Claims for Patent: 5,688,792
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Summary for Patent: 5,688,792
| Title: | Substituted oxazine and thiazine oxazolidinone antimicrobials |
| Abstract: | A compound of structural Formula I: ##STR1## or pharmaceutically acceptable salts thereof wherein: X is O, 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, except when X is O then R.sup.1 can be H, CH.sub.3, CN, CO.sub.2 H, CO.sub.2 R or (CH.sub.2).sub.m R.sup.11 (m is 1 or 2); R.sup.2 is independently H, F or Cl; R.sup.3 is H except when X is O and R.sup.1 is CH.sub.3 then R.sup.3 can be H or CH.sub.3 ; 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; R.sup.11 is hydrogen, OH, OR, OCOR, NH.sub.2, NHCOR or N(R.sup.10).sub.2 ; and n is 0, 1 or 2. 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) |
| Application Number: | 08/617,877 |
| Patent Claims: |
1. A compound of structural Formula I:
or pharmaceutically acceptable salts thereof wherein: X is O; 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, CH.sub.3, CN, CO.sub.2 H, CO.sub.2 R or (CH.sub.2).sub.mu R.sup.11 (m is 1 or 2); R.sup.2 is independently H, F or Cl; R.sup.3 is H except when R.sup.1 is CH.sub.3 then R.sup.3 can be H or CH.sub.3 ; 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; R.sup.11 is hydrogen, OH, OR, OCOR, NH.sub.2, NHCOR or N(R.sup.10).sub.2 ; and n is 0, 1 or 2. 2. The compound of claim 1 wherein each R.sup.2 is fluorine. 3. The compound of claim 1 which is an optically pure enantiomer having the S-configuration at C5 of the oxazolidinone ring. 4. The compound of claim 1 wherein one R.sup.2 is hydrogen and the other is fluorine. 5. The compound of claim 1 wherein R is methyl, OCH.sub.3, CHCl.sub.2, CH.sub.2 OH or hydrogen. 6. The compound of claim 1 which is: (a) (S)-N-[[3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]meth yl]acetamide; (b) (S)-N-[[3-[3-fluoro-4-(1,1-dioxothiomorpholin-4-yl)phenyl]-2-oxo-5-oxazoli dinyl]methyl]acetamide; (c) (S)-N-[[3-[3-fluoro-4-(1-oxothiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidiny l]methyl]acetamide; (d)(S)-N-[[3-[3,5-difluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]me thyl]acetamide; (e) (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]a cetamide; (f) (S)-N-[[3-[3-fluoro-4-[1-[(p-toluenesulfonyl)imino]thiomorpholin-4-yl]phen yl]-2-oxo-5-oxazolidinyl]methyl]acetamide; (g) (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]h ydroxyacetamide; (h) (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]f ormamide; (i) (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]m ethylcarbamate; (j) (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]d ichloroacetamide. 7. 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. 8. The method of claim 7 wherein said compound of Formula I is administered orally, parenterally or topically in a pharmaceutical composition. 9. The method of claim 7 wherein said compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day. 10. The method of claim 9 wherein said compound is administered in an amount of from about 3.0 to about 50 mg/kg of body weight/day. 11. The method of claim 9 wherein said microbial infection is caused by staphylococci, streptococci, enterococci, Bacteroides spp., Clostridia spp., Mycobacterium tuberculosis, Mycobacterium avium or Mycobacterium spp. 12. The compound of claim 1 which is (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]a cetamide. |
