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

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United States Patent (19) 11 Patent Number: 5,981,528 Gravestock (45) Date of Patent: *Nov 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 Tropone-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
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