Claims for Patent: 5,688,792

Summary for Patent: 5,688,792

Title:	Substituted oxazine and thiazine oxazolidinone antimicrobials
Abstract:	PCT No. PCT/US94/08904 Sec. 371 Date Mar. 5, 1996 Sec. 102(e) Date Mar. 5, 1996 PCT Filed Aug. 16, 1994 PCT Pub. No. WO95/07271 PCT Pub. Date Mar. 16, 1995A compound of structural Formula I: erein: X is O, S, SO, SO2, SNR10 or S(O)NR10; R is (a) hydrogen, (b) C1-C8 alkyl optionally substituted with one or more of the following: F, Cl, hydroxy, C1-C8 alkoxy, C1 -C8 acyloxy or -O-CH2-Ph, (c) C3-C6 cycloalkyl, (d) amino, (e) C1-C8 alkylamino, (f) C1-C8 dialkylamino or (g) C1-C8 alkoxy; R1 is H, except when X is O then R1 can be H, CH3, CN, CO2H, CO2R or (CH2)mR11 (m is 1 or 2); R2 is independently H, F or Cl; R3 is H except when X is O and R1 is CH3 then R3 can be H or CH3; R10 is independently H, C1-C4 alkyl (optionally substituted with chloro, fluoro, hydroxy, C1-C8 alkoxy, amino, C1-C8 alkylamino, or C1-C8 dialkylamino) or p-toluenesulfonyl; R11 is hydrogen, OH, OR, OCOR, NH2, NHCOR or N(R10)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):	Michael R. Barbachyn, Steven J. Brickner, Douglas K. Hutchinson
Assignee:	Pharmacia and Upjohn Co
Application Number:	US08/617,877
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.