WO2009027732A1 - Composés hétéroaromatiques 5-6-bicycliques possédant une activité antibactérienne - Google Patents

Composés hétéroaromatiques 5-6-bicycliques possédant une activité antibactérienne Download PDF

Info

Publication number
WO2009027732A1
WO2009027732A1 PCT/GB2008/050734 GB2008050734W WO2009027732A1 WO 2009027732 A1 WO2009027732 A1 WO 2009027732A1 GB 2008050734 W GB2008050734 W GB 2008050734W WO 2009027732 A1 WO2009027732 A1 WO 2009027732A1
Authority
WO
WIPO (PCT)
Prior art keywords
infection
methyl
compound
carbamoyl
compound according
Prior art date
Application number
PCT/GB2008/050734
Other languages
English (en)
Inventor
Brian Dangel
John Irvin Manchester
Brian Sherer
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Publication of WO2009027732A1 publication Critical patent/WO2009027732A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds which demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans.
  • this invention relates to compounds useful for the treatment of bacterial infections in warm-blooded animals such as humans, more particularly to the use of these compounds in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans.
  • bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens.
  • Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity.
  • Gram-positive pathogens for example Staphylococci, Enterococci, Streptococci and mycobacteria, are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established.
  • strains examples include methicillin resistant staphylococcus aureus (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiple resistant Enter ococcus faecium.
  • MRSA methicillin resistant staphylococcus aureus
  • MRCNS methicillin resistant coagulase negative staphylococci
  • Streptococcus pneumoniae and multiple resistant Enter ococcus faecium.
  • Vancomycin is a glycopeptide and is associated with various toxicities, including nephrotoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens. There is also now increasing resistance appearing towards agents such as ⁇ -lactams, quinolones and macrolides used for the treatment of upper respiratory tract infections, also caused by certain Gram negative strains including H. influenzae and M. catarrhalis.
  • DNA gyrase is a member of the type II family of topoisomerases that control the topological state of DNA in cells (Champoux, J. J.; 2001. Ann. Rev. Biochem. 70: 369-413). Type II topoisomerases use the free energy from adenosine triphosphate (ATP) hydrolysis to alter the topology of DNA by introducing transient double-stranded breaks in the DNA, catalyzing strand passage through the break and resealing the DNA.
  • ATP adenosine triphosphate
  • DNA gyrase is an essential and conserved enzyme in bacteria and is unique among topoisomerases in its ability to introduce negative supercoils into DNA.
  • the enzyme consists of two subunits, encoded by gyrA and gyrB, forming an A 2 B 2 tetrameric complex.
  • the A subunit of gyrase (GyrA) is involved in DNA breakage and resealing and contains a conserved tyrosine residue that forms the transient covalent link to DNA during strand passage.
  • the B subunit (GyrB) catalyzes the hydrolysis of ATP and interacts with the A subunit to translate the free energy from hydrolysis to the conformational change in the enzyme that enables strand-passage and DNA resealing.
  • topoisomerase IV Another conserved and essential type II topoisomerase in bacteria, called topoisomerase IV, is primarily responsible for separating the linked closed circular bacterial chromosomes produced in replication. This enzyme is closely related to DNA gyrase and has a similar tetrameric structure formed from subunits homologous to Gyr A and to Gyr B. The overall sequence identity between gyrase and topoisomerase IV in different bacterial species is high. Therefore, compounds that target bacterial type II topoisomerases have the potential to inhibit two targets in cells, DNA gyrase and topoisomerase IV; as is the case for existing quinolone antibacterials (Maxwell, A. 1997, Trends Microbiol. 5: 102-109).
  • DNA gyrase is a well-validated target of antibacterials, including the quinolones and the coumarins.
  • the quinolones ⁇ e.g. ciprofloxacin
  • the quinolones are broad-spectrum antibacterials that inhibit the DNA breakage and reunion activity of the enzyme and trap the GyrA subunit covalently complexed with DNA (Drlica, K., and X. Zhao, 1997, Microbiol. Molec. Biol.
  • cyclothialidine is a poor antibacterial agent showing activity only against some eubacterial species (Nakada, N, 1993, Antimicrob. Agents Chemother. 37: 2656-2661).
  • Synthetic inhibitors that target the B subunit of DNA gyrase and topoisomerase IV are known in the art.
  • coumarin-containing compounds are described in patent application number WO 99/35155
  • 5,6-bicyclic heteroaromatic compounds are described in patent application WO 02/060879
  • pyrazole compounds are described in patent application WO 01/52845 (US patent US6,608,087).
  • AstraZeneca has also published certain applications describing anti-bacterial compounds: WO2005/026149, WO2006/087544, WO2006/087548, WO2006/087543, WO2006/092599, WO2006/092608, WO2007/071965, WO2008/020227, WO2008/020222, WO2008/020229, and WO2008/068470.
  • the compounds of the present invention are regarded as effective against both Gram-positive and certain Gram-negative pathogens.
  • R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl; wherein R 1 may be optionally substituted on carbon by one or more R 5 ;
  • R 2 is selected from hydrogen or Ci_6alkyl; wherein said may be optionally substituted by one or more groups independently selected from halo, cyano, hydroxy, nitro and amino;
  • Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 11 ;
  • R 3 , R 6 , R 7 , R 9 and R 10 are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, Ci_6alkanoyl, Ci_6alkanoyloxy, 7V-(Ci-6alkyl)amino, ⁇ /,N-(Ci-6alkyl)2amino, Ci.6alkanoylamino, ⁇ /-(Ci-6alkyl)carbamoyl, ⁇ /, ⁇ /-(Ci -6 alkyl) 2 carbamoyl, ⁇ /-(Ci.
  • R 4 is a substituent on carbon is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ alkyl, C2-6alkenyl, C 2 - 6 alkynyl, Ci_6alkoxy, ⁇ /-(Ci.
  • Ci.6alkylS(O) a wherein a is 0 to 2, Ci_6alkoxycarbonyl, Ci- ⁇ alkoxycarbonylamino, ⁇ /-(Ci- 6 alkyl)sulphamoyl, ⁇ /,N-(Ci -6 alkyl)2Sulphamoyl, d- ⁇ alkylsulphonylamino, carbocyclyl-R 16 - or heterocyclyl-R 17 -; wherein R 4 may be optionally substituted on carbon by one or more R 18 ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 19 ;
  • R 5 is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci- ⁇ alkyl, C 2 - 6 alkenyl, C2-6alkynyl, Ci_6alkanoyl, Ci_6alkanoyloxy, ⁇ /-(Ci- 6 alkyl)amino, Ci. 6 alkanoylamino and C 3 _ 6 cycloalkyl;
  • R 8 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, Ci -6 alkanoyl, Ci_6alkylsulphonyl, Ci_6alkoxycarbonyl, carbamoyl, TV-(C i-6alkyl)carbamoyl, ⁇ /, ⁇ /-(Ci. 6 alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
  • R 12 , R 13 , R 16 and R 17 are independent selected from a direct bond, -O-, -N(R 20 )-, -C(O)-, -N(R 21 )C(O)-, -C(O)N(R 22 )-, -S(O) 8 -, -SO 2 N(R 23 )- or -N(R 24 )SO 2 -; wherein R 20 , R 21 , R 22 , R 23 and R 24 are independently selected from hydrogen or and s is 0-2; and
  • R ⁇ , R 15 and R 19 are independently selected from Ci_6alkyl, C 3 _ 6 cycloalkyl, Ci-6alkanoyl, Ci- ⁇ alkylsulphonyl, Ci- ⁇ alkoxycarbonyl, carbamoyl, ⁇ /-(Ci- 6 alkyl)carbamoyl, ⁇ /, ⁇ /-(Ci.
  • R 14 and R 18 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-iV-ethylamino, acetylamino, ⁇ /-methylcarbamoyl, iV-ethylcarbamoyl, ⁇ /, ⁇ /-dimethylcarbamoyl, 7V,7V-diethylcarbamoyl, 7V-methyl-7V-ethylcarbamo
  • R 1 , R 2 , R 4 , X 1 , X 2 , X 3 , ring A and n are as defined in formula (I);
  • R 3 is selected from the group consisting of hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C ⁇ aUcyl, C2-6alkenyl, C2-6alkynyl, Ci_6alkoxy, Ci_6alkanoyl, Ci_6alkanoyloxy, ⁇ /-(Ci-6alkyl)amino, ⁇ /, ⁇ /-(Ci-6alkyl)2amino, ⁇ /, ⁇ /-(Ci.
  • R 14 is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifiuoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dime thy lamino, diethylamino, 7V-methyl-7V-ethylamino, acetylamino, 7V-methylcarbamoyl, JV-ethylcarbamoyl, ⁇ iV-dimethylcarbamoyl, 7V,7V-diethylcarbamoyl, TV-methyl-TV-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethy
  • X 2 and X 3 are not both selected from (i) because the bond between -C(X 2 )- and -C(Ring A)- and the bond between -C(Ring A)- and -C(X 3 )- in formula (I) or (V) cannot both be double bonds.
  • the compounds represented by formula (I) or (I') do not include the compounds in Table A.
  • the invention provides pharmaceutical compositions comprising a compound represented by formula (I) or (I'), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • the invention provides a method of inhibiting bacterial DNA gyrase and/or bacterial topoisomerase IV in a warm-blooded animal in need of such treatment, comprising administering to the animal an effective amount of a compound represented by formula (I) or (I'), or a pharmaceutically acceptable salt thereof.
  • the warm-blooded animal is a human.
  • the invention provides a method of producing an antibacterial effect in a warm-blooded animal in need of such treatment, comprising administering to the animal an effective amount of a compound represented by formula (I) or (I'), or a pharmaceutically acceptable salt thereof.
  • the warm-blooded animal is a human.
  • the invention provides a method of treating a bacterial infection in a warm-blooded animal in need thereof, comprising administering to the animal an effective amount of a compound represented by formula (I) or (I'), or a pharmaceutically acceptable salt thereof.
  • the warm-blooded animal is a human.
  • the bacterial infection is selected from the group consisting of community- acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillin- resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and
  • the warm-blooded animal is a human.
  • the invention provides the use of a compound represented by formula (I) or (I'), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the production of an antibacterial effect in a warm-blooded animal.
  • the warm-blooded animal is a human.
  • the invention provides the use of a compound represented by formula (I) or (I'), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warm- blooded animal.
  • the warm-blooded animal is a human.
  • the invention provides the use of a compound represented by formula (I) or (I'), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use the treatment of a bacterial infection in a warm-blooded animal.
  • the bacterial infection is selected from the group consisting of community- acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections, Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci.
  • the warm-blooded animal is a human.
  • the invention provides a compound represented by formula (I) or (I'), or a pharmaceutically acceptable salt thereof, for use in production of an anti-bacterial effect in a warm-blooded animal.
  • the invention provides a compound represented by formula (I) or (I'), or a pharmaceutically acceptable salt thereof, for use in inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animal.
  • the invention provides a compound represented by formula (I) or (I'), or a pharmaceutically acceptable salt thereof, for use in the treatment of a bacterial infection in a warm-blooded animal.
  • the invention provides a compound represented by formula (I) or (I'), or a pharmaceutically acceptable salt thereof, for use in the treatment of community- acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections, Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis or Vancomycin-Resistant Enterococci.
  • alkyl includes both straight and branched chain alkyl groups.
  • alkyl groups include methyl, ethyl, propyl, isopropyl and t-butyl.
  • references to individual alkyl groups such as propyl are specific for the straight chain version only. An analogous convention applies to other generic terms.
  • a "heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)- and a ring sulphur atom may be optionally oxidised to form the S-oxide(s).
  • a “heterocyclyl” is a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked, a -CH 2 - group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxides.
  • a “heterocyclyl” is an unsaturated, carbon-linked, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen.
  • heterocyclyl examples and suitable values of the term "heterocyclyl” are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, pyrazolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, 7V-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine -TV-oxide and quinoline- ⁇ /-oxide.
  • heterocyclyl is imidazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyrazolyl, 1,2,4-triazolyl, pyridyl, benzothiazolyl, isoxazolyl, pyrazinyl, pyrimidinyl and thiazolyl.
  • a “carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a -CH 2 - group can optionally be replaced by a -C(O)-. Particularly “carbocyclyl” is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms.
  • Suitable values for "carbocyclyl” include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.
  • a particular example of “carbocyclyl” is phenyl.
  • An is acetoxy.
  • Examples are methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl.
  • Examples of "Ci- 4 alkoxycarbonylamino" are methoxycarbonylamino, ethoxycarbonylamino, n- and t-butoxycarbonylamino. Examples are methoxy, ethoxy and propoxy.
  • Examples are formamido, acetamido and propionylamino.
  • Examples of "Ci- 4 alkylS(O)a wherein a is 0 to 2" are methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl.
  • Examples of are propionyl and acetyl.
  • Examples of 'W-(d -4 alkyl)amino are methylamino and ethylamino.
  • Examples of 'W,N-(C 1-4 alkyl) 2 amino are di-N-methylamino, di-(7V-ethyl)amino and jV-ethyl-jV-methylamino.
  • Examples of "C2-4alkenyl” are vinyl, allyl and 1-propenyl.
  • Examples of "C 2 - 4 alkynyl” are ethynyl, 1-propynyl and 2-propynyl. Examples of
  • 'W-(Ci. 4 alkyl)sulphamoyl are 7V-(methyl)sulphamoyl and 7V-(ethyl)sulphamoyl.
  • Examples of " ⁇ /, ⁇ /-(Ci-4alkyl)2Sulphamoyl” are ⁇ /, ⁇ /-(dimethyl)sulphamoyl and ⁇ /-(methyl)- ⁇ /-(ethyl)sulphamoyl.
  • Examples of are methylaminocarbonyl and ethylaminocarbonyl. Examples are dimethylaminocarbonyl and methylethylaminocarbonyl.
  • Examples of 'W-(Ci- 4 alkoxy)carbamoyl are methoxyaminocarbonyl and isopropoxyaminocarbonyl.
  • Examples of 'W-(Ci-4alkyl)- ⁇ /-(Ci-4alkoxy)carbamoyl” are ⁇ /-methyl-7V-methoxyaminocarbonyl and N-methyl-TV-ethoxyaminocarbonyl.
  • Examples of 'W-(Ci. 4 alkyl)ureido" are N'-methylureido and N'-isopropylureido.
  • Examples of 'W,iV-(C 1-4 alkyl) 2 ureido" are NW-dimethylureido and N'-methyl-N'-isopropylureido.
  • Examples of 'W-(Ci- 4 alkyl)hydrazinocarbonyl" are N'-methylhydrazinocarbonyl and TV-isopropylhydrazinocarbonyl.
  • Examples of W,N'-(Ci -4 alkyl) 2 hydrazinocarbonyl” are ⁇ W-dimethylhydrazinocarbonyl and 7V'-methyl-7V -isopropylhydrazinocarbonyl.
  • Examples of "Ci -4 alkylsulphonylamino” are methylsulphonylamino, isopropylsulphonylamino and t-butylsulphonylamino.
  • Examples of “Ci ⁇ alkylsulphonylaminocarbonyl” are methylsulphonylaminocarbonyl, isopropylsulphonylaminocarbonyl and t-butylsulphonylaminocarbonyl. Examples are methylsulphonyl, isopropylsulphonyl and t-butylsulphonyl.
  • Examples of “Cs- ⁇ Cycloalkyl” are cyclopropyl and cyclohexyl.
  • Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, tosylate, ⁇ -glycerophosphate, fumarate, hydrochloride, citrate, maleate, tartrate and hydrobromide. Also suitable are salts formed with phosphoric and sulfuric acid.
  • suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, 7V-methylpiperidine, 7V-ethylpiperidine, procaine, dibenzylamine, 7V,7V-dibenzylethylamine, tris-(2-hydroxyethyl)amine, TV-methyl d-glucamine and amino acids such as lysine.
  • the pharmaceutically-acceptable salt is the sodium salt.
  • salts which are less soluble in the chosen solvent may be utilized whether pharmaceutically-acceptable or not.
  • a compound of the formula (I) or (I') or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which inhibits DNA gyrase and / or topoisomerase IV and is not to be limited merely to any one tautomeric form utilized within the formulae drawings.
  • the formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein. The same applies to compound names.
  • compounds of formula (I) or (I') may contain asymmetrically substituted carbon(s) and sulphur atom(s), and accordingly may exist in, and be isolated in, as far as those additional asymmetrically substituted carbon(s) and sulphur atom(s) are concerned, optically-active and racemic forms at those positions. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic or stereoisomeric form, or mixtures thereof, at any additional asymmetrically substituted carbon(s) and sulphur atom(s), which possesses properties useful in the inhibition of DNA gyrase and / or topoisomerase IV.
  • Optically-active forms may be prepared by procedures known in the art for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by enzymatic resolution, by biotransformation, or by chromatographic separation using a chiral stationary phase.
  • Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any polymorphic form, or mixtures thereof, which form possesses properties useful in the inhibition of DNA gyrase and / or topoisomerase IV.
  • H represents any isotopic form of hydrogen including 1 H, 2 H (D), and 3 H (T);
  • C represents any isotopic form of carbon including 12 C, 13 C, and 14 C;
  • O represents any isotopic form of oxygen including 16 O, 17 O and 18 O;
  • N represents any isotopic form of nitrogen including 13 N, 14 N and 15 N;
  • P represents any isotopic form of phosphorous including 31 P and 32 P;
  • S represents any isotopic form of sulfur including 32 S and 35 S;
  • F represents any isotopic form of fluorine including 19 F and 18 F;
  • Cl represents any isotopic form of chlorine including 35 Cl, 37 Cl and 36 Cl; and the like.
  • compounds represented by formula (I) or (I') comprise isomers of the atoms therein in their naturally occurring abundance.
  • 1 H would normally be present in greater than 99.98% abundance; however, a compound of the invention can be enriched in 2 H or 3 H at one or more positions where H is present.
  • R 1 is Ci -6 alkyl.
  • R 1 is ethyl.
  • R 2 is hydrogen.
  • X 1 N-.
  • X 1 C(R 6 )-.
  • X 1 C(R 6 )-; wherein R 6 is hydrogen.
  • X 2 and X 3 is selected from (i) and the other is selected from (ii):
  • X 2 is selected from (i) and X 3 is selected from (ii):
  • X 2 is -O-.
  • X 2 is -S-.
  • X 2 is -N(R 8 )-.
  • X 2 is -C(R 9 XR 10 )-.
  • X 3 is -O-.
  • X 3 is -S-.
  • X 3 is -N(R 8 )-.
  • X 3 is -N(R 8 )-; wherein R 8 is hydrogen or
  • X 3 is -N(R 8 )-; wherein R 8 is Ci -6 alkyl;
  • X 3 is -N(R 8 )-; wherein R 8 is hydrogen or t-butoxycarbonyl.
  • X 3 is -C(R 9 XR 10 )-.
  • Ring A is carbocyclyl
  • Ring A is phenyl
  • Ring A and (R 4 ) n together are 4-cyanophenyl. Ring A and (R 4 ) n together are 3-cyanophenyl.
  • Ring A is heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 11 .
  • Ring A is heterocyclyl
  • Ring A is a pyridyl. Ring A is pyrid-3-yl.
  • Ring A is pyrid-4-yl.
  • Ring A is a thiazolyl
  • Ring A is thiazol-2-yl. Ring A and (R 4 ) n together are 4-carboxy-thiazol-2-yl.
  • Ring A and (R 4 ) n together are 4-carbamoyl-thiazol-2-yl.
  • Ring A and (R 4 ) n together are 4-(7V-methyl-carbamoyl)-thiazol-2-yl.
  • Ring A and (R 4 ) n together are 4-(ethoxycarbonyl)-thiazol-2-yl. Ring A is a triazolyl.
  • Ring A is l,2,4-triazol-3-yl.
  • R 3 is hydrogen
  • R is a heterocyclyl, wherein said heterocyclyl may be optionally substituted on carbon by one or more R 14 ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 15 .
  • R 3 is a piperazinyl
  • R 3 is piperazin-1-yl.
  • R 3 is a morpholinyl
  • R 3 is morpholin-4-yl.
  • R 3 is a piperidinyl.
  • R 3 is piperidin-1-yl.
  • R 3 is pyridyl
  • R 3 is pyrid-4-yl.
  • R 3 is benzothiazolyl.
  • R 3 is benzothiazol-2-yl.
  • R 3 is a phenyl which may be optionally substituted on one or more carbon with one or more independently selected R 14 .
  • R 3 is phenyl
  • R 3 is 3-methyl-phenyl.
  • R 3 is 4-methyl-phenyl.
  • R 3 is 2-fiuoro-phenyl.
  • R 3 is hydrogen
  • R 3 is a heterocyclyl, wherein said heterocyclyl may be optionally substituted on carbon by one or more R 14 ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 15 .
  • R 3 is a piperazinyl
  • R 3 is piperazin-1-yl.
  • R 3 is a morpholinyl.
  • R 3 is morpholin-4-yl.
  • R 3 is a piperidinyl
  • R 3 is piperidin-1-yl.
  • R 3 is pyridyl.
  • R 3 is pyrid-4-yl.
  • R 3 is benzothiazolyl.
  • R 3 is benzothiazol-2-yl.
  • R 3 is a phenyl which may be optionally substituted on one or more carbon with one or more independently selected R 14 .
  • R 3' is phenyl.
  • R 3 is 3-methyl-phenyl.
  • R 3 is 4-methyl-phenyl.
  • R 3 is 2-fluoro-phenyl.
  • R 3 is 4-(moropholinomethyl)-phenyl.
  • R 4 is cyano.
  • R 4 is carboxy
  • R 4 is carbamoyl
  • R 4 is N-methyl-carbamoyl.
  • R 4 is N-ethyl-carbamoyl.
  • R 4 is ethoxycarbonyl.
  • n 0.
  • n 1.
  • R 2 is hydrogen
  • X 1 C(R 6 )-; wherein R 6 is hydrogen;
  • X 3 is -N(R 8 )-; wherein R 8 is hydrogen or Ci_ 6 alkoxycarbonyl; Ring A is pyridyl;
  • R 3 is hydrogen; n is 0; or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 , X 1 , R 3 , R 8 , Ring A, R 4 and n are as described herein above; or a pharmaceutically acceptable salt thereof.
  • R 3 is H.
  • ring A is pyridyl.
  • R 3 is H and ring A and (R 4 ) n together are pyrid-3-yl.
  • R 3 is piperazinyl and ring A together with (R 4 ) n is 4-carboxy-thiazole-2-yl, 4-carbamoyl-thiazol-2- yl or 4-ethoxycarbonyl-thiazol-2-yl.
  • R 3 is morpholino and ring A together with (R 4 ) n is 4-carboxy-thiazole-2-yl, 4-(N-methyl- carbamoyl)-thiazol-2-yl, or 4-ethoxycarbonyl-thiazol-2-yl.
  • R 8 is H or methyl.
  • R 3 is piperdinyl and ring A together with (R 4 ) n is l,2,4-triazol-3-yl, 4-carboxy-thiazole-2-yl, 4-(N-methyl-carbamoyl)- thiazol-2-yl, or 4-carbamoyl-thiazol-2-yl.
  • R 3 is phenyl, 3-methylphenyl, 4-methylphenyl, or 2-fluorophenyl and ring A together with (R 4 ) n is l,2,4-triazol-3-yl, 4-carboxy-thiazole-2-yl, 4-(N-methyl-carbamoyl)-thiazol-2-yl, or 4- ethoxycarbonyl-thiazol-2-yl.
  • R 1 , R 2 , X 1 , R 3 , Ring A, R 4 and n are as described herein above; or a pharmaceutically acceptable salt thereof.
  • R 3 is H
  • ring A together with (R 4 ) n is pyrid-3yl, pyrid-4-yl, 3-cyano-phenyl, or 4-cyanophenyl.
  • a compound of formula (I') which is a compound of formula (IC):
  • R 1 , R 2 , X 1 , R 3 , Ring A, R 4 and n are as described herein above; or a pharmaceutically acceptable salt thereof.
  • R 3 is pyrid-4-yl and ring A together with (R 4 ) n is 4-carboxy-thiazole-2-yl or 4-ethoxycarbonyl-thiazol-2-yl.
  • R 3 ' is benzothiazol-2-yl and ring A together with (R 4 ) n is 4- carboxy-thiazole-2-yl, 4-(N-methyl-carbamoyl)-thiazol-2-yl, or 4-ethoxycarbonyl-thiazol-2- yl.
  • R 3 ' is 4-(morpholinomethyl)-phenyl, and ring A together with (R 4 ) n is 4-carboxy-thiazole-2-yl or 4-ethoxycarbonyl-thiazol-2-yl.
  • R 3 ' is phenyl and ring A together with (R 4 ) n is 4- ethoxycarbonyl-thiazol-2-yl.
  • Particular compounds of the invention are the compounds of the Examples, each of which provides a further independent aspect of the invention.
  • the present invention also comprises any two or more compounds of the Examples.
  • the present invention provides a process for preparing a compound of formula (I) or (I') or a pharmaceutically-acceptable salt thereof.
  • the present invention also provides that the compounds of the formula (I) or (I') and pharmaceutically-acceptable salts thereof, can be prepared by a process as follows (wherein the variables are as defined above unless otherwise stated): Process a) reacting an amine of formula (II):
  • L is a displaceable group. Suitable values for L include chloro, bromo, tosyl and trifluoromethylsulphonyloxy.
  • M is an organometallic reagent
  • suitable values for M include organoboron and organotin reagents, in particular B(OR Z ) 2 where R z is hydrogen or C ⁇ aUcyl for example B(OH) 2 ; and Sn(R y ) 3 where R y is Ci -6 alkyl for example Sn(Bu) 3 .
  • Process a) and Process b) Amines and acids may be coupled together in the presence of a suitable coupling reagent.
  • Standard peptide coupling reagents known in the art can be employed as suitable coupling reagents, or for example carbonyldiimidazole (CDI) and dicyclohexyl-carbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in the presence of a base for example triethylamine, pyridine, or 2,6-di- ⁇ /Ay/-pyridines such as 2,6-lutidine or
  • Suitable solvents include dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and dimethylformamide.
  • the coupling reaction may conveniently be performed at a temperature in the range of -40 to 40 0 C.
  • Suitable activated acid derivatives include acid halides, for example acid chlorides, and active esters, for example pentafluorophenyl esters.
  • the reaction of these types of compounds with amines is well known in the art, for example they may be reacted in the presence of a base, such as those described above, and in a suitable solvent, such as those described above. The reaction may conveniently be performed at a temperature in the range of -40 to 40 0 C.
  • Compounds of formula (III) may be prepared according to the following scheme:
  • L' is CN, CHO, CO 2 H or COCl.
  • Compounds of formula (V) can be prepared in a likewise manner.
  • Process ⁇ Formation of a thiazole-2-yl ring A can be carried out by heating a compound of formula (X) or formula (X') with a compound of formula (XI) in a suitable polar solvent such as an alcohol.
  • Compounds of formula (X) or (X') can be prepared by reacting a compound of formula (XI) or (XI'), respectively, with ammonium sulphide in a suitable polar solvent such as an alcohol, typically, with the addition of heat.
  • a suitable polar solvent such as an alcohol
  • R 3 or R 3 is an amine, such as -NH 2 , N- alkyl amine, N,N-dialkylamine or a non-aromatic heterocycle comprising at least one secondary nitrogen ring member
  • R 3 or R 3 is an amine, such as -NH 2 , N- alkyl amine, N,N-dialkylamine or a non-aromatic heterocycle comprising at least one secondary nitrogen ring member
  • R and R are each independently hydrogen, a Ci_ 6 alkyl, or R and R together with the nitrogen to which they are attached form a heterocycle.
  • a compound of formula (XIa) can be prepared by reacting 2-amino-6-chloro-9- methyl-9H-purine-8-carbonitrile (see J Chem Soc, Perkin Trans I, 1977, 1003 for preparation) with an isocyanate derivative in a manner analogous to that described for Process c).
  • Process g): Formation of a l,2,4-triazol-3-yl ring A can be carried out by heating a compound of formula (XI) or formula (XF) in the presence of hydrazine and a compound of formula (XIII).
  • a compound of formula (XIII) is formic acid it may be used as the solvent for the reaction.
  • Process h Compounds of formula (I) or (I') in which R 3 or R 3 is hydrogen may be reacted with a compound of formula (XIV) or (XIV) by coupling chemistry utilizing an appropriate catalyst.
  • Such reactions are well known in the art. For example, Pd(PPh 3 ) 4 and a suitable base such as sodium carbonate can be utilized. The reactions take place in suitable solvents and may require thermal conditions.
  • Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents, oxidation of substituents, esterification of substituents, amidation of substituents, formation of heteroaryl rings.
  • the reagents and reaction conditions for such procedures are well known in the chemical art.
  • aromatic substitution reactions include the introduction of alkoxides, diazotization reactions followed by introduction of thiol group, alcohol group, halogen group.
  • modifications include; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • the skilled organic chemist will be able to use and adapt the information contained and referenced within the above references, and accompanying Examples therein and also the Examples herein, to obtain necessary starting materials, and products. If not commercially available, the necessary starting materials for the procedures such as those described above may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the above described procedure or the procedures described in the examples.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, a silyl group such as trimethylsilyl or an arylmethyl group, for example benzyl.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.
  • a suitable protecting group for an amino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid
  • an arylmethoxycarbonyl group such as a benzyloxycarbonyl group
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or for example, an allyl group which may be removed, for example, by use of a palladium catalyst such as palladium acetate.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.
  • Optically active forms of a compound of the invention may be obtained by carrying out one of the above procedures using an optically active starting material (formed, for example, by asymmetric induction of a suitable reaction step), or by resolution of a racemic form of the compound or intermediate using a standard procedure, or by chromatographic separation of diastereoisomers (when produced). Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates.
  • an optically active starting material formed, for example, by asymmetric induction of a suitable reaction step
  • Resolution of a racemic form of the compound or intermediate using a standard procedure
  • chromatographic separation of diastereoisomers when produced.
  • Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates.
  • a pure regioisomer of a compound of the invention it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioiso
  • Enzyme Potency Testing Methods Compounds may be tested for inhibition of GyrB ATPase activity using an ammonium molybdate/malachite green-based phosphate detection assay (Lanzetta, P. A., L. J. Alvarez, P. S. Reinach, and O. A. Candia, 1979, 100: 95-97).
  • Assays can be performed in multiwell plates in 100 ⁇ l reactions containing: 50 mM HEPES buffer pH 7.5, 75 mM ammonium acetate, 5.5 mM magnesium chloride, 0.5 mM ethylenediaminetetraacetic acid, 5% glycerol, 1 mM 1 ,4-Dithio-DL-threitol, 200 nM bovine serum albumin, 5 ⁇ g/ml sheared salmon sperm DNA, 2.5 nM E. coli GyrA, 2.5 nM E. coli GyrB, 250 ⁇ M ATP, and compound in dimethylsulfoxide.
  • Reactions can be quenched with 150 ⁇ l of ammonium molybdate/malachite green detection reagent containing 1.2 mM malachite green hydrochloride, 8.5 mM ammonium mo lybdate tetrahydrate, and 1 M hydrochloric acid. Plates can be read in an absorbance plate reader at 650 nm and percent inhibition values may be calculated using dimethylsulfoxide (2%)-containing reactions as 0% inhibition and novobiocin-containing (2 ⁇ M) reactions as 100% inhibition controls. Compound potency can be based on IC50 measurements determined from reactions performed in the presence of 10 different compound concentrations. Inhibition of E. coli GyrA and/or GyrB can be assessed by observing percent inhibition at a given compound concentration.
  • Compounds may be tested for inhibition of topoisomerase IV ATPase activity as described above for GyrB except the lOO ⁇ l reactions may contain the following: 20 mM TRIS buffer pH 8, 50 mM ammonium acetate, 8 mM magnesium chloride, 5% glycerol, 5 mM 1,4-dithio-DL-threitol, 0.005% Brij-35, 5 ⁇ g/ml sheared salmon sperm DNA, 2.5 nM Streptococcus pneumoniae ParE, 160 ⁇ M ATP, and compound in dimethylsulfoxide.
  • Compound potency may be based on IC50 measurements determined from reactions performed in the presence of 10 different compound concentrations.
  • Compound activity against S. pneumoniae can be assessed by observing percent inhibition at a given compound concentration.
  • Inhibition of S. pneumoniae ParE can be assessed by observing percent inhibition at a given compound concentration.
  • Compounds may be tested for inhibition of topoisomerase IV ATPase activity as described above for GyrB except the 30 ⁇ l reactions contained the following: 20 mM TRIS buffer pH 8, 50 mM ammonium acetate, 8 mM magnesium chloride, 5% glycerol, 5 mM 1,4- Dithio-DL-threitol, 0.005% Brij-35, 5 ⁇ g/ml sheared salmon sperm DNA, 1.25 nM S. pneumoniae ParE, 160 ⁇ M ATP, and compound in dimethylsulfoxide.
  • Compound potency may be based on IC50 measurements determined from reactions performed in the presence of 10 different compound concentrations. Inhibition of S.
  • pneumoniae ParE can be assessed by observing percent inhibition at a given compound concentration. Compounds in the following table were tested in an assay substantially similar to the assay described in this paragraph to determine percent inhibition of S. pneumoniae ParE at a compound concentration of 50 ⁇ M:
  • compounds of the invention have IC50 values of ⁇ 200 ⁇ M in one or both assays described herein above.
  • Example 1 showed an IC50 of 20.2 ⁇ M against Streptococcus pneumoniae ParE.
  • the compounds in Table A have IC50 values of >200 ⁇ M against Streptococcus pneumoniae ParE.
  • Compounds may be tested for antimicrobial activity by susceptibility testing in liquid media.
  • Compounds may be dissolved in dimethylsulfoxide and tested in 10 doubling dilutions in the susceptibility assays.
  • the organisms used in the assay may be grown overnight on suitable agar media and then suspended in a liquid medium appropriate for the growth of the organism.
  • the suspension can be a 0.5 McFarland and a further 1 in 10 dilution can be made into the same liquid medium to prepare the final organism suspension in 100 ⁇ L. Plates can be incubated under appropriate conditions at 37 0 C for 24 hrs prior to reading.
  • the Minimum Inhibitory Concentration (MIC) may be determined as the lowest drug concentration able to reduce growth by 80% or more.
  • a compound of the formula (I) or (I'), or a pharmaceutically-acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.
  • compounds of the present invention inhibit bacterial DNA gyrase and / or topoisomerase IV and are therefore of interest for their antibacterial effects.
  • the compounds of the invention inhibit bacterial DNA gyrase and are therefore of interest for their antibacterial effects.
  • the compounds of the invention inhibit topoisomerase IV and are therefore of interest for their antibacterial effects.
  • the compounds of the invention inhibit both DNA gyrase and topoisomerase IV and are therefore of interest for their antibacterial effects.
  • infection or “bacterial infection” refers to a gynecological infection.
  • infection or “bacterial infection” refers to a respiratory tract infection (RTI).
  • RTI respiratory tract infection
  • infection or “bacterial infection” refers to a sexually transmitted disease.
  • infection or “bacterial infection” refers to a urinary tract infection.
  • infection or “bacterial infection” refers to acute exacerbation of chronic bronchitis (ACEB).
  • infection or “bacterial infection” refers to acute otitis media.
  • infection refers to acute sinusitis. In one aspect of the invention “infection” or “bacterial infection” refers to an infection caused by drug resistant bacteria. In one aspect of the invention “infection” or “bacterial infection” refers to catheter-related sepsis. In one aspect of the invention “infection” or “bacterial infection” refers to chancroid. In one aspect of the invention “infection” or “bacterial infection” refers to chlamydia. In one aspect of the invention
  • infection or “bacterial infection” refers to community-acquired pneumonia (CAP).
  • infection or “bacterial infection” refers to complicated skin and skin structure infection.
  • infection or “bacterial infection” refers to uncomplicated skin and skin structure infection.
  • infection or “bacterial infection” refers to endocarditis.
  • infection or “bacterial infection” refers to febrile neutropenia.
  • infection or “bacterial infection” refers to gonococcal cervicitis.
  • infection or “bacterial infection” refers to gonococcal urethritis.
  • infection refers to hospital-acquired pneumonia (HAP). In one aspect of the invention “infection” or “bacterial infection” refers to osteomyelitis. In one aspect of the invention “infection” or “bacterial infection” refers to sepsis. In one aspect of the invention “infection” or “bacterial infection” refers to syphilis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter baumanii. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter haemolyticus .
  • an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter junii. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter johnsonii. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter Iwoffi. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by B acteroides bivius. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by B acteroides fragilis.
  • an “infection” or “bacterial infection” refers to an infection caused by Burkholderia cepacia. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Campylobacter jejuni. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Chlamydia pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Chlamydia urealyticus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Chlamydophila pneumoniae.
  • an “infection” or “bacterial infection” refers to an infection caused by Clostridium difficili. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterobacter aerogenes. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterobacter cloacae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterococcus faecalis . In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterococcus faecium.
  • an “infection” or “bacterial infection” refers to an infection caused by Escherichia coli. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Gardnerella vaginalis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Haemophilus par ainfiuenzae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Haemophilus influenzae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Helicobacter pylori.
  • an “infection” or “bacterial infection” refers to an infection caused by Klebsiella pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Legionella pneumophila. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by
  • an “infection” or “bacterial infection” refers to an infection caused by Methicillin-susceptible Staphylococcus aureus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Moraxella catarrhalis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Morganella morganii. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Mycoplasma pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by N ' eisseria gonorrhoeae.
  • an “infection” or “bacterial infection” refers to an infection caused by Penicillin- resistant Streptococcus pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Penicillin-susceptible Streptococcus pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus magnus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus micros. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by
  • an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus asaccharolyticus . In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus prevotii. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus tetradius. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus vaginalis.
  • an “infection” or “bacterial infection” refers to an infection caused by Proteus mirabilis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Pseudomonas aeruginosa. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Quinolone-Resistant Staphylococcus aureus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Quinolone-Resistant Staphylococcus epidermis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Salmonella typhi.
  • an “infection” or “bacterial infection” refers to an infection caused by Salmonella paratyphi. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Salmonella enteritidis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Salmonella typhimurium. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Serratia marcescens. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Staphylococcus aureus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Staphylococcus epidermidis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by
  • an "infection” or “bacterial infection” refers to an infection caused by Streptococcus agalactiae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Streptococcus pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Streptococcus pyogenes. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Stenotrophomonas maltophilia. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Ureaplasma urealyticum.
  • an “infection” or “bacterial infection” refers to an infection caused by Vancomycin-Resistant Enter ococcus faecium. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by
  • an “infection” or “bacterial infection” refers to an infection caused by Vancomycin-Resistant Staphylococcus aureus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Vancomycin-Resistant Staphylococcus epidermis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Bacteroides spp..
  • an “infection” or “bacterial infection” refers to an infection caused by Burkholderia spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Campylobacter spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Chlamydia spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Chlamydophila spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Clostridium spp..
  • an "infection” or “bacterial infection” refers to an infection caused by Enterobacter spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterococcus spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Escherichia spp.. In one aspect of the invention an “infection” or
  • bacterial infection refers to an infection caused by Gardnerella spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Haemophilus spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Helicobacter spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Klebsiella spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Legionella spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Moraxella spp..
  • an “infection” or “bacterial infection” refers to an infection caused by Morganella spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Mycoplasma spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Neisseria spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Proteus spp..
  • an “infection” or “bacterial infection” refers to an infection caused by Pseudomonas spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Salmonella spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Serratia spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Staphylococcus spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Strep toccocus spp..
  • an “infection” or “bacterial infection” refers to an infection caused by Stenotrophomonas spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Ureaplasma spp.. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by aerobes. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by obligate anaerobes. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by facultative anaerobes. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by gram-positive bacteria.
  • an “infection” or “bacterial infection” refers to an infection caused by gram-negative bacteria. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by gram- variable bacteria. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by atypical respiratory pathogens.
  • a method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt thereof.
  • a method for inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal, such as a human being in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof as defined hereinbefore.
  • a method of treating a bacterial infection in a warm-blooded animal which comprises administering to said animal an effective amount of a compound of formula (I) or (I') or a pharmaceutically acceptable salt thereof as defined hereinbefore.
  • a method of treating a bacterial infection selected from a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, a urinary tract infection, acute exacerbation of chronic bronchitis (ACEB), acute otitis media , acute sinusitis, an infection caused by drug resistant bacteria, catheter-related sepsis, chancroid, chlamydia, community-acquired pneumonia (CAP), complicated skin and skin structure infection, uncomplicated skin and skin structure infection, endocarditis, febrile neutropenia, gonococcal cervicitis, gonococcal urethritis, hospital-acquired pneumonia (HAP), osteomyelitis, sepsis and /or syphilis in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or (I') or a
  • a further feature of the present invention is a compound of formula (I) or (I') and pharmaceutically acceptable salts thereof for use as a medicament.
  • the medicament is an antibacterial agent.
  • a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the production of an anti-bacterial effect in a warm-blooded animal such as a human being.
  • a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal such as a human being.
  • a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a bacterial infection selected from a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, a urinary tract infection, acute exacerbation of chronic bronchitis (ACEB), acute otitis media , acute sinusitis, an infection caused by drug resistant bacteria, catheter-related sepsis, chancroid, chlamydia, community-acquired pneumonia (CAP), complicated skin and skin structure infection, uncomplicated skin and skin structure infection, endocarditis, febrile neutropenia, gonococcal cervicitis, gonococcal urethritis, hospital-acquired pneumonia (HAP), osteomyelitis, sepsis and / or syphilis in a warm-blooded animal such as a human being.
  • a bacterial infection selected from a gynec
  • a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof for use in the production of an anti-bacterial effect in a warm-blooded animal such as a human being.
  • a compound of formula (I) or (I'), or a pharmaceutically acceptable salt thereof for use in the treatment of a bacterial infection in a warm-blooded animal such as a human being.
  • a bacterial infection selected from a gynecological infection, a respiratory
  • the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or (I') or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable diluent or carrier.
  • a pharmaceutical composition which comprises a compound of formula (I) or (I') as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in producing an anti-bacterial effect in a warm-blooded animal, such as a human being.
  • a pharmaceutical composition which comprises a compound of formula (I) or (I') as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal, such as a human being.
  • a pharmaceutical composition which comprises a compound of formula (I) or (I') as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in the treatment of a bacterial infection in a warm-blooded animal, such as a human being.
  • a pharmaceutical composition which comprises a compound of formula (I) or (I') as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in the treatment of a gynecological infection, a respiratory tract infection (RTI), a sexually transmitted disease, a urinary tract infection, acute exacerbation of chronic bronchitis (ACEB), acute otitis media , acute sinusitis, an infection caused by drug resistant bacteria, catheter-related sepsis, chancroid, chlamydia, community-acquired pneumonia (CAP), complicated skin and skin structure infection, uncomplicated skin and skin structure infection, endocarditis, febrile neutropenia, gonococcal cervicitis, gonococcal urethritis, hospital-acquired pneumonia (HAP), osteomyelitis, sepsis and/or syphilis in a warm-blooded animal,
  • RTI respiratory tract infection
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • the compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate
  • granulating and disintegrating agents such as corn starch or algenic acid
  • binding agents such as starch
  • lubricating agents
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • the pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • a daily dose in the range of 1-50 mg/kg is employed.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • one embodiment of the present invention is directed to treating or preventing diseases caused by bacterial infections, wherein the bacteria comprise a GyrB ATPase or topoisomerase IV ATPase enzyme.
  • Treating a subject with a disease caused by a bacterial infection includes achieving, partially or substantially, one or more of the following: the reducing or amelioration of the progression, severity and/or duration of the infection, arresting the spread of an infection, ameliorating or improving a clinical symptom or indicator associated with a the infection (such as tissue or serum components), and preventing the reoccurrence of the infection.
  • preventing a bacterial infection refers to the reduction in the risk of acquiring the infection, or the reduction or inhibition of the recurrence of the infection.
  • a compound of the invention is administered as a preventative measure to a patient, preferably a human, before a surgical procedure is preformed on the patient to prevent infection.
  • the term "effective amount" refers to an amount of a compound of this invention for treating or preventing a bacterial infection is an amount which is sufficient to prevent the onset of an infection, reduce or ameliorate the severity, duration, or progression, of an infection, prevent the advancement of an infection, cause the regression of an infection, prevent the recurrence, development, onset or progression of a symptom associated with an infection, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.
  • compounds of formula (I) or (I') and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in- vitro and in- vivo test systems for the evaluation of the effects of inhibitors of DNA gyrase and / or topoisomerase IV in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • Suitable classes and substances may be selected from one or more of the following: i) other antibacterial agents for example macrolides e.g. erythromycin, azithromycin or clarithromycin; quinolones e.g. ciprofloxacin or levofloxacin; ⁇ -lactams e.g. penicillins e.g.
  • amoxicillin or piperacillin cephalosporins e.g. ceftriaxone or ceftazidime
  • carbapenems e.g. meropenem or imipenem etc
  • aminoglycosides e.g. gentamicin or tobramycin; or oxazolidinones
  • anti-infective agents for example, an antifungal triazole e.g. or amphotericin
  • biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) efflux pump inhibitors.
  • a chemotherapeutic agent selected from: i) one or more additional antibacterial agents; and/or ii) one or more anti-infective agents; and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) one or more efflux pump inhibitors.
  • fast-atom bombardment (FAB) mass spectral data were generally obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected or using Agilent 1 lOOseries LC/MSD equipped with Sedex 75ELSD, run in atmospheric pressure chemical ionization mode and, where appropriate, either positive ion data or negative ion data were collected; mass spectra were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ES); values for m/z are given; generally, only ions which indicate the parent mass are reported;
  • EI electron impact
  • FAB fast atom bombardment
  • ES electrospray
  • each intermediate was generally purified to the standard required for the subsequent stage and was characterized in sufficient detail to confirm that the assigned structure was correct; purity was assessed by high pressure liquid chromatography, thin layer chromatography, or NMR and identity was determined by infra-red spectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate; (vii) the following abbreviations may be used: DMSO is dimethylsulfoxide; CDCI 3 is deuterated chloroform; MS is mass spectroscopy; EtOAc is ethyl acetate;
  • EDC is N-(3-dimethylaminopropyl)-N-ethylcarbodiimide
  • HATU is 2-(lH-7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate methanaminium
  • OAc is acetate
  • THF is tetrahydrofuran
  • MeOH is methanol
  • TFA trifluoroacetic acid
  • Xantphos is 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene
  • the reaction mixture was then refluxed at 100 0 C for 14 h, then cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (3x10 mL). The combine extracts were washed with water (20 mL) and brine, then dried over anhydrous sodium sulphate and concentrated to a residue. The residue was subjected to column chromatography (silica, chloroform-methanol) to yield the title compound.
  • DMSO-d fi ⁇ 1.17 (t, 3H), 3.72 (t, 4H), 3.26 (q, 2H), 4.11 (s, 3H), 4.20 (br s, 4H), 7.74 (s, IH), 7.90 (s, IH), 8.36 (s, IH), 9.03 (t, IH), 9.08 (s, IH).
  • DMSO-d ⁇ ⁇ 1.25 (t, 3H), 2.50 (s, 3H), 2.87 (d, 3H), 3.30 (q, 2H), 4.25 (s, 3H), 7.54 (m, 2H), 8.58 (m, 3H), 9.11 (br s, IH), 9.77 (br s, IH).
  • DMSOd n ⁇ 1.162 (t, 3H), ⁇ 1.35 (t, 3H), ⁇ 3.286 (q, 2H), ⁇ 4.195 (s, 3H), ⁇ 4.38 (q, 2H), ⁇ 7.49 (m, 2H), ⁇ 7.68 (m, IH), ⁇ 8.27 (t, IH), ⁇ 8.77 (s, IH), ⁇ 9.21 (t, IH), ⁇ 9.21 (t, IH), ⁇ 9.85 (s, IH).
  • DMSO-d ⁇ ⁇ 1.16 (t, 3H), ⁇ 1.65-1.694 (m, 6H), ⁇ 3.269 (q, 2H), ⁇ 4.077 (s, 3H), ⁇ 4.25 (bs, 4H), ⁇ 8.568 (s, IH), ⁇ 8.94 (s, IH), ⁇ 9.28 (s, IH).
  • Examples 28-30 The following Examples were prepared by the procedure described in Example 27 from the starting materials (SM) indicated.
  • the reaction slurry was heated to 6O 0 C for 1 hour.
  • Sodium borohydride (0.544 g, 14.40 mmol) was added in a single portion, and the reaction was heated for an additional 12 hours.
  • the progress of the reaction was monitored by LC/MS.
  • the solvent was removed by rotary evaporation.
  • the solid was dissolved in EtOAc and water.
  • the mixture was neutralized with K 2 CO 3 while cooling the mixture in an ice bath.
  • the tin salts precipitated from solution and were removed by filtering the mixture though a pad of Celite.
  • 6-Chloropyridine-2,3-diamine (Intermediate 1, 2.4 g, 16.72 mmol) was dissolved in MeOH (20 mL). Nicotinaldehyde (1.584 mL, 16.72 mmol) was added in a single portion and the reaction was heated to 6O 0 C. Upon reacting, the solution turned red, and LC/MS showed that the condensation product ([M+H] + : 233, 235 for C 11 H 9 CIN4) had formed. The reflux condenser was removed, and the saturated product was aromatized by heating the solution in the presence of air for 4 days. Upon cooling and concentrating a precipitate formed.
  • DMSOd n ⁇ 1.16 (t, 3H), 1.437 (s, 9H), 3.076 (t, 2H), 3.239 (m, 2H), 3.48-3.64 (m, 4H), 4.004 (s, 3H), 4.45 (br s, 2H), 8.94 (br t, IH), 9.1 (br s, IH), 9.8 (br s, IH), 10.04 (br s, IH).
  • DMSO-c ⁇ ⁇ 1.14 (t, 3H), ⁇ 1.60-1.67 (m, 6H), ⁇ 3.23 (q, 2H), ⁇ 3.762 (s, 3H), ⁇ 3.88 (brs, 2H), ⁇ 4.42 (brs, 2H), ⁇ 8.91 (s, IH).
  • Argon gas was purged through a mixture of l-(6-chloro-8-cyano-9-methyl-9H-purin-2-yl)-3- ethyl-urea (Intermediate 19, 100 mg, 0.3577 mmol) in toluene (5 mL) for 15 min, then palladium acetate (6.97 mg, 0.0311 mmol), tri-o-tolylphosphine (24 mg, 0.0789 mmol), potassium phosphate (151.6 mg, 0.715 mmol) were added. The reaction mixture was again purged with argon gas for 10 min and phenylboronic acid (86.5 mg, 0.7148 mmol) was added and the mixture was heated to 80 0 C for 6 h.
  • reaction mixture was cooled to room temperature, then passed through a celite bed.
  • the filtrate was concentrated under reduced pressure to obtain a residue which was stirred in diethyl ether for 10-20 min.
  • the solid which formed was collected by filtration and dried to afford 70 mg (60%) of l-(8-cyano-9-methyl-6- phenyl-9H-purin-2-yl)-3-ethylurea.
  • reaction mixture was heated to 100 0 C for 18 h. After completion of the reaction, the reaction mixture was concentrated to dryness. Water (10 mL) was added to the residue and the suspension that formed was stirred for 20 min. The suspension was filtered and the solid was co-distilled with toluene (2 x 20 mL) to afford 1.05 g (75%) of l-(8-cyano-9-methyl-6- piperidin-l-yl-9H-purin-2-yl)-3 -ethyl-urea as solid.
  • Phosphorus oxychloride (93 mL, 1020.54 mmol) was cooled to 5 0 C using an ice bath. Dry DMF (35 mL) was added slowly with stirring over 30 min to the phosphorus oxychloride. A white precipitate formed during the addition. The reaction mixture was gently warmed (45 0 C) to dissolve the precipitate and produce a clear solution to which was added 2- aminopyrimidine-4,6-diol (24.2 g, 190.40 mmol) in small portions over 1 h, then the mixture was heated at 8O 0 C. The reaction mixture turned a dark red-brown color. After 12 hours, the reaction mixture was cooled to room temperature and excess POCl ⁇ was removed by rotary evaporation.
  • ethyl 2-amino-4-chlorothieno[2,3-d]pyrimidine-6-carboxylate (Intermediate 31, 1 g, 3.88 mmol), pyridin-4-ylboronic acid (0.636 g, 4.66 mmol) and sodium carbonate (0.494 g, 4.66 mmol) were combined and suspended in a 4:1 mixture of dioxane and water.
  • Pd(PPh 3 ) 4 (0.224 g, 0.19 mmol) was added in a single portion.
  • the vessel was sealed and heated to 15O 0 C in the microwave for 30 min.
  • the reaction mixture was diluted with water and methanol, then filtered through a pad of Celite to remove the palladium salts.
  • ethyl 2-amino-4-(pyridin-4-yl)thieno[2,3-d]pyrimidine-6- carboxylate (Intermediate 32, 300 mg, 1.00 mmol), ethyl isocyanate (0.785 mL, 9.99 mmol) and dibutyltin diacetate (2.68 ⁇ L, 9.99 ⁇ mol) were combined and suspended in a 1:1 mixture of THF and toluene.
  • the vessel was sealed and heated to 14O 0 C in the microwave for 60 min.
  • the reaction mixture was diluted with ethyl acetate and washed with water and brine.
  • the organic phase was dried over Na2SO ⁇ filter and concentrate, then purified by flash column chromatography (0-100% EtOAc / hexanes) to afford the title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés représentés par la formule (I) et des sels pharmaceutiquement acceptables de ceux-ci; des procédés de préparation de ces composés, des compositions pharmaceutiques contenant ces composés et l'utilisation de ces composés comme médicaments ainsi que leur utilisation dans le traitement d'infections bactériennes.
PCT/GB2008/050734 2007-08-24 2008-08-22 Composés hétéroaromatiques 5-6-bicycliques possédant une activité antibactérienne WO2009027732A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US95794207P 2007-08-24 2007-08-24
US60/957,942 2007-08-24

Publications (1)

Publication Number Publication Date
WO2009027732A1 true WO2009027732A1 (fr) 2009-03-05

Family

ID=39951715

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2008/050734 WO2009027732A1 (fr) 2007-08-24 2008-08-22 Composés hétéroaromatiques 5-6-bicycliques possédant une activité antibactérienne

Country Status (1)

Country Link
WO (1) WO2009027732A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009131237A1 (fr) * 2008-04-21 2009-10-29 住友化学株式会社 Composition de lutte contre les arthropodes nuisibles, et composé hétérocyclique fusionné
WO2011024004A1 (fr) 2009-08-26 2011-03-03 Astrazeneca Ab Dérivés hétérocycliques de l'urée utiles pour le traitement d'une infection bactérienne
WO2011121555A1 (fr) 2010-03-31 2011-10-06 Actelion Pharmaceuticals Ltd Dérivés d'isoquinoléin-3-ylurée antibactériens
WO2012131588A1 (fr) 2011-03-29 2012-10-04 Actelion Pharmaceuticals Ltd Dérivés de 3-uréidoisoquinoléin-8-yle
US8324239B2 (en) 2010-04-21 2012-12-04 Novartis Ag Furopyridine compounds and uses thereof
US8697708B2 (en) 2010-09-15 2014-04-15 F. Hoffmann-La Roche Ag Azabenzothiazole compounds, compositions and methods of use
CN103819489A (zh) * 2014-03-18 2014-05-28 齐鲁天和惠世制药有限公司 一种青霉烷酸二苯甲酯亚砜的制备方法
EP2923734A1 (fr) * 2009-03-13 2015-09-30 Katholieke Universiteit Leuven, K.U. Leuven R&D Analogues de purines et leur utilisation en tant qu'agents immunosuppresseurs
WO2016071499A1 (fr) 2014-11-06 2016-05-12 Basf Se Composé hétérobicyclique de 3-pyridyle utilisé pour lutter contre les invertébrés nuisibles
CN107207530A (zh) * 2014-12-02 2017-09-26 拜耳作物科学股份公司 作为害虫防治剂的双环化合物
WO2018174288A1 (fr) 2017-03-24 2018-09-27 大正製薬株式会社 Dérivé de 2(1h)-quinolinone
EP3424919A1 (fr) * 2013-09-13 2019-01-09 FMC Corporation Pesticides à base d'azole bicyclique substitué par hétérocycle
CN112745317A (zh) * 2020-12-29 2021-05-04 西南大学 嘌呤噻唑类化合物及其制备方法和应用
US11168093B2 (en) 2018-12-21 2021-11-09 Celgene Corporation Thienopyridine inhibitors of RIPK2
AU2018353759B2 (en) * 2017-10-18 2022-07-14 Hk Inno.N Corporation Heterocyclic compound as a protein kinase inhibitor
CN117229258A (zh) * 2022-06-07 2023-12-15 杭州壹瑞医药科技有限公司 N-四唑基芳基脲类衍生物及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002060879A2 (fr) * 2000-12-15 2002-08-08 Vertex Pharmaceuticals Incorporated Inhibiteurs de la gyrase et utilisations associees
EP1256578A1 (fr) * 2001-05-11 2002-11-13 Pfizer Products Inc. Dérivés de thiazole et leur utilisation comme inhibiteurs de cdk

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002060879A2 (fr) * 2000-12-15 2002-08-08 Vertex Pharmaceuticals Incorporated Inhibiteurs de la gyrase et utilisations associees
EP1256578A1 (fr) * 2001-05-11 2002-11-13 Pfizer Products Inc. Dérivés de thiazole et leur utilisation comme inhibiteurs de cdk

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2009238930B2 (en) * 2008-04-21 2013-07-25 Sumitomo Chemical Company, Limited Harmful arthropod control composition, and fused heterocyclic compound
EP2274983A1 (fr) * 2008-04-21 2011-01-19 Sumitomo Chemical Company, Limited Composition de lutte contre les arthropodes nuisibles, et composé hétérocyclique fusionné
US8242133B2 (en) 2008-04-21 2012-08-14 Sumitomo Chemical Company, Limited Arthropod pest control compositions comprising substituted oxazolo [5,4-b ] pyridines
US8324387B2 (en) 2008-04-21 2012-12-04 Sumitomo Chemical Company, Limited Substituted Oxazolo[5,4-b]pyridines
US8445522B2 (en) 2008-04-21 2013-05-21 Sumitomo Chemical Company, Limited Substituted 2-(4-pyridyl)benzoxazoles, and compositions thereof, for use in arthropod pest control
WO2009131237A1 (fr) * 2008-04-21 2009-10-29 住友化学株式会社 Composition de lutte contre les arthropodes nuisibles, et composé hétérocyclique fusionné
EP2274983A4 (fr) * 2008-04-21 2013-10-30 Sumitomo Chemical Co Composition de lutte contre les arthropodes nuisibles, et composé hétérocyclique fusionné
US8609705B2 (en) 2008-04-21 2013-12-17 Sumitomo Chemical Company, Limited Fused heterocyclic compounds, and compositions thereof, for use in arthropod pest control
EP2923734A1 (fr) * 2009-03-13 2015-09-30 Katholieke Universiteit Leuven, K.U. Leuven R&D Analogues de purines et leur utilisation en tant qu'agents immunosuppresseurs
WO2011024004A1 (fr) 2009-08-26 2011-03-03 Astrazeneca Ab Dérivés hétérocycliques de l'urée utiles pour le traitement d'une infection bactérienne
WO2011121555A1 (fr) 2010-03-31 2011-10-06 Actelion Pharmaceuticals Ltd Dérivés d'isoquinoléin-3-ylurée antibactériens
US8324239B2 (en) 2010-04-21 2012-12-04 Novartis Ag Furopyridine compounds and uses thereof
US8697708B2 (en) 2010-09-15 2014-04-15 F. Hoffmann-La Roche Ag Azabenzothiazole compounds, compositions and methods of use
US8889676B2 (en) 2011-03-29 2014-11-18 Actelion Pharmaceuticals Ltd. 3-ureidoisoquinolin-8-yl derivatives
WO2012131588A1 (fr) 2011-03-29 2012-10-04 Actelion Pharmaceuticals Ltd Dérivés de 3-uréidoisoquinoléin-8-yle
US10822351B2 (en) 2013-09-13 2020-11-03 Fmc Corporation Heterocycle-substituted bicyclic azole pesticides
US11578085B2 (en) 2013-09-13 2023-02-14 Fmc Corporation Heterocycle-substituted bicyclic azole pesticides
EP3424919A1 (fr) * 2013-09-13 2019-01-09 FMC Corporation Pesticides à base d'azole bicyclique substitué par hétérocycle
CN103819489B (zh) * 2014-03-18 2015-10-28 齐鲁天和惠世制药有限公司 一种青霉烷酸二苯甲酯亚砜的制备方法
CN103819489A (zh) * 2014-03-18 2014-05-28 齐鲁天和惠世制药有限公司 一种青霉烷酸二苯甲酯亚砜的制备方法
WO2016071499A1 (fr) 2014-11-06 2016-05-12 Basf Se Composé hétérobicyclique de 3-pyridyle utilisé pour lutter contre les invertébrés nuisibles
CN107207530A (zh) * 2014-12-02 2017-09-26 拜耳作物科学股份公司 作为害虫防治剂的双环化合物
JP2017537913A (ja) * 2014-12-02 2017-12-21 バイエル・クロップサイエンス・アクチェンゲゼルシャフト 有害生物防除剤としての二環式化合物 本出願は、新規二環式化合物、それら化合物を含んでいる組成物、害虫（ａｎｉｍａｌ ｐｅｓｔ）を防除するためのそれらの使用、並びに、それらを調製するための方法及び中間体に関する。
KR20190133667A (ko) 2017-03-24 2019-12-03 다이쇼 세이야꾸 가부시끼가이샤 2(1h)-퀴놀리논 유도체
WO2018174288A1 (fr) 2017-03-24 2018-09-27 大正製薬株式会社 Dérivé de 2(1h)-quinolinone
AU2018353759B2 (en) * 2017-10-18 2022-07-14 Hk Inno.N Corporation Heterocyclic compound as a protein kinase inhibitor
US11524968B2 (en) 2017-10-18 2022-12-13 Hk Inno.N Corporation Heterocyclic compound as a protein kinase inhibitor
US11168093B2 (en) 2018-12-21 2021-11-09 Celgene Corporation Thienopyridine inhibitors of RIPK2
CN112745317A (zh) * 2020-12-29 2021-05-04 西南大学 嘌呤噻唑类化合物及其制备方法和应用
CN117229258A (zh) * 2022-06-07 2023-12-15 杭州壹瑞医药科技有限公司 N-四唑基芳基脲类衍生物及其制备方法和应用

Similar Documents

Publication Publication Date Title
WO2009027732A1 (fr) Composés hétéroaromatiques 5-6-bicycliques possédant une activité antibactérienne
EP2102199B1 (fr) Composés d'urée polycycliques antibactériens
WO2009027733A1 (fr) Dérivés de (2-pyridin-3-ylimidazo[1,2-b]pyridazin-6-yl)urée en tant qu'agents antibactériens
EP2303894A1 (fr) Dérivés de thiazolo [5, 4-b] pyridine et d oxazolo [5,4-b] comme agents antibactériens
US20080312211A1 (en) Antibacterial Pyrrolopyridines, Pyrrolopyrimidines and Pyrroloazepines-154
CA2745063A1 (fr) Derives de l'acide 2-(piperidine-1-yl)-4-heterocyclyl-thiazole-5-carboxylique utilises pour lutter contre les infections bacteriennes
EP2158199B1 (fr) Composés de pipéridine et leurs utilisations
US20090325902A1 (en) Heterocyclic urea derivatives and methods of use thereof
US8569484B2 (en) Heterocyclic urea derivatives and methods of use thereof
EP2300463A1 (fr) Dérivés hétérocycliques d'urée pour le traitement d'infections bactériennes
WO2008020227A2 (fr) Composés chimiques
EP1856103A2 (fr) Derives de pyrrole comme inhibiteurs d'adn gyrase et de topoisomerase
US20100317624A1 (en) Heterocyclic urea derivatives and methods of use thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08788705

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08788705

Country of ref document: EP

Kind code of ref document: A1