein
R is —CH 2 — or —CH 2 CH 2 —;
R 2 and R 3 are independently —H or —F;
X is —CH—;
Y is —SO—, —SO 2 —, or —SONR 4 —; and R 4 is —H or —C 1-4 alkyl.
2. A compound of claim 1 wherein R 2 and R 3 are H.
3. A compound of claim 1 wherein R 2 and R 3 are F.
4. A compound of claim 1 wherein one of the R 2 and R 3 is H, the other one is F.
5. A compound of claim 1 wherein R is —CH 2 —.
6. A compound of claim 1 wherein X is CH.
7. A compound of claim 1 wherein Y is SO 2 .
8. A compound of claim 1 wherein Y is SO.
9. A compound of claim 1 wherein Y is S(═O)NR 4 .
10. A compound of claim 9 wherein R 4 is H or CH 3 .
11. A compound of claim 1 which is a compound of formula Ia, Ib, Ic, or Id.
12. A method for treating bacteria infections comprising administering to a mammal being treated a pharmaceutically effective amount of the compound of claim 1 .
13. The method of claim 12 wherein the compound of claim 1 is administered parenterally, topically, rectally, or intranasally.
14. The method of claim 12 wherein the compound of claim 1 is administered orally.
15. The method of claim 13 wherein parenteral administration is subcutaneous, intravenous, intramuscular, intradermal, intrathecal, intraocular, intravetricular injection.
16. The method of claim 13 wherein said compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day.
17. The method of claim 13 wherein said compound is administered in an amount of from about 1 to about 50 mg/kg of body weight/day.
18. The method of claim 12 wherein said infection is skin infection.
19. The method of claim 12 wherein the infection is eye infection.
20. The method of claim 12 wherein the infection is ear infection.
21. The method of claim 12 wherein said mammal is human.
22. The method of claim 12 wherein said mammal is an animal.
23. A pharmaceutical composition comprising the compound of claim 1 or its pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
24. A compound of claim 1 which is
(1) 2,2-difluoro-N-({(5S-)-3-[3-fluoro-4-(1-imino-1-oxidohexahydro-1λ 4 -thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (Z-isomer),
(2) 2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-imino-1-oxidohexahydro-1λ 4 -thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (E-isomer),
(3) 2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-methylimino-1-oxidohexahydro-1λ 4 -thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (Z-isomer),
(4) 2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-methylimino-1-oxidohexahydro-1λ 4 -thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (E-isomer),
(5) 2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,
(6) 2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (Z-Isomer),
(7) 2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,
(8) 2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,
(9) 2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (E-Isomer),
(10) 2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,
(11) 2,2-difluoro-N-({(5S)-3-[4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (Z-isomer),
(12) 2,2-difluoro-N-({(5S)-3-[3,5-difluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (E-isomer),
(13) 2,2-difluoro-N-({(5S)-3-[4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (E-isomer),
(14) 2,2-difluoro-N-({(5S)-3-[3,5-difluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)henyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (Z-isomer),
(15) 2,2-difluoro-N-({(5S)-3-[4-(1-imino-1-oxidohexahydro-1λ 4 -thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (Z-isomer),
(16) 2,2-difluoro-N-({(5S)-3-[4-(1-imino-1-oxidohexahydro-1λ 4 -thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (E-isomer),
(17) 2,2-difluoro-N-({(5S)-3-[4-(1-methylimino-1-oxidohexahydro-1λ 4 -thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (Z-isomer), or
(18) 2,2-difluoro-N-({(5S)-3-[4-(1-methylimino-1-oxidohexahydro-1-λ 4 ,4-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (E-isomer).