USOO5981528A United States Patent (19) 11 Patent Number: 5,981,528 Gravestock (45) Date of Patent: *Nov. 9, 1999

54). ANTIBIOTIC OXAZOLIDINONE 50735/96 10/1996 Australia ...... CO7D 413/10 DERVATIVES 2154024 1/1996 Canada ...... CO7D 413/04 O127902 12/1984 European Pat. Off...... CO7D 263/20 75 Inventor: Michael Barry Gravestock, 0184170 6/1986 European Pat. Off...... CO7D 263/20 0312000 4/1989 European Pat. Off...... CO7D 263/20 Macclesfield, United Kingdom 0316594 5/1989 European Pat. Off. ... CO7D 263/20 73 Assignee: Zeneca Limited, Kondon O352781 1/1990 European Pat. Off...... CO7D 263/20 (List continued on next page.) * Notice: This patent issued on a continued pros OTHER PUBLICATIONS ecution application filed under 37 CFR 1.53(d), and is subject to the twenty year Abstracts: The 1996 ICAAC (Interscience Congress of patent term provisions of 35 U.S.C. Antimicrobial Agents and Chemotherapy), New Orleans, 41, 154(a)(2). (Spe. 15–18, 1996). Ashtekar, D., et al., “Oxazolidinones, a New Class of 21 Appl. No.: 08/945,160 Synthetic Antituberculosis Agent: In vitro and in vivo Activities of DuP-721 Against Mycobacterium tuberculo 22 PCT Filed: Feb. 20, 1997 sis”, Diagn. Microbiol. Infect. Dis., 14, 465-471, (1991). 86 PCT No.: PCT/GB97/00462 Barbachyn, M., et al., “Identification of a Novel Oxazolidi none (U-100480) with Potent Antimycobacterial Activity”, S371 Date: Oct. 21, 1997 J. Medical Chemistry, 39, 680-685, (1996). Barbachyn, M., et al., “Synthesis and Antibacterial Activity S 102(e) Date: Oct. 21, 1997 of New -Substituted Phenyloxazolidinone Antibac 87 PCT Pub. No.: WO97/30995 terial Agents. 1. Identification of Leads and Importance of the Tropone Substitution Pattern.”, Bioorganic and Medici PCT Pub. Date: Aug. 28, 1997 nal Chemistry Lett., 6, 1003-1008, (1996). Barbachyn, M., et al., “Synthesis and Antibacterial Activity 30 Foreign Application Priority Data of New Tropone-Substituted Phenyloxazolidinone Antibac Feb. 24, 1996 GB United Kingdom ...... 96.O3939 terial Agents. 2. Modification of the Phenyl Ring the Sep. 4, 1996 GB United Kingdom ...... 96.18404 Potentiating Effect of Fluorine Substitution on In Vivo Activity.”, Bioorganic and Medicinal Chemistry Lett., 6, 51) Int. Cl...... A61K 31/445; CO7D 213/44; 1009–1014 (1996). CO7D 237/30; CO7D 241/02 Barry, A., et al., “In Vitro Evaluation of DuP 105 and DuP 52 U.S. Cl...... 514/252; 514/255; 514/256; 721, Two New Oxazolidinone Antimicrobial Agents”, Anti 514/311; 514/326; 514/331; 514/333; 514/340; microbial Agents and Chemotherapy, 32, 150-152, (1988). 514/365; 514/372; 514/374; 514/403; 514/444; Borthwick, A., et al., 514/469; 544/237; 544/238; 544/253; 544/333; “5-(Acetamidomethyl)-3-Aryldihydrofuran-2-ones, and 544/353; 54.6/122; 546/134; 546/209; 546/241 5-(Acetamidomethyl)-3-Aryltetrahydrofuran-2-ones, Two New Classes of Antibacterial Agents”, Med. Chem. Res., 6, 58 Field of Search ...... 546/275, 122, 22–27, (1996). 546/134, 209, 241, 262.4; 514/326,331; Brickner, S., et al., “Oxazolidinone Antibacterial Agents', 544/237, 238, 253,333, 353 Current Pharmaceutical Design, 2, 175-194, (1996). 56) References Cited (List continued on next page.) U.S. PATENT DOCUMENTS Primary Examiner Johann Richter Assistant Examiner Taofiq A Solola 4,287.351 9/1981 Bourgery et al...... 548/232 Attorney, Agent, Or Firm-Schwegman, Lundberg, 4,346,102 8/1982 Langlois et al...... 424/279 Woessner & Kluth PA 4,476,136 10/1984 Dostert et al...... 424/272 4,705,799 11/1987 Gregory ...... 514/376 57 ABSTRACT 4.942,183 7/1990 Gregory et al...... 514/376 4,948,801 8/1990 Carlson et al...... 514/307 The invention concerns a compound of formula (I): 4,977,173 12/1990 Brittelli et al...... 514/376 5,043,443 8/1991 Carlson et al...... 544/112 (I) 5,164,510 11/1992 Brickner ...... 548/231 R 5,182,403 11/1993 Brickner ...... 548/231 5,231,188 7/1993 Brickner ...... 548/221 5,523,403 6/1996 Barbachyn ...... 544/137 N 5,529.998 6/1996 Habich et al. ... 514/233.8 5,547,950 8/1996 Hutchinson et al. . ... 514/252 R1 5,565,571 10/1996 Barbachyn et al...... 546/144 5,574,055 11/1996 Borgulya et al...... 514/376 5,652,238 7/1997 Brickner et al...... 514/235.8 5,688,792 11/1997 Barbachyn et al. ... 514/235.5 wherein R-R, A, B, and D have any of the values defined 5,698,574 12/1997 Reidl et al...... 514/376 in the Specification, or a pharmaceutically acceptable Salt 5,719,154 2/1998 Tucker et al...... 514/252 thereof, as well as pharmaceutical compositions comprising 5,736,545 4/1998 Gadwood et al...... 514/252 Such a compound or Salt, and methods of treating a bacterial FOREIGN PATENT DOCUMENTS infection by administering Such a compound or Salt. 24985/95 2/1996 Australia ...... CO7J 1/OO 8 Claims, No Drawings 5,981,528 Page 2

FOREIGN PATENT DOCUMENTS Eustice, D., et al., “The Mechanism of Action of DuP 721, 0.359 418 A1 3/1990 European Pat. Off...... CO7D 413/04 a New Antibacterial Agent: Effects on Macromolecular O 609905 A1 8/1994 European Pat. Off...... CO7D 413/04 Synthesis”, Biochem. and BiophyS. Res. Comm., 150, 24585.47 1/1981 France ...... CO7D 263/16 965–971, (1988). 2028306 3/1980 United Kingdom. CO7D 263/16 Ford, C., et al., “In Vivo Activities of U-100592 and 2054.575 2/1981 United Kingdom ...... CO7D 263/20 U-100766, Novel Oxazolidinone Antimicrobial Agents, 2053196 2/1981 United Kingdom ...... CO7D 307/02 against Experimental Bacterial Infections, Antimicrobial 2094299 9/1982 United Kingdom ...... CO7D 263/20 Agents and Chemotherapy, 40, 1508-1513, (1996). 2 141716 1/1985 United Kingdom ...... CO7D 263/20 Grega, K., et al., “RegioSelective Metalation of Fluoroa 93/09 103 5/1993 WIPO ...... CO7D 263/20 nilines. An Application to the Synthesis of Fluorinated 933/23384 11/1993 WIPO . CO7D 263/20 Oxazolidinone Antibacterial Agents”, J. Org. Chem., 60, 94/O1110 1/1994 WIPO . ... A61K 31/42 5255-5261, (1995). 94/13649 6/1994 WIPO ...... CO7D 263/20 955/07271 3/1995 WIPO ...... CO7D 263/20 Gregory, W., et al., “Antibacterials. Synthesis and Structure 955/14684 6/1995 WIPO ...... CO7D 263/20 -Activity Studies of 3-Aryl-2-oxooxazolidines. 1. The B 95/25106 9/1995 WIPO ...... CO7D 413/10 Group”, J. Med. Chem., 32, 1673–1681, (1989). 96/13502 5/1996 WIPO ...... CO7D 413/10 Gregory, W., et al., “Antibacterials. Synthesis and Structure 96/15130 5/1996 WIPO . ... CO7D 491/048 -Activity Studies of 3-Aryl-2-oxooxazolidines. 2. The A 96/23788 8/1996 WIPO ...... CO7D 413/10 Group”, J. Med. Chem., 33, 2569-2578, (1990). 96/35691 11/1996 WIPO ...... CO7D 487/04 Hutchinson, D., et al., “Piperazinyl Oxazolidinones: Struc 97/09328 3/1997 WIPO ...... CO7D 413/10 ture Activity Relationshipd of a New Class of Oxazolidinone 97/10223 3/1997 WIPO ...... CO7D 263/20 Antibacterial Agents”, Abstract. InterScience Congress of 97/10235 3/1997 WIPO ...... CO7D 307/52 Antimicrobial Agents and Chemotherapy, 8-14, (Sep. 97/14690 4/1997 WIPO ...... CO7D 307/58 97/19089 5/1997 WIPO ...... CO7D 498/04 17–20, 1995). 97/21708 6/1997 WIPO ...... CO7D 413/12 Jones, R., et al., “In Vitro Antimicrobial Activities and 97/27188 7/1997 WIPO ...... CO7D 413/10 Spectra of U-100592 and U-100766, Two Novel Fluori 97/30981 8/1997 WIPO ...... CO7D 263/20 nated Oxazolidinones”, Antimicrobial Agents and Chemo 97/37980 10/1997 WIPO ...... CO7D 263/24 therapy, 40, 720–726, (1996). Jorgensen, J., et al., “In Vitro Activities of the Oxazolidinone OTHER PUBLICATIONS Antiobiotics U-100592 and U-100766 against Staphylococ ccus aureus and Coagulase-Negative StaphylococcuS Spe Brickner, S., et al., “Synthesis and Antibacterial Activity of cies”, Antimicrobial Agents and Chemotherapy, 41, U-100592 and U-100766, Tow Oxazolidinone Antibactieral 465–467, (Feb. 1997). Agents for the Potential Treatment of Multidrug-Resistant Kaatz, G., et al., “In Vitro Activities of Oxazolidinone Gram-Positive Bacterial Infections”, J. Medical ChemSitry, Compounds U100592 and U100766 against Staphylococcus 39, 673–679, (1996). aureus and StaphylococcuS epidermis, Antimicrobial Brumfitt, W., et al., “Antibacterial Oxazolidinones: In Vitro Agents and Chemotherapy, 40, 799-801, (1996). Activity of a New Analogue, E3709, Diagn. Microbiol. Lin, A., et al., “The Oxazolidinone Eperezolid Binds to the Infect. Dis., 15, 621-625, (1992). 50s Ribosomal Subunit and Competes with Binding of Brumfitt, W., et al., “In-vitro Microbiological Activities of Chloramphenicol and Lincomycin, Antimicrobial Agents DuP 105 and DuP 721, Novel Synthetic Oxazolidinones”,J. and Chemotherapy, 41, 2127–2131, (1997). Antimicrobial Chemotherapy, 21, 711-720, (1988). Lizondo, J., et al., “Linezolid U-100766, Drugs of the Brumfitt, W., et al., “Variation in Response of Gram-Posi Future, 21, 1116-1123, (1996). tive cocci to the Combination DuP 721 and ciprofloxacin', Lund, J., et al., “HyperSegmented Megakaryocytes and J. Antimicrob. Chemotherapy, 24, 465-466, (1989). Megakaryocytes with Multiple Separate Nuclei in Dogs Daly, J., et al., “Activity and Mechanism of Action DuP 105 Treated with PNU-100592, and Oxazolidinone Antibiotic', and DuP 721, New Oxazolidinone Compounds”, J. Antimi Toxicologic Pathology, 25, 339–343, (1997). crobial Chemotherapy, 21, 721-730, (1988). Maple, P., et al., “Comparative in-vitro activity of vacomy Denis, A., et al., “5-Aryl-betagamma Butenolide, A New cin, teicoplanin, ramoplanin (formerly A16686), paldimy Class of Antibacterial Derived from the N-Aryl Oxazolidi cin, DuP 721 and DuP 105 against methicillin and gentami none DUP 721, Bioorganic and Medicinal Chemistry Lett., cin resistant Staphylococcus aureus', J. Antimicrobial 4, 1925–1930, (1994). Chemotherapy, 23, 517-525, (1989). Dostert, P., et al., “Structural Modifications in Oxazolidi Mason, E., et al., “In Vitro Activities of Oxazolidinones none Series Leading to Type A or B Selective Monoamine U-100592 and U-100766 against Penicillin-Resistant and Oxidase Inhibitors”, Int. Congress Series; Excerpta Medica, Cephalosporin-Resistant Strains of StreptococcuS pneumo 564, 197–208, (1982). niae', Antimicrobial Agents and ChemOtherapy, 40, Eliopoulos, G., et al., “In Vitro Activities of New Oxazoli 1039–1040, (1996). dinone Antimicrobial Agents against Enterococci', Antimi Mini, E., et al., “Comparative in Vitro Activity of the New crobial Agents and Chemotherapy, 40, 1745-1747, (1996). Oxazolidinones DuP 721 and DuP 105 against Staphylococ Eustice, D., et al., “An Automated Pulse Labelling Method cus and Streptococci”, Eur: J. Clin. Microbiol. Infect. Dis., for Structure-Activity Relationship Studies with Antibacte 8, 256–260, (1989). rial Oxazolidinones', Drugs Exp. Clin. Res., 16, 149-155, Mulazimoglu, L., et al., “In Vitro Activities of Two Novel (1990). Oxazolidinones (U100592 and U100766), a New Fluoro Eustice, D., et al., “Mechanism of Action of DuP 721: quinolone (Trovafloxacin), and Dalfopristin-Quinupristin Inhibition of an Early Event during Initiation of Protein against StaphylococcuS aureus and StaphylococcuS epider Synthesis”, Antimicrobial Agents and Chemotherapy, 32, mis”, Antimicrobial Agents and Chemotherapy, 40, 1218–1222, (1988). 2428–2430, (1996). 5,981,528 Page 3

Neu, H., et al., “In Vitro Activities of Two Oxazolidinone Silverman, R., et al., “The Oxazolidinone Antibacterial Antimicrobial Agents DuP 721 and DuP 105”, Antimicrobial Agent DuP 105 Does Not Act On Cell Wall Biosynthesis Or Agents and Chemotherapy, 32, 580-583, (1988). On A Beta-Lactamase”, Biochemical and Biophysical Park, C., et al., “Antibacterials. Synthesis and Structure-Ac Research Comm., 195, 1077–1080, (1993). tivity Studies of 3-Aryl-2-oxooxazolidines. 4. Multi Slee, A., et al., “Oxazolidinones, a New Class of Synthetic ply-Substituted Aryl Derivatives”, J. Med. Chem., 53, Antibacterial Agents: In Vitro and In Vivo Activities of DuP 1156–1165, (1992). 105 and DuP 721, Antimicrobial Agents and Chemo Ranaldi, G., et al., “Transport of the Antibacterial Agent therapy, 31, 1791–1797, (1987). Oxazolidin-2-One and Derivatives across Intestinal Spangler, S., et al., “Activities of RPR 106972 (a New Oral (Caco-2) and Renal (MDCK) Epithelial Cell Lines”, Anti Streptogramin), Cefditoren (a New Oral Cephalosporin), microbial Agents and Chemotherapy, 40, 652-658, (1996). Two New Oxazolidinones (U-100592 and U-100766), and Schaadt, R., et al., “Serum Inhibitory Titers and Serum Other Oral and Parenteral Agents against 203 Penicillin Bactericidal Titers for Human Subjects Receiving Multiple -Susceptible and -Resistant Pneumoccocci”, Antimicrobial Doses of the Antibacterial Oxazolidinones Eperezolid and Agents and Chemotherapy, 40, 481-484, (1996). Linezolid”, Diagn. Microbiol. Infect. Dis., 28, 201-204, Takagi, H., et al., “Safety Pharmacology Evaulation of the (1997). Schaus, S., et al., “Dynamic Kinetic Resolution of Epichlo Oxazolidinone, U-100766”, Abstract. Society of Toxicolo rohydrin via Enantioselective Catalytic Ring Operation with gists Annual Meeting, 110, (1996). TMSN3. Practical Synthesis of Aryl Oxazolidinone Anti Wang, C., et al., “Chiral Synthesis of DUP 721, A New bacterial Agents”, Tetrahedron Lett., 37, 7937-7940, (1996). Antibacterial Agent”, Tetrahedron, 45, 1323–1326, (1989). Scholl, J., et al., Micellar Electrokinetic Chromatography as Worth, S., et al., “Quality Control Guidelines for Amoxicil a Generalized Alternatives to High-Performance Liquid lin, Amoxicillin-Clavulanate, Azithromycin, Piperacil Chromatography for Purity Determination of a Class of lin-Tazobactam, Roxithromycin, Ticarcillin, Ticarcil Investigational Antibacterail Drugs, J. Of Chromatography lin-Clavulanate,Trovafloxacin (CP 99.219), U-100592, and B., 695, 147–156, (1997). U-100766 for Various National Committee . . . , Diagn. Seneci, P., et al., “Synthesis and Antimicrobial Activity of Microbiol. Infect. Dis, 24, 87–91, (1996). Oxazolidin-2-ones and Related Heterocycles”, J. Chem. Zurenko. G., et al., In Vitro Activities of U-100592 and Soc. Perkin Trans. 1, 16, 2345-2351, (1994). U-100766, Novel Oxazolidinone Antibacterial Agents, Anti Shinabarger, D., et al., “Mechanism of Action of Oxazoli microbial Agents and Chemotherapy, 40, 839-845, (1996). dinones: Effects of Linezolid and Eperezolid on Translation Zurenko, G., et al., “Oxazolidinone antibacterial agents: Reactions”, Antimicrobial Agents and Chemotherapy, 41, development of the clinical candidates epereZolid and lin 2132–2136, (1997). eZolid", Exp. Opin. Invest. Drugs, 6, 151-158, (1997). 5,981528 1 2 ANTIBIOTIC OXAZOLIDINONE DERVATIVES (I) R4 R6 R2 O This Appl. is a 371 of PCT/GB97/00462 FILED Feb. 20, )-( y 1997. D A. N The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing an Oxazolidinone ring. This invention further relates to pro ceSSes for their preparation, to intermediates useful in their 1O preparation, to their use as therapeutic agents and to phar wherein: maceutical compositions containing them. R" is hydroxy, chloro, fluoro, (1-4C)alkanesulfonyloxy, The international microbiological community continues amino, azido, (1-4C)alkoxy, (1-4C)alkylthio, (1-4C) alkylaminocarbonyloxy, to express Serious concern that the evolution of antibiotic 15 resistance could result in Strains against which currently or of the formula –NHC(=O)R wherein R is available antibacterial agents will be ineffective. In general, hydrogen, (1-4C) alkoxy, amino, chloromethyl, bacterial pathogens may be classified as either Gram dichloromethyl, cyanomethyl, methoxymethyl, positive or Gram-negative pathogens. Antibiotic compounds acetylmethyl, methylamino, dimethylamino or (1-4C) with effective activity against both Gram-positive and alkyl, Gram-negative pathogens are generally regarded as having or R' is of the formula-NHS(O),(1-4C)alkyl wherein n a broad spectrum of activity. The compounds of the present is 0, 1 or 2; invention are regarded primarily as effective against Gram R° and Rare independently hydrogen or fluoro; D is O, positive pathogens because of their particularly good activ S, SO, SO or NR7; 25 when D is O, R" and R are independently hydroxy, ity against Such pathogens. bromo, oxo (=O), (1-4C)alkyl, (1-4C)alkanoylamino Gram-positive pathogens, for example Staphylococci, (1-4C)alkyl, hydroxy-(1-4C)alkyl, carboxy, (1-4C) Enterococci, Streptococci and mycobacteria, are particularly alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl important because of the development of resistant Strains (wherein AR is as defined hereinbelow) or indepen which are both difficult to treat and difficult to eradicate from dently as defined for R7 hereinbelow; the hospital environment once established. Examples of when D is S, SO, SO or NR7, R and R are indepen Such Strains are methicillin resistant StaphylococcuS dently oxo (=O), (1-4C)alkyl, (1-4C)alkanoylamino (MRSA), methicillin resistant coagulase negative staphylo (1-4C)alkyl, hydroxy-(1-4C)alkyl, carboxy, (1-4C) cocci (MRCNS), penicillin resistant Streptococcus pneumo alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl niae and multiply resistant Enterococcus faecium. 35 (wherein AR is as defined hereinbelow) or indepen The major clinically effective antibiotic for treatment of dently as defined for R7 hereinbelow; Such resistant Gram-positive pathogens is Vancomycin. Van R is hydrogen, (1-4C)alkyl, hydroxy, (1-4C)alkoxy or comycin is a glycopeptide and is associated with nephro (2-4C)alkanoyloxy; toxicity and ototoxicity. Furthermore, and most importantly, 40 >A-B- is of the formula >C=C(R)-, >CHCHR- or antibacterial resistance to Vancomycin and other glycopep >C(OH)CHR'- (>represents two single bonds) tides is also appearing. This resistance is increasing at a wherein R" is hydrogen or (1-4C)alkyl; Steady rate rendering these agents leSS and less effective in R" is hydrogen, cyano, 2-((1-4C)alkoxycarbonyl)ethenyl, the treatment of Gram-positive pathogens. 2-cyanoethenyl, 2-cyano-2-((1-4C) alkyl)ethenyl, 45 2-(1-4C)alkylaminocarbonyl)ethenyl, AR (as defined The present inventors have discovered a class of antibi hereinbelow) or a ring System (optionally otic compounds containing an oxazolidinone ring which has mono-Substituted in the 1- or 2-position of the tetrazole useful activity against Gram-positive pathogens including ring) wherein the tetrazole ring System is joined to the MRSA and MRCNS and, in particular, against various nitrogen in NR7 by a ring carbon atom; Strains exhibiting resistance to Vancomycin and against E. 50 or R7 is of the formula R'CO-, R'SO - or R'CS faecium Strains resistant to both aminoglycosides and clini wherein R' is AR (as defined hereinbelow), cyclopentyl cally used B-lactans. or cyclohexyl (wherein the last two-mentioned We have now discovered a narrow range of compounds cycloalkyl rings are optionally mono- or disubstituted that is not Suggested by the art and which has good activity by Substituents independently selected from (1-4C) against a broad range of Gram-positive pathogens including 55 alkyl (including geminal disubstitution), hydroxy, organisms known to be resistant to most commonly used (1-4C)alkoxy, (1-4C)alkylthio, acetamido, (1-4C) alkanoyl, cyano and trifluoromethyl), (1-4C) antibiotics. In comparison with compounds described in the alkoxycarbonyl, hydrogen, amino, trifluoromethyl, art (for example Walter A. Gregory et all in J.Med.Chem. (1-4C) alkylamino, di((1-4C) alkyl)amino, 2,3- 1990, 33, 2569-2578 and Chung-Ho Park et all in J.Med 60 dihydro-5-oxothiazolo-3,2-Apyrimidin-6-yl, 2-(2- Chem. 1992, 35, 1156-1165) the compounds also possess a furyl)ethenyl, 2-(2-thienyl)ethenyl, 2-phenylethenyl favourable toxicological profile. (wherein the phenyl Substituent is optionally Substi Accordingly the present invention provides a compound tuted by up to three Substituents independently Selected of the formula (I): from (1-1 C) alkoxy, halo and cyano), 3,4- 65 5,981528 3 4 dihydropy ran-2-yl, coumal-5-yl, 5-methoxy-4- N-((5S)-3-(4-(2-oxo-5,6-dihydropyran-4-yl)phenyl)-2- oXopyran-2-yl, N-acetylpyrrollidin-2-yl, 5-oxo OXooxazolidin-5-ylmethyl)acetamide is excluded. tetrahydrofuran-2-yl, benzopyranone or (1-10C)alkyl ln this specification a 5- or 6-membered heteroaryl and wherein (1-10C)alkyl is optionally substituted by heteroaryl (monocyclic) ring means a 5- or 6-membered hydroxy, cyano, halo, (1-10C)alkoxy, trifluoromethyl, aryl ring wherein 1, 2 or 3 of the ring atoms are Selected from (1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C) nitrogen, oxygen and Sulfur. Particular examples of 5- or alkoxy-(1-4C)alkoxy, (1-4C) alkanoyl, (1-4C) 6-membered heteroaryl ring Systems are , , alkoxycarbonyl, amino, (1-4C)alkylamino, di((1-4C) , , , , , alkyl)amino, (1-6C) alkanoylamino, (1-4C) , , , isothiazole, and alkoxycarbonylamino, N-(1-4C) alkyl-N-(2-6C) . alkanoylamino, (1-4C)alkylS(O)NH-, (1-4C)alkylS In this specification a 5/6 or 6/6 bicyclic heteroaryl ring (O)((1-4C)alkyl)N-, fluoro(1-4C)alkylS(O)NH-, System and heteroaryl (bicyclic) ring means an aromatic fluoro(1-4C)alkylS(O)((1-4C)alkyl)N-, phosphono, bicyclic ring System comprising a 6-membered ring fuised to (1-4C) alkoxy (hydroxy) phosphoryl, di-(1-4C) either a 5 membered ring or another 6 membered ring, the alkoxyphosphoryl, (1-4C)alkylS(O), phenylS(O) 15 bicyclic ring System containing 1 to 4 heteroatoms Selected — (wherein the phenyl group is optionally substituted from nitrogen, oxygen and Sulfur. Particular examples of 5/6 by up to three Substituents independently Selected from and 6/6 bicyclic ring Systems are , benzofiran, (1-4C)alkoxy, halo and cyano), or CY (as defined ben Zoimidazole, , ben Zisothiazole, hereinbelow), wherein p is 1 or 2 and q is 0.1 or 2); be n Zoxazole, ben ZiSoxazole, pyridoimidazole, or R' is of the formula RC(O)O(1-6C)alkyl wherein pyrimidoimidazole, , , , R" is an optionally substituted 5- or 6-membered , and naphthyridine. heteroaryl, optionally Substituted phenyl, (1-4C) In this specification a 4-, 5- or 6-membered cycloalkyl alkylarnino, benzyloxy-(1-4C)alkyl or optionally Sub ring means a cyclobutyl, cyclopentyl or cyclohexyl ring; stituted (1-10C)alkyl; and a 5- or 6-membered cycloalkenyl ring a means cycl or R' is of the formula R'-O- wherein R' is optionally 25 pentenyl or cyclohexenyl ring. Substituted (1-6C)alkyl; In this specification the term alkyl includes Straight or R7 is of the formula ROC(R)=CH(C=O)-, RC chained and branched structures. For example, (1-6C)alkyl (=O)C(=O)-, R=N=C(R)C(=O)– or RNHC(R) includes propyl, isopropyl and tert-butyl. However, refer =CHC(=O)— wherein R is (1-6C)alkyl, R is ences to individual alkyl groupS Such as “propyl” are spe hydrogen or (1-6C)alkyl, or R and R together form a cific for the Straight chained version only, and references to (3-4C)alkylene chain, R is hydrogen, (1-6C)alkyl, individual branched chain alkyl groupS. Such as "isopropyl hydroxy(1-6C)alkyl, (1-6C)alkoxy(1-6C) alkyl, are specific for the branched chain version only. A similar amino, (1-4C) alkylamino, di-(1-4C) alkylamino, convention applies to other radicals, for example halo(1-4C) (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, hydroxy alkyl includes 1-bromoethyl and 2-bromoethyl. 35 Particular optional Substituents for alkyl, phenyl (and (2-6C)alkoxy, (1-4C)alkylamino(2-6C)alkoxy, di phenyl containing moieties) and naphthyl groups and ring (1-C) alkylamino(2-6C)alkoxy, R is (1-6C)alkyl, carbon atoms in heteroaryl (mono or bicyclic) rings in R', hydroxy or (1-6C)alkoxy, R" is hydrogen or (1-6C) R', R and AR include halo, (1-4C)alkyl, hydroxy, nitro, alkyl, R is hydrogen, (1-6C)alkyl, optionally substi carbamoyl, (1-4C) alkylcarbamoyl, di-((1-4C) alkyl) tuted phenyl or an optionally substituted 5- or 40 carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, amino, 6-membered heteroaryl and R is hydrogen or (1-6C) (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-4C)alkyl S(O) alk)yl; -, (wherein q is 0, 1 or 2), carboxy, (1-4C) or R7 is of the formula RCH(R') (CH) - wherein m alkoxycarbonyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C) is 0 or 1, R' is fluoro, cyano, (1-4C)alkoxy, (1-4C) alkanoyl, (1-4C) alkoxy, (1-4C) alkanoylamino, alkylsulfonyl, (1-4C)alkoxycarbonyl or hydroxy, 45 benzoylamino, benzoyl, phenyl (optionally Substituted by up (provided that when m is 0, R is not fluoro or to three substituents selected from halo, (1-4C)alkoxy or hydroxy) and R' is hydrogen or (1-4C)alkyl; wherein cyano), furan, pyrrole, pyrazole, imidazole, triazole, AR is optionally Substituted phenyl, optionally Substi pyrimidine, pyridazine, pyridine, isoxazole, oxazole, tuted phenyl(1-4C)alkyl, optionally substituted 5- or isothiazole, thiazole tiophene, hydroxyimino(1-4C)alkyl, 6-membered heteroaryl, optionally Substituted naph 50 (1-4C) alkoxyimino(1-4C)alkyl, hydroxy-(1-4C) alkyl, thyl or an optionally substituted 5/6 or 6/6 bicyclic halo-(1-4C) alkyl, nitro(1-4C)alkyl, amino(1-4C)alkyl, heteroaryl ring System, in which the bicyclic heteroaryl cyano (1-4C) alkyl, (1-4C) alkane Sulfonamido, ring Systems may be linked via an atom in either of the aminosulfonyl, (1-4C)alkylaminosulfonyl and di-((1-4C) rings comprising the bicyclic System, and wherein the alkyl)aminosulfonyl. The phenyl and naphthyl groups and mono- and bicyclic heteroaryl ring Systems are linked 55 heteroaryl (mono- or bicyclic) rings in R', R and AR may via a ring carbon atom; be mono- or disubstituted on ring carbon atoms with Sub wherein CY is a 4-, 5- or 6-membered cycloalkyl ring, a stituents independently selected from the above list of 5- or 6-membered cycloalkenyl ring, naphthoxy, particular optional Substituents. thiophen-2-yl, indol-1-yl, indol-3-yl, pyrimidin-2- Particular optional Substituents for ring nitrogen atoms ylthio, 1,4-benzodioxan-6-yl, Sulfolan-3-yl, pyridin-2- 60 when R is tetrazole, in heteroaryl groups in R', R', R and yl; wherein any of the afore-mentioned ring Systems in AR, and in the nitrogen-containing rings in CY, which can CY may be optionally substituted by up to three Sub be Substituted without becoming quaternised include (1-4C) Stituents independently selected from halo, (1-4C)alkyl alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkanoyl. (including geminal disubstitution when CY is a Examples of halo groups include fluoro, chloro and cycloalkyl or cycloalkenyl ring), acyl, oxo and nitro 65 bromo; examples of (1-4C)alkyl, include methyl, ethyl, and (1-4C)alkyl, and pharmaceutically-acceptable Salts propyl and isopropyl; examples of (1-6C)alkyl include thereof; except that methyl, ethyl, propyl, isopropyl, pentyl and hexyl, examples 5,981528 S 6 of (1-10C)alkyl include methyl, ethyl, propyl, isopropyl, examples of phenyl(1-4C)alkyl include benzyl and phen pentyl, hexyl, heptyl, octyl and nonyl; examples of (1-4C) ethyl; examples of phenylS(O), wherein q is 0, 1 or 2 are alkylamino include methylamino, ethylamino and propy phenylthio, phenylsulfinyl and phenylsulfonyl respectively; lamino; examples of di-((1-4C) alkyl)amino include examples of (1-4C)alkylcarbamoyl include methylcarbar dimethylamino, N-ethyl-N-methylamino, diethylamino, 5 noyl and ethylcarbamoyl; examples of di((1-4C)alkyl) N-methyl-N-propylamino and dipropylamino; examples of carbamoyl include di(methyl)carbarnoyl and di(ethyl) (1-4C)alkylS(O)- wherein q is 0, 1 or 2 include carbamoyl; examples of a (3-4C) alkylene chain are methylthio, ethylthio, methylsulfinyl, ethylsulfmyl, methyl trimethylene or tetramethylene. examples of (2–4C)alkenyl include allyl and vinyl; examples of (2-4C)alkynyl include sulfonyl and ethylsulfonyl; examples of (1-4C) ethynyl and 2-propynyl; examples of (1-4C)alkanoyl alkaneSulfonyloxy include methylsulfonyloxy, ethylsulfony include formyl, acetyl and propionyl, examples of loxy and propylsulfonyloxy; examples of (1-4C)alkylthio hydroxyimino(1-4C)alkyl include hydroxyiminomethyl, include methylthio and ethylthio; examples of (1-4C) 2-(hydroxyimino)ethyl and 1-(hydroxyimino)ethyl; alkylsulfonyl include methylsulfonyl and ethylsulfonyl; examples of (1-4C)alkoxyimino-(1-4C) alkyl include examples of (1-4C)alkylaminocarbonyloxy include methy methoxy imi no methyl, ethoxy imi no methyl, laminocarbonyloxy and ethylaminocarbonyloxy; examples 15 1-(methoxyimino)ethyl and 2-(methoxyimino)ethyl, of (1-4C) alkanoylamino-(1-4C) alkyl include examples of hydroxy(1-4C)alkyl and hydroxy(1-6C)alkyl formamidomethyl, acetamidomethyl and acetamidoethyl, include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl examples of (1-6C)alkoxy-(1-6C) alkyl include and 3-hydroxypropyl; examples of halo(1-4C)alkyl include, methoxymethyl, ethoxymethyl and 2-methoxyethyl; halomethyl, 1-haloethyl, 2-haloethyl, and 3-halopropyl; examples of (1-4C) alkoxy carbonyl include examples of nitro(1-4C) alkyl include nitromethyl, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl, 1-nitroethyl, 2-nitroethyl and 3-nitropropyl; examples of examples of (2-4C)alkanoyloxy include acetyloxy and pro amino(1-4C)alkyl include aminomethyl, 1-aminoethyl, pionyloxy; examples of (1-4C)alkoxy include methoxy, 2-aminoethyl and 3-aminopropyl; examples of cyano(1-4C) ethoxy and propoxy; examples of (1-6C)alkoxy include alkyl include cyanomethyl, 1-cyanoethyl, 2-cyanoethyl and methoxy, ethoxy, propoxy and pentoxy, examples of 25 3-cyanopropyl; examples of (1-4C)alkanesulfonamido hydroxy-(2-6C)alkoxy include 2-hydroxyethoxy and include methaneSulfonamido and ethaneSulfonamido; 3-hydroxypropoxy; examples of (1-4C)alkylamino-(2-6C) examples of (1-4C)alkylaminosulfonyl include methylami alko Xy include 2-methyla mino ethoxy and noSulfonyl and ethylaminoSulfonyl; and examples of di 2-ethylaminoethoxy; examples of di-(1-4C)alkylamino (1-4C)alkylaminosulfonyl include dimethylaminosulfonyl, (2-6C)alkoxy include 2-dimethylaminoethoxy and diethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl. 2-diethylaminoethoxy; examples of (1-4C)alkoxy-(1-4C) Suitable pharmaceutically-acceptable Salts include acid alkoxy and (1-6C)alkoxy-(1-6C)alkoxy include addition Salts. Such as methaneSulfonate, fumarate, methoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy and hydrochloride, hydrobromide, citrate, maleate and Salts 3-methoxypropoxy; examples of (1-4C)alkoxy-(1-4C) formed with phosphoric and Sulfuric acid. In another aspect alkoxy-(1-4C)alkoxy include 2-(methoxymethoxy)ethoxy, 35 Suitable Salts are base SaltS Such as an alkali metal Salt for 2-(2-methoxyethoxy)ethoxy, 3-(2-methoxyethoxy)propoxy example Sodium, an alkaline earth metal Salt for example and 2-(2-ethoxyethoxy)ethoxy; examples of (1-4C) calcium or magnesium, an organic amine Salt for example alkanoylamino and (1-6C) alkanoylamino include triethylamine, morpholine, N-methylpipe ridine, formamido, acetamido and propionylamino; examples of N-ethylpipe ridine, procaine, dibenzylamine, N,N- (1-4C)alkoxycarbonylamino include methoxycarbony 40 dibenzylethylamine or amino acids for example lysine. lamino and ethoxycarbonylamino; examples of N-(1-4C) There may be more than one cation or anion depending on alkyl-N-(2-6C)alkanoylamino include N-methylacetamido, the number of charged functions and the Valency of the N-ethylacetamido and N-methylpropionamido; examples of cations or anions. A preferred pharmaceutically-acceptable (1-4C)alkylS(O)NH- wherein p is 1 or 2 include Salt is the Sodium Salt. methylsulfinylamino, methylsulfonylamino, ethylsulfiny 45 However, to facilitate isolation of the salt during lamino and ethylsulfonylamino; examples of (1-4C)alkylS preparation, Salts which are leSS Soluble in the chosen (O)(1-4C)alkyl)NH- wherein p is 1 or 2 include Solvent may be preferred whether pharmaceutically methylsulfinylmethylamino, methylsulfonylmethylamino, acceptable or not. 2-(ethylsulfinyl)ethylamino and 2-(ethylsulfonyl) The compounds of the formula (I) may be administered in ethylamino; examples of fluoro(1-4C)alkylS(O)NH 50 the form of a pro-drug which is broken down in the human wherein p is 1 or 2 include trifluoromethylsulfmylamino and or animal body to give a compound of the formula (I). trifluoromethylsulfonylamino; examples of fluoro(1-4C) Examples of pro-drugs include in-vivo hydrolysable esters alkylS(O)((1-4C)alkyl)NH- wherein p is 1 or 2 include of a compound of the formula (I). trifluoromethylsulfinylmethylamino and trifluoromethylsul An in-vivo hydrolysable ester of a compound of the fonylmethylamino examples of (1-4C)alkoxy(hydroxy) 55 formula (I) containing carboxy or hydroxy group is, for phosphoryl include methoxy (hydroxy)phosphoryl and example, a pharmaceutically-acceptable ester which is ethoxy(hydroxy)phosphoryl; examples of di-(1-4C) hydrolysed in the human or animal body to produce the alkoxyphosphoryl include di-methoxyphosphoryl, parent acid or alcohol. Suitable pharmaceutically-acceptable di-ethoxyphosphoryl and ethoxy(methoxy)phosphoryl; esters for carboxy include (1-6C)alkoxymethyl esters for examples of 2-((1-4C)alkoxycarbonyl)ethenyl include 60 example methoxyrnethyl, (1-6C)alkanoyloxymethyl esters 2-(methoxycarbonyl)ethenyl and 2-(ethoxycarbonyl) for example pivaloyloxymethyl, phthalidyl esters, (3-8C) ethenyl; examples of 2-cyano-2-((1-4C) alkyl)ethenyl cycloalkoxycarbonyloxy(1-6C)alkyl esters for example include 2-cyano-2-methyle the nyl and 2-cyano-2- 1-cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2-onylmethyl ethylethenyl; examples of 2-((1-4C)alkylaminocarbonyl) esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; ethenyl include 2-(methylaminocarbonyl)ethenyl and 65 and (1-6C)alkoxycarbonyloxyethyl esters for example 2-(ethylaminocarbonyl)ethenyl; examples of benzyloxy 1-methoxycarbonyloxyethyl and may be formed at any (1-4C)alkyl include benzyloxymethyl and benzyloxyethyl; carboxy group in the compounds of this invention. 5,981528 7 8 An in-vivo hydrolysable ester of a compound of the when D is O, R" and R are independently hydrogen, formula (I) containing a hydroxy group includes inorganic hydroxy, bromo, oxo (=O), (1-4C)alkyl, carboxy, esterS Such as phosphate esters and C-acyloxyalkyl ethers (1-4C)alkoxycarbonyl or independently as defined for and related compounds which as a result of the in-vivo R7 hereinbelow; hydrolysis of the ester breakdown to give the parent hydroxy when D is S, SO, SO or NR", R' and Rare indepen group. Examples of C-acyloxyalkyl ethers include dently hydrogen, oxo (=O), (1-4C)alkyl, carboxy, acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A (1-4C)alkcoxycarbonyl or independently as defined for Selection of in-vivo hydrolysable ester forming groups for R7 hereinbelow; hydroxy include alkanoyl, benzoyl, phenylacetyl and Sub R is hydrogen, (1-4C)alkyl, hydroxy, (1-4C)alkoxy or Stituted benzoyl and phenylacetyl, alkoxycarbonyl (to give (2-4C)alkanoyloxy; alkyl carbonate esters), dialkylcarbamoyl and 1O N-(dialkylarninoethyl)-N-alkylcarbamoyl (to give >A-B- is of the formula >C=C(R), >CHCHR or carbamates), dialkylaminoacetyl and carboxyacetyl. >C(OH)CHR'- (>represents two single bonds) The compounds of the present invention have a chiral wherein R" is hydrogen or (1-4C)alkyl; centre at the C-5 position of the Oxazolidinone ring. The D is O, S, SO, SO, or NR7; 15 where in R is hydrogen, cyano, 2-((1-4C) pharmaceutically active enantiomer is of the formula: alkoxycarbonyl)ethenyl, 2-(1-4C)alkylaminocarbonyl) ethenyl, optionally Substituted phenyl, optionally Sub (IA) stituted phenyl(1-4C)alkyl, optionally substituted 5- or R 6-membered heteroaryl, optionally Substituted naph thyl or optionally substituted 5/6 or 6/6 bicyclic het eroaryl ring System wherein the heteroaryl ring Systems N &H R1 are joined to the the nitrogen by a ring carbon atom; or R7 is of the formula R'CO- or R'SO wherein R' is (1-4C)alkoxycarbonyl, amino, (1-4C) 25 alkylamino, di((1-4C) alkyl)amino or (1-6C) alkyl The present invention includes the pure enantiomer wherein (1-6C)alkyl is optionally substituted by depicted above or mixtures of the 5R and 5S enantiomers, hydroxy, cyano, amino, (1-4C)alkoxy, (1-4C)alkanoyl, for example a racemic mixture. If a mixture of enantiomers (1-4C) alkylamino, di((1-4C)alkyl)amino, (2-6C) is used, a larger amount (depending upon the ratio of the alkanoylamino, N-(1-4C) alkyl-N-(2-6C) enantiomers) will be required to achieve the same effect as alkanoylamino, (1-4C)alkylS(O)NH-, (1-4C)alkylS the same weight of the pharmaceutically active enantiomer. (O)((1-4C) alkyl)N-, phosphono, (1-4C)alkoxy For the avoidance of doubt the enantiomer depicted above (hydroxy)phoryl, di-(1-4C) alkoxyphosphoryl or could be either 5R or 5S depending upon the value of R". For (1-4C)alkylS(O), wherein p is 1 or 2 and q is 0, 1 or example, when R' is acetamido, the enantiomer depicted 2); above is the 5S enantiomer and when R' is hydroxy, the 35 or R' is of the formula RC(O)O(1-6C)alkyl wherein enantiomer depicted above is the 5R enantiomer. R'' is optionally substituted 5- or 6-membered Furthermore, Some compounds of the formula (I) may heteroaryl, optionally Substututed phenyl or optionally have other chiral centres, and Some compounds of the Substituted (1-6C)alkyl; formula (I) may exist as one or more regioisomers. It is to 40 or R' is of the formula R'O– wherein R' is optionally be understood that the invention encompasses all Such Substituted (1-6C)alkyl; optical, diastereo- and regio-isomers that possess antibacte or R7 is of the formula ROC(R)=CH(C=O)-, RC rial activity. (=O)C(=O)-, R=N=C(R)C(=O)– or RNHC(R) The invention relates to all tautomeric forms of the =CHC(=O)— wherein R is (1-6C)alkyl, R is compounds of the formula (I) that possess antibacterial hydrogen or (1-6C)alkyl or R and R together form a activity. 45 (3-4C)alkylene chain, R is hydrogen, (1-6C)alkyl, It is also to be understood that certain compounds of the hydroxy(1-6C)alkyl, (1-6C)alkoxy(1-6C) alkyl, formula (I) can exist in Solvated as well as unsolvated forms amino, (1-4C) alkylamino, di-(1-4C) alkylamino, Such as, for example, hydrated forms. It is to be understood (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, hydroxy that the invention encompasses all Such Solvated forms 50 (2-6C)alkoxy, (1-4C)alkylamino(2-6C)alkoxy, di which possess antibacterial activity. (1-4C)alkylamino(2-6C)alkoxy, R is (1-6C)alkyl, In a preferred aspect of the invention there is provided a hydroxy or (1-6C)alkyl, R' is hydrogen or (1-6C) compound of the formula (I) as defined above, except that in alkyl, R is (1-6C)alkyl, phenyl or a 5- or 6-membered the defmition of R and R, neither R' nor R can be oxo heteroaryl and R is hydrogen or (1-6C)alkyl; (=O). 55 or R7 is of the formula RCH(R') (CH-)- wherein m In another aspect the present invention provides a com is 0 or 1, R' is fluoro, cyano, (1-4C)alkoxy, (1-4C) pound of the formula (I) wherein: alkylsulfonyl, (1-4C)alkoxycarbonyl or hydroxy; R" is hydroxy, chloro, fluoro, (1-4C)alkanesulfonyloxy, (provided that when m is 0, R is not fluoro or amino, azido, (1-4C)alkoxy, (1-4C)alkylthio, (1-4C) hydroxy) and R' is hydrogen or (1-4C)alkyl; alkylaminocarbonyloxy, or of the formula -NHC 60 and pharmaceutically-acceptable Salts thereof; except that (=O)R’ wherein R is hydrogen, (1-4C)alkoxy, N-((5S)-3-(4-(2-oxo-5,6-dihydropyran-4-yl)phenyl)-2- amino, chloromethyl, dichloromethyl, cyanomethyl, OXooxazolidin-5-ylmethyl)acetamide; methoxymethyl, acetylmethyl, methylamino, dimethy N-((5S)-3-(3-ethyl-4-(2-oxo-5,6-dihydrothiapyran-4-yl) lamino or (1-4C)alkyl; phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide and or R' is of the formula-NHS(O)(1-4C)alkyl wherein n 65 N-(5S)-3-(3-hydroxy-4-(2-oxo-1,2,5,6- is 0, 1 or 2; tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5- R° and R are independently hydrogen or fluoro; ylmethyl)acetamide are excluded. 5,981528 9 10 In a preferred aspect of the invention there is provided a acceptable salts thereof, wherein the substituents A, B, D, R' compound of the formula (I) as defined above in the section to R'' and other optional substituents mentioned above have relating to another aspect of the present invention, except the values disclosed hereinbefore, or any of the following that R" is hydrogen (rather than hydrogen or (1-4C)alkyl). values: In another preferred aspect of the invention there is 5 (a) Preferably R' is hydroxy, chloro, fluoro, provided a compound of the formula (I) as defined above in methaneSulfonyloxy, amino, azido, methoxy, methylthio, the Section relating to another aspect of the present methylaminocarbonyloxy, or of the formula -NHC invention, except that in the definition of R' and R, neither (=O)R" wherein R" is hydrogen, methoxy, amino, R" nor R can be oxo (=O). chloromethyl, dichloromethyl, cyano methyl, In a further aspect the present invention provides a methoxymethyl, acetylmethyl, methylamino, dimethy compound of the formula (I) wherein: lamino or (1-4C)alkyl or R' is of the formula-NHS(O) R" is of the formula-NHC(=O)(1-4C)alkyl or -NHS (1-4C)alkyl wherein n is 0, 1 or 2. (O),(1-4C)alkyl wherein n is 0, 1 or 2; (b) More preferably R' is hydroxy, chloro, fluoro, R° and R are independently hydrogen or fluoro; methanesulfonyloxy, or of the formula -NHC(=O)R" R" and R are independently hydrogen, or methyl; 15 wherein R is hydrogen, methoxy, amino, chloromethyl, >A-B- is of the formula >C=CH, >CHCH, or >C(OH) dichloromethyl, cyanomethyl, methoxymethyl, acetylm CH- (>represents two Single bonds) ethyl or (1-4C)alkyl or R' is of the formula -NHS(O) wherein R" is hydrogen or (1-4C)alkyl; (1-4C)alkyl wherein n is 0, 1 or 2. D is O, S, SO, SO or NR7; (c) Yet more preferably R' is hydroxy, or of the formula wherein R is hydrogen, optionally Substituted phenyl, -NHC(=O)R" wherein R is (1-4C)alkyl or R' is of the optionally Substituted phenyl(1-4C)alkyl, optionally formula -NHS(O)(1-4C)alkyl wherein n is 0, 1 or 2. Substituted 5- or 6-membered heteroaryl, optionally (d) Yet more preferably R' is of the formula –NHC(=O) Substituted naphthyl or optionally substituted 5/6 or 6/6 (1-4C)alkyl or -NHS(O)(1-4C)alkyl. bicyclic heteroaryl ring System wherein the heteroaryl (e) Yet more preferably R' is of the formula –NHC(=O) 25 (1-4C)alkyl. ring systems are joined to the the nitrogen in NR7 by a (f) Most preferably R' is acetamido. ring carbon atom; (g) In another aspect R is hydroxy. or R7 is of the formula R'CO- or R'SO (h) Preferably, at least one of R and R is hydrogen. wherein R' is amino, (1-4C)alkylamino, di((1-4C)alkyl) (i) Preferably R is hydrogen or (1-4C)alkyl. amino or (1-6C)alkyl wherein (1-6C)alkyl is option (j) Most preferably one of R and R is hydrogen and the ally Substituted by hydroxy, cyano, amino, or (1-4C) other is fluoro. alkylS(O), wherein q is 1 or 2); (k) Preferably >A-B- is of the formula >C=CH- or or R' is of the formula RC(O)O(1-6C)alkyl wherein >CHCH-. R'' is optionally substituted 5- or 6-membered (1) Most preferably >A-B- is of the formula >C=CH-. heteroaryl, optionally Substututed phenyl or optionally 35 (m) Preferably R' and R are independently hydrogen, Substituted (1-6C)alkyl; (1-4C) alkyl, carboxy, (1-4C)alkoxycarbonyl, or R' is of the formula R'-O- wherein R' is optionally hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl. Substituted (1-6C)alkyl; (n) More preferably, R" and Rare independently hydrogen, or R7 is of the formula RCH(R') (CH)— wherein m AR-oxymethyl or AR-thiomethyl. Especially preferred is is 0 or 1, R' is fluoro, cyano, (1-4C)alkoxy, (1-4C) 40 AR when it is optionally substituted phenyl, phenyl alkylsulfonyl, (1-4C)alkoxycarbonyl or hydroxy; (1-4C) alkyl, naphthyl, furan, pyrrole, pyrazole, (provided that when m is 0, R is not fluoro or imidazole, triazole, pyrimidine, pyridazine, pyridine, hydroxy) and R'' is hydrogen or (1-4C)alkyl; isoxazole, oxazole, isothiazole, thiazole or thiophene. and pharmaceutically-acceptable Salts thereof. (o) Most preferably R' or R is hydrogen. In the Sections above relating to another aspect of the 45 (p) Preferably R is hydrogen or (1-4C)alkyl. present invention, and to a further aspect of the present (q) More preferably R is hydrogen or methyl. invention, 5- or 6-membered heteroaryl means a 5- or (r) Most preferably R is hydrogen. 6-membered aryl ring wherein 1, 2 or 3 of the ring atoms are (s) Preferably D is O, S or of the formula NR7. Selected from nitrogen, oxygen and Sufilur. Particular (t) Preferably D is O. examples of Such 5- or 6-membered heteroaryl ring Systems 50 (u) Preferred substituents for phenyl and carbon atoms in are imidazole, triazole, pyrimidine, pyridazine, pyridine, heteroaryl (mono- and bicyclic) ring Systems in R and isoxazole, oxazole, isothiazole, thiazole and thiophene. R' include halo, (1-4C)alkyl, hydroxy, nitro, amino, Also, in the Sections above relating to another aspect of cyano, (1-4C)alkylS(O)- and (1-4C)alkoxy. the present invention, and to a further aspect of the present (v) Preferred optional substituents for (1-6C)alkyl in R'' are invention, a 5/6 or 6/6 bicyclic heteroaryl ring system 55 hydroxy, cyano, amino, (1-4C)alkylamino, di((1-4C) means an aromatic bicyclic ring System comprising a alkyl)amino, (1-4C)alkylS(O), (wherein p is 1 or 2), 6-membered ring fused to either a 5 membered ring or carboxy, (1-4C)alkoxycarbonyl, (1-4C)alkoxy, piper another 6 membered ring, the bicyclic ring System contain aZino or morpholino. ing 1 to 4 heteroatoms Selected from nitrogen, oxygen and (w) Preferred optional substituents for (1-6C)alkyl in R' sulfur. Particular examples of 5/6 and 6/6 bicyclic ring 60 are hydroxy, (1-4C)alkoxy, cyano, amino, (1-4C) Systems are , benzoirnidazole, benzothiophene, alkylamino, di(Calkyl)amino, (1-4C)alkylS(O)— ben ZiSothiazole, ben Zoxazole, ben ZiSoxazole, (wherein p is 1 or 2). pyridoimidazole, pyrimidoimidazole, quinoline, (x) Preferably the ring systems in AR are unsubstituted. quinoxaline, quinazoline, phthalazine, cinnoline and naph (y) Preferably the 5/6 or 6/6 bicyclic ring system in R", R, thyridine. 65 R7 or R' is unsubstituted. Particularly preferred compounds of the invention com (z) Preferably 5- or 6-membered heteroaryl rings in R", R, prise a compound of the formula (I), or pharmaceutically R7, R' or R'' are unsubstituted. 5,981528 11 12 (a1) Preferably 5- or 6-membered heteroaryl in R' is pyridyl or imidazol-1-yl. (IC) (b1) Preferably R' is (1-6C)alkyl. Most preferably R' is R4 R2 O tert-butyl or methyl. (c1) Preferably R' is cyano or fluoro. y (d1) Preferably R'' is hydrogen. R7-N N (e1) Preferably R' is (1-4C)alkoxycarbonyl, hydroxy / \-- R1 (1-4C) alkyl, (1-4C) alkyl, (1-4C) alkylamino, R5 dimethylamino(1-4C)alkyl, (1-4C)alkoxymethyl, (1-4C) 1O alkanoylmethyl, (1-4C)alkanoyloxy(1-4C)alkyl, (1-5C) wherein R' is hydroxy or acetamido; R is hydrogen or alkoxy or 2-cyanoethyl. fluoro; R' and R are independently hydrogen. (f1) More preferably R' is methoxycarbonyl, AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl, hydroxy methyl, methyl, methyla mino, phenyl(1-4C)alkyl, naphthyl, fuliran, pyrrole, pyrazole, dimethylaminomethyl, methoxymethyl, acetoxymethyl, 15 imidazole, triazole, pyrimidine, pyridazine, pyridine, methoxy, methylthio, naphthyl, tert-butoxy or isoxazole, oxazole, isothiazole, thiazole or thiophene), hydroxy, bromo, (1-4C) alkyl, carboxy, (1-4C) 2-cyanoethyl. alkoxycarbonyl, hydroxymethyl, (1-4C)alkoxymethyl or (g1) Preferably R' is hydrogen, cyano, benzyl, pyrimidyl, carbamoyl and R is cyano, pyrimidin-2-yl, tetrazol-5-yl, imidazolyl, triazolyl or of the formula R' CO- or 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl or R7 is of R'SO the formula R'CO- or R'SO - (wherein R' is (h1) Preferably R' is hydrogen, cyano, benzyl, hydrogen, (1-4C)alkyl optionally Substituted by hydroxy, methoxycarbonyl, tert-butoxycarbonyl, hydoxyacetyl, (1-4C)alkoxy, (1-4C) alkylS(O), (1-4C)alkylamino, dimethylaminoacetyl, acetyloxymethylcarbonyl, (1-4C) alkanoyl, naphthoxy, (2-6C)alkanoylamino or methoxyacetyl, methoxalyl, methylcarbamoyl or meth 25 (1-4C)alkylS(O)NH- wherein p is 1 or 2 and q is 0, 1 or aneSulfonyl. 2), phenyl, naphthyl, imidazole, triazole, pyrimidine, (i1) Preferably when R' is benzopyranone it is 4-oxo pyridazine, pyridine, isoxazole, oxazole, isothiazole, benzopyran-2-yl. thiazole, thiophene, benzofuran, benzoimidazole, benzothiophene, be nZiSothiazole, benzo Xa Zole, (1) Preferably CY is naphthoxy, especially naphth-1-oxy or benzisoxazole, pyridoimidazole, pyrimidoimidazole, naphth-2-oxy. quinoline, quinoxaline, quinazoline, phthalazine, cinnoline Therefore, especially preferred compounds of the present or naphthyridine, or R' is of the formula RC(O)O(1-6C) invention are of the formula (IB): alkyl wherein R' is (1-6C)alkyl), or R is of the formula RC(=O)C(=O)— wherein R is (1-6C)alkoxy; and (IB) 35 pharmaceutically-acceptable Salts thereof. Of the above especially preferred compounds of the invention of the formula (IC), particularly preferred com pounds are those wherein R is acetamido; R is hydrogen or fluoro; R' and R are independently hydrogen, 40 AR-oxymethyl or AR-thiomethyl wherein AR is phenyl, phenyl(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole or thiophene, wherein R' is hydroxy or acetamido; R is hydrogen or hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl and R7 45 is cyano, pyrimidin-2-yl, tetrazol-5-yl, 2-cyanoethenyl, fluoro and R' and Rare independently hydrogen, hydroxy, 2-cyano-2-((1-4C)alkyl)ethenyl, or R7 is of the formula bromo, (1-4C) alkyl, carboxy, (1-4C)alkoxycarbonyl, R'CO- or R'SO - (wherein R' is hydrogen, (1-4C) hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl; and alkyl optionally substituted by hydroxy, (1-4C)alkylS(O), pharmaceutically-acceptable Salts thereof. (1-4C)alkanoyl or naphthoxy wherein q is 0, 1 or 2), phenyl, Of the above especially preferred compounds of the 50 naphthyl, imidazole, triazole, pyrimidine, pyridazine, formula (IB), particularly preferred compounds are those pyridine, isoxazole, oxazole, isothiazole, thiazole, wherein R is acetamido; R is hydrogen or fluoro and R' thiophene, benzofuran, benzoimidazole, benzothiophene, and R are independently hydrogen, hydroxy, bromo, be nZ is othiazole, ben Zoxazole, be n ZiSoxazole, (1-4C) alkyl, carboxy, (1-4C) alkoxycarbonyl, pyridoimidazole, pyrimidoimidazole, quinoline, hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl; and 55 quinoxaline, quinazoline, phthalazine, cinnoline or pharmaceutically-acceptable Salts thereof. naphthyridine, or R' is of the formula RC(O)O(1-6C) Further especially preferred compounds of the invention alkyl wherein R' is (1-6C)alkyl), or R is of the formula are of the formula (IB) wherein R is acetamido; R is RC(=O)C(=O)— wherein R is (1-6C)alkoxy; and hydrogen or fluoro and R' and R are independently pharmaceutically-acceptable Salts thereof. 60 Of the above particularly preferred compounds of the hydrogen, AR-oxymethyl or AR-thiomethyl (wherein AR is invention of the formula (IC), especially preferred com phenyl, phenyl(1-4C) alkyl, naphthyl, furan, pyrrole, pounds are those wherein R is acetamido; R is hydrogen pyrazole, imidazole, triazole, pyrimidine, pyridazine, or fluoro; R' and R are hydrogen and R7 is cyano, pyridine, isoxazole, oxazole, isothiazole, thiazole or pyrimidin-2-yl, tetrazol-5-yl, 2-cyanoethenyl, 2-cyano-2- thiophene); and pharmaceutically-acceptable Salts thereof. 65 ((1-4C)alkyl)ethenyl, or R7 is of the formula R'CO- or Further, especially preferred compounds of the invention R'SO - (wherein R' is hydrogen, (1-4C) alkyl are of the formula (IC): optionally substituted by hydroxy, (1-4C)alkylS(O), or 5,981528 13 14 (1-4C)alkanoyl wherein q is 0, 1 or 2), phenyl, naphthyl, or R is of the formula RC(=O)C(=O)— wherein R is imidazole, triazole, pyrimidine, pyridazine, pyridine, (1-6C)alkoxy; and pharmaceutically-acceptable salts isoxazole, oxazole, isothiazole, thiazole, thiophene, thereof. benzofuran, ben Zoimidazole, benzothiophene, Of the above chiefly preferred compounds of the inven ben ZiSothiazole, ben Zoxazole, ben ZiSoxazole, tion of the formula (IC), particular chiefly preferred com pyridoimidazole, pyrimidoimidazole, quinoline, pounds are those wherein R is acetamido; R is hydrogen quinoxaline, quinazoline, phthalazine, cinnoline or or fluoro; R' and Rare hydrogen; and R7 is pyrimidin-2-yl, naphthyridine, or R' is of the formula RC(O)O(1-6C) 2-cyanoethenyl, 2-cyano-2-(1-4C)alkyl)ethenyl, or R is of alkyl wherein R' is (1-6C)alkyl), or R7 is of the formula the formula R'SO - (wherein R' is hydrogen or (1-4C) RC(=O)C(=O)— wherein R is (1-6C)alkoxy; and alkyl optionally substituted by hydroxy or (1-4C)alkylS pharmaceutically-acceptable Salts thereof. (O), wherein q is 0, 1 or 2), or R' is of the formula Of the above particularly preferred compounds of the R'C(O)O(1-6C)alkyl wherein R'' is (1-6C)alkyl), or R7 is invention of the formula (IC), further especially preferred of the formula RC(=O)C(=O)— wherein R is (1-6C) compounds are those wherein R is acetamido; R is hydro alkoxy; and pharmaceutically-acceptable Salts thereof. gen or fluoro; R' and R5 are independently hydrogen, 15 Of the above particular especially preferred compounds of AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl, the invention of the formula (IC), the most preferred are phenyl(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole, those wherein R' is acetamido; R is hydrogen or fluoro; R' imidazole, triazole, pyrimidine, pyridazine, pyridine, and R are hydrogen; and R7 is pyrimidin-2-yl, or R7 is of isoxazole, oxazole, isothiazole, thiazole or thiophene), the formula R'CO- (wherein R' is hydrogen or (1-4C) hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl and R' alkyl optionally substituted by hydroxy or (1-4C)alkylS is cyano, pyrimidin-2-yl, tetrazol-5-yl, 2-cyanoethenyl, (O), wherein q is 0, 1 or 2), or R" is of the formula 2-cyano-2-((1-4C)alkyl)ethenyl, or R is of the formula R'(O)O(1-6C)alkyl wherein R' is (1-6C)alkyl), or R7 is R'CO-(wherein R' is hydrogen, (1-4C)alkyloptionally of the formula RC(=O)C(=O)— wherein R is (1-6C) substituted by hydroxy, (1-4C) alkylS(O), or (1-4C) alkoxy; and pharmaceutically-acceptable Salts thereof. alkanoyl wherein q is 0, 1 or 2), phenyl, naphthyl, imidazole, 25 Of the above particular chiefly preferred compounds of triazole, pyrimidine, pyridazine, pyridine, isoxazole, the invention of the formula (IC), the most preferred are oxazole, isothiazole, thiazole, thiophene, benzofuran, those wherein R' is acetamido; R is hydrogen or fluoro; R' ben Zoimidazole, benzothiophene, ben ZiSothiazole, and R are hydrogen; and R7 is pyrimidin-2-yl, or R7 is of be n Zoxazole, ben ZiSoxazole, pyridoimidazole, the formula R'SO-- (wherein R" is hydrogen or (1-4C) pyrimidoimidazole, quinoline, quinoxaline, quinazoline, alkyl optionally substituted by hydroxy or (1-4C)alkylS phthalazine, cinnoline or naphthyridine, or R' is of the (O), wherein q is 0, 1 or 2), or R' is of the formula formula R'(O)O(1-6C)alkyl wherein R'' is (1-6C)alkyl), R'C(O)O(1-6C)alkyl wherein R'' is (1-6C)alkyl), or R7 is or R7 is of the formnula RC(=O)C(=O)- wherein R is of the formula RC(=O)C(=O)- wherein R is (1-6C) (1-6C)alkoxy; and pharmaceutically-acceptable salts alkoxy; and pharmaceutically-acceptable Salts thereof. thereof. 35 Particular compounds of the present invention are: Of the above particularly preferred compounds of the N-((5S)-3-(4-(1-tert but oxycarbonyl-1,2,5,6- invention of the formula (IC), chiefly preferred compounds tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5- are those wherein R' is acetamido; R is hydrogen or fluoro; ylmethyl)acetamide; R" and R are independently hydrogen, AR-oxymethyl or N-((5S)-3-(4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2- AR-thiomethyl (wherein AR is phenyl, phenyl(1-4C)alkyl, 40 OXooxazolidin-5-ylmethyl)acetamide; naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, N-((5S)-3-(4-(1-methoxy carbonyl-1,2,5,6- isothiazole, thiazole or thiophene), hydroxymethyl, (1-4C) tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5- alkoxymethyl or carbamoyl and R is cyano, pyrimidin-2-yl, ylmethyl)acetamide; tetrazol-5-yl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl) 45 N-((5S)-3-(4-(1-methylsulfonyl-1,2,5,6-tetrahydropyrid ethenyl, or R7 is of the formula R'SO - (wherein R' is 4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide; hydrogen, (1-4C)alkyl optionally Substituted by hydroxy, N-((5S)-3-(4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid (1-4C)alkylS(O), or (1-4C)alkanoyl wherein q is 0, 1 or 2), 4-yl)phenyl)2-oxooxazolidin-5-ylmethyl)acetamide; phenyl, naphthyl, imidazole, triazole, pyrimidine, N-((5S)-3-(4-(1-dimethylaminoacetyl-1,2,5,6- pyridazine, pyridine, isoxazole, oxazole, isothiazole, 50 tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5- thiazole, thiophene, benzofuran, benzoimidazole, ylmethyl)acetamide; benzothiophene, ben ZiSothiazole, benzo Xazole, N-((5S)-(4-(2,3-dihydropy ran-4-yl)-phenyl)-2- benzisoxazole, pyridoimidazole, pyrimidoimidazole, OXooxazolidin-5-ylmethyl)acetamide; quinoline, quinoxaline, quinazoline, phthalazine, cinnoline N-((5S)-(4-(2,3-dihydrothiapyran-4-yl)phenyl)-2- or naphthyridine, or R' is of the formula RC(O)O(1-6C) 55 OXooxazolidin-5-ylmethyl)acetamide; alkyl wherein R' is (1-6C)alkyl), or R7 is of the formula N-((5S)-(4-(2,3-dihydrooxothiapyran-4-ylphenyl)-2- RC(=O)C(=O)— wherein R is (1-6C)alkoxy; and OXooxazolidin-5-ylmethyl)acetamide; pharmaceutically-acceptable Salts thereof. N-((5S)-(4-(2,3-dihydrodioxothiapyrany-4-yl)phenyl)-2- Of the above further especially preferred compounds of OXooxazolidin-5-ylmethyl)acetamide; the invention of the formula (IC), particular especially 60 preferred compounds are those wherein R is acetamido; R N-((5S)-3-(3-fluoro-4-(1-benzyl-1,2,5,6-tetrahydropyrid is hydrogen or fluoro; R" and R are hydrogen; and R7 is 4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide; pyrimidin-2-yl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl) N-((5S)-3-(3-fluoro-4-(1,2,5,6-tetrahydropyrid-4-yl) ethenyl, or R7 is of the formula R'CO- (wherein R' is phenyl)-2-oxo-oxazolidin-5-ylmethyl)acetamide; hydrogen or (1-4C)alkyl optionally substituted by hydroxy 65 N-((5S)-3-(3-fluoro-4-(1-tertbutoxycarbonyl-1,2,5,6- or (1-4C)alkylS(O), wherein q is 0, 1 or 2), or R' is of the tetrahydropy rid-4-yl)phenyl)-2-oxo-5- formula RC(O)O(1-6C)alkyl wherein R' is (1-6C)alkyl), Oxazolidinylmethyl)acetamide;

5,981528 17 18 N-((5S)-3-(4-(1-(naphth-2-ylsulfonyl)-1,2,5,6- Examples of hydroxy protecting groups include lower tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5- alkenyl groups (egallyl); lower alkanoyl groups (eg acetyl); ylmethyl)acetamide; lower alkoxycarbonyl groups (eg t-butoxycarbonyl); lower N-((5S)-3-(4-(1-(naphth-2-oxyacetyl)-1,2,5,6- alkenyloxycarbonyl groups (eg allyloxycarbonyl), aryl tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5- lower alkoxycarbonyl groups (eg benzoyloxycarbonyl, ylmethyl)acetamide; p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, N-((5S)-3-(4-(1-(methylthioacetyl)-1,2,5,6- p-nitrobenzyloxycarbonyl); tri lower alkyl/arylsilyl groups tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5- (e.g. trim ethylsily l, t-butyl dimethylsily 1, ylmethyl)acetamide; t-butyldiphenylsilyl); aryl lower alkyl groups (eg benzyl) and pharmaceutically-acceptable Salts thereof. groups; and triaryl lower alkyl groups (eg triphenylmethyl). In a further aspect the present invention provides a Examples of amino protecting groups include formyl, process for preparing a compound of formula (I) or a aralkyl groups (eg benzyl and Substituted benzyl, eg pharmaceutically-acceptable Salt thereof. The compounds of p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, formula (I) may be prepared by deprotecting a compound of and triphenylmethyl), di-p-anisylmethyl and furylmethyl formula (II): groups; lower alkoxycarbonyl (eg t-butoxycarbonyl); lower 15 alkenyloxycarbonyl (eg allyloxycarbonyl), aryl lower (II) alkoxycarbonyl groups (eg benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, trialkylsilyl (eg trimethylsilyl and t-butyldimethylsilyl); alkylidene (eg methylidene); ben Zylidene and Substituted benzylidene groups. Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, metal- or R19 R3 enzymically-catalysed hydrolysis, for groupS. Such as 25 o-nitrobenzyloxycarbonyl, photolytically and for groups wherein R, R and Rare as hereinabove defined, R is R' Such as Sillyl groups, fluoride. or protected R, R is R or protected R, R is R' or Examples of protecting groups for amide groups include protected R', >A1-B1- is >A-B- or protected >A-B- and D1 aralkoxymethyl (eg. benzyloxymethyl and Substituted is D in which functional groups are optionally protected; and benzyloxymethyl); alkoxymethyl (eg. methoxymethyl and thereafter, if necessary, forming a phannaceutically trimethylsilylethoxymethyl); tri alkyl/arylsilyl (e.g. acceptable Salt. trimethylsilyl, t-butyldimethylsily, t-butyldiphenylsilyl); tri Protecting groups may be removed by any convenient alkyl/arylsilyl oxy methyl (e.g. method as described in the literature or known to the skilled t-butyl dimethylsilyl oxy methyl, chemist as appropriate for the removal of the protecting t-butyldiphenylsilyloxymethyl), 4-alkoxyphenyl (e.g. group in question, Such methods being chosen So as to effect 35 4-methoxyphenyl); 2,4-di(alkoxy)phenyl (e.g. 2,4- removal of the protecting group with minimum disturbance dimethoxyphenyl), 4-alkoxybenzyl (eg. 4-methoxybenzyl); of groups elsewhere in the molecule. 2,4-di(alkoxy)benzyl (eg. 2,4-di(methoxy)benzyl); and alk Specific examples of protecting groups are given below 1-enyl (e.g. allyl, but-1-enyl and Substituted vinyl eg. for the sake of convenience, in which “lower” signifies that 2-phenylvinyl). the group to which it is applied preferably has 1-4 carbon 40 Aralkoxymethyl, groups may be introduced onto the atoms. It will be understood that these examples are not amide group by reacting the latter group with the appropriate exhaustive. Where specific examples of methods for the aralkoxymethyl chloride, and removed by catalytic hydro removal of protecting groups are given below these are genation. Alkoxymethyl, trialkyl/arylsilyl and trialkyl/silyl Similarly not exhaustive. The use of protecting groups and groups may be introduced by reacting the amide with the methods of deprotection not specifically mentioned is of 45 appropriate chloride and removing with acid, or in the case course within the Scope of the invention. of the Sillyl containing groups fluoride ions. The alkoxyphe A carboxy protecting group may be the residue of an nyl and alkoxybenzyl groups are conveniently introduced by ester-forming aliphatic or araliphatic alcohol or of an ester arylation or alkylation with an appropriate halide and forming silanol (the said alcohol or Silanol preferably con removed by oxidation with ceric ammonium nitrate. Finally taining 1-20 carbon atoms). 50 alk-1-enyl groups may be introduced by reacting the amide Examples of carboxy protecting groups include Straight or with the appropriate aldehyde and removed with acid. branched chain (1-12C)alkyl groups (eg isopropyl, t-butyl); For further examples of protecting groupS. See one of the lower alkoxy lower alkyl groups (eg methoxymethyl, many general texts on the Subject, for example, Protective ethoxymethyl, isobutoxymethyl, lower aliphatic acyloxy Groups in Organic Synthesis by Theodora Green (publisher: lower alkyl groups, (e.g. a c e to Xy methyl, 55 John Wiley & Sons). pro pionyl oxy methyl, butyryl oxy methyl, In another aspect of the present invention the compounds pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl of the formulae (I) and (II) and pharmaceutically-acceptable group S (eg 1-methoxy carbonyl oxyethyl, Salts thereof can be prepared: 1-ethoxycarbonyloxyethyl), aryl lower alkyl groups (eg (a) by modifying a Substituent in or introducing a Sub p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl 60 stituent into another compound of formula (I) or (II); and phthalidyl); tri(lower alkyl)silyl groups (eg trimethylsi (b) when R or R is of the formula –NHS(O),(1-4C) lyl and t-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl, wherein n is 1 or 2, by oxidising a compound of alkyl groups (eg trimethylsilylethyl); and (2–6C)alkenyl the formula (I) or (II) wherein n is 0 or, when n is 2 by groups (eg allyl and Vinylethyl). oxidising a compound of the formula (I) or (II) wherein Methods particularly appropriate for the removal of car 65 n is 1, boxyl protecting groups include for example acid-, metal- or (c) when R or R is of the formula –NHC(=O)R’ or enzymically-catalysed hydrolysis. NHS(O),(1-4C)alkyl, introducing the group -C(=O) 5,981528 19 20 R or -S(O),(1-4C)alkyl into a compound of the formula (III); (IX)

(III)

D1 At N R19 Ral R25 s B1 NH2 1O (h) when D is NR7 and R7 is R'CO- or R'S(O), , wherein n is 2, by reaction of a compound of formula (X) with a compound of the formula (XI) or (XII), (d) when R' or R is hydroxy, by reacting a compound wherein n is 2: of the formula (V) with a compound of formula (VI): 15 (X) (V) R18 R6 R2 O R18 R6 R2 ) ( y ) ( 2O NH A1 N H 21 D1 A1 N OR / R20 / B1 B1 R19 R3 R19 R3 O 25 (XI) (VI) R10COL2 O (XII) (N- R22 RSOL2 O (i) when R' or R is azido, by reacting a compound of the formula (XIII) with a source of azide: e) when >A1-B1- is >C=CR'-, by reacting a com (XIII) pound of the formula (VII) with a ompound of the 35 R18 R6 R2 O formula (VIII): )-( y D1 A1 N (VII) /

R19 R3 R26

(j) when R' or R' is amino, by reducing a compound of R3 45 the formula (I) or (II) wherein R' or R' is azido; (k) when R' or R' is chloro, fluoro, (1-4C) (VIII) alkanesulfonyloxy, or (1-4C)alkylaminocarbonyloxy, R18 R6 or R' is of the formula-N(COR)CO(1-4C)alkyl; from a compound of the formula (I) and (II) wherein R' 50 or R is hydroxy; or D1 / L1 (l) when R' or R' is chloro, (1-4C)alkylthio or (1-4C) alkoxy, from a compound of the formula (XIII); R19 Ral wherein R, R, R and R'' are as hereinabove defined; R' is R' or protected R'; R is (1-6C)alkyl or benzyl; 55 R’ is of the formula (1-4C)alkyl or -S(O),(1-4C) (f) when >A1-B1- is >CHCH(R')-, by catalytic hydro alkyl; R is (1-4C)alkyl, R' is an optionally substi genation of a compound of the formula (I) or (II) tuted phenyl group; R is hydrogen, -COR or wherein >A1-B1- is >C=CR'-; -SOR"; R is mesyloxy or tosyloxy; R7 is (1-4C) alkyl or benzyl; n is 0, 1 or 2 unless otherwise stated (g) when >A1-B 1- is >C=CR'-, by elimination of the 60 above; L' is an iodo or triflate leaving group; L is a elements of water, or HOCOR, or HOSOR" from leaving group, Such as, for example, hydroxy or chloro; a compound of the formula (IX) (ie. when R is -H, and Y is a trialkyltin residue or a boronate acid or ester –COR or – SOR"). residue, 65 5,981528 21 22 and thereafter if necessary: i) removing any protecting romethane or THF, in the presence of an organic base Such groups, as triethylamine and in a temperature range of 0° C. to ii) forming a pharmaceutically-acceptable salt. ambient temperature, or the amino compound may be Methods for converting substituents into other substitu reacted with the appropriate acid in the presence of 1-(3- ents are known in the art. For example an alkyithio group dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride may be oxidised to an alkylsulfinyl or alkySulfonyl group, a and an organic base Such as triethylamine, in an organic cyano group reduced to an amino group, a nitro group Solvent Such as dichloromethane, in a temperature range of reduced to an amino group, a hydroxy group alkylated to a O C. to ambient temperature. methoxy group, a hydroxy group thiomethylated to an When R is methylamino, the -CONHMe group may be arylthiomethyl or a heteroarylthiomethyl group (see, for introduced into the compound of the formula (III) by react example, Tet. Lett., 585, 1972), a carbonyl group converted ing the latter compound with methyl isocyanate in an to a thiocarbonyl group (e.g. using LawSSons reagent) or a organic Solvent Such as THF or acetonitrile, in a temperature bromo group converted to an alkylthio group. range of O C. to ambient temperature. Compounds of the formula (I) or (II) wherein R' or R' When R is dimethylamino, the -CONMe group may be is -NHS(O), (1-4C)alkyl can be prepared by oxidising a introduced into the compound by of the formula (III) by compound of the formula (I) or (II) with Standard reagents 15 reacting the latter compound with dimethylcarbamoyl chlo known in the art for the oxidation of a thio group to a Sulfinyl ride and triethylamine in an organic Solvent Such as THF or or Sulfonyl group. For example, a thio group may be acetonitrile, in a temperature range of 0° C. to ambient oxidised to a Sulfinyl group with a peracid Such as temperature. m-chloroperoxybenzoic acid and oxidising agents Such as Standard reaction conditions for the conversion of a potassium permanganate can be used to convert a thio group compound of the formula (III) to a compound of the formula to a sulfonyl group. Compounds of the formula (I) or (II) (I) or (II) wherein R or R' is sulfonamido are known in the wherein R' or R” is -NHS(1-4C)alkyl can be prepared by art. For example, a compound of the formula (III) could be reacting compounds of the formula (III) with a reagent Such converted to a compound of the formula (I) or (II) wherein as (1-4C)alkylSC1. R' or R' is (1-4C)alkylSONH- by reacting the former When R is (1-4C)alkyl, the group -C(=O)(1-4C)alkyl 25 compound with a Sulfonyl chloride, for example, meSyl may be introduced into a compound of the formula (III) by chloride, in a mild base Such as pyridine or triethylamine. Standard acetylation procedures. For example. the amino Alternatively compounds of the formula (I) or (II) group may be acetylated to give an acetamido group using wherein R' or R' is (1-4C)alkylSONH- or (1-4C) the Schotten-Baumann procedure i.e. reacting the compound alkylSONH- may be prepared by reacting a compound of of the formula (I) or (II) wherein R or R is amino with the formula (III) with a compound of the formula (IV): acetic anhydride in aqueous Sodium hydroxide and THF in a temperature range of 0° C. to ambient temperature. Pref (IV) erably the acylation is carried out in situ following the catalytic hydrogenation of a compound of the formula (I) or (II) wherein R' or R' (is azido, by performing the hydro 35 genation in the presence of acetic anhydride. When R is hydrogen, the -CHO group may be intro duced into the compound of the formula (III) by reacting the O latter compound with formic acetic anhydride, in an inert organic Solvent Such as THF, in a temperature range of 0° C. 40 The compound of the formula (IV) may be prepared by to ambient temperature, or by reacting it with ethyl formate oxidising a compound of the formula (IVA): in an inert organic Solvent in the temperature range of 50-100° C. When R is (1-4C)alkoxy, the -COO(1-4C)alkyl group (IVA) may be introduced into the compound of the formula (III) by 45 reacting the latter compound with (1-4C) alkyl chloroformate, in the presence of an organic base Such as triethylamine, in an organic Solvent Such as dichloromethane and in a temperature range of O C. to ambient temperature. When R is amino, the -CONH group may be intro 50 duced into the compound of the formula (III) by reacting the latter compound either with potassium cyanate in aqueous with Standard oxidising agents known for the conversion of acid (eg hydrochloric acid) in a temperature range of ambi a thio group to a Sulfmyl or Sulfonyl group. ent temperature to 40 C. or with phenyl carbamate in glyme Compounds of the formula (IVA) can be prepared by at reflux. 55 reacting phthalimide with an alkylthiochloride (1-4C) When R is chloromethyl, dichloromethyl, cyanomethyl alkylSCI). or methoxymethyl, the -C(=O)R group may be intro A compound of the formula (III) may be prepared as duced into the compound of the formula (III) by reacting the described in process (). latter compound with the appropriate acid chloride under Compounds of the formulae (V) and (VI) are conve Standard conditions. The acid chloride may be prepared from 60 niently reacted together in the presence of a strong base Such the appropriate acid. When R is acetylmethyl, the as butyl lithium, lithium hexamethyldisilazide, sodium -C(=O)R group may be introduced into the amino com hydride, or lithium diisopropylamide. The reaction is con pound by reacting the latter compound with diketene, in an Veniently carried out in an inert Solvent Such as tetrahydro inert organic Solvent Such as THF, in a temperature range of furan (THF), dimethylformamide (DMF), N,N'- O C. to ambient temperature. 65 dimethylpropyleneurea (DMPU) Alternatively, the compound of the formula (III) may be or N-methylpyrrolidone in a temperature range of -78 C. to reacted with the appropriate acid anhydride, in dichlo -50 C. for the deprotonation and cyclisation. Suitable 5,981528 23 24 values for R' include ethyl, butyl and benzyl and suitable heated to 80 C. Alternatively, silver oxide may be used in values for R’ include ethyl and n-propyl, preferably place of the base, in which case the reaction may be carried n-propyl. out at a lower temperature. When Y is a boronate ester, A compound of the formula (V) is conveniently prepared preferably L' is iodo. Suitable boronate esters include lower by reacting a chloroformate of the formula (ClCOOR) alkyl and cyclic boronate esters. with a compound of the formula (VA): A compound of the formula (VII) wherein Y is trimeth ylstannyl may be prepared by methods known in the art (for (VA) example by using methods similar to those described in R18 R6 R 2 Patent Application No. WO 9413649 from a compound of the formula (VII) wherein Y is iodo or bromo). Alternatively compounds of the formula (VII) wherein Y is a cyclic D1 A1 boronate ester as in (VIIA): / B1 (VIIA) R19 15 R2 O wherein R-R and >A1-B1- are as hereinabove defined. R y The reaction is conveniently carried out in the presence of an B N inorganic or organic base Such as Sodium bicarbonate or an amine base Such as dimethylaniline, the former in a Solvent c/ \-- R20 Such as acetone/water and the latter in an organic Solvent R3 Such as THF, toluene, DMF or acetonitrile. A compound of the formula (VA) wherein >A1-B1- is may be prepared from a compound of the formula (VII) >C=CH-, may be prepared by reacting a compound of the wherein Y is iodo or bromo, by sequential treatment with a formula (VIII) with a compound of the formula (VB). 25 Suitable Pd catalyst Such as PdCl(dppf), potassium acetate and the pinacol ester of diboron in a polar Solvent Such as (VB) DMSO (for example see J.Org. Chem., 1995, 60, 7508–7510). A compound of the formula (VII), wherein Y is iodo may be prepared by reacting a compound of the formula (VIIB) with iodine monochloride in the presence of trifluoroacetic acid or with iodine and silver triflate:

(VIIB) 35 The reaction between compounds of the formulae (VIII) and (VB) wherein L is bromo or iodo may be is carried out by treating (VB) with an organolithium species Such as 1-butyl methyl in an inert solvent such as THF at a low temperature, such as -78. C., followed by the addition of an 40 anhydrous Zinc halide Such as Zinc chloride, in a temperature range of 0° C. to ambient temperature, to generate the organozinc chloride (VB), wherein L' is ZnCl. Treatment of When Y is bromo, a compound of the formula (VII) may the organozinc chloride in Situ with a compound of the be prepared by brominating a compound of the formula formula (VIII) followed by a suitable palladium Ocatalyst 45 (VIIB) using standard bromination methods. For example, such as Pd(PPh3), in the temperature range of 0° C. to by reacting a compound of the formula (VIIB) with ambient temperature, results in the cross-coupled product N-bromosuccinimide or bromine. (VA) after brief treatment with dilute acid to hydrolyse the A compound of the formula (VIIB) may be prepared by Stabase protected amine. forming the oxazolidinone ring from the amino group of a A compound of the formula (VB) may be prepared by 50 treatment of p-iodo or p-bromoaniline with the stabase compound of the formula (VIIC) using a similar method to reagent (1,2-bis(chlorodimethylsilyl)ethane) in the presence that described for the preparation of a compound of the of an organic base Such as triethylamine. formula (I) or (II) from a compound of the formula (VA): The reaction between compounds of the formulae (VII) and (VIII), wherein Y is trialkyltin and L' is triflate is 55 (VIIC) conveniently carried out in the presence of a palladium (O) catalyst such as Pd(PPh3) or Pd(dba) in a temperature range of 0-115 C. Preferably the trialkyltin group is trim ethyltin. A suitable value for L' is iodo or trifluoromethyl Sulfonyloxy. 60 When Y is a boronate acid or ester, the reaction may be carried out under conditions known for the Suzuki reaction i.e. in the presence of a palladium (0) catalyst Such as Pd(PPh)) or Pd(dba), in a water-miscible organic solvent The resulting compound of the formula (VIIB) in which Such as dimethylformamide or 1,2-dimethoxyethane and in 65 R’ is hydroxy may be converted to other compounds of the the presence of a mild base Such as Sodium acetate or Sodium formula (VIIB) using similar methods to those described for bicarbonate which is added in water. The reaction is then the formation of a compound of the formula (I) or (II) from 5,981528 25 26 a compound of the formula (I) or (II) wherein R' or R' is A compound of the formula (I) or (II) wherein >A1-B1 hydroxy, via a compound of the formula (III). is of the formula >CHCH(R')- may be prepared from a A compound of the formula (VIII) wherein D1 is compound of the formula (I) or (II) wherein >A1-B1- is R''CON-, S or O and L' is triflate may be prepared by >C=CR'-, by catalytic hydrogenation, using a suitable treating a compound of the formula (VIIIA) with lithium catalyst Such as palladium-on-carbon in an appropiate inert diisopropylamide in an inert Solvent Such as THF, at a low or acidic Solvent Such as acetic acid. Where an optically temperature, for example -78. C., followed by N-phenyl active form of compounds of the formula (VI) is used in triflamide (for example, see methods described in Synthesis, previous steps, reduction of the >A1-B1- double bond will 993–95 (1991)). produce diastereoisomers which may be separated. Where a particular diastereoisomer is of choice, a chiral asymnietry (VIIIA) inducing catalyst for the reduction can be used. The reaction between a compound of the formula (X) and R18 R6 (XI) or (XII) is conveniently carried out under similar conditions to those described for the acetylation or Sulfo nylation of a compound of the formula (II). D O 15 A compound of the formula (I) or (II) wherein R' or R' is azido may be prepared, for example, by reacting a compound of the formula (XIII) with sodium azide in an R19 Ra1 inert Solvent Such as DMF in a temperature range of ambient to 100° C., normally in the region of 75° C.-85° C. A Alternatively, a compound of the formula (VIII) wherein compound of the formula (XIII) may be prepared by con L' is iodo may be prepared by treating a hydrazone of a verting the hydroxy group in a compound of the formula (I) compound of formula (VIIIA) with iodine in the presence of or (II) wherein R' or R' is hydroxy into a tosyloxy or triethylamine (for example see methods detailed in Tet. meSyloxy group by Standard methods known in the art. For Letts., 24, 1605–1608 (1983)). example, by reacting the compound of the formula (I) or (II) Compounds of the formula (VIII) wherein D1 is R'CH (R')(CH)-N-, aryl-N- or heteroaryl(mono or 25 with tosyl chloride or mesyl chloride in the presence of a bicyclic)-N can be prepared by elaboration of the piperidone mild base Such as triethylamine, or pyridine. ring from the appropiate aryl- or heteroarylamine, by reac Suitable reducing agents for reducing azido to amino in a tion with ethyl acrylate to give the corresponding compound of the formula (I) or (II) include triethylamine/ diethylaiylimino-bb'-dipropionate, which can then be cyc hydrogen Sulfide, triphenylphosphine or phosphite ester, or lised under Diekimann conditions to the give corresponding hydrogen in the presence of a catalyst. More specifically the piperidone b-ketoester, followed by decarboxylation with reduction of the azido group may be carried out by heating heating in acid (see methods described in J.Chem.Soc., it in an aprotic Solvent, Such as 1,2-dimethoxyethane, in the 5110–5118 (1962)). presence of P(OMe) and Subsequently heating in 6N aque Alternatively, a compound of the formula (VIII) wherein ous hydrochloric acid, or reacting it with hydrogen in the D1 is heteroaryl-N- may be prepared by reacting an appro 35 presence of palladium on carbon in a solvent such as DMF piately Substituted heterocycle containing a leaving group or ethyl acetate. For further details on the reduction of azides Such as chloro, bromo or iodo with the appropriate to aminessee U.S. Pat. No. 4,705,799. The azido compound 4-piperidone at an elevated temperature, in an inert Solvent may be reduced and converted to a compound of the formula and optionally with an acid trapping agent. (I) or (II), wherein R' or R' is acetamido, in situ using Suitable catalysts for the catalytic hydrogenation of a 40 acetic anhydride in DMF. compound of the formula (I) or (II) wherein >A1-B1- is A compound of the formula (I) or (II) wherein R' or R' >C=C(R')- include Raney nickel, platinum metal or its is fluoro may be prepared by reacting a compound of the oxide, rhodium, Zinc oxide, palladium-on-charcoal and formula (I) or (II) wherein R' or R' is hydroxy (hydroxy Wilkinson's catalyst (RhCl(Ph-P). Catalyic hydrogenation compound) with a fluorinating agent Such as diethylamino is conveniently carried out in the temperature range 0 C. to 45 Sulfur trifluoride in an organic Solvent Such as dichlo 150 C., but preferably at ambient temperature and pressure, romethane in the temperature range of O C. to ambient unless Wilkinson's catalytic is used in which case a tem temperature. perature of approximately 50° C. and pressure of approxi When R' or R' is chloro, the compound of the formula mately 50 atmospheres are preferable. (I) or (II) may be formed by reacting the hydroxy compound A compound of the formula (IX) may be prepared by 50 with a chlorinating agent. For example, by reacting the reacting an intermediate of the formula (VB) with magne hydroxy compound with thionyl chloride, in a temperature sium to form a Grignard reagent, or alternatively with range of ambient temperature to reflux, optionally in a n-butyl lithium to form a lithiated species (as above), and chlorinated Solvent Such as dichloromethane or by reacting then reacting the Grignard reagent or lithiated Species with the hydroxy compound with carbon tetrachloride/triphenyl a compound of formula (VIIIA). The product (VA), wherein 55 phosphine in dichloromethane, in a temperature range of 0 >A1-B1- is of the formula >C(OH)CH(R)- may then be C. to ambient temperature. elaborated as previously detailed for the compound of the The (1-4C)alkanesulfonyloxy compound may be pre formula (V), but with optional protection of the hydroxyl pared by reacting the hydroxy compound with (1-4C) grOup. alkaneSulfonyl chloride in the presence of a mild base Such The dehydration of a compound of the formula (IX) to 60 as triethylamine or pyridine. give a compound of formula (I) or (II) wherein >A1-B1- is The (1-4C) alkylaminocarbonyloxy compound may be of the formula >C=CR'- may be carried out using agents prepared by reacting the hydroxy compound with (1-4C) Such as polyphosphoric acid, trifluoroacetic acid. trifluoro alkyl cyanate in an organic Solvent Such as THF or acetic anhydride. p-toluenesulfonic acid, Sulfuiric acid, thio acetonitrile, in the presence of triethylamine, in a tempera nyl chloride etc., in an inert Solvent Such as toluene, and at 65 ture range of 0° C. to 50° C. elevated temperatures. Suitable protection of the group R' A compound of the formula (II) wherein R is of the may be necessary as appropriate. formula -N(COR)CO(1-4C)alkyl is conveniently pre 5,981528 27 28 pared by reacting a compound of the formula (I) and (II) parenteral administration. For these purposes the com wherein R' or R' is hydroxy with an amide of the formula pounds of this invention may be formulated by means HN(COR)CO(1-4C)alkyl under Mitsunobu conditions. known in the art into the form of, for example, tablets, For example, in the presence of tri-n-butylphosphine and capsules, aqueous or oily Solutions or Suspensions, (lipid) 1,1'-(aZodicarbonyl)dipiperidine in an organic Solvent Such emulsions, dispersible powders, Suppositories, ointments, as THF, and in the temperature range 0 C-60 C., but creams, drops and Sterile injectable aqueous or oily Solutions preferably at ambient temperature. Details of analogous or Suspensions. Mitsunobu reactions are contained in Tsunoda et al, Tet. In addition to the compounds of the present invention the Letts., 34, 1639, (1993). Amides of the formula pharmaceutical composition of this invention may also HN(COR)CO(1-4C)alkyl may be prepared by standard contain or be co-administered with one or more known procedures of organic chemistry which are within the ordi drugs selected from other clinically useful antibacterial nary skill of an organic chemist. agents (for example f-lactams or aminoglycosides). These A compound of the formula (I) or (II) wherein R' or R' may include penicillins, for example oxacillin or fluclox is chloro may also be prepared from a compound of the acillin and carbapenems, for example meropenem or formula (XIII), by reacting the latter compound with lithium 15 imipenem, to broaden the therapeutic effectiveness against chloride and crown ether, in a Suitable organic Solvent Such methicillin-resistant Staphylococci. Compounds of this as THF, in a temperature range of ambient temperature to invention may also contain or be co-administered with reflux. A compound of the formula (I) or (II) wherein R' or bactericidal/permeability-increasing protein product (BPI) R’ is (1-4C)alkylthio or (1-4C)alkoxy may be prepared by or efflux pump inhibitors to improve activity against gram reacting the compound of the formula (XIII) with sodium negative bacteria and bacteria resistant to antimicrobial thio(1-4C)alkoxide or sodium (1-4C)alkoxide respectively, agents. in an alcohol or THF, in a temperature range of 0° C. to A Suitable pharmaceutical composition of this invention is reflux. one Suitable for oral administration in unit dosage form, for It is also possible to convert one R group into another R' example a tablet or capsule which contains between 100 mg group as a final Step in the preparation of a compound of the 25 and 1 g of the compound of this invention. formula (I) or (II) (see the specific examples). In another aspect a pharmaceutical composition of the When an optically active form of a compound of the invention is one Suitable for intravenous, Subcutaneous or formula (I) is required, it may be obtained by carrying out intramuscular injection. one of the above procedures using an optically active Each patient may receive, for example, a daily Starting material, or by resolution of a racemic form of the intravenous, Subcutaneous or intramuscular dose of 5 compound or intermediate using a Standard procedure. mgkg-' to 20 mgkg- of the compound of this invention. the Similarly, when a pure regioisomer of a compound of the composition being administered 1 to 4 times per day. The formula (I) is required, it may be obtained by carrying out intravenous, Subcutaneous and intramuscular dose may be one of the above procedures using a pure regioisomer as a given by means of a bolus injection. Alternatively the Starting material, or by resolution of a mixture of the 35 intravenous dose may be given by continuous infusion over regioisomers or intermediates using a Standard procedure. a period of time. Alternatively each patient will receive a According to a further feature of the invention there is daily oral dose which is approximately equivalent to the provided a compound of the formula (I), or a daily parenteral dose, the composition being administered 1 pharmaceutically-acceptable Salt thereof, for use in a to 4 times per day. method of treatment of the human or animal body by 40 Antibacterial Activity therapy. The pharmaceutically-acceptable compounds of the According to a further feature of the present invention present invention are usefull antibacterial agents having a there is provided a method for producing an antibacterial good Spectrum of activity in vitro against Standard Gram effect in a warm blooded animal, Such as man, in need of positive organisms, which are used to Screen for activity Such treatment, which comprises administering to Said ani 45 against pathogenic bacteria. Notably, the pharmaceutically mal an effective amount of a compound of the present acceptable compounds of the present invention Show activ invention, or a pharmaceutically-acceptable Salt thereof. ity against enterococci, pneumococci and methicillin resis The invention also provides a compound of the formula tant Strains of S. aureus and coagulase negative (I), or a pharmaceutically-acceptable Salt thereof, for use as Staphylococci. The antibacterial Spectrum and potency of a a medicament; and the use of a compound of the formula (I) 50 particular compound may be determined in a Standard test of the present invention, or a pharmaceutically-acceptable System. Salt thereof, in the manufacture of a novel medicament for The antibacterial properties of the compounds of the use in the production of an antibacterial effect in a warm invention may also be demonstrated in-vivo in conventional blooded animal, Such as man. tests. No overt toxicity or other untoward effects are In order to use a compound of the formula (I) or a 55 observed when compounds of the formula I are so tested. pharmaceutically-acceptable Salt thereof for the therapeutic The following results were obtained on a standard in-vitro treatment of mammals including humans, in particular in test system. The activity is described in terms of the mini treating infection, it is normally formulated in accordance mum inhibitory concentration (MIC) determined by the with Standard pharmaceutical practice as a pharmaceutical agar-dilution technique with an inoculum size of 10 CFU/ composition. 60 Spot. Therefore in another aspect the present invention provides Staphylococci were tested on agar. using an inoculum of a pharmaceutical composition which comprises a compound 10 CFU/spot and an incubation temperature of 37° C. for 24 of the formula (I) or a pharmaceutically-acceptable Salt hours-Standard test conditions for the expression of methi thereof and a pharmaceutically-acceptable diluent or carrier. cillin resistance. The pharmaceutical compositions of this invention may 65 Streptococci and enterococci were tested on agar Supple be administered in Standard manner for the disease condition mented with 5% defibrinated horse blood, an inoculum of that it is desired to treat, for example by oral, rectal or 10 CFU/spot and an incubation temperature of 37°C. in an 5,981528 29 30 atmosphere of 5% carbon dioxide for 48 hours-blood is (vii) in which required for the growth of Some of the test organisms. MPLC is medium pressure chromatography TLC is thin layer chromatography MIC (ug/ml) DMSO is dimethylsulfoxide Organism Example 1 CDCl is deuterated chloroform UZ,4f14 Staphylococcu.S. aureus. MS is mass spectroscopy Oxford 1.O ESP is electrospray Nowb. Res 0.5 C is chemical ionization MROS 0.5 DMF is N,N-dimethylformamide MROR 0.5 THF is tetrahydrofuran Coagulase Negative Staphylococcus LDA is lithium diisopropylamide TFA is trifluoroacetic acid MS O.25 NMP is N-methylpyrrolidone MR 1.O dba is dibenzylideneacetone Streptococcus pyogenes 15 C2O3 1.O REFERENCE EXAMPLE 1. Enterococcus faecalis 1.O Bacilius Subtilis O.25 (5S)-Acetamidomethyl-3-(4-trimethyltinphenyl) Oxazolidin-2-one Hexamethyldistannane (1.77 g) followed by Pd(PPh3)Cl. Novb. Res=Novobiocin resistant (155 mg) was added to a partial Solution of MRQS=methicillin resistant quinolone sensitive 5S-acetamidomethyl-3-(4-iodophenyl)oxazolidin-2-one MRQR=methicillin resistant quinolone resistant (1.84 g) in dioxan (25 ml). The vessel was purged well with 25 argon and the reaction mixture was stirred at 95-100° C. for MR=methicillin resistant 6 hours, after which the reaction was judged as complete by MS=methicillin sensitive TLC. The solution was decanted from a film of black gum The invention is now illustrated but not limited by the which had separated, and evaporated. The title product was following Examples in which unless otherwise Stated: isolated as an oil by MPLC (Merck 9385 silica using as eluant a mixture of methanol and dichloromethane increas i) evaporations were carried out by rotary evaporation in ing in polarity from 5% to 10% methanol) which crystallised vacuo and work-up procedures were carried out after in 59% yield (1.19 g) on trituration with ether. See also WO removal of residual solids by filtration; Patent 94-13649 (23.06.94) for preparation of Reference (ii) operations were carried out at ambient temperature, Example 1. that is in the range 18-26 C. and in air unless other 35 NMR (300 MHz, DMSO-D6): 8 0.25(s.9H), 1.84(s.3H), wise Stated, or unless the skilled person would other 3.42(t.2H), 3.74(d of d.1H), 4.10(t,1H).7.50(m.4H), 4.70(m, wise work under an inert atmosphere; 1H), 8.22(t, 1H). MS: ESP+ (M+H)=397. (iii) column chromatography (by the flash procedure) was REFERENCE EXAMPLE 2 performed on Merck Kieselgel silica (Art. 9385) unless 40 N-((5S)-3-(3-Fluoro-4-(1-tert-butoxycarbonyl-1,2,5, otherwise Stated; 6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5- (iv) yields are given for illustration only and are not ylmethyl)acetamide necessarily the maximum attainable, Lithium chloride (1.53 g) was added to a stirred solution (v) the end-products of the formula I generally have 45 of of t-butyl-1,2,3, 6-tetrahydro 4 Satisfactory microanalyses and their structures were (trifluoromethylsulfonyloxy)pyridine-1-carboxylate (4.97g) confirmed by NMR and mass spectral techniques in NMP (50 ml), followed by Pd(dba) (550 mg) and the proton magnetic resonance spectra were determined in vessel was purged well with argon. After Stirring for 5 DMSO-D6 unless otherwise stated using a Varian minutes at ambient temperature, a solution of N-(5S)-3-(3- Gemini 2000 spectrometer operating at a field strength 50 fluoro4-trimethyltinphenyl)-2-oxooxazolidin-5-ylmethyl) acetamide (4.99 g, WO Patent 94-13649, 23.06.94) in NMP of 300 MHz, or a Brukier AM250 spectrometer oper (20 ml) was added. The reaction mixture was stirred at ating at a field strength of 250 MHz; chemical shifts are ambient temperature for 5 hours. then at 50 C. for 18 hours. reported in parts per million downfield from tetram TLC (ethyl acetate) indicated that the reaction was complete. ethysilane as an internal standard (Ó Scale) and peak 55 A 2.0M aqueous potassium fluoride solution (12 ml) was multiplicities are shown thus: S, Singlet; d, doublet, AB added and the reaction mixture Stirred at ambient tempera or dd, doublet of doublets, t, triplet, m, multiplet; ture for 1% hours. Water was added and the product was fast-atom bombardment (FAB) mass spectral data were extracted with ethyl acetate. The organic phase was washed obtained using a Platform spectrometer (Supplied by with water, brine, dried over anhydrous Sodium Sulfate and Micromass) run in electrospray and, where appropriate, 60 evaporated to a gum. The title compound was isolated as a gel in 68% yield (4.39 g) by MPLC (Merck 9385 silica, either positive ion data or negative ion data were using as eluant a mixture of methanol (3.5%) and collected; dichloromethane), and used in Subsequent steps without (vi) intermediates were not generally fuilly characterised further purification. and purity was in general assessed by thin layer 65 NMR (300 MHz, DMSO-D6): 8 2.40(m, 1H), 3.40(m, chromatographic, infra-red (IR), mass spectral (MS) or 3H), 3.50(m, 1H), 3.70(m, 1H), 3.98(m, 2H), 4.10(m, 1H), NMR analysis; and 4.70(m, 1H), 5.95(m, 1H), 7.35(m, 3H), 8.20(t, 1H). 5,981528 31 32 REFERENCE EXAMPLE 3 Concentrated HCl (50 ml) was added and reflux was con 5,6-Dihydro-4-trifluoromethylsulfonyloxy-2H-pyran tinued for a further 4 hours. The reaction mixture was basified, with cooling, with 40% aqueous sodium hydroxide LDA/THF (31.5 ml of 1.92M solution) was slowly added to a stirred solution of tetrahydro-4H-pyran-4-one (5.5 g) in Solution and extracted with ether. Addition of aqueous THF (30 ml) at -70° C., under argon. The mixture was ammonium hydroxide solution avoided problems with stirred for 30 minutes at -70° C. and then a solution of insoluble partial Salts. The organic phase was washed with N-phenyl triflimide (21.6 g) in THF (30 mls) was added. The brine, dried over anhydrous Sodium Sulfate and evaporated mixture was allowed to warm to ambient temperature and well giving the title compound as a Viscous gum in 96% stirred for 18 hours. The reaction mixture was evaporated yield (32.33 g). and Subjected to chromatography by MPLC on Alumina NMR (300 MHz DMSO-D6): 8 2.35(s, 2H), 2.55(t.2H), (ICN, N32-63, using as eluant a mixture of ethyl acetate 2.98(d, 2H). 3.53(s, 2H), 5.35(s, 2H), 5.75(s, 1H), 6.29(m, (5%) and iso-hexane). The product was distilled by Kugel 2H), 6.95(t, 1H), 7.30(m, 5H). MS: ESP+ (M+H)=283. ruhr (100° C./10 mm). Remaining traces of the triflimide reagent were removed by a second MPLC (Silica, using as REFERENCE EXAMPLE 7 eluant a mixture of ethyl acetate (5%) and iso-hexane) 15 followed by a Second Kugelruhr distillation, giving the title N-Benzyloxycarbonyl-3-fluoro-4-(1-benzyl-1,2,5,6- compound as a colourless oil in 40% yield (5.1 g), which tetrahydropyrid-4-yl)aniline was stored at -20° C. NMR (300 MHz, CDC1): 8 2.24(m.2H), 3.90(m.2H), Dibenzyl dicarbonate (43 g) was slowly added to a stirred 4.25(m.2H), 5.82(m.1H). solution of Reference Example 6 (28.2 g) in dichlo romethane (200 ml) at 0–5 C. The reaction mixture was REFERENCE EXAMPLE 4 allowed to warm to ambient temperature and stirred for 18 1-(4-Bromo-3-fluorophenyl)-2.2.5.5-tetramethyl-1,2, hours. The Solution was evaporated to an oil which was 5-azadisilalidine triturated with ether. Sticky, insoluble material was dis Triethylamine (56.8 g) was added to a stirred solution of 25 carded and the filtrate was purified by chromatography 4-bromo-3-fluoroaniline(42.75 g, JCS, 2815 (1958)) in (MPLC on Silica, using as eluant a mixture of ethyl acetate dichloromethane (400 ml) followed by the slow addition, (25%) and iso-hexane). The product was taken into ethyl with ice-bath cooling, of a Solution of 1,2-bis acetate and precipitated as the HCl Salt by addition of a (chlorodimethylsilyl)ethane (50.79 g) in dichloromethane mixture of HCl and ethyl acetate. The resulting product was (100 ml). After stirring for 2 days, an NMR of a worked up filtered off, washed with ethyl acetate and dried under Sample showed that the reaction was complete. The reaction Vacuum to give the title product. mixture was washed with ice cold 2N aqueous NaHPO and water, dried over anhydrous magnesium Sulfate and Yield=10.2 g (23%) evaporated to give a brown oil. The title compound was NMR (300 MHz, DMSO-D6): 8 2.61(m, 1H), 2.85(m, isolated in 93% yield (69.4 g) by vacuum distillation, 1H), 3.20(m, 1H), 3.53(m, 1H), 3.75(s, 2H), 4.40(t, 2H), (bp=105-110° C./0.2 bar). 35 5.15(s, 2H), 5.95(s, 1H), 7.35(m, 11H), 7.60(m. 2H). MS: NMR (300 MHz CDC1): 8 0.22 (s, 12H), 0.85 (s, 8H), ESP+ (M+H)=417. 6.52 (d of d, 1H), 6.65 (d of d, 1H), 7.30 (t, 1H). REFERENCE EXAMPLE 8 REFERENCE EXAMPLE 5 N-tert-Butoxycarbonyl-N-(5R)-3-(3-fluoro-4-(N- 4-(1-Benzyl-4-hydroxy-4-piperidyl)-3-fluoroaniline 40 benzyl-1,2,5,6-tetrahydropyrid-4-ylphenyl)-2- n-Butyllithium/hexane (129 ml of 1.40M) was slowly OXooxazolidin-5-ylmethyl)acetamide added to a stirred solution of Reference Example 4 (59.76 g) in dry THF (300 ml) at -70° C. under argon. The solution BOC-acetamide (2.85g, Chem. Pharm. Bull.Jap.36, 3125 was stirred for 5 minutes, then a solution of N-benzyl-4- (1988) was added to a stirred partial solution of Example 13 piperidone (37.8 g) in THF (150 ml) was slowly added. The 45 (4.55g) in dry THF (80 ml) and the mixture cooled to 0-4 reaction mixture was allowed to warm to ambient tempera C. under argon. Tributylphosphine (3.62 g) was added, ture and stirred for 3 hours. The reaction mixture was then followed by portion-wise addition of 1,1'-(azodicarbonyl)- quenched by the addition of ice, followed by water, then dipiperidine (4.51 g). The reaction mixture was stirred for 30 acidified to

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 5,981528 Page 1 of 1 DATED : November 9, 1999 INVENTOR(S) : Michael Barry Gravestock

It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Column 57 Line 21, insert -- wherein (1-10C)alkyl is optionally substituted by hydroxy, benzyloxy, cyano, halo, (1-10C)alkoxy, trifluoromethyl, (1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy (1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkanoyl, (1-4C)alkoxycarbonyl, amino, (1-4C) alkylamino, di((1-4C)alkyl)amino, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino, N-(1-4C)alkyl-N-(2-6C)alkanoylamino, (1-4C)alkylS(O)NH-, (1-4C)alkylS(O)(1-4C) alkyl)N-, fluoro(1-4C)alkylS(O)NH-, fluoro(1-4C)alkylS(O)(1-4C)alkyl)N-, phosphono, (1-4C)alkoxy(hydroxy)phosphoryl, di-(1-4C)alkoxyphosphoryl, (1-4C) alkylS(O), phenylS(O)- (wherein the phenyl group is optionally substituted by up to three substituents independently selected from (1-4C)alkoxy, halo and cyano), or CY (as defined hereinbelow), wherein p is 1 or 2 and q is 0, 1 or 2 -- between “(1-10C)alkyl” and “:”.

Signed and Sealed this Fourteenth Day of January, 2003

JAMES E ROGAN Director of the United States Patent and Trademark Office Adverse Decision in Interference Patent No. 5,981,528, Michael Barry Gravestock, ANTIBIOTIC OXAZOLDINONE DERIVATIVES, Interference No. 105,273, final judgment adverse to the patentees rendered, October 11, 2005, as to claims 1-6, 8. (Official Gazette, March 14, 2006)