Phenicol antibacterial agents
View Patent ↗The present invention provides novel phenicol derivatives, their use for the treatment of infections in mammals, pharmaceutical compositions containing these novel compounds, and methods for the preparation of these compounds.
1. A compound of formula I
wherein R 1 is —H, —C(O)—R 3 , —C 1 -C 6 alkyl, or —CN;
R 2 is -C 1 -C 6 alkyl optionally substituted with one to three halo, or —C 3 -C 6 cyclopropyl;
R 3 is —C 1 — C 6 alkyl;
W is
or absent;
X and Y are each independently halo;
Z is —C 1 -C 2 alkyl-, —C 3 -C 4 cycloalkyl- or absent;
or an isomer thereof, or a pharmaceutical acceptable salt thereof.
2. A compound of claim 1 wherein X and Y are each chloro, or X and Y are each fluoro.
3. A compound of claim 1 wherein W is
4. A compound of claim 3 of formula II
5. A compound of claim 4 wherein R 1 is —H or —CN, R 2 is —CH 3 , and Z is —CH 2 —or absent.
6. A compound of claim 5 selected from the group consisting of:
2,2-difluoro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(6-(S-methylsulfonimidoyl)-pyridin-3-yl)phenyl)propan-2-yl)acetamide;
2,2-difluoro-N-{(1S,2R)-1-fluoromethyl-2-hydroxy-2-[4-(6-N-(cyano) methyl pyridine sulfoximine-3-yl)phenyl]-ethyly}-acetamide;
2,2dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(6-(S-methylsulfonimidoyl)-pyridin-3-yl)phenyl)propan-2-yl)acetamide;
2, 2-difluoro-N-{(1 S, 2R)-1-fluoromethyl-2-hydroxy-2-[4-(6(S-methylsulfonimidoylmethyl) pyridine-3-yl)-phenyl]-ethyl}-acetamide; and
2, 2-difluoro-N-{(1 S, 2R)-1-fluoromethyl-2-hydroxy-2-[4- (6-N-[(cyano) methyl]-methyl pyridine sulfoximine-3-yl)-phenyl]-ethyl}-acetamide.
7. A compound of claim 1 wherein W is absent and Z is absent.
8. A compound of claim 7 of formula III
9. A compound of claim 8 wherein R 1 is —H or —CN and R 2 is —CH 3 or —CH 2 —F.
10. A compound of claim 9 selected from the group consisting of 2, 2-dichloro-N-((1R, 2S)-3-fluoro-1-hydroxy-1-(4-(S-methylsulfonimidoyl) phenyl) propan-2-yl) acetamide;
2,2-dichloro-N-[(1 S, 2R)-1-fluoromethyl-2-hydroxy-2-(4-(cyano)methyl-phenyl sulfoximine)-ethyl]-acetamide;
2,2-difluoro-N-[(1 S, 2R)-1-fluoromethyl-2-hydroxy-2-(4-(cyano)methyl-phenyl sulfoximine)-ethyl]-acetamide;
2,2-dichloro-N-((1R,2S)-3-fluoro-1-(4-(S-(fluoromethyl) sulfonimidoyl) phenyl)-1-hydroxypropan-2-yl) acetamide; and
2,2-dichloro-N-((1 R, 2S)-3-fluoro-1-(4-(S-(fluoromethyl) sulfonimidoyl) phenyl)-1-hydroxypropan-2-yl) acetamide.
11. A compound of claim 1 wherein W is
Z is absent, R 1 is —H, and R 2 is —CH 3 .
12. A compound of claim 11 of formula IV
13. A compound of claim 12 wherein X and Y are each chloro or X and Y are each fluoro.
14. A compound of claim 13 selected from the group consisting of:
2,2-difluoro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(6-(S-methylsulfonimidoyl)-pyridin-3-yl)phenyl)propan-2-yl)acetamide;
2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(6-(S-methylsulfonimidoyl)-pyridin-3-yl)phenyl)propan-2-yl)acetamide; and
2, 2-difluoro-N-{(1 S, 2R)-1-fluoromethyl-2-hydroxy-2[4-(6(S-methylsulfonimidoylmethyl) pyridine-3-yl)-phenyl]-ethyl}-acetamide.
15. A pharmaceutical composition comprising a compound selected from the group consisting of:
2,2-difluoro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(6-(S-methylsulfonimidoyl)-pyridin-3-yl)phenyl)propan-2-yl)acetamide;
2,2-difluoro-N-{(1S,2R)-1-fluoromethyl-2-hydroxy-2-[4-(6-N-(cyano) methyl pyridine sulfoximine-3-yl)-phenyl]-ethyl}-acetamide;
2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(6-(S-methylsulfonimidoyl)-pyridin-3-yl)phenyl)propan-2-yl)acetamide;
2, 2-difluoro-N-{(1 S, 2R)-1-fluoromethyl-2-hydroxy-2[4-(6-(S-methylsulfonimidoylmethyl) pyridine-3-yl)-phenyl]-ethyl}-acetamide;
2, 2-difluoro-N-{(1 S, 2R)-1-fluoromethyl-2-hydroxy-2[4-(6-N-f(cyano) methyl]-methyl pyridine sulfoximine-3-yl)-phenyll-ethyl}-acetamide;
2, 2-dichloro-N-((1R, 2S)-3-fluoro-1-hydroxy-1-(4-(S-methylsulfonimidoyl) phenyl) propan-2-yl) acetamide;
2,2-dichloro-N-[(1S, 2R)-1-fluoromethyl-2-hydroxy-2-(4-(cyano)-methyl-phenyl sulfoximine)-ethyl]-acetamide;
2,2-difluoro-N-[(1S, 2R)-1-fluoromethyl-2-hydroxy-2-(4-(cyano)-methyl-phenyl sulfoximine)-ethyl]-acetamide;
2,2-dichloro-N-((1R,2S)-3-fluoro-1-(4-(S-(fluoromethyl) sulfonimidoyl) phenyl)-1-hydroxypropan-2-yl) acetamide; and
2,2-dichloro-N-((1 R, 2S)-3-fluoro-1-(4-(S-(fluoromethyl) sulfonimidoyl) phenyl)-1-hydroxypropan-2-yl) acetamide, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
16. The composition according to claim 15 wherein the compound is selected from the group consisting of:
2,2-difluoro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(6-(S-methylsulfonimidoyl)-pyridin-3-yl)phenyl)propan-2-yl)acetamide;
2,2-difluoro-N-{(1S,2R)-1-fluoromethyl-2-hydroxy-2-[4-(6-N-(cyano) methyl pyridine sulfoximine-3-yl)-phenyl]-ethyl}-acetamide;
2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(6-(S-methylsulfonimidoyl)-pyridin-3-yl)phenyl)propan-2-yl)acetamide;
2, 2-difluoro-N-{(1 S, 2R)-1-fluoromethyl-2-hydroxy-2-[4-(6-(S-methylsulfonimidoylmethyl) pyridine-3-yl)-phenyl]-ethyl}-acetamide; and
2, 2-difluoro-N-{(1 S, 2R)-1-fluoromethyl-2-hydroxy-2-[4-(6-N-[(cyano) methyl]-methyl pyridine sulfoximine-3-yl)-phenyl]-ethyl}-acetamide.
17. The composition according to claim 16 wherein the compound is selected from 2,2-difluoro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(6-(S-methylsulfonimidoyl)-pyridin-3-yl)phenyl)propan-2-yl)acetamide or 2, 2-difluoro-N-{(1 S, 2R)-1-fluoromethyl-2-hydroxy-2-[4-(6-(S-methylsulfonimidoylmethyl) pyridine-3-yl)-phenyl]-ethyl}-acetamide.
18. A method for controlling or treating infections in livestock by administering to an animal in need thereof a therapeutically effective amount of a compound selected from the group consisting of:
2,2-difluoro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(6-(S-methylsulfonimidoyl)-pyridin-3-yl)phenyl)propan-2-yl)acetamide;
2,2-difluoro-N-{(1S,2R)-1-fluoromethyl-2-hydroxy-2 [-4-(6-N-(cyano) methyl pyridine sulfoximine-3-yl)-phenyl]-ethyl}-acetamide;
2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(6-(S-methylsulfonimidoyl)-pyridin-3-yl)phenyl)propan-2-yl)acetamide;
2, 2-difluoro-N-{(1 S, 2R)-1-fluoromethyl-2-hydroxy-2-[4-(6-(S-methylsulfonimidoylmethyl) pyridine-3-yl)-phenyl]-ethyl}-acetamide;
2, 2-difluoro-N-{(1 S, 2R)-1-fluoromethyl-2-hydroxy-2[4-(6-N-[((cyano) methyl]-methyl pyridine sulfoximine-3-yl)-phenyl]-ethyl}-acetamide;
2, 2-dichloro-N-((1R, 2S)-3-fluoro-1-hydroxy-1-(4-(S-methylsulfonimidoyl) phenyl) propan-2-yl) acetamide;
2,2-dichloro-N- [(1S, 2R)-1-fluoromethyl-2-hydroxy-2-(4-(cyano)-methyl-phenyl sulfoximine)-ethyl]-acetamide;
2,2-difluoro-N- [(1S, 2R)-1-fluoromethyl-2-hydroxy-2-(4-(cyano)-methyl-phenyl sulfoximine)-ethyl]-acetamide;
2,2-dichloro-N-((1R,2S)-3-fluoro-1-(4-(S-(fluoromethyl) sulfonimidoyl) phenyl)-1-hydroxypropan-2-yl) acetamide; and
2,2-dichloro-N-((1 R, 2S)-3-fluoro-1-(4-(S-(fluoromethyl) sulfonimidoyl) phenyl)-1-hydroxypropan-2-yl) acetamide, or a pharmaceutically acceptable salt thereof.
19. The method of claim 18 wherein the compound is selected from the group consisting of:
2,2-difluoro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(6-(S-methylsulfonimidoyl)-pyridin-3-yl)phenyl)propan-2-yl)acetamide;
2,2-difluoro-N-{(1S,2R)-1-fluoromethyl-2-hydroxy-2-[4-(6-N-(cyano) methyl pyridine sulfoximine-3-yl)-phenyl]-ethyl}-acetamide;
2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(6-(S-methylsulfonimidoyl)-pyridin-3-yl)phenyl)propan-2-yl)acetamide;
2, 2-difluoro-N-{(1 S, 2R)-1-fluoromethyl-2-hydroxy-2-[4-(6-(S-methylsulfonimidoylmethyl) pyridine-3-yl)-phenyl]-ethyl}-acetamide; and
2, 2-difluoro-N-{(1 S, 2R)-1-fluoromethyl-2-hydroxy-2-[4-(6-N- [((cyano) methyl]-methyl pyridine sulfoximine-3-yl)-phenyl]-ethyl}-acetamide, or a pharmaceutically acceptable salt thereof.
20. The method of claim 19 wherein the compound is selected from from 2,2-difluoro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(6-(S-methylsulfonimidoyl)-pyridin-3-yl)phenyl)propan-2-yl)acetamide or 2, 2-difluoro-N-{(1 S, 2R)-1-fluoromethyl-2-hydroxy-2-[4-(6-(S-methylsulfonimidoylmethyl) pyridine-3-yl)-phenyl]-ethyl}-acetamide, or a pharmaceutically acceptable salt thereof.