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Substituted Oxazine and Thiazine Oxazolidinone

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Substituted Oxazine and Thiazine Oxazolidinone Europaisches Patentamt (19) European Patent Office Office europeenpeen des brevets EP 0 71 7 738 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) intci.e: C07D 263/20, A61K 31/42, of the grant of the patent: C07D 417/10, C07D 413/10 20.10.1999 Bulletin 1999/42 (86) International application number: (21) Application number: 94925765.3 PCT/US94/08904 Date of 16.08.1994 (22) filing: (87) International publication number: WO 95/07271 (16.03.1995 Gazette 1995/12) (54) SUBSTITUTED OXAZINE AND THIAZINE OXAZOLIDINONE ANTIMICROBIALS SUBSTITUIERTE OXAZINE UND THIAZINE OXAZOLIDINONE ALS ANTIMIKROBIELLE MITTEL AGENTS ANTIMICROBIENS OXAZOLIDINONE A SUBSTITUTION OXAZINE ET THIAZINE (84) Designated Contracting States: • BRICKNER, Steven, J. AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL Portage, Ml 49002 (US) PT SE • HUTCHINSON, Douglas, K. Designated Extension States: Kalamazoo, Ml 49001 (US) LTSI (74) Representative: Perry, Robert Edward et al (30) Priority: 09.09.1993 US 119279 GILL JENNINGS & EVERY 11.04.1994 US 226158 Broadgate House 7 Eldon Street (43) Date of publication of application: London EC2M 7LH (GB) 26.06.1996 Bulletin 1996/26 (56) References cited: (73) Proprietor: PHARMACIA & UPJOHN COMPANY EP-A-0 127 902 EP-A- 0 184 170 Kalamazoo, Michigan 49001 (US) EP-A- 0 352 781 WO-A-93/09103 WO-A-93/23384 (72) Inventors: • BARBACHYN, Michael, R. Kalamazoo, Ml 49001 (US) DO 00 CO Is- Is- Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice the Patent Office of the Notice of shall be filed in o to European opposition to European patent granted. opposition a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. a. 99(1) European Patent Convention). LU Printed by Jouve, 75001 PARIS (FR) EP 0 717 738 B1 Description Background of the Invention 5 [0001] The subject invention discloses oxazine and thiazine oxazolidinone derivatives. The compounds 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, Myco- bacterium avium and Mycobacterium spp.. 10 Information Disclosure [0002] The present compounds are similar to piperazine containing ring structures such as those disclosed in the publications below except that the distal nitrogen atom is replaced with an oxygen, sulfur, sulfinyl, sulfonyl, sulfimidoyl is or sulfonimidoyl. The instant compounds are unique in that typically the unsubstituted piperazinyl oxazolidinone com- pounds have little useful antibacterial activity whereas the activity observed for the corresponding oxazine and thiazine derived oxazolidinones is high. [0003] PCT/US93/03570 application discloses oxazolidinones containing a substituted diazine moiety and their uses as antimicrobials. 20 [0004] PCT/US92/08267 application discloses substituted aryl and heteroaryl-phenyloxazolidinones useful as anti- bacterial agents. [0005] PCT/US89/03548 application discloses 5'indolinyl-5p-amidomethyloxazolidinones, 3-(fused-ring substituted) phenyl-5p-amidomethyloxazolidinones, and 3-(nitrogen substituted)phenyl-5p-amidomethyloxazolidinones which are useful as antibacterial agents. 25 [0006] Other references disclosing various oxazolidinones include US Patent 4,801 ,600, 4,921 ,869, Gregory W. A., et al., J. Med. Chem., 32, 1673-81 (1989); Gregory W. A., et al., J. Med. Chem., 33, 2569-78 (1990); Wang C, et al., Tetrahedron, 45, 1323-26 (1989); and Brittelli, etal., J. Med. Chem., 35, 1156 (1992). [0007] European Patent Publication 352,781 discloses phenyl and pyridyl substituted phenyl oxazolidinones. [0008] European Patent Publication 316,594 discloses 3-substituted styryl oxazolidinones. 30 [0009] European Patent Publication 312,000 discloses phenylmethyl and pyridinylmethyl substituted phenyl oxazo- lidinones. Summary of the Invention 35 [0010] In one aspect the subject invention is a compound of structural Formula I: 40 45 or pharmaceutical^ acceptable salts thereof wherein: X is O, S, SO or S02; 50 R is (a) hydrogen, (b) C-,-C8 alkyl optionally substituted with one or more of the following: F, CI, hydroxy, C-,-C8 alkoxy, C^C, acyloxy or 0-CH2-Ph, 55 (c) C3-C6 cycloalkyl, (d) amino, (e) C-|-C8 alkylamino, (f) C-|-C8 dialkylamino, or 2 EP 0 717 738 B1 (g) CrC8 alkoxy; R1 is H, except when X is O then R1 can be H or (CH2)mR11 (m is 1 or 2); R2 is independently H, F or CI; 5 R3 is H except when X is O and R1 is CH3 then R3 can be H or CH3; R11 is hydrogen, OH, OR, NH2 or NHCOR; and n is 0, 1 or 2. [0011] Preferred compounds where n is 0 are: 10 (a) (S)-N-[[3-[3-fluoro-4-(3-thiazolidinyl)phenyl]-2-oxo-5-oxazolidinyl\ methyljacetamide; (b) (S)-N-[[3-[3-fluoro-4-(1 , 1 -dioxothiazolidin-3-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide; (c) (S)-N-[[3-[3-fluoro-4-(1 -oxothiazolidin-3-yl)phenyl]-2-oxo-5-oxazolidinyl] methyljacetamide; or (d) (S)-N-[[3-[3-fluoro-4-(3-oxazolidinyl)]phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide. 15 [001 2] Preferred compounds where n is 1 are: (a) (S)-N-[[3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide; (b) (S)-N-[[3-[3-fluoro-4-(1 , 1 -dioxothiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide; 20 (c) (S)-N-[[3-[3-fluoro-4-(1-oxothiomorpholin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide; (d) (S)-N-[[3-[3,5-difluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide; (e) (S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl] methyljacetamide; (f) (S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]hydroxyacetamide; (g) (S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]formamide; 25 (h) (S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]methylcarbamate; or (i) (S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]dichloroacetamide. [001 3] Preferred compounds where n is 2 are: 30 (a) (S)-N-[[3-[3-fluoro-4-(hexahydrothiazepin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide; (b) (S)-N-[[3-[3-fluoro-4-(1 , 1 -dioxohexahydrothiazepin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide; (c) (S)-N-[[3-[3-fluoro-4-(1-oxohexahydrothiazepin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide; or (d) (S)-N-[[3-[3-fluoro-4-(hexahydrooxazepin4-yl)]phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide. 35 [0014] The compound can be administered in a pharmaceutical composition either orally, parenterally or topically. Preferably, the compound is administered in an amount of from about 0.1 to about 100 mg/kg of body weight/day, more preferably, from about 3.0 to about 50 mg/kg of body weight/day. Detailed Description of the Invention 40 [0015] The present invention discloses oxazine and thiazine oxazolidinones of structural Formula I as defined above. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, par- ticularly 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 My- 45 cobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.. [0016] The carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the min- imum and maximum number of carbon atoms in the moiety, i.e., the prefix Cj-Cj defines the number of carbon atoms present from the integer "i" to the integer "j" inclusive. Thus, C1 -C3 alkyl refers to alkyl of 1 -3 carbon atoms, inclusive, or methyl, ethyl, propyl, and isopropyl; C-|-C8 alkyl is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyland isomeric so forms thereof. [0017] The term C-,-C8 alkylamino means an amino moiety (-NH-) containing one alkyl moiety having 1 to 8 carbon atoms. The term C-,-C8 dialkylamino means an amino moiety containing two alkyl moieties having 1 to 8 carbon atoms, for example, propylamine and dipropylamino respectively. The C-,-C8 alkyl or C1-C4 alkyl groups can be optionally substituted with chloro, fluoro, hydroxy, C^Cg alkoxy, amino, C^Cg alkylamino, C-,-Cg dialkylamino or -0-CH2Ph where 55 "Ph" is phenyl. "Acyloxy" are groups such as methylcarbamate, ethylcarbamate,etc. Such optionally substituted C-,- C8 alkyl groups can include 1-chloropropyl, 1-fluoropropyl 3-chloropropyl, 3-fluoro propyl, 1 -hydroxy butyl, 2-hydroxy butyl, 1-methoxypropyl, 1-octyloxy propyl, 1 -amino propyl, 1-aminooctyl, 1-butylaminopropyl, 1-dibutylaminopropyland the like. 3 EP 0 717 738 B1 [0018] Pharmaceutically acceptable salts means acid addition salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, me- sylate, maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate and the like when a basic group is present. These salts may be in hydrated form. 5 [0019] The benzene ring, in addition to being unsubstituted, can be substituted with one or more halogen atoms in the series fluorine or chlorine. Thus, the R2 groups can be independently either hydrogen atoms or halogen atoms in a variety of substitution patterns. [0020] The R2 substituents are preferably both fluorine and, more preferably, fluorine and H. [0021] The preferred absolute configuration at C-5 of the oxazolidinone ring of compounds claimed in this invention 10 is as represented in the structure of Formula I. This absolute configuration is called (S) under the Cahn-lngold-Prelog nomenclature system. It is this (S)-enantiomer which is antibacterially active.
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