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Details for Patent: 5,880,118

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Details for Patent: 5,880,118

Title: Substituted oxazine and thiazine oxazolidinone antimicrobials
Abstract:A compound of the Formula I: ##STR1## or pharmaceutically acceptable salts thereof wherein X, R, R.sup.1, R.sup.2, R.sup.3 and n are as defined in the disclosure. The oxazine and thiazine oxazolidinone derivatives are useful antimicrobial agents effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci, and enterococci as well as anaerobic organisms such as Bacteroides spp. and Clostridia spp. species, and acid-fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
Inventor(s): Barbachyn; Michael R. (Kalamazoo, MI), Brickner; Steven J. (Portage, MI), Hutchinson; Douglas K. (Kalamazoo, MI)
Assignee: Pharmacia & Upjohn Company (Kalamazoo, MI)
Filing Date:Jul 02, 1997
Application Number:08/886,965
Claims:1. A compound of structural Formula I:

or pharmaceutically acceptable salts thereof wherein: X is S, SO, SO.sub.2 SNR.sup.10 or S(O)NR.sup.10 ;

R is (a) hydrogen,

(b) C.sub.1 -C.sub.8 alkyl optionally substituted with one or more of the following: F, Cl, hydroxy, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 acyloxy or --O--CH.sub.2 --Ph,

(c) C.sub.3 -C.sub.6 cycloalkyl,

(d) amino,

(e) C.sub.1 -C.sub.8 alkylamino,

(f) C.sub.1 -C.sub.8 dialkylamino or

(g) C.sub.1 -C.sub.8 alkoxy;

R.sup.1 is H;

R.sup.2 is independently H, F or Cl;

R.sup.3 is H; R.sup.10 is independently H, C .sub.1 -C.sub.4 alkyl (optionally substituted with chloro, fluoro, hydroxy, C.sub.1 -C.sub.8 alkoxy, amino, C.sub.1 -C.sub.8 alkylamino, or C.sub.1 -C.sub.8 dialkylamino) or p-toluenesulfonyl; and

n is 0, 1 or 2.

2. The compound of claim 1 wherein X is S, SO or SO.sub.2.

3. The compound of claim 2 wherein each R.sup.2 is fluorine.

4. The compound of claim 1 wherein n is 1 and X is S, SO or SO.sub.2.

5. The compound of claim 1 which is an optically pure enantiomer having the S-configuration at C5 of the oxazolidinone ring.

6. The compound of claim 1 wherein one R.sup.2 is hydrogen and the other is fluorine.

7. The compound of claim 1 wherein R is methyl, OCH.sub.3, CHCl.sub.2, CH.sub.2 OH or hydrogen.

8. The compound of claim 1 which is:

(a) (S)--N--[[3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]me thyl]acetamide;

(b) (S)--N--[[3-[3-fluoro-4-(1,1-dioxothiomorpholin-4-yl)phenyl]-2-oxo-5-oxazo lidinyl]methyl]acetamide;

(c) (S)--N--[[3-[3-fluoro-4-(1-oxothiomorpholin-4-yl)phenyl] -2-oxo-5-oxazolidinyl]methyl]acetamide; and

(d) (S)--N--[[3-[3-fluoro-4-[1-[(p-toluenesulfonyl)imino]thiomorpholin-4-yl]ph enyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.

9. The compound of claim 1 where n is O and X is S, SO or SO.sub.2.

10. The compound of claim 9 wherein one R.sup.2 is hydrogen and the other is fluorine.

11. The compound of claim 9 which is:

(a) (S)--N--[[3-[3-fluoro-4-(3-thiazolidinyl)phenyl]-2-oxo-5-oxazolidinyl]meth yl]acetamide;

(b) (S)--N--[[3-[3-fluoro-4-(1,1-dioxothiazolidin-3-yl)phenyl]-2-oxo-5-oxazoli dinyl] methyl] acetamide; or

(c) (S)--N--[[3-[3-fluoro-4-(1-oxothiazolidin-3-yl)phenyl]-2-oxo-5-oxazolidiny l]methyl]acetamide.

12. The compound of claim 1 where n is 2 and X is S, SO or SO.sub.2.

13. The compound of claim 12 wherein one R.sup.2 is hydrogen and the other is fluorine.

14. The compound of claim 12 which is:

(a) (S)--N--[[3-[3-fluoro-4-(hexahydrothiazepin-4-yl)phenyl]-2-oxo-5-oxazolidi nyl]methyl]acetamide;

(b) (S)--N--[[3-[3-fluoro-4-(1,1-dioxohexahydrothiazepin-4-yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]acetamide; or

(c) (S)--N--[[3-[3-fluoro-4-(l-oxohexahydlrothiazepin-4-yl)phenyl]-2-oxo-5-oxa zolidinyl]methyl]acetamide.

15. A method useful in treating microbial infections in patients comprising:

administering to a patient in need thereof an effective amount of a compound of Formula I as shown in claim 1.

16. The method of claim 15 wherein said compound of Formula I is administered orally, parenterally or topically in a pharmaceutical composition.

17. The method of claim 15 wherein said compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day.

18. The method of claim 17 wherein said compound is administered in an amount of from about 3.0 to about 50 mg/kg of body weight/day.

19. The method of claim 15 wherein said microbial infection is caused by staphylococci, streptococci, enterococci, Bacteroides spp., Clostridia spp., Mycobacterium tuberculosis, Mycobacterium avium or Mycobacterium spp..

20. A compound selected from the group consisting of:

(a) (S)--N--[[3-[3-fluoro-4-(3-oxazolidinyl)]phenyl]-2-oxo-5-oxazolidinyl] methyl]acetamide; and

(b) (S)--N--[[3-[3-fluoro-4-(hexahydrooxazepin-4-yl)]phenyl]-2-oxo-5-oxazolidi nyl]methyl]acetamide.
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