Oxazolidinone derivatives
View Patent ↗The present invention relates to novel derivatives of oxazolidinone, a method thereof and pharmaceutical compositions comprising the derivatives for use in an antibiotic. The oxazolidinone derivatives of the present invention show inhibitory activity against a broad spectrum of bacteria and lower toxicity. The prodrugs, prepared by reacting the compound having hydroxyl group with amino acid or phosphate, have an excellent efficiency on solubility thereof against water. Further, the derivatives of the present invention may exert potent antibacterial activity versus various human and animal pathogens, including Gram-positive bacteria such as, Staphylococci, Enterococci and Streptococci anaerobic microorganisms such as Bacteroides and Clostridia, and acid-resistant microorganisms such as Mycobacterium tuberculosis and Mycobacterium avium . Accordingly, the compositions comprising the oxazolidinone are used in an antibiotic.
1. An oxazolidinone derivative of Formula (I), or a pharmaceutically acceptable salt thereof
wherein,
Het is selected from the group consisting of tetrazolyl and oxadiazolyl;
ring A is unsubstituted or has at least one fluorine substituent;
R 7 is
a) H, or
b) PO(OH) 2 or PO(O) 2 −2 (M + ) 2 , wherein M + is a pharmaceutically acceptable metal cation,
R 3 is hydrogen, C 1-4 alkyl group that is unsubstituted, or substituted with cyano, —(CH 2 )m-OR 7 or ketone; and
m is 0, 1, 2, 3, or 4.
2. The oxazolidinone derivative of claim 1
wherein R 7 is
b) PO(OH) 2 or PO(O) 2 −2 (M + ) 2 , wherein M + is a pharmaceutically acceptable metal cation, and
wherein the oxazolidinone derivative has a solubility of greater than 30 mg/mL.
3. The oxazolidinone derivative of claim 2
wherein the oxazolidinone derivative has a solubility of greater than 50 mg/mL.
4. The oxazolidinone derivative of claim 1 ,
wherein R 7 is PO(OH) 2 or PO(O) 2 −2 (M + ) 2 , wherein M + is a pharmaceutically acceptable metal cation.
5. The oxazolidinone derivative of claim 4 ,
wherein M + is Na + .
6. The oxazolidinone derivative of claim 1
wherein R 7 is H.
7. The oxazolidinone derivative of claim 1
wherein Het is oxadiazolyl.
8. The oxazolidinone derivative of claim 1
wherein Het is tetrazolyl.
9. The oxazolidinone derivative of claim 8 , which is
10. The oxazolidinone derivative of claim 4 , which is
11. The oxazolidinone derivative of claim 10 , wherein R 1 is hydrogen and R′ 1 is fluorine.
12. The oxazolidinone derivative of claim 10 wherein R 7 is —H.
13. The oxazolidinone derivative of claim 10 , wherein R 7 is selected from the group consisting of PO(OH) 2 and PO(O) 2 −2 (M + ) 2 , wherein M + is a pharmaceutically acceptable metal cation.
14. The oxazolidinone derivative of claim 12 , wherein R 3 is methyl.
15. The oxazolidinone derivative of claim 13 , wherein R 3 is methyl.
16. The oxazolidinone derivative of claim 10 , wherein the pharmaceutically acceptable salt is formed with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methane sulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid, trifluoroacetic acid, galacturonic acid, embonic acid, glutamic acid and aspartic acid.
17. The oxazolidinone derivative of claim 16 , wherein the acid is hydrochloric acid or trifluoroacetic acid.
18. The oxazolidinone derivative of claim 10 , having the structure
wherein R 7 is H, PO(OH) 2 or PO(O) 2 −2 (M + ) 2 , wherein M + is a pharmaceutically acceptable metal cation.
19. The oxazolidinone derivative of claim 18 wherein M + is Na + .
20. A compound selected from the group consisting of
Compound 16) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl,
Compound 27) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazole-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyl oxazolidin-2-one trifluoroacetic acid,
Compound 39) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3,5-difluorophenyl)-5-hydroxymethyl oxazolidin-2-one,
Compound 48) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyloxymethyl oxazolidin-2-one hydrochloride,
Compound 51) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-alanyloxy)methyl oxazolidin-2-one trifluoroacetic acid,
Compound 52) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-alanyloxy)methyl oxazolidin-2-one hydrochloride,
Compound 53) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-valyloxy)methyl oxazolidin-2-one trifluoroacetic acid,
Compound 54) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-valyloxy)methyl oxazolidin-2-one hydrochloride,
Compound 55) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-prolinyloxy)methyl oxazolidin-2-one trifluoroacetic acid,
Compound 56) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-prolinyloxy)methyl oxazolidin-2-one hydrochloride,
Compound 57) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(β-alanyloxy)methyl oxazolidin-2-one trifluoroacetic acid,
Compound 58) (R)-3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(β-alanyloxy)methyl oxazolidin-2-one hydrochloride, and
Compound 60) (R)-[3-(4-(2-(2-methyl-[1,3,4]oxadiazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl disodiumphosphate.
21. A pharmaceutical composition comprising the oxazolidinone derivative of claim 1 and a pharmaceutically acceptable carrier.
22. A pharmaceutical composition of claim 21 , wherein the pharmaceutical composition is an injectable composition.
23. A method of treating a bacterial infection in a subject, comprising administering to the subject an effective amount of the oxazolidinone derivative of claim 1 .
24. The method of claim 23 , wherein the bacterial infection results from a Gram-positive bacterium.
25. The method of claim 24 , wherein the Gram-positive bacterium is selected from the group consisting of Staphylococcus, Enterococcus, Streptococcus, Bacteroides, Clostridium , and Mycobacterium.
26. The method of claim 25 , wherein the bacterium is selected from the group consisting of Staphylococcus, Enterococcus , and Streptococcus.
27. The oxazolidinone derivative of claim 8 , wherein R 1 is hydrogen and R′ 1 is fluorine.
28. The oxazolidinone derivative of claim 8 wherein R 7 is —H.
29. The oxazolidinone derivative of claim 8 , wherein R 7 is PO(OH) 2 or PO(O) 2 −2 (M + ) 2 , wherein M + is a pharmaceutically acceptable metal cation.
30. The oxazolidinone derivative of claim 28 , wherein R 3 is methyl.
31. The oxazolidinone derivative of claim 29 , wherein R 3 is methyl.
32. The oxazolidinone derivative of claim 8 , wherein the pharmaceutically acceptable salt is formed with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methane sulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid, trifluoroacetic acid, galacturonic acid, embonic acid, glutamic acid and aspartic acid.
33. The oxazolidinone derivative of claim 32 , wherein the acid is hydrochloric acid or trifluoroacetic acid.