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WO2021009212A1 - Dérivés de quinolone antibactériens - Google Patents

Dérivés de quinolone antibactériens Download PDF

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Publication number
WO2021009212A1
WO2021009212A1 PCT/EP2020/069978 EP2020069978W WO2021009212A1 WO 2021009212 A1 WO2021009212 A1 WO 2021009212A1 EP 2020069978 W EP2020069978 W EP 2020069978W WO 2021009212 A1 WO2021009212 A1 WO 2021009212A1
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Prior art keywords
methyl
dihydro
oxo
amino
pyrazino
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PCT/EP2020/069978
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English (en)
Inventor
Daniel Ritz
Georg Rueedi
Susanne Schroeder
Cornelia Zumbrunn
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Idorsia Pharmaceuticals Ltd
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Publication of WO2021009212A1 publication Critical patent/WO2021009212A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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

  • the present invention concerns novel antibacterial compounds, pharmaceutical compositions containing said compounds and the use of these compounds as medicaments e.g. in the treatment of bacterial infections.
  • These compounds are useful antimicrobial agents effective against a variety of human and veterinary pathogens including among others Gram-positive and Gram-negative aerobic and anaerobic bacteria and especially against resistant strains of Pseudomonas aeruginosa and Enterobacteriaceae such as Klebsiella pneumoniae.
  • aureus is resistant to beta-lactams, quinolones and now even to vancomycin; S. pneumoniae is becoming resistant to penicillin or quinolone antibiotics and even to new macrolides; Enteroccocci are quinolone and vancomycin resistant and beta-lactam antibiotics are inefficacious against these strains; Enterobacteriacea are cephalosporin- and quinolone-resistant and carbapenems are losing their efficacy (e.g. carbapenem-resistant Klebsiella pneumoniae ); P.
  • aeruginosa is beta-lactam and quinolone resistant.Furthermore, the incidence of multidrug-resistant Gram-negative strains such as Enterobacteriaceae and Pseudomonas aeruginosa, is steadily increasing and new emerging organisms such as Acinetobacter spp. or Clostridium difficile, which have been selected during therapy with the currently used antibiotics, are becoming a real problem in hospital settings (S. L. Solomon et al., Antibiotic Resistance Threats In the United States: Stepping Back from the Brink, Academy of Family Physician, page 940 Volume 89, Number 12, June 15, 2014). Therefore, there is a high medical need for new antibacterial agents with advantageous properties which overcome these multidrug resistances in bacteria, especially Pseudomonas aeruginosa and Enterobacteriaceae such as Klebsiella pneumoniae.
  • WO 2014/178008 and WO 2017/029602 disclose certain antibacterial compounds.
  • the present invention provides novel antibacterial compounds which have advantageous pharmacological properties.
  • V represents 0 or S (especially 0);
  • R 1 represents Ci4-alkyl (especially methyl or ethyl) or C3-5-cycloalkyl (especially cyclopropyl);
  • alkyl refers to a saturated straight or branched hydrocarbon chain containing one to six carbon atoms. Examples are methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, sec- butyl, iso-butyl, n-pentyl, 1 , 1 -dimethylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 3-pentyl, 2-pentyl, 1 ,2- dimethylpropyl and 2-methylbutyl.
  • Cx-y-alkyl (x and y each being an integer), used alone or in combination, refers to a saturated straight or branched hydrocarbon chain with x to y carbon atoms.
  • C 14-alkyl alone or in combination with other groups, means saturated, branched or straight chain groups with one to four carbon atoms.
  • Examples of Ci4-alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, sec-butyl and iso-butyl; especially mehyl or ethyl.
  • cycloalkyl used alone or in combination, refers to a saturated monocyclic hydrocarbon ring containing three to six carbon atoms.
  • C x-y -cycloalkyl (x and y each being an integer), refers to a saturated monocyclic hydrocarbon ring containing x to y carbon atoms.
  • Examples of C3-5-cycloalkyl group are cyclopropyl, cyclobutyl and cyclopentyl; especially cyclopropyl.
  • a further embodiment relates to the compounds according to any one of embodiments 1 ) or 2), wherein R 1 represents Ci4-alkyl (especially methyl or ethyl).
  • a further embodiment relates to the compounds according to any one of embodiments 1 ) or 2), wherein R 1 represents C3-5-cycloalkyl (especially cyclopropyl).
  • a further embodiment relates to the compounds according to any one of embodiements 1 ) to 6), which are also compounds of Formula II (i.e. the fragment 1 ,4-cyclohexylen in Formula I has the stereochemical designation as depicted in Formula II)
  • a further embodiment relates to the compounds according to embodiement 1 ), selected from a group consisting of:
  • a further embodiment relates to the compounds according to embodiement 1 ), selected from a group consisting of: 6-fluoro-1 -methyl-4-oxo-7-(((1 r,4r)-4-((((3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1 ,4]thiazin-6- yl)methyl)amino)methyl)cyclohexyl)amino)-1 ,4-dihydro-1 ,8-naphthyridine-3-carboxylic acid;
  • said compounds are typically converted to the compounds of embodiment 1), wherein R 2 represents hydrogen.
  • the compounds according to any one of embodiments 1) to 9) are particularly active against bacteria and bacteria-like organisms. They may therefore be particularly suitable in human and veterinary medicine for the prophylaxis and chemotherapy of local and systemic infections caused by these pathogens as well as disorders related to bacterial infections comprising pneumonia, otitis media, sinusitis, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Moraxella catarrhalis, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, or Peptostreptococcus spp.; pharyngitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Corynebacterium diphtheriae, or Actinobacillus haemolyticum ; respiratory tract infections related to infection by
  • blood and tissue infections including endocarditis and osteomyelitis, caused by S. aureus, S. haemolyticus, including strains resistant to known antibacterials such as, but not limited to, beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines and macrolides; uncomplicated skin and soft tissue infections and abscesses, and puerperal fever related to infection by S. aureus, coagulase-negative staphylococci (i.e., S. epidermidis, S. haemolyticus, etc.), S.
  • coagulase-negative staphylococci i.e., S. epidermidis, S. haemolyticus, etc.
  • aureus or coagulase-negative staphylococcal species urethritis and cervicitis; sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae ; toxin diseases related to infection by S. aureus (food poisoning and toxic shock syndrome), or Groups A, B and C streptococci; conjunctivitis, keratitis, and dacrocystitis related to infection by C. trachomatis, N. gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes or Listeria spp.
  • the preceding lists of infections and pathogens are to be interpreted merely as examples and in no way as limiting.
  • the compounds according to one of embodiments 1) to 9) may be used for the preparation of a medicament, and are suitable, for the prevention or treatment of a bacterial infection selected from the group consisting of respiratory tract infections, otitis media, meningitis, skin and soft tissue infections (whether complicated or uncomplicated), pneumonia (including hospital acquired pneumonia), bacteremia, endocarditis, intraabdominal infections, gastrointestinal infections, urinary tract infections, sexually transmitted infections, foreign body infections, osteomyelitis, Lyme disease, topical infections, or ophthalmological infections, and notably for the prevention or treatment of a bacterial infection selected from the group consisting of respiratory tract infections, otitis media, meningitis, skin and soft tissue infections (whether complicated or uncomplicated), pneumonia (including hospital acquired pneumonia) and bacteremia.
  • a bacterial infection selected from the group consisting of respiratory tract infections, otitis media, meningitis, skin and soft tissue infections (whether complicated or uncomplicated), pneumonia (including hospital acquired pneumonia) and bacteremia.
  • the compounds according to one of embodiments 1) to 9) may further be useful for the preparation of a medicament, and are suitable, for the treatment of infections that are mediated by Gram positive bacteria (such as Staphylococcus aureus, Bacillus cereus, Bacillus anthracis, Corynebacterium spp. and Propionibacterium acnes), notably by Gram positive bacteria selected from the group consisting of Bacillus cereus, Bacillus anthracis and Propionibacterium acnes.
  • the compounds according to one of embodiments 1) to 9) can be used for the preparation of a medicament, and are suitable, for the treatment of a bacterial infection mediated by Staphylococcus aureus (especially quinolone-resistant Staphylococcus aureus bacteria).
  • the compounds according to one of embodiments 1) to 9) may further be useful for the preparation of a medicament, and are suitable, for the treatment of infections that are mediated by Gram negative bacteria (such as E. coli, Klebsiella pneumoniae and other Enterobacteriaceae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Neisseria meningitidis, Moraxella catarrhalis and Bacteroides spp), notably by Gram negative bacteria selected from the group consisting of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Moraxella catarrhalis and Neisseria meningitidis.
  • Gram negative bacteria such as E. coli, Klebsiella pneumoniae and other Enterobacteriaceae, Pseudomonas aeruginosa, Stenotrophomonas mal
  • the compounds of Formula I according to any one of embodiments 1 ) to 9), and the pharmaceutically acceptable salts thereof can be used for the preparation of a medicament, and are suitable, for the treatment of a bacterial infection mediated by Klebsiella pneumoniae bacteria (especially multidrug- resistant or quinolone-resistant Klebsiella pneumoniae bacteria) and Pseudomonas aeruginosa.
  • One aspect of this invention therefore relates to the use of the compounds according to one of embodiments 1) to 9) for the manufacture of a medicament for the prevention or treatment of a bacterial infection (in particular one of the previously mentioned infections mediated by Gram negative bacteria or one of the previously mentioned infections mediated by Gram positive bacteria).
  • Another aspect of this invention relates to the use of at least one of the compounds according to embodiments 1) to 9) as a medicament.
  • compositions comprising at least one of the compounds according to embodiments 1) to 9) and further at least one therapeutically inert excipient.
  • a pharmaceutical composition according to the present invention contains at least one of the compounds according to embodiments 1 ) to 9) as active agent and optionally carriers and/or diluents and/or adjuvants, and may also contain additional known antibiotics.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5,“Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of Formula I or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants. Species like pigs, ruminants, horses, dogs, cats and poultry can be treated with the compounds according to one of embodiments 1 ) to 9).
  • the compounds according to embodiments 1 ) to 9) can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or, in particular for parenteral administration (especially intravenous application).
  • Another aspect of the invention concerns a method for the prevention or the treatment, preferably the treatment, of a bacterial infection in a patient, comprising the administration to said patient of a pharmaceutically active amount of a compound of Formula I according to one of embodiments 1 ) to 9) or a pharmaceutically acceptable salt thereof.
  • the invention provides a method for the prevention or the treatment of a bacterial infection mediated by Gram negative bacteria (in particular a bacterial infection mediated by Klebsiella pneumonia bacteria, and especially by multidrug-resistant or quinolone-resistant Klebsiella pneumonia bacteria and Pseudomonas aeruginosa bacteria) in a patient, comprising the administration to said patient of a pharmaceutically active amount of a compound of Formula I according to one of embodiments 1) to 9) or a pharmaceutically acceptable salt thereof.
  • Gram negative bacteria in particular a bacterial infection mediated by Klebsiella pneumonia bacteria, and especially by multidrug-resistant or quinolone-resistant Klebsiella pneumonia bacteria and Pseudomonas aeruginosa bacteria
  • the invention further provides a method for the prevention or the treatment, preferably the treatment, of a bacterial infection mediated by Gram positive bacteria (in particular a bacterial infection mediated by Staphylococcus aureus bacteria, especially by quinolone-resistant Staphylococcus aureus bacteria) in a patient, comprising the administration to said patient of a pharmaceutically active amount of a compound of Formula I according to one of embodiments 1 ) to 9) or a pharmaceutically acceptable salt thereof.
  • a bacterial infection mediated by Gram positive bacteria in particular a bacterial infection mediated by Staphylococcus aureus bacteria, especially by quinolone-resistant Staphylococcus aureus bacteria
  • the compounds of Formula I according to this invention may also be used for cleaning purposes, e.g. to remove pathogenic microbes and bacteria from surgical instruments, catheters and artificial implants; to make a surface, room or an area aseptic.
  • the compounds of Formula I could be contained in a solution, suspension/emulssion, spray, gel and/or dry powder formulation.
  • the compounds according to embodiments 1) to 9) may also be used for veterinary applications, such as treating infections in livestock and companion animals. They may further constitute substances for preserving inorganic and organic materials in particular all types of organic materials for example polymers, lubricants, paints, fibres, leather, paper and wood.
  • the compounds according to any one of embodiments 1) to 9) are suitable for the use as active chemotherapeutic compounds in human and veterinary medicine and as substances for preserving inorganic and organic materials in particular all types of organic materials for example polymers, lubricants, paints, fibers, leather, paper and wood.
  • the present invention also includes isotopically labelled, especially 2 H (deuterium) labelled compounds of Formula I, which compounds are identical to the compounds of Formula I except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • Isotopically labelled, especially 2 FI (deuterium) labelled compounds of Formula I and salts thereof are within the scope of the present invention.
  • the compounds of Formula I are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of Formula I are not isotopically labelled at all. Isotopically labelled compounds of Formula I may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
  • salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound.
  • salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound.
  • 'Flandbook of Pharmaceutical Salts. Properties, Selection and Use.’ P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008
  • 'Pharmaceutical Salts and Co- crystals Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.
  • room temperature refers to a temperature of 25°C.
  • the compounds of Formula I can be prepared in accordance with the present invention using the procedures described hereafter.
  • LC-MS was used to alternatively characterized the compounds (Thermo Finnigan MSQPIus with Agilent G4220A).
  • the analytical LC-MS data was obtained using the following respective conditions: LCMS1 data: Column: Zorbax SB-Aq, 3.5 mhh, 4.6 x 50 mm; Injection volume: 1 L; Column oven temperature: 40°C; Pump: Dionex HPG-3200RS; Makeup pump: Dionex ISO-3100SD; DAD: Dionex DAD-30000RS; MS: Thermo MSQ Plus; ELSD: Sedere Sedex 85; Detection: UV 210 nm, ELSD and MS; MS ionization mode: ESI+; Eluents: A: H 2 0 + 0.04% TFA; and B: MeCN; Flow rate: 4.5 mL/min; Gradient: 5% B (0.00 min - 0.01 min), 5% B to 95% B (0.01 min - 1.00 min), 9
  • HPLC pumps Gilson 333/334 or equivalent; Autosampler: Gilson LH215 (with Gilson 845z injector) or equivalent; Degasser: Dionex SRD-3200 or equivalent; Make-up pump: Dionex ISO-3100A or equivalent; DAD detector: Dionex DAD-3000 or equivalent; MS detector: Single quadrupole mass analyzer; Thermo Finnigan MSQ Plus or equivalent; MRA splitter: MRA100-000 flow splitter or equivalent; Column: Zorbax SB-AQ 30x75 mm 5 pm; Flow rate: 75 mL/min (for columns with dimension 30x75 mm); Mobile phase: gradient mode A: Water + 0.5% formic acid (acidic conditions); A: Water + 0.5% ammonium hydroxid solution (25%) (basic conditions); B: Acetonitrile.
  • BB1-2 7-chloro-1 -ethyl-6-fluoro-4-oxo-1 ,4-dihydro-[1 ,8]naph- thyridine-3-carboxylic acid is commercially available (CAS 79286-73-0));
  • BB1-3 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1 ,4-dihydro-[1 ,8]naphthyridine-3-carboxylic acid is commercially available (CAS 100361-18-0);
  • BB3-1 3-Oxo-4-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-2H-pyrazino[2,3-b][1 ,4]thiazine-6- carbaldehyde
  • Step 2 6-((E)-Styryl)-4-(2-trimethylsilanyl-ethoxymethyl)-4H-pyrazino[2,3-b][1 , 4]th i azi n-3-one
  • the mixture was cooled to rt, EA and water were added and the two layers were separated.
  • the org. layer was washed 3x with water, washed with brine, dried over MgSC , filtered and concentrated under reduced pressure.
  • the crude was then purified by FC using CombiFlash (24g S1O2 column; gradient: heptane to heptane/EA 3/1 in 16 min).
  • the desired product was obtained as a yellow oil (0.81 g, 68% yield).
  • Step 3 3-Oxo-4-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-2H-pyrazino[2,3-b][1 ,4]thiazine-6-carbaldehyde.
  • Step 1 6-Chloro-4-(2-trimethylsilanyl-ethoxymethyl)-4H-pyrazino[2,3-b][1 ,4]oxazin-3-one
  • Step 2 4-(2-T rimethylsilanyl-ethoxymethyl)-6-vinyl-4H-pyrazino[2,3-b][1 ,4]oxazin-3-one
  • 6-Chloro-4-(2-trimethylsilanyl-ethoxymethyl)-4H-pyrazino[2,3-b][1 ,4]oxazin-3-one (853 mg, 2.7 mmol, 1 eq) and Tetrakis(triphenylphosphine)palladium (0) (156 mg, 0.135 mmol, 0.05 eq) were weighed into a flask and suspended in dioxane (10.8 mL). Tributyl(vinyl)tin 97% (1.63 mL, 5.4 mmol, 2 eq) was added and the mixture degassed (vacuum/ ⁇ , 5 times). The flask was heated to 100°C, sealed and stirred at this temperature for 4h.
  • Step 3 3-Oxo-4-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-2H-pyrazino[2,3-b][1 ,4]oxazine-6-carbaldehyde
  • the wet coupling product was suspended in THF/H20 9: 1 (120 mL) and triphenylphosphine (6557 mg, 25 mmol, 1 eq) was added. The mixture was heated at 60°C for 24h. The mixture was cooled to rt, filetred and the residue washed with TBME, dried at hv. The desired building block was obtained as a beige solid (7.6 g, 87% yield over 2 steps).
  • Example 1 6-fluoro-1-methyl-4-oxo-7-(((1 r,4r)-4-((((3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]thiazin-6- yl)methyl)amino)methyl)cyclohexyl)amino)-1,4-dihydro-1 ,8-naphthyridine-3-carboxylic acid
  • Example 1.1 A solution of Example 1.1 (3800 mg, 5.78 mmol, 1 eq) in DCM (55 mL) was treated with TFA (4.42 mL, 57.8 mmol, 10 eq) and stirred at rt for 6h. Complete conversion. The mixture was concenrtated in vacuo and azeotroped once with toluene. The residue was crystallised from MeOH (55ml) and the mixture basified by addition of ammonia 25% (4 eq). The resulting fine suspension was stirred at rt for 45 min, filetred washed with little MeOH, and dried at hv on. The title compound was obtained as a yellowish solid (3.1 g, 100%).
  • Example 2 6-fluoro-1-methyl-4-oxo-7-(((1 r,4r)-4-((((3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-6- yl)methyl)amino)methyl)cyclohexyl)amino)-1,4-dihydro-1 ,8-naphthyridine-3-carboxylic acid
  • Example 2.1 Starting with Example 2.1 and following the procedure of Example 1.2, the title compound was obtained as an off-white solid (64%).
  • Example 3 1-ethyl-6-fluoro-4-oxo-7-(((1 r,4r)-4-((((3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1 ,4]thiazin-6- yl)methyl)amino)methyl)cyclohexyl)amino)-1,4-dihydro-1 ,8-naphthyridine-3-carboxylic acid
  • Example 3.1 Starting with Example 3.1 and following the procedure of Example 1.2, the title compound was obtained as an off-white solid (42%) after purification by preparative HPLC (column: Zorbax, acidic conditions, polar gradient, as specified in the analytical methods).
  • Example 4 1-ethyl-6-fluoro-4-oxo-7-(((1 r,4r)-4-((((3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1 ,4]oxazin-6- yl)methyl)amino)methyl)cyclohexyl)amino)-1,4-dihydro-1 ,8-naphthyridine-3-carboxylic acid
  • Example 4.1 Starting with Example 4.1 and following the procedure of Example 1.2, the title compound was obtained as an off-white solid (43%) after purification by preparative HPLC (column: Zorbax, acidic conditions, polar gradient, as specified in the analytical methods).
  • Example 5 1-cyclopropyl-6-fluoro-4-oxo-7-(((1 r,4r)-4-((((3-oxo-3,4-dihydro-2H-pyrazino[2,3- b][1,4]thiazin-6-yl)methyl)amino)methyl)cyclohexyl)amino)-1 ,4-dihydro-1 ,8-naphthyridine-3-carboxylic acid 5.1.
  • Example 5.1 Starting with Example 5.1 and following the procedure of Example 1.2, the title compound was obtained as an off-white solid (34%) after purification by preparative HPLC (column: Zorbax, acidic conditions, polar gradient, as specified in the analytical methods ).
  • Example 6 1-cyclopropyl-6-fluoro-4-oxo-7-(((1 r,4r)-4-((((3-oxo-3,4-dihydro-2H-pyrazino[2,3- b][1,4]oxazin-6-yl)methyl)amino)methyl)cyclohexyl)amino)-1 ,4-dihydro-1 ,8-naphthyridine-3-carboxylic acid
  • Example 6.1 Starting with Example 6.1 and following the procedure of Example 1.2, the title compound was obtained as an off-white solid (56%) after purification by preparative HPLC (column: Zorbax, acidic conditions, polar gradient, as specified in the analytical methods).
  • Example 7 6-fluoro-1-methyl-4-oxo-7-(((1 r,4r)-4-((((3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]thiazin-6- yl)methyl)(((phosphonooxy)methoxy)carbonyl)amino)methyl)cyclohexyl)amino)-1,4-dihydro-1 ,8- naphthyridine-3-carboxylic acid 7.1.
  • Example 1.1 250 mg, 0.38 mmol, 1 eq
  • DCM dimethylethyl sulfate
  • NaHC03 sat 4 mL
  • chloromethyl chloroformate 0.0372 mL, 0.418 mmol, 1.1 eq
  • the resulting solution was stirred vigorously for 2h at rt.
  • the mixture was diluted with DCM and water.
  • the phases were separated and the aq. layer was extracted with DCM once more.
  • the combined org. layers were washed with brine, dried over MgS04 and concentrated under reduced pressure to give the title intermediate as a yellow foam (272mg, 95% yield).
  • Example 7.1 270 mg, 0.36 mmol, 1 eq
  • DME DME
  • Tetra-n-butylammonium di-tert-butylphosphate 199 mg, 0.432 mmol, 1.2 eq
  • the mixture was cooled to rt and partitioned between EA and water.
  • the organic layer was washed with water and brine, dried over MgS0 4 and concentrated under reduced pressure to give the desired intermediate (322 mg, 97% yield) as a yellow foam which was used in the next step without purification.
  • LCMS1 ESI, m/z
  • t R 1.22 min, 924.75 [M+H + ]
  • Example 7.2 A solution of Example 7.2 (320 mg, 0.346 mmol, 1 eq) in DCM (5 mL) was cooled to 0°C and treated with TFA (0.663 mL, 8.66 mmol, 25 eq). The yellow solution was then stirred at 0°C for 2h. TBME (7 mL) was added to the solution, and the resulting suspension was stirred at 0°C for 5min, filtered and the solid was dried at hv for 5min. The resulting yellow solid was suspended in MeOH (5 mL) and 25% NH 4 OH (0.333 mL, 8.66 mmol, 25 eq) was added. The resulting mixture was then stirred at rt for 30min.
  • Example 8 6-fluoro-1-methyl-4-oxo-7-(((1 r,4r)-4-((((3-oxo-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-6- yl)methyl)(((phosphonooxy)methoxy)carbonyl)amino)methyl)cyclohexyl)amino)-1,4-dihydro-1,8- naphthyridine-3-carboxylic acid
  • Example 2.1 To a yellow solution of Example 2.1 (250 mg, 0.39 mmol, 1 eq) in DCM (4 mL) and NaHCCH sat (4 mL) was added chloromethyl chloroformate (0.0381 mL, 0.428 mmol, 1.1 eq). The resulting solution (two layers) was stirred vigorously for 2h at rt. The mixture was diluted with DCM and water. The phases were separated and the aq. layer was extracted with DCM once more. The combined org. layers were washed with brine, dried over MgS04 and concentrated under reduced pressure to give the title intermediate (285 mg, 100% yield) as an off-white foam which was used in the next step without further purification.
  • Example 8.1 (280 mg, 0.381 mmol, 1 eq) in DME (5 mL) was treated with Tetra-n- butylammonium di-tert-butylphosphate (21 1 mg, 0.458 mmol, 1.2 eq) and heated at 55°C for 5h. The mixture was cooled to rt and partitioned between EA and water. The organic layer was washed with water and brine, dried over MgS04 and concentrated under reduced pressure to give the desired intermediate (345 mg, 100% yield) as a off-white foam which was used in the last step without further purification.
  • Example 8.2 (340 mg, 0.374 mmol, 1 eq) in DCM (5 mL) was cooled to 0°C and treated with TFA (0.717 mL, 9.36 mmol, 25 eq). The yellow solution was then stirred at 0°C for 3h. TBME (7mL) was added to the solution and the resulting suspension was stirred at 0°C for 5min, filtered and the solid was dried at hv for 5min. The resulting solid was suspended in MeOH (5 mL) and 25% NH 4 OH (0.361 mL, 9.36 mmol, 25 eq) was added. The resulting mixture was then stirred at rt for 20min, and concentrated under reduced pressure.
  • MICs Minimal inhibitory concentrations
  • Staphylococcus aureus A798 is a multiply resistant strain (in particular quinolone-resistant)
  • Klebsiella pneumoniae A651 and Acinetobacter baumannii T6474 are both multiply resistant strains (in particular quinolone-resistant)
  • E. coli ATCC25922 and Moraxella catarrhalis A894 are both quinolone-sensitive strains.
  • Table 1 hereafter (MICs in mg/L).
  • Examples 7 and 8 of the present invention were tested against wild-type E. coli A- 1261 in the presence of alkaline phosphatase (from bovine intestinal mucosa: Sigma P6774-2KU; Lot: SLBB1 168), and in the absence of an alkaline phosphatase.
  • alkaline phosphatase from bovine intestinal mucosa: Sigma P6774-2KU; Lot: SLBB1 168
  • the corresponding antibacterial test results are given in Table 2 hereafter (MICs in mg/L).
  • CHO cells mammalian cell assays
  • Cell were fixed, the cytoplasm was stained with CellmaskRed, DNA was stained with Hoechst 33342 (Mutat Res. 630: 1-13, 2007).
  • the microtiterplates were read with a high-content screening microscope (Opera Phenix, Perkin Elmer) and cells, nuclei and micronuclei scored with an optimized algorithm using the manufacturer's Harmony Software.
  • Cytotoxicity was determined by calculating the quotient of the number of valid cells in compound-treated samples and the number of valid cells in DMSO-only- treated samples and plotting the number as fraction of valid cells against compound-concentration.
  • Cells were detected according to their cytoplasmic staining and defined as being valid if they contain 1 to 2 intact regular-shaped nuclei.
  • Micronucleii associated with valid cells were enumerated and induction of micronuclei formation tabulated as ratio versus untreated cells if the fraction of valid cells was 30.4 after baseline correction. Based on data obtained with known antibiotics, the threshold for significant increase was set at 2-fold.
  • the compounds according to the present invention not only show excellent antimicrobial activity against several bacterial strains (Table 1 ), they also exhibit superior pharmacological properties (Tables 3 and 4).
  • the compounds according to Examples 7 and 8 exhibit antimicrobial activity in biologically relevant environment via formation of the compound of Examples 1 and 2 (Table 2).

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Abstract

L'invention concerne des composés de formule I qui sont utiles en tant qu'agents antibactériens en médecine.
PCT/EP2020/069978 2019-07-16 2020-07-15 Dérivés de quinolone antibactériens WO2021009212A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007125952A1 (fr) 2006-04-28 2007-11-08 Shionogi & Co., Ltd. Derive amine ayant une activite antagoniste du recepteur y5 du npy
WO2011037433A2 (fr) 2009-09-28 2011-03-31 Lg Life Sciences Ltd. Utilisation d'un dérivé de quinolone contenant un groupe 7-(4-aminométhyl-3-oxime)pyrrolidine qui est capable d'induire un facteur de stimulation des colonies de granulocytes pour le traitement de la neutropénie et la restauration de l'hématopoïèse
WO2014178008A1 (fr) 2013-05-02 2014-11-06 Actelion Pharmaceuticals Ltd Derivés de quinolone
WO2017029602A2 (fr) 2015-08-16 2017-02-23 Glaxosmithkline Intellectual Property Development Limited Composés à utiliser dans des applications antibactériennes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007125952A1 (fr) 2006-04-28 2007-11-08 Shionogi & Co., Ltd. Derive amine ayant une activite antagoniste du recepteur y5 du npy
WO2011037433A2 (fr) 2009-09-28 2011-03-31 Lg Life Sciences Ltd. Utilisation d'un dérivé de quinolone contenant un groupe 7-(4-aminométhyl-3-oxime)pyrrolidine qui est capable d'induire un facteur de stimulation des colonies de granulocytes pour le traitement de la neutropénie et la restauration de l'hématopoïèse
WO2014178008A1 (fr) 2013-05-02 2014-11-06 Actelion Pharmaceuticals Ltd Derivés de quinolone
WO2017029602A2 (fr) 2015-08-16 2017-02-23 Glaxosmithkline Intellectual Property Development Limited Composés à utiliser dans des applications antibactériennes

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"Approved standard", 2006, CLINICAL AND LABORATORY STANDARDS INSTITUTE, article "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically"
"Handbook of Pharmaceutical Salts", 2008, WILEY-VCH, article "Properties, Selection and Use"
"Pharmaceutical Salts and Co-crystals", 2012, RSC PUBLISHING
MUTAT RES., vol. 630, 2007, pages 1 - 13
REMINGTON: "The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS, article "Pharmaceutical Manufacturing"
S. L. SOLOMON ET AL.: "Antibiotic Resistance Threats In the United States: Stepping Back from the Brink", ACADEMY OF FAMILY PHYSICIAN, vol. 89, no. 12, 15 June 2014 (2014-06-15), pages 940

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