Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• Mycoplasma spp. Mycoplasma spp., Ureaplasma spp., Chlamydia trachomatis or Chlamydia pneumoniae in a subject in need thereof comprising administering an effective amount of (2R,4S,4aS)-11-ftuoro-2,4-dimethyl-8-[ ⁇ 4S ⁇ -4-methyl-2-oxo-1 ,3-oxazolidin-3-yfji-1 ,2,4,4a- tetrahydro-2'H,6H-spiro[1 ,4-oxazino[4,3-a3[1 ,2]oxazolo 4,5-g]quinoline-5,5'-pyr!rnidine]- 2 4 Q' ⁇ VH,d'H ⁇ -tnom, or a pharmaceutically acceptable salt thereof, to the subject.
• Francisella spp. Yersina spp., Mycoplasma spp., Ureaplasma spp., Chlamydia trachomatis or Chlamydia pneumoniae.
• ther is provided the use of ⁇ 2R,4S,4aS)-11 -fluoro-2,4-dimethyl-8- [(4$)-4-methyl-2-oxo-1 ,3-oxa20lidin ⁇ 3 ⁇ ylj[ ⁇ 1 a][1 ⁇ joxazo ⁇ -gjqutnoltne-S.S -pyrimidinej-Z ⁇ '.e'il ⁇ ,3 ⁇ )- ⁇ , or a pharmaceuticaiiy acceptable salt thereof, in the manufacture of a medicament for treating a bacterial infection caused by one or more bacterium selected from Badiius anthracis. Bacillus cereus,
• Ureaplasma spp. Chlamydia trachomatis or Chlamydia pneumoniae.
• bacteria! infections caused by one or more bacterium selected from Bacillus anthracis, Bacillus cereus, Burkholderia spp., Brucella spp., Frandsella spp., Yersina spp. , Mycoplasma spp,, Ureaplasma spp.
• Chlamydia trachomatis or Chlamydia pneumoniae by administering to a subject in need thereof an effective amount of (2 ,4S,4aS)-11-fiuoro-2,4-dimethyt-8- (4S)-4-methyi-2-oxo-1 ,3-oxazQlidin-3-yl3-1 ,2,4,4a- tetrahydrQ ⁇ 2'H,6H-spirGl1 ,4 ⁇ oxazino[4,3-a3 ⁇
• bacterial infection includes infections caused by one or more species of Gram-negative, Gram-positive, or atypical bacteria.
• the bacteria! infection is caused by Bacillus anthracis or Bacillus cereus.
• the bacterial infection is caused by Burkholderia spp,, for example, Burkholderia mallei, Burkholderia pseudomelia! and Burkhofderia cepacia.
• the bacteria! infection is caused by Brucella spp., for example, Brucella meliiensis, Brucella abortus, Brucella cams, Brucella suis and Brucella ovis.
• the bacterial infection is caused by Francisella spp. , for example, Francisella iularensis, Francisella novicida and Francisella philomiragia,
• the bacterial infection is caused by Yersina spp., for example, Yersinia pestis and Yersinia enteroco!ltica.
• the bacterial infection is caused by Mycoplasma spp., for example Mycoplasma gallisepticum, Mycoplasma genitalium, Mycoplasma aemofe!ls. Mycoplasma hominls. Mycoplasma hyopneumonlae, Mycoplasma ovipneumoniae and Mycoplasma pneumoniae.
• the bacterial infection is caused by Ureaplasma spp., for example, Ureaplasma parvum and Ureaplasma urealytscum
• the bacterial infection is caused by Chlamydia trachomatis or Chlamydia pneumoniae.
• the bacteria are resistant to one or more antibacteria!s other than (2/? 5 4S,4aS)-11 -f!uoro-2,4-dimethyl-8-[ ⁇ 4S)-4-methyl-2-oxo-1 ,3-0xa2oiidin-3-yi]- 1 ,2 A4a « tetrahydro2'W,6W-spiro[1 ,4-oxazino[4,3-a][1 ⁇ Joxazoto ⁇ S-oJquinoline-S, ⁇ - pyrimidinei ⁇ 2 ⁇ 4 ⁇ 6 13 ⁇ 43'HHrione.
• the language “resistance” and "antibacterial resistance” refers to bacteria that are able to survive exposure to one or more antibacterial agents.
• the bacteria is resistant to one or more of an aminoglycoside antibiotic (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, spectinomycin), an ansamycin antibiotic ⁇ e.g., rifaximin, streptomycin), a carbapenem antibiotic ⁇ e.g., ertapenem, doripenem, imipenem/cilastatin, meropenem), a cephalosoprin antibiotic (e.g., cefadroxil, cefaxoiin, cefatoiin, cefalexin, cefaclor, cefamandoie, cefoxitin, cefprozil, cefuroxime, ceftsime, cefdinir, cefditoren, cef
• amoxaciliin ampicillin, azlociilin, carbenicillin, cioxaciliin, dicloxaciS!in, fiucloxacillin, mezlocillin, methiciliin, nafcillin, oxacillin, penicillin, piperaciflin, temociliin, ticarciiiin), amoxici!iin/ciavu!ante,
• ampiciSin/sulbactam, piperacilSin/tazobactam, ticarcillin/ciavuianate, a quino!one antibacterial e.g., ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levoffoxacin, lomefioxacin, oxifSoxacin, nalidixic acid, norfloxacin, ofloxacin, trovafioxin, grepafloxacin, sparfioxacin, temafloxacin
• a suf!onamide antibiotic e.g. , mafenide. sulfacetamide, sulfadiazine, silver sulfadiazine, suifadimethoxine, sulfamethizole, sulfamethoxazole, sulfanamide,
• the bacteria is resistant to doxycycline.
• the bacteria is resistant to levofloxacin and/or ciprofloxacin.
• the bacteria is resistant to azithromycin.
• the bacteria is resistant to tetracycline.
• a method of treating a subject suffering from a sexually transmitted bacteria! infection comprising administering to the subject an effective amount of a (2f?,4S,4a$)-1 1-fluoro-2 ! 4-dimethyl-8-[(4S)-4-methyi-2-oxo-1 ,3- oxazolidin-3-y!]-1 ,4-oxazino[4,3-a][1 ,2]oxa2oSo[4,5- g]quinoline-5 ( 5-pynmidine]-2 , l 4 , ,6 , (1 * H l 3 , H)-trione, or a pharmaceutically acceptable salt thereof.
• a method for treating an anthrax infection, glanders, melioidosis, a pulmonary infection in a subject suffering from cystic fibrosis, brucellosis, tularemia, plague, sepsis, yersiniosis, pelvic inflammatory disease, atypical pneumonia, nonspecific urethritis, pneumonia, bronchopulmonary dysplasia or meningitis in a subject in need thereof comprising administering an effective amount of (2 4S,4aS ⁇ -11-fiuoi -2,4- dimethyl-8-[(4S)-4-methyl-2-oxo-1 ,3-oxazoiidsn-3-yli-1 ,2,4 > 4a-ietrahydro-2'H > eH-sp!ro[1 > 4- o az ⁇ o[4,3- ][1 ,23oxazolo 4,5-g] ui oiine-5,5'- yrimid
• treat includes the reduction or inhibition of enzyme or protein activity related to a bacterial infection in a subject, amelioration of one or more symptoms of a bacterial infection in a subject, or the slowing or delaying of progression of a bacterial infection in a subject.
• treatment includes the reduction or inhibition of enzyme or protein activity related to a bacterial infection in a subject, amelioration of one or more symptoms of a bacterial infection in a subject, or the slowing or delaying of progression of a bacterial infection in a subject.
• treatment also includes the reduction or inhibition of the bacterial growth, replication or a reduction or inhibition of the bacterial load of bacteria in a subject.
• subject includes, for example, primates, cows, horses, pigs, sheep, dogs, cats, rabbits, rats, birds (including wild and domestic birds, such as turkeys, geese, chickens, ducks and the like) and mice, in some embodiments, the subject is a primate, for example, a human, in some embodiments, the subject is suffering from a Gram-positive bacterial infection, in some embodiments, the subject is suffering from a Gram-negaitve bacteriai infection, in some embodiments, the subject is suffering from an atypical bacteriai infection, in some embodiments, the subject is in need of treatment (e.g., the subject would benefit biologically or medicai!y from treatment).
• the subject is suffering from a significant underlying disease state that complicates the response to treatment of a bacteriai infection, for example cystic fibrosis, in some embodiments, the subject is suffering from one or more bacteriai infections (e.g., co-infecied by two or more bacterial infections). In some embodiments, the subject is suffering from an infection caused by Neisseria gonorrhoeae, in some embodiments, the subject is co-infected with Chlamydia trachomatis and Neisseria gonorrhoeae. In some embodiments, the subject is at risk of contracting a sexually transmitted bacterial infection (e.g., a Chlamydia trachomatis or Neisseria gonorrhoeae infection).
• a sexually transmitted bacterial infection e.g., a Chlamydia trachomatis or Neisseria gonorrhoeae infection.
• the language "effective amount” includes an amount of (2 ,4S,4aS)-11-fluoro-2,4- di methy!-8-[ ⁇ 4$H-methyl-2 ⁇
• the language "effective amount" includes the amount of (2 ?,4S,4aS)-11- fiuorQ ⁇ 2 ( 4-d!methyi ⁇ 8-[(4 SH ⁇
• intermediate 4 was prepared from Intermediate 2 using (4S)-4-methyl-1 ,3-oxazoitdin-2- one (synthesized according to the procedure described in Nishiyama, T.; Matsui, Shigeki; Yamada, F. J. Het. Chem, (1986), 23(5), 1427-9) in a method similar to the one described for the synthesis of intermediate 3.
• Compound 1 is an investigational inhibitor of the supercoi!ing and decatenation activity of the DNA gyrase and topoisomerase iV with activities against several different types of bacteria. Preliminary data suggest this agent maintains activity against organisms that are resistant to other agents such as fluoroquinolones and tetracyclines, including agents of sexually transmitted infections such as Neisseria gonorrhoeae. The present study was undertaken to increase knowledge of the in vitro activities of Compound 1 against additional human pathogens by testing a small number of clinical isolates and reference strains representing five species of moi!icutes that are important human pathogens.
• CLSi Clinical Laboratory Standards Institute
• Strains tested included organisms that contained the tet gene, which mediates tetracycline resistance, mutations in 23S ribosomal RNA that confers macrolide resistance, and others that contained mutations in DMA gyrase and/or topoisomerase IV that confer resistance to fluoroquinolones.
• Mycoplasma genttatium (n - 5)
• Uu Ureapiasma urealyticum.
• Up Ureapiasma parvum,
• BAl bronchoa!veoiar Savage fluid,
• CSF cerebrospinal fluid, ETA - endotracheal aspirate
• Ureapiasma species were identified by real-time PGR as previously described (Xiao et al. Detection and characterization of human Ureapiasma species and serovars by real-time PCR. J. Clin. Microbiol. 2010,48, 2715-2723). Three clinical isolates were shown to be a mixture of both species, which sometimes occurs (Xiao et at Extensive horizontal gene transfer in ureap!asmas from humans questions the utility of serotyping for diagnostic purposes. J. Clin, Microbiol. 2011 , 49, 2818-2826).
• Presence of tetM in M. omsnis and Ureapiasma species was determined by PCR in the UAB Diagnostic Mycoplasma Laboratory.
• the assa employed for this investigation was the broth micro-dilution minima! inhibitory concentration (MIC) assay that was published in "Methods for Antimicrobial Susceptibility Testing of Human Mycoplasmas. Approved Guideline, CLSI Document M43-A" (CIS! 20 ), This assay employs 96 well microtiter plates into which a defined inoculum of the organism to be tested is added to doubling dilutions of antimicrobial agents in smail volumes. P!ates were incubated until the growth control changed color. The MIC endpoint was then determined by lack of color change in broth containing a pH indicator. Specific aspects of the procedures that were used follow.
• Inoculum Preparation of Inoculum. Organisms were thawed to room temperature and diluted in appropriate prewarmed media in 50 mL conical tubes to yield a final inoculum of approximately 10 4 CFU/mL. At least 5 mis of inoculum was prepared for each drug, based on testing 8 dilutions in duplicate and appropriate controls. If more dilutions were needed to achieve endpoint ICs, an additional volume of inoculum was prepared, inoculated broths were incubated aerobicalSy at 37 0 C for 2 hours prior to use to allow mycoplasmas to become metabolicaiiy active prior to inoculating microtiter plates. Due to their more rapid growth rates, ureaplasmas were incubated for only one hour prior to inoculating the plates.
• Antimicrobia! agents were serially diluted using a 0.025 mL multichannel pipette, beginning at the 2nd well, and continuing through well 8, discarding the final 0.025 ml.
• a solvent control was prepared in well 9 by incorporating 0,025 mL of the highest concentration (1 :10 dilution in sterile deionized water) of solvent used to dissolve the antimicrobial agent being tested if any substance other than water was used as a solvent. 0. 75 mL of the desired dilution of inoculated media that has been prewarmed for 2 hours was added to each well in rows 1 -9 and 12. Well 12 served as the growth control. Inocula were added starting with well 12 and working backwards to well 1 to prevent drug carryover.
• M!Cs were recorded as the lowest concentration of antimicrobial agent inhibiting color change in broth medium at the time when the organism control well first showed color change.
• a positive reaction for growth of Ureaplasma spp. in 10B broth was evidenced by a color change from yellow to pink in the organism control well (i.e. well 12).
• a positive reaction for M. hominis in Mycoplasma broth was evidenced by a color change from pink to deeper red in the organism growth control well ⁇ i.e. well 2).
• M hominis grows on either SP4 or mycopiasma agar; M hominis and commensal respiratory Mycoplasma species produce fried egg colonies whereas; M. pneumoniae and M. genit&lium produce small spherical colonies.
• AS agar plates yield brown granular colonies for U aptasma species and would also detect contaminating Mycopiasma species or bacteria. Any turbidity in the growth control well indicates bacterial contamination and invalidates the results.
• Compound 1 showed in vitro activity comparable to that of levofloxacin and doxycycline.
• Compound 1 MIC range 0.5-1 pg/mL) was less potent than azithromycin (MiC range 0.001 pg/mL ⁇ . M, pn m n e.
• the MICgo for Compound 1 (1 pg/mL) was equivalent to that of ievofioxacin and 4-foid higher than doxycyc!ine (0.25 pg/mL). Most M.
• pneumoniae isolates had azithromycin MiCs ⁇ 0.001 pg/mL, but two strains were chosen for testing because they had azithromycin MICS of 16 and 32 pg/mL and contained mutations in 23S ribosomai RNA.
• Compound 1 maintained in vitm potency against these two macroiide-resistant isolates comparable to that for those isolates that were fully macro! ide-susceptibie.
• M hominis.
• Compound 1 had the lowest overall activity against M. hominis with the MICgo of 4 pg/mL and a maximum MIC value of 8 pg/mL Doxycycline MiCs for M. hominis isolates without tetM ranged from 0.018-0.083 pg/mL, while M!Cs for those three with tetM were 4 pg/mL.
• Corresponding tetracycline MiCs were 32 pg/mL for those isolates.
• Compound 1 (4 pg/mL) was 8 ⁇ fold greater than that of levofloxacin (0.25 pg/mL) and was equivending to that of azithromycin, a drug that is not usually very active against this species. Without having information on achievable drug concentrations for Compound 1 , it is not possible to indicate whether these M!Cs would be considered susceptible or resistant.
• Umaptasma species The ICso for Compound 1 was 1 pg/mL, making it comparable to levofloxacin in potency. There was no difference in Compound 1 MiCs against levofloxacin-resistant ureap!asmas and levofloxacin-susceptible isolates.
• M!Cs for Compound 1 were not affected with its MiCs ranging from 0.5-2 pg/mL versus 4-8 pg/mL for doxycycline, but M!C 3 ⁇ 4 > for doxycycline-susceptible organisms (0.125 pg/mL) was 8-fold more active than Compound 1 (1 pg/mL).
• Compound 1 was 4-foid more potent than azithromycin (MICso of 1 vs 4 pg/mL).
• Mycoplasma genitaitum (n - 5) MICs ⁇ pg/ml)
• Mycoplasma pneumoniae (n - 12) ICs ( g/mL)
• Mycoplasma and Ureapiasma species thai infect humans can cause significant disease in the respiratory tracts as well as the urogenital tracts, in addition to N.
• M. genitalium and Umapiasma u alyticum can cause male urethritis and M. genitalium also causes female cervicitis and pelvic inflammatory disease (Wastes KB, Taylor-Robinson D. Mycoplasma and Ureapiasma.
• Compound 1 may be a potentially useful agent for further development as a possible treatment for infections caused by human mycoplasmas and ureaplasmas in the urogenital tract or respiratory tract.
• comparator compounds doxycycline, Ievofioxacin and chloramphenicol
• Compound 1 Three (3) comparator compounds (doxycycline, Ievofioxacin and chloramphenicol) and Compound 1 were screened for antibacterial activity against multiple isolates each of Bacillus anthracis (B. anthracis), Burkhoideria mallei (B. mallei), Burkhoideria pseudomall&i (S. pseudomaliei), Brucella abortus (B. abortus), Brucella melitensis (B. melitensis), Brucella suis (B. suis), Franciseila tuiarensis ⁇ F. tularensis) and Yersina pestis (Y. pestis).
• Bacillus anthracis B. anthracis
• Burkhoideria mallei B. mallei
• Burkhoideria pseudomall&i S. pseudomaliei
• Brucella abortus
• Testing was conducted utilizing the broth microdslution methodology outlined b CLSI guidelines. Briefly, testing was conducted using 96-wefl, U-bottom microplates with an assay volume of 0.2 ml/weli. Plates containing appropriate broth and two-fold dilutions of the test compounds were inoculated wit a targeted concentration of 5.0 x 105 CFU/ ' mL (5.0 x 104 CFU/welS) of bacterial agent and subsequently incubated for 24 -72 hours depending on the agent. Following incubation, the plates were read visually and individual welis scored for turbidity, partial clearing or complete clearing. The MIC was reported as the lowest concentration ⁇ g/mL) of drug that visually inhibited growth of the organism. Growth medium, inoculum preparation and incubation conditions are provided below in Table 7. Table 7. Growth Medium, inoculum Preparation and incubation Conditions

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