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Claims for Patent: 7,816,379

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Claims for Patent: 7,816,379

Title:Oxazolidinone derivatives
Abstract: 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 Staphylococi, Enterococci and Streptococi, 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.
Inventor(s): Rhee; Jae Keol (Suwan, KR), Im; Weon Bin (Yongin-si, KR), Cho; Chong Hwan (Yongin-si, KR), Choi; Sung Hak (Seongnam-si, KR), Lee; Tae Ho (Yongin-si, KR)
Assignee: Dong-A Pharm. Co., Ltd. (Seoul, KR)
Application Number:10/596,412
Patent Claims: 1. A method for preparing an oxazolidinone derivative of Formula (I): ##STR00078## or a pharmaceutically acceptable salt thereof wherein, R.sub.1 and R'.sub.1 are independently hydrogen or fluorine; R.sub.2 is --NR.sub.5R.sub.6, --OR.sub.7, fluorine, alkylphosphate, monophosphate or a metal salt of monophosphate; R.sub.5 and R.sub.6 are independently hydrogen or C.sub.1-4 alkyl; R.sub.7 is hydrogen, C.sub.1-3 alkyl or acylated amino acid, wherein the amino acid is alanine, glycine, proline, isoleucine, leucine, phenylalanine, .beta.-alanine or valine; R.sub.3 is hydrogen, C.sub.1-4 alkyl group that is unsubstituted, or substituted with cyano, --(CH.sub.2).sub.m--OR.sub.7 or ketone; and m is 0, 1, 2, 3, or 4; the method comprises the steps of: reacting a compound of Formula (III) wherein Y is halogen: ##STR00079## with a tin compound to provide a compound of Formula (IV) wherein Z is C.sub.1-4 alkyl: ##STR00080## reacting the compound of Formula (IV) with a compound of Formula (VI): ##STR00081## under conditions selected to give a compound of Formula (V): ##STR00082## optionally reacting the compound of Formula (V) under conditions selected to give the compound of Formula (I).

2. The method of claim 1, comprising reacting the compound of Formula (V) under conditions selected to give the compound of Formula (I), wherein the reacting step further comprises the compound of Formula (V) under conditions to react the R.sub.2 hydroxyl group of Formula (V) to form R.sub.2 selected from the group consisting of --NR.sub.5R.sub.6, --OR.sub.7, fluorine, alkylphosphate, monophosphate and a metal salt of the monophosphate of the compound of Formula (I).

3. A method for preparing an oxazolidinone derivative of Formula (I): ##STR00083## or a pharmaceutically acceptable salt thereof wherein, R.sub.1 and R'.sub.1 are independently hydrogen or fluorine; R.sub.2 is --NR.sub.5R.sub.6, --OR.sub.7, fluorine, alkylphosphate, monophosphate or a metal salt of monophosphate; R.sub.5 and R.sub.6 are independently hydrogen or C.sub.1-4 alkyl; R.sub.7 is C.sub.1-3 alkyl or acylated amino acid, wherein the amino acid is alanine, glycine, proline, isoleucine, leucine, phenylalanine, .beta.-alanine or valine; R.sub.3 is hydrogen, C.sub.1-4 alkyl group that is unsubstituted, or substituted with cyano, --(CH.sub.2).sub.m--OR.sub.7 or ketone; and m is 0, 1, 2, 3, or 4; wherein the method comprises: reacting the R.sub.2 hydroxy group of Formula (V) ##STR00084## under conditions selected to give R.sub.2 selected from the group consisting of --NR.sub.5R.sub.6, --OR.sub.7, fluorine, alkylphosphate, monophosphate and a metal salt of monophosphate.

4. The method of claim 3, wherein the alkylphosphate is ditetrabutylester.

5. The method of claim 3, further comprising reacting the compound of Formula (I), wherein R.sub.7 is the acylated amino acid, with an acid under conditions selected to form a pharmaceutically acceptable salt.

6. The method of claim 3, wherein the acid is hydrochloric acid or trifluoroacetic acid.

7. The method of claim 3, wherein the reacting step comprises reacting the compound of Formula (V) with phosphorous oxy chloride to give the compound of Formula (I) wherein R.sub.2 is monophosphate.

8. The method of claim 3, wherein the reacting step comprises reacting the compound of Formula (I) wherein R.sub.2 is monophosphate with a metallic salt to give the compound of Formula (I) wherein R.sub.2 is a metal salt of the monophosphate or a disodium salt of the monophosphate.

9. The method of claim 3, wherein R.sub.1 is hydrogen and R.sub.1' is fluorine.

10. The method of claim 3, wherein R.sub.2 is --OR.sub.7 and R.sub.7 is the acylated amino acid.

11. The method of claim 3, wherein R.sub.2 is selected from the group consisting of alkylphosphate, monophosphate and a metal salt of the monophosphate.

12. The method of claim 3, wherein R.sub.3 is methyl.

13. The method of claim 3, wherein the compound of Formula (I) is selected from the group consisting of Compound 12) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl- oxymethyl oxazolidin-2-one trifluoroacetic acid; Compound 18) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-fluoro- methyl oxazolidin-2-one; Compound 20) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val- yloxy)methyl oxazolidin-2-one trifluoroacetic acid; Compound 33) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methox- ymethyl oxazolidin-2-one; Compound 38) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3,5-difluorophenyl)-5-hy- droxymethyl oxazolidin-2-one; Compound 40) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(N,N-d- imethylaminomethyl)oxazolidin-2-one; Compound 41) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(N-met- hylaminomethyl)oxazolidin-2-one; Compound 42) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala- nyloxy)methyl oxazolidin-2-one trifluoroacetic acid; Compound 43) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val- yloxy)methyl oxazolidin-2-one hydrochloride; Compound 44) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala- nyloxy)methyl oxazolidin-2-one hydrochloride; Compound 45) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl- oxymethyl oxazolidin-2-one hydrochloride; Compound 46) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-pro- linyloxy)methyl oxazolidin-2-one trifluoroacetic acid; Compound 47) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-pro- linyloxy)methyl oxazolidin-2-one hydrochloride; Compound 49) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta- .-alanyloxy)methyl oxazolidin-2-one trifluoroacetic acid; Compound 50) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta- .-alanyloxy)methyl oxazolidin-2-one hydrochloride; Compound 59) (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5- -oxazolidinyl]methyl disodiumphosphate; Compound 61) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydrox- ymethyl oxazolidin-2-one; Compound 62) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl- oxymethyl oxazolidin-2-one trifluoroacetic acid; Compound 63) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl- oxymethyl oxazolidin-2-one hydrochloride; Compound 64) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala- nyloxy)methyl oxazolidin-2-one trifluoroacetic acid; Compound 65) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala- nyloxy)methyl oxazolidin-2-one hydrochloride; Compound 66) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val- yloxy)methyl oxazolidin-2-one trifluoroacetic acid; Compound 67) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val- yloxy)methyl oxazolidin-2-one hydrochloride; Compound 68) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta- .-alanyloxy)methyl oxazolidin-2-one trifluoroacetic acid; Compound 69) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta- .-alanyloxy)methyl oxazolidin-2-one hydrochloride; Compound 70) (R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5- -oxazolidinyl]methyl disodiumphosphate; Compound 72) mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2- -oxo-5-oxazolidinyl]methyl]phosphate; and Compound 73) mono-[(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2- -oxo-5-oxazolidinyl]methyl]phosphate.

14. The method of claim 3, wherein the compound of Formula (I) has the structure ##STR00085## wherein R.sub.2 is an alkylphosphate, a monophosphate, or a metal salt of the monophosphate.

15. The method of claim 14, wherein the compound has R stereochemistry.

16. The method of claim 3, wherein the compound of Formula (I) has the structure ##STR00086## wherein R.sub.2 is an alkylphosphate, a monophosphate, or a metal salt of the monophosphate.

17. The method of claim 16, wherein the compound has R stereochemistry.

18. The method of claim 3, wherein the compound of Formula (I) has the structure ##STR00087## wherein R.sub.2 is an alkylphosphate, a monophosphate or a metal salt of the monophosphate.

19. The method of claim 18, wherein the compound has R stereochemistry.

20. The method of claim 3, wherein the compound of Formula (I) has the structure ##STR00088## wherein R.sub.2 is an alkylphosphate, a monophosphate, or a metal salt of the monophosphate.

21. The method of claim 20, wherein the compound has R stereochemistry.

22. The method of claim 3, wherein the compound of Formula (I) is ##STR00089##

23. The method of claim 3, wherein the compound of Formula (I) is ##STR00090##

24. An oxazolidinone derivative of Formula (I), or a pharmaceutically acceptable salt thereof: ##STR00091## wherein, R.sub.1 and R'.sub.1 are independently hydrogen or fluorine; R.sub.2 is --NR.sub.5R.sub.6, --OR.sub.7, fluorine, alkylphosphate, monophosphate or a metal salt of phosphate; R.sub.5 and R.sub.6 are independently hydrogen or C.sub.1-4 alkyl; R.sub.7 is hydrogen, C.sub.1-3 alkyl or acylated amino acid, wherein the amino acid is alanine, glycine, proline, isoleucine, leucine, phenylalanine, .beta.-alanine or valine; R.sub.3 is hydrogen, C.sub.1-3 alkyl group that is unsubstituted, or substituted with cyano, --(CH.sub.2).sub.m--OR.sub.7 or ketone; and m is 0, 1, 2, 3, or 4.

25. The compound of claim 24, wherein R.sub.1 is hydrogen and R.sub.1' is fluorine.

26. The compound of claim 24, wherein R.sub.2 is --OH.

27. The compound of claim 24, wherein R.sub.2 is --OR.sub.7 and R.sub.7 is the acylated amino acid.

28. The compound of claim 24, wherein R.sub.2 is selected from the group consisting of alkylphosphate, monophosphate and a metal salt of the monophosphate.

29. The compound of claim 24, wherein R.sub.3 is methyl.

30. The compound of claim 24, wherein the pharmaceutically acceptable salt is formed with an acid selected from the group consisting of hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methane sulfonic acid, glyeonic acid, succinic acid, 4-toluenesulfonic acid, trifluoroacetic acid, galuturonic acid, embonic acid, glutamic acid and aspartic acid.

31. The compound of claim 30, wherein the acid is hydrochloric acid or trifluoroacetic acid.

32. The compound of claim 24, which is selected from the group consisting of Compound 10) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydrox- ymethyl oxazolidin-2-one; Compound 12) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl- oxymethyl oxazolidin-2-one trifluoroacetic acid; Compound 18) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-fluoro- methyl oxazolidin-2-one; Compound 20) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val- yloxy)methyl oxazolidin-2-one trifluoroacetic acid; Compound 33) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-methox- ymethyl oxazolidin-2-one; Compound 38) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3,5-difluorophenyl)-5-hy- droxymethyl oxazolidin-2-one; Compound 40) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(N,N-d- imethylaminomethyl)oxazolidin-2-one; Compound 41) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(N-met- hylaminomethyl)oxazolidin-2-one; Compound 42) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala- nyloxy)methyl oxazolidin-2-one trifluoroacetic acid; Compound 43) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val- yloxy)methyl oxazolidin-2-one hydrochloride; Compound 44) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala- nyloxy)methyl oxazolidin-2-one hydrochloride; Compound 45) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl- oxymethyl oxazolidin-2-one hydrochloride; Compound 46) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-pro- linyloxy)methyl oxazolidin-2-one trifluoroacetic acid; Compound 47) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-pro- linyloxy)methyl oxazolidin-2-one hydrochloride; Compound 49) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta- .-alanyloxy)methyl oxazolidin-2-one trifluoroacetic acid; Compound 50) (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta- .-alanyloxy)methyl oxazolidin-2-one hydrochloride; Compound 59) (R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5- -oxazolidinyl]methyl disodiumphosphate; Compound 61) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydrox- ymethyl oxazolidin-2-one; Compound 62) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl- oxymethyl oxazolidin-2-one trifluoroacetic acid; Compound 63) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-glycyl- oxymethyl oxazolidin-2-one hydrochloride; Compound 64) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala- nyloxy)methyl oxazolidin-2-one trifluoroacetic acid; Compound 65) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-ala- nyloxy)methyl oxazolidin-2-one hydrochloride; Compound 66) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val- yloxy)methyl oxazolidin-2-one trifluoroacetic acid; Compound 67) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(L-val- yloxy)methyl oxazolidin-2-one hydrochloride; Compound 68) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta- .-alanyloxy)methyl oxazolidin-2-one trifluoroacetic acid; Compound 69) (R)-3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-(.beta- .-alanyloxy)methyl oxazolidin-2-one hydrochloride; Compound 70) (R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2-oxo-5- -oxazolidinyl]methyl disodiumphosphate; Compound 72) mono-[(R)-[3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2- -oxo-5-oxazolidinyl]methyl]phosphate; and Compound 73) mono-[(R)-[3-(4-(2-(1-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-2- -oxo-5-oxazolidinyl]methyl]phosphate.

33. The compound of claim 24, having the structure ##STR00092## wherein R.sub.2 is hydroxyl, an alkylphosphate, a monophosphate, or a metal salt of the monophosphate.

34. The compound of claim 33, wherein R.sub.2 is hydroxyl, the monophosphate, or a disodium salt of the monophosphate.

35. The compound of claim 33, which has R stereochemistry.

36. The compound of claim 24, having the structure ##STR00093## wherein R.sub.2 is hydroxyl, an alkylphosphate, a monophosphate, or a metal salt of the monophosphate.

37. The compound of claim 36, which has R stereochemistry.

38. The compound of claim 24, having the structure ##STR00094## wherein R.sub.2 is hydroxyl, an alkylphosphate, a monophosphate or a metal salt of the monophosphate.

39. The compound of claim 38, which has R stereochemistry.

40. The compound of claim 24, having the structure ##STR00095## wherein R.sub.2 is hydroxyl, an alkylphosphate, a monophosphate, or a metal salt of the monophosphate.

41. The compound of claim 40, which has R stereochemistry.

42. A compound having the formula ##STR00096##

43. A compound having the formula ##STR00097##

44. A compound having the formula ##STR00098##

45. A pharmaceutical composition comprising the compound of claim 24.

46. A method of treating a bacterial infection in a subject, comprising administering to the subject the compound of claim 24.

47. The method of claim 45, wherein the bacterial infection results from a Gram-positive bacterium.

48. The method of claim 46, wherein the Gram-positive bacterium is selected from the group consisting of Staphylococcus, Enterococcus, Streptococcus, Bacteroides, Clostridium, and Mycobacterium.

49. The method of claim 47, wherein the bacterium is selected from the group consisting of Staphylococcus, Enterococcus, and Streptococcus.
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