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WO2019111020A1 - ß-LACTONE COMPOUNDS - Google Patents

ß-LACTONE COMPOUNDS Download PDF

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Publication number
WO2019111020A1
WO2019111020A1 PCT/GB2018/053567 GB2018053567W WO2019111020A1 WO 2019111020 A1 WO2019111020 A1 WO 2019111020A1 GB 2018053567 W GB2018053567 W GB 2018053567W WO 2019111020 A1 WO2019111020 A1 WO 2019111020A1
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Prior art keywords
compound
pharmaceutically acceptable
alkyl
acceptable salt
formula
Prior art date
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PCT/GB2018/053567
Other languages
French (fr)
Inventor
Christopher J. Schofield
Christopher T. LOHANS
Ho Ting Henry CHAN
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Oxford University Innovation Limited
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Publication of WO2019111020A1 publication Critical patent/WO2019111020A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems

Definitions

  • the present invention relates to b-lactone compounds that may be useful as inhibitors of b-lactamases.
  • the present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of bacterial infections.
  • b-Lactamases are the most commonly encountered cause of resistance to b-lactam antibiotics, which are the most frequently prescribed class of antibacterial drug world-wide [1- 3] b-lactamases render b-lactams inactive through two steps that involve acylation and de acylation, which ultimately results in hydrolysis of the b-lactam ring [4, 5]
  • SBL serine b-lactamase
  • MBL zinc ion-dependent metallo-b- lactamase
  • B1 , B2 and B3 Clinically useful b-lactamase inhibitors are being sought, but the varying chemistries and active site architectures of the different classes makes the development of cross-class inhibitors extremely challenging [8-10]
  • Clavulanic acid is an example of a b-lactam-based inhibitor principally of class A SBLs that has been used clinically for many years. Most commonly it is used in combination with penicillin derivatives, such as amoxycillin and ticarcillin, to enhance their bactericidal effects against some b-lactamase-carrying isolates of species such as E. coli and K.
  • Clavulanate and the related compounds tazobactam and sulbactam are in effect irreversible inhibitors whose activity arises from fragmentation of the acyl-enzyme complex formed by reaction with the active-site serine nucleophile, to generate inactivated species
  • avibactam is a hoh-b-lactam-based b-lactamase inhibitor containing a diazobicyclo heterocyclic core structure which acylates SBLs, at least some cases reversibly, and has a broader spectrum of activity than clavulanic acid.
  • MBLs are particularly concerning because they hydrolyse most known b-lactam antibiotics, including the so called ‘last resort’ b-lactam antibiotics, such as some carbapenems, and they confer resistance to b-lactam antibiotics in many pathogens. No clinically useful MBL inhibitors are presently available [20]
  • the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.
  • the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a bacterial infection in a warm-blooded animal, such as man.
  • the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a bacterial infection in a warm-blooded animal, such as man, in combination with a b-lactam antibiotic.
  • the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a gram-positive bacterial infection in a warm-blooded animal, such as man.
  • the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a gram-positive bacterial infection in a warm-blooded animal, such as man, in combination with a b-lactam antibiotic.
  • the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a gram-negative bacterial infection in a warm-blooded animal, such as man.
  • the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a gram-negative bacterial infection in a warm-blooded animal, such as man, in combination with a b-lactam antibiotic.
  • the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of gram-positive and/or gram-negative bacterial infections.
  • the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of gram-positive and/or gram-negative bacterial infections in combination with a b-lactam antibiotic.
  • the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of gram-positive and/or gram-negative bacterial infections.
  • the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of gram-positive and/or gram-negative bacterial infections in combination with a b-lactam antibiotic.
  • the present invention provides a method of treating a gram-positive and/or gram-negative bacterial infection, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides a method of treating a gram-positive and/or gram-negative bacterial infection, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in combination with a b-lactam antibiotic.
  • the present invention provides a pharmaceutical composition as defined herein which comprises a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.
  • the present invention provides a pharmaceutical composition as defined herein, for use in the treatment of gram-positive and/or gram-negative bacterial infections in a warm-blooded animal, such as man.
  • the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the production of a b-lactamase inhibitory effect.
  • the present invention provides a method of inhibiting a bacterial b- lactamase in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention also provides a combination product comprising a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and a b-lactam antibiotic.
  • a combination product comprising a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and a b-lactam antibiotic in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the combination product of the present invention provides for the administration of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and a b-lactam antibiotic.
  • the combination product may be in the form of a combined preparation of the compound as defined herein and the b-lactam antibiotic; it may include additional antibiotics or b-lactamase inhibitors.
  • the combination product may comprise a kit of parts comprising separate formulations of the compound as defined herein and the b- lactam antibiotic. The separate formulations of the compound as defined herein and the b- lactam antibiotic may be administered sequentially, separately and/or simultaneously.
  • the separate formulations of the compound as defined herein and the b-lactam antibiotic of the combination product are administered simultaneously (optionally repeatedly). In another embodiment, the separate formulations of the compound as defined herein and the b-lactam antibiotic of the combination product are administered sequentially (optionally repeatedly). In another embodiment, the separate formulations of the compound as defined herein and the b-lactam antibiotic of the combination product are administered separately (optionally repeatedly). Where the administration of the separate formulations of the compound as defined herein and the b-lactam antibiotic of the combination product is sequential or separate, the delay in administering the second formulation should not be such as to lose the beneficial effect of the combination therapy.
  • the present invention provides a combination product comprising a compound as defined herein, or a pharmaceutically-acceptable salt or solvate thereof, and a b-lactam antibiotic, or a pharmaceutically-acceptable salt thereof, for use sequentially, separately and/or simultaneously in the treatment of bacterial infections in a warm-blooded animal, such as man.
  • a combination product which comprises a kit of parts comprising the following components:
  • the kit of parts is for the treatment of bacterial infections in a warm-blooded animal, such as man.
  • the kit of parts comprises:
  • a first container comprising a a compound as defined herein, or a pharmaceutically- acceptable salt or solvate thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier;
  • a second container comprising a b-lactam antibiotic, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier; and a container means for containing said first and second containers.
  • the kit of parts further comprises instructions on how to administer the components sequentially, separately and/or simultaneously.
  • references to“treating” or“treatment” include prophylaxis as well as the alleviation of established symptoms of a condition.
  • “Treating” or“treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • A“therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • “alkyl” includes both straight and branched chain alkyl groups and analogues thereof. References to individual alkyl groups such as“propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as“isopropyl” are specific for the branched chain version only.
  • “(1- 6C)alkyl” includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl and f-butyl.
  • “phenyl(1-6C)alkyl” includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.
  • (m-nC) or "(m-nC) group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • (3-7C)cycloalkyl means a hydrocarbon ring containing from 3 to 7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • “(1-4C)alkoxy” refers to oxygen-linked straight and branched chain alkyl groups containing from 1 to 4 carbon atoms, for example, methoxy, ethoxy, /- propoxy, n-propoxy, n- butoxy or f-butoxy.
  • “(1-3C)fluoroalkyl” refers to 1 to 3 carbon alkyl groups bearing one of more fluoro substituents, for example, fluoromethyl, difluoromethyl, trifluoromethyl or 2,2,2-trifluoroethyl.
  • halo refers to fluoro, chloro, bromo and iodo.
  • heterocycloalkyl means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s).
  • heterocycloalkyl includes both monovalent species and divalent species.
  • Monocyclic heterocycloalkyl rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring.
  • Bicyclic heterocycloalkyl rings contain from about 7 to about 17 ring atoms, suitably from 7 to 12 ring atoms.
  • Bicyclic heterocycloalkyl rings may be fused, spiro, or bridged ring systems.
  • heterocycloalkyl groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers.
  • Heterocycloalkyls containing nitrogen include, for example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like.
  • Typical sulfur containing heterocycloalkyls include tetrahydrothienyl, dihydro-1 , 3-dithiol, tetrahydro-2/-/-thiopyran, and hexahydrothiepine.
  • heterocycloalkyls include 2 , 3-d i hyd roth i azoly 1 , 2, 5-di hydrothiazolyl , 4,5-dihydrothiazolyl, dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl.
  • the oxidized sulfur heterocycles containing SO or SO2 groups are also included.
  • examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1 ,1 -dioxide and thiomorpholinyl 1 ,1 -dioxide.
  • heterocycloalkyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, 1 ,1 -dioxide, thiomorpholinyl, thiomorpholinyl 1 ,1- dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl, in particular azetidinyl, pyrrolidinyl or piperidinyl.
  • any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom.
  • bridged ring systems is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131-133, 1992.
  • bridged heterocycloalkyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza- bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidine.
  • heteroaryl or“heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur.
  • heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members.
  • the heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings.
  • Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen.
  • the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • heteroaryl examples include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthy
  • Heteroaryl also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur.
  • partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-
  • heteroaryl groups examples include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • bicyclic heteroaryl groups containing a six-membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.
  • aryl means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms.
  • aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In a particular embodiment, an aryl is phenyl.
  • optionally substituted refers to either groups, structures, or molecules that are substituted and those that are not substituted.
  • the term“wherein a/any CH, CH2, CH 3 group or heteroatom (i.e. NH) within a R 1 group is optionally substituted” suitably means that (any) one of the hydrogen radicals of the R 1 group is substituted by a relevant stipulated group.
  • phrase“compound of the invention” means those compounds which are disclosed herein, both generically and specifically.
  • the present invention relates to a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as shown below:
  • R 1 is selected from the group consisting of:
  • R 2 is hydrogen or methyl
  • R 4 is hydrogen or (1-4C)alkyl
  • X is NR 12 , O, S or a bond
  • R 6 is hydrogen, (1-4C)alkyl, halo, hydroxy or (1-4C)alkoxy;
  • R 9 is hydrogen, (1-4C)alkyl or aryl, wherein (1-4C)alkyl or aryl are optionally substituted with one or more of hydroxy, (1-4C)alkoxy, halo, (1-3C)fluoroalkyl or C0 2 R 16 ;
  • R 11 is hydroxy, (1-4C)alkoxy or NR 17 R 18 ;
  • R 8 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 18 , R 19 , R 20 and R 21 are each independently selected from hydrogen or (1-3C)alkyl.
  • Particular compounds of the invention include, for example, compounds of formula I, or pharmaceutically acceptable salts and/or solvates thereof, wherein, unless otherwise stated, each of R 1 , R 2 , R 3 , R 4 , X, R 5 , R 6 , R 7 , R 9 , R 11 and R 17 and any associated substituent groups has any of the meanings defined hereinbefore or in any of paragraphs (1) to (57) hereinafter:-
  • R 2 is hydrogen
  • R 2 is methyl
  • R 3 is (1-4C)alkyl optionally substituted with one or more of NR 7 R 8 , halo
  • R 8 , R 9 , R 10 and R 11 are as described herein;
  • R 3 is (1-4C)alkyl substituted with NR 7 R 8 ; wherein R 7 and R 8 are as described herein;
  • R 3 is (1-4C)alkyl optionally substituted with one or more halo;
  • R 3 is methyl optionally substituted with one or more halo
  • R 3 is methyl
  • R 3 is trifluoromethyl
  • R 3 is f-butyl
  • R 3 is heterocycloalkyl optionally substituted with one or more of of NR 7 R 8 ,
  • R 3 is heterocycloalkyl selected from:
  • R 3 is heterocycloalkyl selected from:
  • R 3 is selected from:
  • R 3 is selected from:
  • R 4 is hydrogen
  • R 4 is methyl
  • R 4 is f-butyl
  • X is NR 12 ;
  • X is a bond and R 5 is (1-4C)alkyl
  • R 5 is hydrogen
  • R 6 is hydrogen
  • R 6 is methyl; (43) R 6 is f-butyl;
  • R 9 is Ci- 4 alkyl or aryl each optionally substituted with one or more of hydroxy, Ci- 4alkoxy, halo, Ci-3fluoroalkyl or CO2R 16 ;
  • R 9 is Ci- 4 alkyl optionally substituted with one or more of hydroxy, Ci- 4 alkoxy, halo or
  • R 9 is methyl optionally substituted with one or more of hydroxy, Ci- 4 alkoxy, halo or
  • R 9 is methyl
  • R 9 is aryl optionally substituted with one or more of hydroxy, Ci- 4 alkoxy, halo, Ci- 3fluoroalkyl or CO2R 16 ;
  • R 9 is phenyl optionally substituted with one or more of hydroxy, Ci- 4 alkoxy, halo, Ci- 3fluoroalkyl or CO2H;
  • R 9 is phenyl substituted with CO2H
  • R 11 is NR 17 R 18 ; wherein R 17 and R 18 are as described herein;
  • R 11 is NR 17 R 18 ; wherein R 17 is hydrogen, Ci- 4 alkyl or SC>2NR 19 R 20 and R 18 , R 19 and R 20 are hydrogen or methyl;
  • R 11 is NR 17 R 18 ; wherein R 17 is SC ⁇ Nhh and R 18 is hydrogen or methyl;
  • R 11 is NR 17 R 18 ; wherein R 17 is SC ⁇ Nhh and R 18 is hydrogen;
  • R 1 to R 21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
  • R 1 , R 3 to R 21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
  • R 3 to R 21 are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
  • R 3 to R 21 are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
  • R 3 to R 21 are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
  • R 3 is as defined in any one of paragraphs (8) to (24) above, such as any one of paragraphs (19) to (24), for example as defined in paragraph (24).
  • R 2 to R 21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
  • R 2 to R 21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
  • R 4 to R 21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
  • R 2 to R 21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
  • R 2 to R 21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
  • R 4 to R 21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
  • a heteroaryl or heterocycloalkyl group as defined herein is a monocyclic heteroaryl or heterocycloalkyl group comprising one, two or three heteroatoms selected from N, O or S.
  • a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.
  • a heterocycloalkyl group is a 4-, 5-, 6- or 7-membered heterocyclyl ring comprising one, two or three heteroatoms selected from N, O or S.
  • a heterocycloalkyl group is a 4-, 5- or 6-membered ring comprising one, two or three heteroatoms selected from N, O or S [e.g. azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl]
  • an aryl group is phenyl
  • R 1 is as defined in any one of paragraphs (1) to (5) above.
  • R 2 is as defined in any one of paragraphs (6) to (7) above.
  • R 3 is as defined in any one of paragraphs (8) to (24) above. More suitably,
  • R 3 is as defined in any one of paragraphs (19) to (24). Most suitably, R 3 is as defined in paragraph (24).
  • R 4 is as defined in any one of paragraphs (25) to (27) above. More suitably, R 4 is methyl.
  • Suitable, X is as defined in any one of paragraphs (28) to (34) above.
  • R 5 is as defined in any one of paragraphs (35) to (40) above.
  • R 6 is as defined in any one of paragraphs (41) to (43) above.
  • R 7 is as defined in any one of paragraphs (44) to (46) above.
  • R 9 is as defined in any one of paragraphs (47) to (53) above.
  • R 11 is as defined in any one of paragraphs (54) to (57) above.
  • Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following:
  • a compound, or a pharmaceutically acceptable salt or solvate thereof selected from one of the following compounds:
  • the various functional groups and substituents making up the compounds of the formula I are typically chosen such that the molecular weight of the compound of the formula I does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 700, or less than 650, or less than 600. More preferably, the molecular weight is less than 550 and, for example, is 500 or less
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • an inorganic or organic acid for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn-lngold-Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a“racemic mixture”.
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess b-lactamase inhibitory activity.
  • the present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H(D), and 3 H (T);
  • C may be in any isotopic form, including 12 C, 13 C, and 14 C;
  • O may be in any isotopic form, including 16 0 and 18 0; and the like.
  • tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • N-oxides Compounds of formula I containing an amine function may also form N-oxides.
  • a reference herein to a compound of the formula I that contains an amine function also includes the N-oxide.
  • one or more than one nitrogen atom may be oxidised to form an N-oxide.
  • Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g.
  • the compounds of formula I may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached.
  • pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the formula I and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the formula I.
  • the present invention includes those compounds of the formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the formula I may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • pro-drug Various forms of pro-drug have been described, for example in the following documents:- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of formula I containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically acceptable esters for carboxy include Ci- 6 alkyl esters such as methyl, ethyl and tert- butyl, Ci- 6 alkoxymethyl esters such as methoxymethyl esters, Ci- 6 alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, C3-8cycloalkylcarbonyloxy- Ci- 6 alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters,
  • 2-oxo-1 ,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1 ,3-dioxolen-4-ylmethyl esters and Ci- 6 alkoxycarbonyloxy- Ci- 6 alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the formula I containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include Ci-ioalkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci- l oalkoxycarbonyl groups such as ethoxycarbonyl, A/,/ ⁇ /-(Ci ⁇ carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a Ci-4alkylamine such as methylamine, a (Ci-4alkyl)2amine such as dimethylamine, A/-ethyl-/ ⁇ /-methylamine or diethylamine, a Ci- 4alkoxy- C ⁇ alkylamine such as 2-methoxyethylamine, a phenyl-Ci-4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a Ci-4alkylamine such as methylamine
  • a (Ci-4alkyl)2amine such as dimethylamine
  • a suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with Ci-ioalkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, /V-alkylaminomethyl, L/,L/- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and
  • the in vivo effects of a compound of the formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the formula I. As stated hereinbefore, the in vivo effects of a compound of the formula I may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
  • the compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.
  • reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or f-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 by, for example, 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 te/f-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric 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 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 with hydrazine.
  • 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, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • 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, sodium hydroxide or ammonia.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • 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 f-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.
  • a base such as sodium hydroxide
  • a f-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.
  • Resins may also be used as a protecting group.
  • b-lactam antibiotics include carbapenems (e.g. meropenem, faropenem, imipenem, ertapenem, doripenem, panipenem/betamipron and biapenem as well as razupenem, tebipenem, lenapenem and tomopenem), ureidopenicillins (e.g. piperacillin), carbacephems (e.g. loracarbef) and cephalosporins (e.g.
  • cefpodoxime ceftazidime, cefotaxime, ceftriaxone, ceftobiprole, and ceftaroline.
  • suitable b-lactam antibacterial agents include, for example, aztreonam, temocillin, piperacillin, cefpodoxime, ceftazidime, cefotaxime, ceftriaxone, meropenem, faropenem, imipenem, loracarbef, ceftobiprole and ceftaroline.
  • the b-lactam antibiotic is selected from azetreonam, ceftazidime, meropenem, ertrapenem, imipenem or faropenem.
  • compositions [00130] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • solid oral forms may contain, together with the active compound, diluents, such as, for example, lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, such as, for example, silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; such as, for example, starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, such as, for example, starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as, for example, lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • diluents such as, for example, lactose, dextrose, sac
  • 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, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral or parenteral administration is preferred. Most suitably, oral administration is preferred.
  • 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/or preservative agents.
  • An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) 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.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the condition, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration may also be suitable, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
  • the present invention provides compounds that function as inhibitors of b- lactamases and/or penicillin-binding proteins.
  • the present invention also provides a method of inhibiting bacterial infection, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, in combination with a b-lactam antibiotic.
  • the present invention also provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
  • the present invention also provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a bacterial infection in a warm-blooded animal, such as man.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a bacterial infection in man.
  • the treatment may be prophylactic (i.e. intended to prevent disease).
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of serine b-lactamase activity.
  • Class A serine b-lactamases that may be inhibited by compounds of the present invention include TEM-1 , SHV-1 , SFC-1 , CTX-M-15 and KPC-2.
  • Class C serine b-lactamases are also termed AmpC b-lactamases.
  • Class D serine b-lactamases that may be inhibited by compounds of the present invention include OXA-10, OXA-23, OXA-48 and BPU-1.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of class D serine b- lactamase activity.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of metallo ⁇ -lactamase activity.
  • Class B metallo ⁇ -lactamases that may be inhibited by compounds of the present invention include NDM-1 , L1 and CphA.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which serine b-lactamase and/or metallo ⁇ -lactamase activity is implicated.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of penicillin-binding protein activity.
  • bacterial infection will be understood to refer to the invasion of bodily tissue by any bacterial microorganisms that proliferate, resulting in tissue injury that can progress to disease.
  • the bacterial infection may be caused by gram-negative or gram-positive bacteria.
  • the bacterial infection may be caused by bacteria from one or more of the following families; Clostridium, Pseudomonas, Escherichia, Klebsiella, Enterococcus, Enterobacter, Serratia, Stenotrophomonas, Aeromonas, Morganella, Yersinia, Salmonella, Proteus, Pasteurella, Haemophilus, Citrobacter, Burkholderia, Brucella, Moraxella, Mycobacterium, Streptococcus or Staphylococcus.
  • Clostridium, Pseudomonas, Escherichia, Klebsiella, Enterococcus, Enterobacter, Streptococcus and Staphylococcus include Clostridium, Pseudomonas, Escherichia, Klebsiella, Enterococcus, Enterobacter, Streptococcus and Staphylococcus.
  • the bacterial infection may, for example, be caused by one or more bacteria selected from Moraxella catarrhalis, Brucella abortus, Burkholderia cepacia, Citrobacter species, Escherichia coli, Haemophilus Pneumonia, Klebsiella Pneumonia, Pasteurella multocida, Proteus mirabilis, Salmonella typhimurium, Clostridium difficile, Yersinia enterocolitica Mycobacterium tuberculosis, Staphylococcus aureus, group B streptococci, Streptoc
  • the patient in need thereof is suitably a human, but may also include, but is not limted to, primates (e.g. monkeys), commercially farmed animals (e.g. horses, cows, sheep or pigs) and domestic pets (e.g. dogs, cats, guinea pigs, rabbits, hamsters or gerbils).
  • primates e.g. monkeys
  • commercially farmed animals e.g. horses, cows, sheep or pigs
  • domestic pets e.g. dogs, cats, guinea pigs, rabbits, hamsters or gerbils.
  • the patient in need thereof may be any warm-blooded animal that is capble of being infected by a bacterium.
  • the compounds of the present invention, or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e. , at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intraderrmal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, sub
  • the compounds of the present invention may also be used in methods for the detection of b-lactamases.
  • a suitable antibacterial agent may also be used in methods for the detection of b-lactamases.
  • the compounds of formula (I) may be modified to enable various types of assays known is the literature, such as those using spectroscopic such as fluorescence or luminescence based methods.
  • a sample containing bacteria which is suspected of expressing b-lactamases can be cultured (a) in the presence of a beta-lactam antibiotic agent; and (b) in the presence of the antibiotic combination of the invention.
  • the bacteria are seen to grow under conditions (a), this suggests that a beta-lactamase, able to hydrolyse the antibiotic agent, is causing resistance of the bacteria to the antibiotic agent.
  • the bacteria do not grow under condition (b), i.e. in the presence of a compound of the present invention and a suitable antibacterial agent, then the beta-lactamases present have been inhibited.
  • the method can be used to determine whether bacteria express b-lactamase enzymes.
  • Fig. 1 shows the percentage inhibition of a panel of eight b-lactamase enzymes (CTX-M-15, SFC-1 , NDM-1 , L1 , AmpC, OXA-10, OXA-23 & OXA-48) by Example 1 at 0.1 mM (right-hand bar), 0.5 mM (middle bar) and 1 mM (left-hand bar) concentrations.
  • Fig. 2 shows the percentage inhibition of a panel of ten b-lactamase enzymes (CTX-M-15, SFC-1 , KPC-2, AmpC, OXA-10, OXA-23, OXA-48, BPU-1 , NDM-1 & L1) by Example 4 at 0.1 mM (right-hand bar), 0.5 mM (middle bar) and 1 mM (left-hand bar) concentrations.
  • CX-M-15 ten b-lactamase enzymes
  • Fig. 3 shows the percentage inhibition of a panel of ten b-lactamase enzymes (CTX-M-15, SFC-1 , KPC-2, AmpC, OXA-10, OXA-23, OXA-48, BPU-1 , NDM-1 & L1) by Example 6 at 0.1 mM (right-hand bar), 0.5 mM (middle bar) and 1 mM (left-hand bar) concentrations.
  • CX-M-15 ten b-lactamase enzymes
  • Fig. 4 shows a section of (A) the 13 C-NMR spectra and (B) the 1 H-NMR spectra of 977 mM meropenem-derived lactone (Example 4) incubated with 483 mM of SBL OXA-10 and 9.77 mM of 13 C-labelled NaHCOs at various time points (0.1 , 1.8, 3.5, 5.2 and 7.0 hours) post incubation.
  • Fig. 5 shows a section of the 1 H-NMR spectra of (A) meropenem and (B) 977 mM meropenem incubated with 483 mM of SBL OXA-10 and 9.77 mM of 13 C-labelled NaHCOs at 0.1 hours post-incubation.
  • Carbapenems were from Glentham Life Sciences (biapenem, doripenem, ertapenem), Molekula (meropenem, imipenem), Ark Pharma (tebipenem) and Ontario Chemicals Inc. (panipenem). Infrared spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer. Mass spectra were acquired using a Waters Micromass LOT Premier XE spectrometer fitted with an Acquity UPLC system. All enzymes were expressed and purified as previously described in the literature [21 , 22]
  • NMR spectra were acquired using a Bruker Avance III 700 MHz spectrometer equipped with a TCI inverse cryoprobe, and a Bruker AVI 11 HD 600 MHz spectrometer equipped with a BB-F/ 1 H Prodify N 2 cryoprobe. Unless otherwise stated, samples were prepared in 50 mM sodium phosphate, pH 7.5, 10 % D2O. Water suppression was accomplished by pre-saturation or by excitation sculpting with perfect echo. All spectra were acquired at 298 K. Chemical shift assignments for intact carbapenems were made using 5 mM samples, on the basis of 1 H, COSY, HSGC, and HMBC spectra.
  • the major hydrolysis product and major lactone product both possess an (S)- configuration at C-2, the attachment point of the SR 3 group. Lactones derived from ertapenem, biapenem, doripenem, tebipenem and meropenem were prepared in this manner.
  • Lactones derived from biapenem, doripenem and meropenem were isolated as per the following procedure:
  • Carbapenem (4-5 g) was dissolved in 1 mL of 50 mM sodium phosphate, pH 7.5. To this, OXA-48 was added to a final concentration of 20 mM, and the mixture was incubated at room temperature for 5-6 h. The mixture was passed through a 10K MWCO 0.5 mL Amicon centrifugal filter, and the carbapenem-derived lactone was purified from the filtrate by HPLC. The HPLC purification employed a C18 semi-preparative column with mobile phases (A) water with 0.1 % TFA, and (B) acetonitrile with 0.1 % TFA.
  • I b-hydrogen-carbapenems were not degraded to b-lactones by wild-type OXA-48 enzyme. Instead a mutant OXA-48 enzyme was prepared with serine-70 mutated to cysteine (S70C). This mutant OXA-48 was used to degrage I b-hydrogen-carbapenems to yield a mixture of hydrolysis product and lactone product.
  • OXA-48 S70C was generated by site-directed mutagenesis.
  • the mutation was installed using primers 1 (5’-ctatt gggaa tttta aaggt acatg cgggt aaaaa tgctt ggttc-3’) and 2 (5’-gaacc aagca ttttt acccg catgt acctt taaaa ttccc aatag-3’) using standard conditions.
  • the mutated plasmid was transformed with Escherichia coli BL21 (DE3) for protein expression.
  • the transformed E. coli was cultured in 2TY to an optical density of 0.6, and protein expression was induced with IPTG.
  • the harvested culture was lysed by sonication, and OXA-48 S70C was purified by nickel-affinity chromatography and size-exclusion chromatography.
  • the purified protein was buffer exchanged into 50 mM sodium phosphate, pH 7.5, aliquoted, and frozen on liquid nitrogen.
  • Carbapenem derivatives (IV) are synthesised from the commercially available enol phosphate precursor (III), by reaction with R 3 -SH in the presence of base (such as DIPEA), followed by hydrogenolysis of the acid protecting group, according to known procedures as described by Sunagawa et al. ( J . Antibiotics, 1991 , 44, 459-462):
  • Pyrroline-based b-lactone derivatives (II) are formed from the corresponding carbapenems (IV) by OXA-48 enzymatic degradation as described hereinbefore.
  • Substituted pyrrole scaffolds (V) can be prepared by many synthetic routes, such as described by Barton et al. ( Tetrahedron , 1990, 7587-7598), Estevez et al. ( Chem . Soc. Rev. 2014, 43, 4633-4657) and Gilchrist (J. Chem. Soc. Perkin Trans. 1, 2001 , 2491-2515).
  • Intermediate (VI) is formed by the radical alkylation of pyrrole (V) with f-butyl-2-iodoacetate according to the procedure of Makhynya et al. ( Eur . J. Org. Chem. 2007, 1287-1293) and is then protected at the pyrrole N-atom by a suitable protecting group, such as Boc to give intermediate (VII).
  • Intermediate (VII) undergoes an enantio- and diastereoselective aldol reaction with aldehyde R 2 CHO, in the presence of (-)-diisopinocampheylboron triflate, according to the methodology of Paterson et al. ( Tetrahedron , 1990, 46, 4663-4684).
  • the resultant alcohol-ester (VIII) is hydrolysed to the corresponding alcohol-acid (IX) under acidic conditions, such as the use of TFA.
  • acidic conditions such as the use of TFA.
  • Substituted pyridine scaffolds (XI) can be prepared by various synthetic approaches, such as described by Wang et al. ( Organometallics , 2013, 4882-4891) and Gilchrist (J. Chem. Soc. Perkin Trans. 1, 2001 , 2491-2515)
  • Pyridine precursor (XI) undergoes an enantio- and diastereoselective aldol reaction with aldehyde R 2 CHO, in the presence of (-)-diisopinocampheylboron triflate, according to the methodology of Paterson et al. ( Tetrahedron , 1990, 46, 4663-4684).
  • the resultant alcohol- ester (XII) is hydrolysed to the corresponding alcohol-acid (XIII) under acidic conditions, such as the use of TFA.
  • Treatment of intermediate (XIII) with 4-bromobenzenesulfonyl chloride in the presence of base, such as pyridine according to the procedure of Pu et al. ( J.Org . Chem. 1991 , 56, 1280-1283), followed by hydrogenolysis of the benzyl ester to the acid gives pyridine-based b-lactone compounds (XIV).
  • the enzyme was pre-incubated with ertapenem or Example 1 for 10 min prior to the addition of FC-5. Assays were performed in triplicate using 384-well black pclear ® plates (Greiner Bio-One) at 25 °C and measured with a PHERAstar FS microplate reader (BMG Labtech). IC50 values were determined using eight different concentrations of ertapenem and ertapenem lactone, and nonlinear regression analysis was performed using Prism 7 (GraphPad).
  • Example 1 inhibited all the b-lactamases tested at high concentrations.
  • Class D SBLs OXA-10, OXA-23 and OXA-48
  • class B MBLs NVM-1 and L1
  • Example 1 having IC50 values of 790 nM against OXA-10, 1.2 mM against OXA-23 and 940 nM against OXA-48.
  • Ertapenem had IC50 values of 1.9 nM against OXA-10, 65 nM against OXA-23 and 10 nM against OXA-48.
  • b-Lactamase inhibiton by Example 4 (meropenem-derived lactone)
  • Example 4 (1 mM, 0.5 mM, 0.1 mM) on the hydrolysis of the fluorogenic substrate FC-5 [23] (5 mM) was tested with the following b-lactamases at the following concentrations - CTX-M-15 (50 pM), SFC-1 (500 pM), New Delhi metallo ⁇ -lactamase-1 (NDM-1 ; 10 pM), L1 (50 pM), AmpC (500 pM), OXA-10 (1 nM), OXA-23 (12.5 nM), OXA-48 (12.5 nM), KPC-2 (500 pM) and BPU-1 (5 nM) [21 , 24] Reactions were carried out in 100 mM sodium phosphate, pH 7.5, 0.01 % Triton X-100 (for CTX-M-15, SFC-1 , AmpC, OXA-10, OXA- 23, and OXA-48), or 50 mM HEPES, pH 7.5, 0.01 %
  • Example 4 The enzyme was pre-incubated with Example 4 for 10 min prior to the addition of FC-5. Assays were performed in triplicate using 384-well black pclear ® plates (Greiner Bio-One) at 25 °C and measured with a PHERAstar FS microplate reader (BMG Labtech). IC50 values were determined using eight different concentrations of meropenem lactone, and nonlinear regression analysis was performed using Prism 7 (GraphPad).
  • Example 4 inhibited the majority of the b-lactamases tested at high concentrations.
  • Class D SBLs OXA-10, OXA-23, OXA-48 and BPU-1
  • class B MBLs NVM-1 and L1 were inhibited strongly, with Example 4 having IC50 values of 2.34 mM against OXA-10 and 314 mM against L1.
  • b-Lactamase inhibiton by Example 6 imipenem-derived lactone
  • Example 6 (1 mM, 0.5 mM, 0.1 mM) on the hydrolysis of the fluorogenic substrate FC-5 [23] (5 mM) was tested with the following b-lactamases at the following concentrations - CTX-M-15 (50 pM), SFC-1 (500 pM), New Delhi metallo ⁇ -lactamase-1 (NDM-1 ; 10 pM), L1 (50 pM), AmpC (500 pM), OXA-10 (1 nM), OXA-23 (12.5 nM), OXA-48 (12.5 nM), KPC-2 (500 pM) and BPU-1 (5 nM) [21 , 24] Reactions were carried out in 100 mM sodium phosphate, pH 7.5, 0.01 % Triton X-100 (for CTX-M-15, SFC-1 , AmpC, OXA-10, OXA- 23, and OXA-48), or 50 mM HEPES, pH 7.5, 0.01 %
  • Example 6 The enzyme was pre-incubated with Example 6 for 10 min prior to the addition of FC-5. Assays were performed in triplicate using 384-well black pclear ® plates (Greiner Bio-One) at 25 °C and measured with a PHERAstar FS microplate reader (BMG Labtech). IC50 values were determined using eight different concentrations of imipenem lactone, and nonlinear regression analysis was performed using Prism 7 (GraphPad).
  • Example 6 inhibited all the b-lactamases tested at high concentrations.
  • Class D SBLs OXA-10, OXA-23, OXA-48
  • class B MBLs NDM-1 and L1 were typically inhibited more strongly, with Example 6 having an IC50 value of 3.69 mM against OXA-10.
  • Fig. 4A suggests that during the first 2 hours of the incubation with OXA-10, the majority of the OXA-10 exists as an acylated covalent complex with the lactone; after 3.5 hours the uncomplexed state of the enzyme increasingly predominates.
  • Fig. 4B shows the stability of the lactone even when incubated with a very high concentration of OXA-10; it takes more than 2 hours for the lactone to be fully degraded by OXA-10.
  • Van Boeckel, T.P., et al. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. The Lancet Infectious Diseases. 14(8): p. 742- 750.
  • Versporten, A. , et al . Antibiotic use in eastern Europe: a cross-national database study in coordination with the WHO Regional Office for Europe. Lancet Infectious Diseases, 2014. 14(5): p. 381-387.

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Abstract

The present invention relates to certain β-lactone compounds that may be useful as inhibitors of bacterial beta-lactamases. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of a bacterial infection.

Description

b-LACTONE COMPOUNDS
INTRODUCTION
[0001] The present invention relates to b-lactone compounds that may be useful as inhibitors of b-lactamases. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of bacterial infections.
BACKGROUND OF THE INVENTION
[0002] The effective treatment of many fatal bacterial infections is underpinned by the administration of a course of b-lactam antibiotics. However, increasing resistance to b-lactam antibiotics is reducing the effectiveness of b-lactam antibiotics, thereby necessitating the need for improved antibiotic treatments.
[0003] b-Lactamases are the most commonly encountered cause of resistance to b-lactam antibiotics, which are the most frequently prescribed class of antibacterial drug world-wide [1- 3] b-lactamases render b-lactams inactive through two steps that involve acylation and de acylation, which ultimately results in hydrolysis of the b-lactam ring [4, 5] There are hundreds of b-lactamases known, but they can be grouped based on amino acid sequence into the serine b-lactamase (SBL) classes A, C and D, and the zinc ion-dependent metallo-b- lactamase (MBL) classes B1 , B2 and B3 [6, 7] Clinically useful b-lactamase inhibitors are being sought, but the varying chemistries and active site architectures of the different classes makes the development of cross-class inhibitors extremely challenging [8-10]
[0004] Clavulanic acid is an example of a b-lactam-based inhibitor principally of class A SBLs that has been used clinically for many years. Most commonly it is used in combination with penicillin derivatives, such as amoxycillin and ticarcillin, to enhance their bactericidal effects against some b-lactamase-carrying isolates of species such as E. coli and K. pneumoniae [11- 14] Clavulanate (and the related compounds tazobactam and sulbactam) are in effect irreversible inhibitors whose activity arises from fragmentation of the acyl-enzyme complex formed by reaction with the active-site serine nucleophile, to generate inactivated species [15] In contrast, avibactam is a hoh-b-lactam-based b-lactamase inhibitor containing a diazobicyclo heterocyclic core structure which acylates SBLs, at least some cases reversibly, and has a broader spectrum of activity than clavulanic acid. The potency of avibactam against Class A, C and some Class D SBLs is attributed in part to the stabilization of the carbamoyl complex by the formation of a stable acyl-enzyme complex due to interactions with polar residues present in the active site [16-18] Avibactam has recently been licenced for clinical use in partnership with the oxy-amino cephalosporin ceftazidime, though the combination is not universally efficacious and has no activity against MBL-producing bacteria [17, 19]
[0005] MBLs are particularly concerning because they hydrolyse most known b-lactam antibiotics, including the so called ‘last resort’ b-lactam antibiotics, such as some carbapenems, and they confer resistance to b-lactam antibiotics in many pathogens. No clinically useful MBL inhibitors are presently available [20]
[0006] Thus, there remains a need for new treatments to combat b-lactamase-mediated antibacterial resistance.
[0007] The present invention was devised with the foregoing in mind.
SUMMARY OF THE INVENTION
[0008] In one aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
[0009] In an aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.
[0010] In an aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a bacterial infection in a warm-blooded animal, such as man.
[0011] In an aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a bacterial infection in a warm-blooded animal, such as man, in combination with a b-lactam antibiotic.
[0012] In an aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a gram-positive bacterial infection in a warm-blooded animal, such as man.
[0013] In an aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a gram-positive bacterial infection in a warm-blooded animal, such as man, in combination with a b-lactam antibiotic.
[0014] In an aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a gram-negative bacterial infection in a warm-blooded animal, such as man.
[0015] In an aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of a gram-negative bacterial infection in a warm-blooded animal, such as man, in combination with a b-lactam antibiotic.
[0016] In an aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of gram-positive and/or gram-negative bacterial infections.
[0017] In an aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for the treatment of gram-positive and/or gram-negative bacterial infections in combination with a b-lactam antibiotic.
[0018] In an aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of gram-positive and/or gram-negative bacterial infections.
[0019] In an aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of gram-positive and/or gram-negative bacterial infections in combination with a b-lactam antibiotic.
[0020] In an aspect, the present invention provides a method of treating a gram-positive and/or gram-negative bacterial infection, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
[0021] In an aspect, the present invention provides a method of treating a gram-positive and/or gram-negative bacterial infection, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in combination with a b-lactam antibiotic.
[0022] In another aspect, the present invention provides a pharmaceutical composition as defined herein which comprises a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.
[0023] In another aspect, the present invention provides a pharmaceutical composition as defined herein, for use in the treatment of gram-positive and/or gram-negative bacterial infections in a warm-blooded animal, such as man.
[0024] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, for use in the production of a b-lactamase inhibitory effect. [0025] In another aspect, the present invention provides a method of inhibiting a bacterial b- lactamase in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof.
[0026] The present invention also provides a combination product comprising a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and a b-lactam antibiotic. In particular, there is provided a combination product comprising a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and a b-lactam antibiotic in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
[0027] The combination product of the present invention provides for the administration of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, and a b-lactam antibiotic. The combination product may be in the form of a combined preparation of the compound as defined herein and the b-lactam antibiotic; it may include additional antibiotics or b-lactamase inhibitors. Alternatively, the combination product may comprise a kit of parts comprising separate formulations of the compound as defined herein and the b- lactam antibiotic. The separate formulations of the compound as defined herein and the b- lactam antibiotic may be administered sequentially, separately and/or simultaneously. In one embodiment, the separate formulations of the compound as defined herein and the b-lactam antibiotic of the combination product are administered simultaneously (optionally repeatedly). In another embodiment, the separate formulations of the compound as defined herein and the b-lactam antibiotic of the combination product are administered sequentially (optionally repeatedly). In another embodiment, the separate formulations of the compound as defined herein and the b-lactam antibiotic of the combination product are administered separately (optionally repeatedly). Where the administration of the separate formulations of the compound as defined herein and the b-lactam antibiotic of the combination product is sequential or separate, the delay in administering the second formulation should not be such as to lose the beneficial effect of the combination therapy. Thus, the present invention provides a combination product comprising a compound as defined herein, or a pharmaceutically-acceptable salt or solvate thereof, and a b-lactam antibiotic, or a pharmaceutically-acceptable salt thereof, for use sequentially, separately and/or simultaneously in the treatment of bacterial infections in a warm-blooded animal, such as man.
[0028] In another aspect, there is provided a combination product which comprises a kit of parts comprising the following components:
a compound as defined herein, or a pharmaceutically-acceptable salt or solvate thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier; and a b-lactam antibiotic, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier,
wherein the components are provided in a form which is suitable for sequential, separate and/or simultaneous administration.
[0029] The kit of parts is for the treatment of bacterial infections in a warm-blooded animal, such as man.
[0030] In one embodiment, the kit of parts comprises:
a first container comprising a a compound as defined herein, or a pharmaceutically- acceptable salt or solvate thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier;
a second container comprising a b-lactam antibiotic, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically acceptable adjuvant, diluent or carrier; and a container means for containing said first and second containers.
[0031] In one embodiment, the kit of parts further comprises instructions on how to administer the components sequentially, separately and/or simultaneously.
[0032] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0033] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.
[0034] It is to be appreciated that references to“treating” or“treatment” include prophylaxis as well as the alleviation of established symptoms of a condition. “Treating” or“treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. [0035] A“therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
[0036] In this specification the term“alkyl” includes both straight and branched chain alkyl groups and analogues thereof. References to individual alkyl groups such as“propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as“isopropyl” are specific for the branched chain version only. For example,“(1- 6C)alkyl” includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl and f-butyl. A similar convention applies to other radicals, for example“phenyl(1-6C)alkyl” includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.
[0037] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.
[0038] “(3-7C)cycloalkyl” means a hydrocarbon ring containing from 3 to 7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
[0039]“(1-4C)alkoxy” refers to oxygen-linked straight and branched chain alkyl groups containing from 1 to 4 carbon atoms, for example, methoxy, ethoxy, /- propoxy, n-propoxy, n- butoxy or f-butoxy.
[0040]“(1-3C)fluoroalkyl” refers to 1 to 3 carbon alkyl groups bearing one of more fluoro substituents, for example, fluoromethyl, difluoromethyl, trifluoromethyl or 2,2,2-trifluoroethyl.
[0041] The term“halo” refers to fluoro, chloro, bromo and iodo.
[0042] The term“heterocycloalkyl” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). The term heterocycloalkyl includes both monovalent species and divalent species. Monocyclic heterocycloalkyl rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycloalkyl rings contain from about 7 to about 17 ring atoms, suitably from 7 to 12 ring atoms. Bicyclic heterocycloalkyl rings may be fused, spiro, or bridged ring systems. Examples of heterocycloalkyl groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycloalkyls containing nitrogen include, for example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycloalkyls include tetrahydrothienyl, dihydro-1 , 3-dithiol, tetrahydro-2/-/-thiopyran, and hexahydrothiepine. Other heterocycloalkyls include 2 , 3-d i hyd roth i azoly 1 , 2, 5-di hydrothiazolyl , 4,5-dihydrothiazolyl, dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycloalkyls containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1 ,1 -dioxide and thiomorpholinyl 1 ,1 -dioxide. A suitable value for a heterocycloalkyl group which bears 1 or 2 oxo (=0) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocycloalkyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, 1 ,1 -dioxide, thiomorpholinyl, thiomorpholinyl 1 ,1- dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl, in particular azetidinyl, pyrrolidinyl or piperidinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom.
[0043] By“bridged ring systems” is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocycloalkyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza- bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidine.
[0044] The term“heteroaryl” or“heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
[0045] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1 H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2, 1-b]thiazolyl, imidazo[1 ,2-b][1 ,2,4]triazinyl. “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-
1.2.3.4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro- benzo[1 ,4]dioxinyl, benzo[1 ,3]dioxolyl, 2,2-dioxo-1 ,3-dihydro-2-benzothienyl, 4, 5,6,7- tetrahydrobenzofuranyl, indolinyl, 1 ,2,3,4-tetrahydro-1 ,8-naphthyridinyl,
1.2.3.4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2/-/-pyrido[3,2-b][1 ,4]oxazinyl.
[0046] Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
[0047] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
[0048] Particular examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.
[0049] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups. [0050] The term“aryl” means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In a particular embodiment, an aryl is phenyl.
[0051] This specification also makes use of several composite terms to describe groups comprising more than one functionality. Such terms will be understood by a person skilled in the art. For example“(1-3C)alkylR11” refers to (1-3C)alkyl wherein one of the hydrogen radicals is substituted by an R11 group.
[0052] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. The term“wherein a/any CH, CH2, CH3 group or heteroatom (i.e. NH) within a R1 group is optionally substituted” suitably means that (any) one of the hydrogen radicals of the R1 group is substituted by a relevant stipulated group.
[0053] Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
[0054] The phrase“compound of the invention” means those compounds which are disclosed herein, both generically and specifically.
Compounds of the invention
[0055] In one aspect, the present invention relates to a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as shown below:
Figure imgf000010_0001
Wherein R1 is selected from the group consisting of:
Figure imgf000010_0002
R2 is hydrogen or methyl;
R3 is (1-4C)alkyl, (3-7C)cycloalkyl or heterocycloalkyl, each optionally substituted with one or more of NR7R8, hydroxy, (1-3C)alkyl, (1-4C)alkoxy, halo, (1-3C)fluoroalkyl, C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1-3C)alkylR11 , heterocycloalkyl, (3-7C)cycloalkyl, heteroaryl or aryl;
R4 is hydrogen or (1-4C)alkyl;
X is NR12, O, S or a bond;
R5 is hydrogen, (1-4C)alkyl, (3-7C)cycloalkyl, heterocycloalkyl, heteroaryl or aryl, wherein (1- 4C)alkyl, (3-7C)cycloalkyl, heterocycloalkyl, heteroaryl or aryl are optionally substituted with one or more of NR7R8, hydroxy, (1-3C)alkyl, (1-4C)alkoxy, halo, (1-3C)fluoroalkyl, C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1-3C)alkylR11 , heterocycloalkyl, (3-7C)cycloalkyl, heteroaryl or aryl;
R6 is hydrogen, (1-4C)alkyl, halo, hydroxy or (1-4C)alkoxy;
R7 is hydrogen, (1-4C)alkyl, SO(1-3C)alkyl, S02(1-3C)alkyl, S02NR13R14, aryl or CH=NR15;
R9 is hydrogen, (1-4C)alkyl or aryl, wherein (1-4C)alkyl or aryl are optionally substituted with one or more of hydroxy, (1-4C)alkoxy, halo, (1-3C)fluoroalkyl or C02R16;
R11 is hydroxy, (1-4C)alkoxy or NR17R18;
R17 is hydrogen, (1-4C)alkyl, SO(1-3C)alkyl, S02(1-3C)alkyl, S02NR19R2°, aryl or CH=NR21 ; and
R8, R10, R12, R13, R14, R15, R16, R18, R19, R20 and R21 are each independently selected from hydrogen or (1-3C)alkyl.
[0056] Particular compounds of the invention include, for example, compounds of formula I, or pharmaceutically acceptable salts and/or solvates thereof, wherein, unless otherwise stated, each of R1 , R2, R3, R4, X, R5, R6, R7, R9, R11 and R17 and any associated substituent groups has any of the meanings defined hereinbefore or in any of paragraphs (1) to (57) hereinafter:-
Figure imgf000011_0001
Figure imgf000012_0001
(6) R2 is hydrogen;
(7) R2 is methyl;
(8) R3 is (1-4C)alkyl or heterocycloalkyl, each optionally substituted with one or more of NR7R8, hydroxy, (1-3C)alkyl, (1-4C)alkoxy, halo, C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1-3C)alkylR11 , heterocycloalkyl, (3-7C)cycloalkyl, heteroaryl and aryl; wherein R7, R8, R9, R10 and R11 are as described herein;
(9) R3 is (1-4C)alkyl or heterocycloalkyl, each optionally substituted with one or more of NR7R8, halo, C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1-3C)alkylR11and heterocycloalkyl; wherein R7, R8, R9, R10 and R11 are as described herein;
(10) R3 is (1-4C)alkyl optionally substituted with one or more of NR7R8, halo
C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1-3C)alkylR11and heterocycloalkyl; wherein R7,
R8, R9, R10 and R11 are as described herein;
(1 1) R3 is (1-4C)alkyl optionally substituted with NR7R8, C(=0)NR9R1°, C(=NH)(1- 3C)alkyl and heterocycloalkyl; wherein R7, R8, R9 and R10 are as described herein;
(12) R3 is (1-4C)alkyl substituted with NR7R8; wherein R7 and R8 are as described herein;
(13) R3 is (1-4C)alkyl substituted with NR7R8; wherein R7 is CH=NR15 and R8 is hydrogen;
(14) R3 is (1-4C)alkyl optionally substituted with one or more halo;
(15) R3 is methyl optionally substituted with one or more halo;
(16) R3 is methyl;
(17) R3 is trifluoromethyl;
(18) R3 is f-butyl;
(19) R3 is heterocycloalkyl optionally substituted with one or more of of NR7R8,
C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1-3C)alkylR11and heterocycloalkyl; wherein R7,
R8, R9, R10 and R11 are as described herein; (20) R3 is heterocycloalkyl optionally substituted with C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1-3C)alkylR11and heterocycloalkyl; wherein R9, R10 and R11 are as described herein;
(21) R3 is heterocycloalkyl selected from:
Figure imgf000013_0001
wherein said heterocycloalkyl is optionally substituted with C(=0)NR9R1°, C(=NH)(1- 3C)alkyl, (1-3C)alkylR11and heterocycloalkyl; wherein R9, R10 and R11 are as described herein;
(22) R3 is heterocycloalkyl selected from:
Figure imgf000013_0002
wherein said heterocycloalkyl is optionally substituted with C(=0)NR9R1°, C(=NH)(methyl), CH2-R11and heterocycloalkyl; wherein R9, R10 and R11 are as described herein;
(23) R3 is selected from:
Figure imgf000013_0003
(24) R3 is selected from:
Figure imgf000014_0001
(25) R4 is hydrogen;
(26) R4 is methyl;
(27) R4 is f-butyl;
(28) X is NR12;
(29) X is O;
(30) X is S;
(31) X is a bond;
(32) X is a bond and R5 is hydrogen;
(33) X is a bond and R5 is (1-4C)alkyl optionally substituted with one or more of NR7R8, hydroxy, (1-4C)alkoxy, halo, C(=0)NR9R1°, C(=NH)(1-3C)alkyl, heterocycloalkyl, (3- 7C)cycloalkyl, heteroaryl or aryl;
(34) X is a bond and R5 is (1-4C)alkyl;
(35) R5 is hydrogen;
(36) R5 is (1-4C)alkyl optionally substituted with one or more of NR7R8, hydroxy, (1- 4C)alkoxy, halo, C(=0)NR9R1°, C(=NH)(1-3C)alkyl, heterocycloalkyl, (3-7C)cycloalkyl, heteroaryl or aryl;
(37) R5 is (3-7C)cycloalkyl optionally substituted with one or more of NR7R8, hydroxy, (1- 3C)alkyl, (1-4C)alkoxy, halo, (1-3C)fluoroalkyl, C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1- 3C)alkylR11 , heterocycloalkyl, (3-7C)cycloalkyl, heteroaryl or aryl;
(38) R5 is heterocycloalkyl optionally substituted with one or more of NR7R8, hydroxy, (1- 3C)alkyl, (1-4C)alkoxy, halo, (1-3C)fluoroalkyl, C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1- 3C)alkylR11 , heterocycloalkyl, (3-7C)cycloalkyl, heteroaryl or aryl;
(39) R5 is heteroaryl optionally substituted with one or more of NR7R8, hydroxy, (1- 3C)alkyl, (1-4C)alkoxy, halo, (1-3C)fluoroalkyl, C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1- 3C)alkylR11 , heterocycloalkyl, (3-7C)cycloalkyl, heteroaryl or aryl;
(40) R5 is aryl optionally substituted with one or more of NR7R8, hydroxy, (1-3C)alkyl, (1- 4C)alkoxy, halo, (1-3C)fluoroalkyl, C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1-3C)alkylR11 , heterocycloalkyl, (3-7C)cycloalkyl, heteroaryl or aryl;
(41) R6 is hydrogen;
(42) R6 is methyl; (43) R6 is f-butyl;
(44) R7 is hydrogen, Ci-4alkyl or CH=NR15 wherein R15 is hydrogen or methyl;
(45) R7 is hydrogen, methyl or CH=NH;
(46) R7 is CH=NH;
(47) R9 is Ci-4alkyl or aryl each optionally substituted with one or more of hydroxy, Ci- 4alkoxy, halo, Ci-3fluoroalkyl or CO2R16;
(48) R9 is Ci-4alkyl optionally substituted with one or more of hydroxy, Ci-4alkoxy, halo or
CO2R16;
(49) R9 is methyl optionally substituted with one or more of hydroxy, Ci-4alkoxy, halo or
CO2R16;
(50) R9 is methyl;
(51) R9 is aryl optionally substituted with one or more of hydroxy, Ci-4alkoxy, halo, Ci- 3fluoroalkyl or CO2R16;
(52) R9 is phenyl optionally substituted with one or more of hydroxy, Ci-4alkoxy, halo, Ci- 3fluoroalkyl or CO2H;
(53) R9 is phenyl substituted with CO2H;
(54) R11 is NR17R18; wherein R17 and R18 are as described herein;
(55) R11 is NR17R18; wherein R17 is hydrogen, Ci-4alkyl or SC>2NR19R20 and R18, R19 and R20 are hydrogen or methyl;
(56) R11 is NR17R18; wherein R17 is SC^Nhh and R18 is hydrogen or methyl;
(57) R11 is NR17R18; wherein R17 is SC^Nhh and R18 is hydrogen;
[0057] In one embodiment of the present invention, there is provided a compound of formula IA:
Figure imgf000015_0001
wherein R1 to R21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
[0058] In one embodiment of the present invention, there is provided a compound of formula IB:
Figure imgf000015_0002
(IB)
wherein R1 , R3 to R21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
[0059] In one embodiment of the present invention, there is provided a compound of formula IC:
Figure imgf000016_0001
wherein R3 to R21 are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
[0060] In one embodiment of the present invention, there is provided a compound of formula
Figure imgf000016_0002
wherein R3 to R21 are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
[0061] In one embodiment of the present invention, there is provided a compound of formula
Figure imgf000016_0003
wherein R3 to R21 are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof. [0062] In an embodiment of the present invention, there is provided a compound of formula IA, IB, 1C, ID or IE wherein R3 is as defined in any one of paragraphs (8) to (24) above, such as any one of paragraphs (19) to (24), for example as defined in paragraph (24).
[0063] In an embodiment of the present invention, there is provided a compound of formula IC, ID or IE wherein R3 is as defined in any one of paragraphs (8) to (24) above, such as any one of paragraphs (19) to (24), for example as defined in paragraph (24), and wherein R4 is as defined in any one of paragraphs (25) to (27) above, such as any one of paragraphs (25) to (26).
[0064] In one embodiment of the present invention, there is provided a compound of formula
Figure imgf000017_0001
wherein R2 to R21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
[0065] In one embodiment of the present invention, there is provided a compound of formula IG:
Figure imgf000017_0002
wherein R2 to R21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
[0066] In one embodiment of the present invention, there is provided a compound of formula IH:
Figure imgf000018_0001
wherein R4 to R21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
[0067] In one embodiment of the present invention, there is provided a compound of formula IJ:
Figure imgf000018_0002
wherein R2 to R21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
[0068] In one embodiment of the present invention, there is provided a compound of formula IK:
Figure imgf000018_0003
wherein R2 to R21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
[0069] In one embodiment of the present invention, there is provided a compound of formula IL:
Figure imgf000019_0001
wherein R4 to R21 and X are as defined hereinbefore; or a pharmaceutically acceptable salt or solvate thereof.
[0070] In one embodiment, there is provided a compound of formula IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL wherein R4 is methyl; or a pharmaceutically acceptable salt or solvate thereof.
[0071] In one embodiment, there is provided a compound of formula IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK or IL, wherein R4 is hydrogen; or a pharmaceutically acceptable salt or solvate thereof.
[0072] In one embodiment, there is provided a compound of formula IJ, IK or IL, wherein R6 is methyl; or a pharmaceutically acceptable salt or solvate thereof.
[0073] In one embodiment, there is provided a compound of formula IJ, IK or I L, wherein R6 is hydrogen; or a pharmaceutically acceptable salt or solvate thereof.
[0074] In one embodiment, there is provided a compound of formula IJ, IK or IL, wherein R4 and R6 are (1-4C)alkyl; or a pharmaceutically acceptable salt or solvate thereof.
[0075] In one embodiment, there is provided a compound of formula IJ, IK or IL, wherein R4 and R6 are both methyl; or a pharmaceutically acceptable salt or solvate thereof.
[0076] In one embodiment, there is provided a compound of formula IJ, IK or IL, wherein R4 and R6 are both hydrogen; or a pharmaceutically acceptable salt or solvate thereof.
[0077] In one embodiment, there is provided a compound of formula IJ, IK or I L, wherein R4 is hydrogen and R6 is (1-4C)alkyl; or a pharmaceutically acceptable salt or solvate thereof.
[0078] In one embodiment, there is provided a compound of formula formula IJ, IK or IL, wherein R4 is (1-4C)alkyl and R6 is hydrogen; or a pharmaceutically acceptable salt or solvate thereof.
[0079] Suitably, a heteroaryl or heterocycloalkyl group as defined herein is a monocyclic heteroaryl or heterocycloalkyl group comprising one, two or three heteroatoms selected from N, O or S.
[0080] Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.
[0081] Suitably, a heterocycloalkyl group is a 4-, 5-, 6- or 7-membered heterocyclyl ring comprising one, two or three heteroatoms selected from N, O or S. Most suitably, a heterocycloalkyl group is a 4-, 5- or 6-membered ring comprising one, two or three heteroatoms selected from N, O or S [e.g. azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl]
[0082] Suitably an aryl group is phenyl.
[0083] Suitably, R1 is as defined in any one of paragraphs (1) to (5) above.
[0084] Suitably, R2 is as defined in any one of paragraphs (6) to (7) above.
[0085] Suitably, R3 is as defined in any one of paragraphs (8) to (24) above. More suitably,
R3 is as defined in any one of paragraphs (19) to (24). Most suitably, R3 is as defined in paragraph (24).
[0086] Suitably, R4 is as defined in any one of paragraphs (25) to (27) above. More suitably, R4 is methyl.
[0087] Suitable, X is as defined in any one of paragraphs (28) to (34) above.
[0088] Suitably, R5 is as defined in any one of paragraphs (35) to (40) above.
[0089] Suitably, R6 is as defined in any one of paragraphs (41) to (43) above.
[0090] Suitably, R7 is as defined in any one of paragraphs (44) to (46) above.
[0091] Suitably, R9 is as defined in any one of paragraphs (47) to (53) above.
[0092] Suitably, R11 is as defined in any one of paragraphs (54) to (57) above.
[0093] Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following:
Figure imgf000020_0001
Figure imgf000021_0001
[0094] In an embodiment, there is provided a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from one of the following compounds:
Figure imgf000021_0002
[0095] The various functional groups and substituents making up the compounds of the formula I are typically chosen such that the molecular weight of the compound of the formula I does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 700, or less than 650, or less than 600. More preferably, the molecular weight is less than 550 and, for example, is 500 or less
[0096] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
[0097] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn-lngold-Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a“racemic mixture”.
[0098] The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess b-lactamase inhibitory activity.
[0099] The present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H, 2H(D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; and O may be in any isotopic form, including 160 and180; and the like.
[00100] It is also to be understood that certain compounds of the formula I may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess b-lactamase inhibitory activity.
[00101] It is also to be understood that certain compounds of the formula I may exhibit polymorphism, and that the invention encompasses all such forms that possess b-lactamase inhibitory activity.
[00102] Compounds of the formula I may exist in a number of different tautomeric forms and references to compounds of the formula I include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by formula I. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
Figure imgf000023_0001
keto enol enolate
[00103] Compounds of formula I containing an amine function may also form N-oxides. A reference herein to a compound of the formula I that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady ( Syn . Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane. [00104] The compounds of formula I may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the formula I and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the formula I.
[00105] Accordingly, the present invention includes those compounds of the formula I as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the formula I may be a synthetically-produced compound or a metabolically-produced compound.
[00106] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
[00107] Various forms of pro-drug have been described, for example in the following documents:- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);
b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);
c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5“Design and Application of Pro-drugs”, by H. Bundgaard p. 1 13-191 (1991);
d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);
f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);
g) T. Higuchi and V. Stella,“Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor),“Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.
[00108] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of formula I containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include Ci-6alkyl esters such as methyl, ethyl and tert- butyl, Ci-6alkoxymethyl esters such as methoxymethyl esters, Ci-6alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, C3-8cycloalkylcarbonyloxy- Ci-6alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters,
2-oxo-1 ,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1 ,3-dioxolen-4-ylmethyl esters and Ci-6alkoxycarbonyloxy- Ci-6alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.
[00109] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the formula I containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include Ci-ioalkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci- loalkoxycarbonyl groups such as ethoxycarbonyl, A/,/\/-(Ci ^carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, /V-alkylaminomethyl, A/./V-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(Ci-4alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
[00110] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a Ci-4alkylamine such as methylamine, a (Ci-4alkyl)2amine such as dimethylamine, A/-ethyl-/\/-methylamine or diethylamine, a Ci- 4alkoxy- C^alkylamine such as 2-methoxyethylamine, a phenyl-Ci-4alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
[00111] A suitable pharmaceutically acceptable pro-drug of a compound of the formula I that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with Ci-ioalkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, /V-alkylaminomethyl, L/,L/- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and
4-(Ci-4alkyl)piperazin-1-ylmethyl.
[00112] The in vivo effects of a compound of the formula I may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the formula I. As stated hereinbefore, the in vivo effects of a compound of the formula I may also be exerted by way of metabolism of a precursor compound (a pro-drug).
[00113] Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
Synthesis
[00114] The compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.
[00115] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.
[00116] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.
[00117] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. [00118] For examples of protecting groups see one of the many general texts on the subject, for example,‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.
[00119] Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
[00120] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or f-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. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a te/f-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric 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 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 with hydrazine.
[00121] 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, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, 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, sodium hydroxide or ammonia. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
[00122] 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 f-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.
[00123] Resins may also be used as a protecting group.
[00124] The methodology employed to synthesise a compound of formula I will vary depending on the nature of R1 to R21 and X, and any substituent groups associated therewith. Suitable processes for their preparation are described further in the accompanying Examples.
[00125] Once a compound of formula I has been synthesised by any one of the processes defined herein, the processes may then further comprise the additional steps of:
(i) removing any protecting groups present;
(ii) converting the compound formula I into another compound of formula I;
(iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and/or
(iv) forming a prodrug thereof.
[00126] An example of (ii) above is when a compound of formula I is synthesised and then one or more of the groups R1 to R21 and X, may be further reacted to change the nature of the group and provide an alternative compound of formula I.
[00127] The resultant compounds of formula I can be isolated and purified using techniques well known in the art. b-Lactam Antibiotics
[00128] It will be understood by the person skilled in the art that any suitable b-lactam antibiotic or analogue thereof may be used in the present invention. Non limiting examples of suitable b-lactam antibiotics include carbapenems (e.g. meropenem, faropenem, imipenem, ertapenem, doripenem, panipenem/betamipron and biapenem as well as razupenem, tebipenem, lenapenem and tomopenem), ureidopenicillins (e.g. piperacillin), carbacephems (e.g. loracarbef) and cephalosporins (e.g. cefpodoxime, ceftazidime, cefotaxime, ceftriaxone, ceftobiprole, and ceftaroline). Specific examples of suitable b-lactam antibacterial agents include, for example, aztreonam, temocillin, piperacillin, cefpodoxime, ceftazidime, cefotaxime, ceftriaxone, meropenem, faropenem, imipenem, loracarbef, ceftobiprole and ceftaroline.
[00129] In an embodiment, the b-lactam antibiotic is selected from azetreonam, ceftazidime, meropenem, ertrapenem, imipenem or faropenem.
Pharmaceutical Compositions [00130] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier. For example, solid oral forms may contain, together with the active compound, diluents, such as, for example, lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, such as, for example, silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; such as, for example, starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, such as, for example, starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as, for example, lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical compositions may be manufactured in by conventional methods known in the art, such as, for example, by mixing, granulating, tableting, sugar coating, or film coating processes.
[00131] The 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, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing). Suitably, oral or parenteral administration is preferred. Most suitably, oral administration is preferred.
[00132] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
[00133] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
[00134] 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 individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) 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.
[00135] The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the condition, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
[00136] In using a compound of formula I as defined herein for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
Therapeutic Uses and Applications
[00137] The present invention provides compounds that function as inhibitors of b- lactamases and/or penicillin-binding proteins.
[00138] The present invention also provides a method of inhibiting bacterial infection, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, in combination with a b-lactam antibiotic.
[00139] The present invention also provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
[00140] The present invention also provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a bacterial infection in a warm-blooded animal, such as man. The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a bacterial infection in man. In one embodiment, the treatment may be prophylactic (i.e. intended to prevent disease).
[00141] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of serine b-lactamase activity.
[00142] Class A serine b-lactamases that may be inhibited by compounds of the present invention include TEM-1 , SHV-1 , SFC-1 , CTX-M-15 and KPC-2.
[00143] Class C serine b-lactamases are also termed AmpC b-lactamases.
[00144] Class D serine b-lactamases that may be inhibited by compounds of the present invention include OXA-10, OXA-23, OXA-48 and BPU-1.
[00145] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of class D serine b- lactamase activity.
[00146] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of metallo^-lactamase activity.
[00147] Class B metallo^-lactamases (carbapenemases) that may be inhibited by compounds of the present invention include NDM-1 , L1 and CphA.
[00148] Furthermore, the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which serine b-lactamase and/or metallo^-lactamase activity is implicated.
[00149] The present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of penicillin-binding protein activity.
[00150] The term "bacterial infection" will be understood to refer to the invasion of bodily tissue by any bacterial microorganisms that proliferate, resulting in tissue injury that can progress to disease.
[00151] The bacterial infection may be caused by gram-negative or gram-positive bacteria. For example, the bacterial infection may be caused by bacteria from one or more of the following families; Clostridium, Pseudomonas, Escherichia, Klebsiella, Enterococcus, Enterobacter, Serratia, Stenotrophomonas, Aeromonas, Morganella, Yersinia, Salmonella, Proteus, Pasteurella, Haemophilus, Citrobacter, Burkholderia, Brucella, Moraxella, Mycobacterium, Streptococcus or Staphylococcus. Particular examples include Clostridium, Pseudomonas, Escherichia, Klebsiella, Enterococcus, Enterobacter, Streptococcus and Staphylococcus. The bacterial infection may, for example, be caused by one or more bacteria selected from Moraxella catarrhalis, Brucella abortus, Burkholderia cepacia, Citrobacter species, Escherichia coli, Haemophilus Pneumonia, Klebsiella Pneumonia, Pasteurella multocida, Proteus mirabilis, Salmonella typhimurium, Clostridium difficile, Yersinia enterocolitica Mycobacterium tuberculosis, Staphylococcus aureus, group B streptococci, Streptococcus Pneumonia, and Streptococcus pyogenes, e.g. from E. coli and K. pneumoniae.
[00152] It will be understood by a person skilled in the art that the patient in need thereof is suitably a human, but may also include, but is not limted to, primates (e.g. monkeys), commercially farmed animals (e.g. horses, cows, sheep or pigs) and domestic pets (e.g. dogs, cats, guinea pigs, rabbits, hamsters or gerbils). Thus, the patient in need thereof may be any warm-blooded animal that is capble of being infected by a bacterium.
Routes of Administration
[00153] The compounds of the present invention, or pharmaceutical compositions comprising these compounds, may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e. , at the site of desired action).
[00154] Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intraderrmal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
Diagnostic uses
[00155] The compounds of the present invention, or pharmaceutical compositions comprising these compounds in combination with a suitable antibacterial agent, may also be used in methods for the detection of b-lactamases. It will be appreciated that the compounds of formula (I) may be modified to enable various types of assays known is the literature, such as those using spectroscopic such as fluorescence or luminescence based methods. Thus, in one variation a sample containing bacteria which is suspected of expressing b-lactamases can be cultured (a) in the presence of a beta-lactam antibiotic agent; and (b) in the presence of the antibiotic combination of the invention. If the bacteria are seen to grow under conditions (a), this suggests that a beta-lactamase, able to hydrolyse the antibiotic agent, is causing resistance of the bacteria to the antibiotic agent. However, if the bacteria do not grow under condition (b), i.e. in the presence of a compound of the present invention and a suitable antibacterial agent, then the beta-lactamases present have been inhibited. The method can be used to determine whether bacteria express b-lactamase enzymes.
List of Figures
Fig. 1 shows the percentage inhibition of a panel of eight b-lactamase enzymes (CTX-M-15, SFC-1 , NDM-1 , L1 , AmpC, OXA-10, OXA-23 & OXA-48) by Example 1 at 0.1 mM (right-hand bar), 0.5 mM (middle bar) and 1 mM (left-hand bar) concentrations.
Fig. 2 shows the percentage inhibition of a panel of ten b-lactamase enzymes (CTX-M-15, SFC-1 , KPC-2, AmpC, OXA-10, OXA-23, OXA-48, BPU-1 , NDM-1 & L1) by Example 4 at 0.1 mM (right-hand bar), 0.5 mM (middle bar) and 1 mM (left-hand bar) concentrations.
Fig. 3 shows the percentage inhibition of a panel of ten b-lactamase enzymes (CTX-M-15, SFC-1 , KPC-2, AmpC, OXA-10, OXA-23, OXA-48, BPU-1 , NDM-1 & L1) by Example 6 at 0.1 mM (right-hand bar), 0.5 mM (middle bar) and 1 mM (left-hand bar) concentrations.
Fig. 4 shows a section of (A) the 13C-NMR spectra and (B) the 1 H-NMR spectra of 977 mM meropenem-derived lactone (Example 4) incubated with 483 mM of SBL OXA-10 and 9.77 mM of 13C-labelled NaHCOs at various time points (0.1 , 1.8, 3.5, 5.2 and 7.0 hours) post incubation.
Fig. 5 shows a section of the 1 H-NMR spectra of (A) meropenem and (B) 977 mM meropenem incubated with 483 mM of SBL OXA-10 and 9.77 mM of 13C-labelled NaHCOs at 0.1 hours post-incubation.
EXAMPLES
Abbreviations
Bn Benzyl
Boc t-Butoxycarbonyl
DIPEA Diisopropylethylamine
DMAP Dimethylaminopyridine
DMSO Dimethylsulfoxide
EtOAc Ethyl acetate
HPLC High performance liquid chromatography KPC-2 K. pneumoniae carbapenemase-2
LCMS Liquid chromatography-mass spectrometry
MBL Metallo-beta-lactamase
MWCO Molecular Weight Cut-Off
NDM-1 New Delhi Metallo-beta-lactamase-1
NMR Nuclear Magnetic Resonance
Pyr Pyridine
SBL Serine-beta-lactamase
TFA Trifluoroacetic acid
Materials and Methods
[00156] Standard experimental procedures were followed for synthesis; some of these are defined below.
General
[00157] Carbapenems were from Glentham Life Sciences (biapenem, doripenem, ertapenem), Molekula (meropenem, imipenem), Ark Pharma (tebipenem) and Ontario Chemicals Inc. (panipenem). Infrared spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer. Mass spectra were acquired using a Waters Micromass LOT Premier XE spectrometer fitted with an Acquity UPLC system. All enzymes were expressed and purified as previously described in the literature [21 , 22]
NMR Spectroscopy
[00158] NMR spectra were acquired using a Bruker Avance III 700 MHz spectrometer equipped with a TCI inverse cryoprobe, and a Bruker AVI 11 HD 600 MHz spectrometer equipped with a BB-F/1 H Prodify N2 cryoprobe. Unless otherwise stated, samples were prepared in 50 mM sodium phosphate, pH 7.5, 10 % D2O. Water suppression was accomplished by pre-saturation or by excitation sculpting with perfect echo. All spectra were acquired at 298 K. Chemical shift assignments for intact carbapenems were made using 5 mM samples, on the basis of 1 H, COSY, HSGC, and HMBC spectra. Chemical shift assignments for the lactone products were made using a sample consisting of 5 mM lactone product (for ertapenem, biapenem, doripenem and meropenem) (HPLC-purified), based on 1 H, COSY, HSGC, and HMBC spectra. The concentrations of enzymes and carbapenems used to test for product formation are as stated in the relevant figures. Stereochemical analysis of the ertapenem lactone product was carried out using a 1 D SPFGSE 1 H,1 H-NOESY pulse sequence employing water pre-saturation and a 300 s mixing time.
Preparation of Carbapanem-derived I b-methyl-lactones
[00159] I b-methyl-carbapenems were degraded using the class D SBL OXA-48 to yield a mixture of hydrolysis product and lactone product:
Figure imgf000035_0001
carbapenem hydrolysis product carbapenem-derived lactone
[00160] The major hydrolysis product and major lactone product both possess an (S)- configuration at C-2, the attachment point of the SR3 group. Lactones derived from ertapenem, biapenem, doripenem, tebipenem and meropenem were prepared in this manner.
Example 1 - Ertapanem-derived (2S)-lactone
Figure imgf000035_0002
[00161] A mixture of 10 mM ertapenem and 25 mM OXA-48 in 50 mM sodium phosphate, pH 7.5, was incubated at room temperature for 4 h. Enzyme was removed by passing the reaction mixture through an Amicon Ultra-0.5 mL centrifugal filter (3 kDa molecular weight cut-off). The filtered enzymatic products were purified on a JASCO high-pressure liquid chromatography (HPLC) platform equipped with PU-2086 Plus preparative scale pumps. A SunFire™ Prep C18 column (10 x 150 mm, 5 pm particle size; Waters) was used. Mobile phases (A) water with 0.1 % trifluoroacetic acid (TFA), and (B) acetonitrile with 0.1 % TFA were used at an overall flow- rate of 3 mL/min, while elution was monitored at 254 nm. The enzymatic products were separated using a gradient running from 10 % B to 50 % B over 15 min. Collected fractions were frozen on liquid nitrogen and lyophilized. The identities of the eluted peaks were determined by mass spectrometry and NMR spectroscopy.
[00162] The 1 H- and 13C-NMR chemical shift assignments for Example 1 are listed in Table 1. Table 1
Figure imgf000036_0002
Figure imgf000036_0001
[00163] Lactones derived from biapenem, doripenem and meropenem were isolated as per the following procedure:
[00164] Carbapenem (4-5 g) was dissolved in 1 mL of 50 mM sodium phosphate, pH 7.5. To this, OXA-48 was added to a final concentration of 20 mM, and the mixture was incubated at room temperature for 5-6 h. The mixture was passed through a 10K MWCO 0.5 mL Amicon centrifugal filter, and the carbapenem-derived lactone was purified from the filtrate by HPLC. The HPLC purification employed a C18 semi-preparative column with mobile phases (A) water with 0.1 % TFA, and (B) acetonitrile with 0.1 % TFA. A solvent gradient as used, from 10 % B to 40 % B over the span of 15 min, and elution was monitored at 230 nm. The desired fractions were combined, frozen on liquid nitrogen, and lyophilized. Purity was confirmed by NMR spectroscopy. Example 2 - Biapenem-derived lactone
Figure imgf000037_0001
[00165] The 1H- and 13C-NMR chemical shift assignments for Example 2 are listed in Table 2.
Table 2
Figure imgf000037_0004
Figure imgf000037_0002
Example 3 - Doripenem-derived lactone
Figure imgf000037_0003
[00166] The 1H- and 13C-NMR chemical shift assignments for Example 3 are listed in Table 3.
Table 3
Figure imgf000038_0003
Figure imgf000038_0001
Example 4 - Meropenem-derived lactone
Figure imgf000038_0002
[00167] The 1H- and 13C-NMR chemical shift assignments for Example 4 are listed in Table 4.
Table 4
Figure imgf000038_0004
Figure imgf000039_0003
Figure imgf000039_0001
Example 5 - Tebipenem-derived lactone
Figure imgf000039_0002
[00168] 2 mM tebipenem was mixed with 5 mM OXA-48 in 50 mM sodium phosphate (pH 7.5), 10 % D2O, and the lactone product was characterised by NMR [via 1 H, correlation spectroscopy (COSY), heteronuclear single quantum coherence (HSQC), and heteronuclear multiple bond correlation (HMBC) experiments]. The 1H- and 13C-NMR chemical shift assignments for Example 5 are listed in Table 5.
Table 5
Figure imgf000039_0004
Figure imgf000040_0003
Figure imgf000040_0001
Preparation of Carbapanem-derived I b-hydrogen-lactones
[00169] I b-hydrogen-carbapenems were not degraded to b-lactones by wild-type OXA-48 enzyme. Instead a mutant OXA-48 enzyme was prepared with serine-70 mutated to cysteine (S70C). This mutant OXA-48 was used to degrage I b-hydrogen-carbapenems to yield a mixture of hydrolysis product and lactone product.
Figure imgf000040_0002
carbapenem hydrolysis product carbapenem-derived lactone
[00170] OXA-48 S70C was generated by site-directed mutagenesis. Using template plasmid pNIC-Bio3-OXA-48 (without the C-terminal biotinylation sequence), the mutation was installed using primers 1 (5’-ctatt gggaa tttta aaggt acatg cgggt aaaaa tgctt ggttc-3’) and 2 (5’-gaacc aagca ttttt acccg catgt acctt taaaa ttccc aatag-3’) using standard conditions. The mutated plasmid was transformed with Escherichia coli BL21 (DE3) for protein expression. The transformed E. coli was cultured in 2TY to an optical density of 0.6, and protein expression was induced with IPTG. The harvested culture was lysed by sonication, and OXA-48 S70C was purified by nickel-affinity chromatography and size-exclusion chromatography. The purified protein was buffer exchanged into 50 mM sodium phosphate, pH 7.5, aliquoted, and frozen on liquid nitrogen.
Example 6 - Imipenem-derived lactone
Figure imgf000041_0001
[00171] 2 mM imipenem was mixed with 50 mM OXA-48 S70C in 50 mM sodium phosphate (pH 7.5), 10 % D2O, and the lactone product was characterised by NMR [via 1 H, correlation spectroscopy (COSY), heteronuclear single quantum coherence (HSQC), and heteronuclear multiple bond correlation (HMBC) experiments]. The 1H- and 13C-NMR chemical shift assignments for Example 6 are listed in Table 6.
Table 6
Figure imgf000041_0003
Figure imgf000041_0002
Example 7 - Panipenem-derived lactone
Figure imgf000042_0001
[00172] 2 mM panipenem was mixed with 50 mM OXA-48 S70C in 50 mM sodium phosphate (pH 7.5), 10 % D2O, and the lactone product was characterised by NMR [via 1 H, correlation spectroscopy (COSY), heteronuclear single quantum coherence (HSQC), and heteronuclear multiple bond correlation (HMBC) experiments]. The 1H- and 13C-NMR chemical shift assignments for Example 7 are listed in Table 7.
Table 7
Figure imgf000042_0003
Figure imgf000042_0002
Preparation of Synthetic b-lactones
Pyrroline-based b-lactones [00173] Carbapenem derivatives (IV) are synthesised from the commercially available enol phosphate precursor (III), by reaction with R3-SH in the presence of base (such as DIPEA), followed by hydrogenolysis of the acid protecting group, according to known procedures as described by Sunagawa et al. ( J . Antibiotics, 1991 , 44, 459-462):
Figure imgf000043_0001
[00174] Pyrroline-based b-lactone derivatives (II) are formed from the corresponding carbapenems (IV) by OXA-48 enzymatic degradation as described hereinbefore.
Pyrrole-based b-lactones
[00175] Substituted pyrrole scaffolds (V) can be prepared by many synthetic routes, such as described by Barton et al. ( Tetrahedron , 1990, 7587-7598), Estevez et al. ( Chem . Soc. Rev. 2014, 43, 4633-4657) and Gilchrist (J. Chem. Soc. Perkin Trans. 1, 2001 , 2491-2515).
Figure imgf000044_0001
Intermediate (VI) is formed by the radical alkylation of pyrrole (V) with f-butyl-2-iodoacetate according to the procedure of Makhynya et al. ( Eur . J. Org. Chem. 2007, 1287-1293) and is then protected at the pyrrole N-atom by a suitable protecting group, such as Boc to give intermediate (VII). Intermediate (VII) undergoes an enantio- and diastereoselective aldol reaction with aldehyde R2CHO, in the presence of (-)-diisopinocampheylboron triflate, according to the methodology of Paterson et al. ( Tetrahedron , 1990, 46, 4663-4684). The resultant alcohol-ester (VIII) is hydrolysed to the corresponding alcohol-acid (IX) under acidic conditions, such as the use of TFA. Treatment of intermediate (IX) with 4- bromobenzenesulfonyl chloride in the presence of base, such as pyridine, according to the procedure of Pu et al. ( J.Org . Chem. 1991 , 56, 1280-1283), followed by hydrogenolysis of the benzyl ester to the acid gives pyrrole-based b-lactone compounds (X).
Pyridine-based b-lactones
[00176] Substituted pyridine scaffolds (XI) can be prepared by various synthetic approaches, such as described by Wang et al. ( Organometallics , 2013, 4882-4891) and Gilchrist (J. Chem. Soc. Perkin Trans. 1, 2001 , 2491-2515)
Figure imgf000045_0001
Pyridine precursor (XI) undergoes an enantio- and diastereoselective aldol reaction with aldehyde R2CHO, in the presence of (-)-diisopinocampheylboron triflate, according to the methodology of Paterson et al. ( Tetrahedron , 1990, 46, 4663-4684). The resultant alcohol- ester (XII) is hydrolysed to the corresponding alcohol-acid (XIII) under acidic conditions, such as the use of TFA. Treatment of intermediate (XIII) with 4-bromobenzenesulfonyl chloride in the presence of base, such as pyridine, according to the procedure of Pu et al. ( J.Org . Chem. 1991 , 56, 1280-1283), followed by hydrogenolysis of the benzyl ester to the acid gives pyridine-based b-lactone compounds (XIV).
Biological activity
b-Lactamase inhibitor! by ertapenem and Example 1 (ertapenem-derived lactone)
[00177] The impact of ertapenem (1 mM, 0.5 mM, 0.1 mM) and Example 1 (1 mM, 0.5 mM, 0.1 mM) on the hydrolysis of the fluorogenic substrate FC-5 [23] (5 mM) was tested with the following b-lactamases at the following concentrations - CTX-M-15 (50 pM), SFC-1 (500 pM), New Delhi metallo^-lactamase-1 (NDM-1 ; 10 pM), L1 (50 pM), AmpC (500 pM), OXA-10 (1 nM), OXA-23 (12.5 nM), and OXA-48 (12.5 nM) [21 , 24] Reactions were carried out in 100 mM sodium phosphate, pH 7.5, 0.01 % Triton X-100 (for CTX-M-15, SFC-1 , AmpC, OXA-10, OXA-23, and OXA-48), or 50 mM HEPES, pH 7.5, 10 pM ZnS04, 10 pg/mL BSA, 0.01 % Triton X-100 (for NDM-1 and L1). The enzyme was pre-incubated with ertapenem or Example 1 for 10 min prior to the addition of FC-5. Assays were performed in triplicate using 384-well black pclear® plates (Greiner Bio-One) at 25 °C and measured with a PHERAstar FS microplate reader (BMG Labtech). IC50 values were determined using eight different concentrations of ertapenem and ertapenem lactone, and nonlinear regression analysis was performed using Prism 7 (GraphPad).
[00178] The inhibitory activity of Example 1 against the panel of 8 b-lactamases is shown in Figure 1. Example 1 inhibited all the b-lactamases tested at high concentrations. Class D SBLs (OXA-10, OXA-23 and OXA-48) and class B MBLs (NDM-1 and L1) were inhibited strongly, with Example 1 having IC50 values of 790 nM against OXA-10, 1.2 mM against OXA-23 and 940 nM against OXA-48. Ertapenem had IC50 values of 1.9 nM against OXA-10, 65 nM against OXA-23 and 10 nM against OXA-48. b-Lactamase inhibiton by Example 4 (meropenem-derived lactone)
[00179] The impact of Example 4 (1 mM, 0.5 mM, 0.1 mM) on the hydrolysis of the fluorogenic substrate FC-5 [23] (5 mM) was tested with the following b-lactamases at the following concentrations - CTX-M-15 (50 pM), SFC-1 (500 pM), New Delhi metallo^-lactamase-1 (NDM-1 ; 10 pM), L1 (50 pM), AmpC (500 pM), OXA-10 (1 nM), OXA-23 (12.5 nM), OXA-48 (12.5 nM), KPC-2 (500 pM) and BPU-1 (5 nM) [21 , 24] Reactions were carried out in 100 mM sodium phosphate, pH 7.5, 0.01 % Triton X-100 (for CTX-M-15, SFC-1 , AmpC, OXA-10, OXA- 23, and OXA-48), or 50 mM HEPES, pH 7.5, 10 mM ZnS04, 10 pg/mL BSA, 0.01 % Triton X- 100 (for NDM-1 and L1). The enzyme was pre-incubated with Example 4 for 10 min prior to the addition of FC-5. Assays were performed in triplicate using 384-well black pclear® plates (Greiner Bio-One) at 25 °C and measured with a PHERAstar FS microplate reader (BMG Labtech). IC50 values were determined using eight different concentrations of meropenem lactone, and nonlinear regression analysis was performed using Prism 7 (GraphPad).
[00180] The inhibitory activity of Example 4 against the panel of 10 b-lactamases is shown in Figure 2. Example 4 inhibited the majority of the b-lactamases tested at high concentrations. Class D SBLs (OXA-10, OXA-23, OXA-48 and BPU-1) and class B MBLs (NDM-1 and L1) were inhibited strongly, with Example 4 having IC50 values of 2.34 mM against OXA-10 and 314 mM against L1. b-Lactamase inhibiton by Example 6 (imipenem-derived lactone)
[00181] The impact of Example 6 (1 mM, 0.5 mM, 0.1 mM) on the hydrolysis of the fluorogenic substrate FC-5 [23] (5 mM) was tested with the following b-lactamases at the following concentrations - CTX-M-15 (50 pM), SFC-1 (500 pM), New Delhi metallo^-lactamase-1 (NDM-1 ; 10 pM), L1 (50 pM), AmpC (500 pM), OXA-10 (1 nM), OXA-23 (12.5 nM), OXA-48 (12.5 nM), KPC-2 (500 pM) and BPU-1 (5 nM) [21 , 24] Reactions were carried out in 100 mM sodium phosphate, pH 7.5, 0.01 % Triton X-100 (for CTX-M-15, SFC-1 , AmpC, OXA-10, OXA- 23, and OXA-48), or 50 mM HEPES, pH 7.5, 10 mM ZnS04, 10 pg/mL BSA, 0.01 % Triton X- 100 (for NDM-1 and L1). The enzyme was pre-incubated with Example 6 for 10 min prior to the addition of FC-5. Assays were performed in triplicate using 384-well black pclear® plates (Greiner Bio-One) at 25 °C and measured with a PHERAstar FS microplate reader (BMG Labtech). IC50 values were determined using eight different concentrations of imipenem lactone, and nonlinear regression analysis was performed using Prism 7 (GraphPad).
[00182] The inhibitory activity of Example 6 against the panel of 10 b-lactamases is shown in Figure 3. Example 6 inhibited all the b-lactamases tested at high concentrations. Class D SBLs (OXA-10, OXA-23, OXA-48) and class B MBLs (NDM-1 and L1) were typically inhibited more strongly, with Example 6 having an IC50 value of 3.69 mM against OXA-10.
NMR degradation studies
[00183] The stability of carbapenems and carbapenem-derived lactones according to the present invention towards SBLs was investigated by NMR spectroscopy.
OXA-10 & Example 4 (meropenem-derived lactone)
[00184] 977 mM of meropenem-derived lactone (Example 4) was incubated with 483 mM of SBL OXA-10 and 9.77 mM of 13C-labelled NaHCOs in 170 pL 50 mM sodium phosphate, pH 7.5, 10 % D2O at room temperature. 13C -NMR (Fig. 4A) and 1 H-NMR (Fig. 4B) spectra were acquired at various time points (0.1 , 1.8, 3.5, 5.2 and 7.0 hours) post-incubation. The Relabelled NaHCOs present in the sample introduces a 13C-label at the carbamylated lysine residue in the active site of OXA-10, so that changes in the lactamase active site can be observed by 13C -NMR spectroscopy. Fig. 4A suggests that during the first 2 hours of the incubation with OXA-10, the majority of the OXA-10 exists as an acylated covalent complex with the lactone; after 3.5 hours the uncomplexed state of the enzyme increasingly predominates. Fig. 4B shows the stability of the lactone even when incubated with a very high concentration of OXA-10; it takes more than 2 hours for the lactone to be fully degraded by OXA-10.
OXA-10 & meropenem
[00185] 977 mM of meropenem was incubated with 483 mM of SBL OXA-10 and 9.77 mM of 13C-labelled NaHCOs in 50 mM sodium phosphate, pH 7.5, 10 % D2O at room temperature. 1 H-NMR spectra were acquired before addition of OXA-10, and 5 minutes (approx. 0.1 hr) after addition of OXA-10 (Figs. 5A & 5B show a section of the respective spectra). Fig. 5B shows that after as little as 5 mins incubation with the same high concentration of OXA-10, meropenem has been fully degraded. [00186] The carbapenem-derived lactones of the present invention show significantly improved stability towards SBLs compared to the equivalent carabapenems.
[00187] While specific embodiments of the invention have been described for the purpose of reference and illustration, various modifications will be apparent to a person skilled in the art without departing from the scope of the invention as defined by the appended claims.
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Claims

1. A compound according to Formula I:
Figure imgf000050_0001
wherein:
R1 is selected from the group consisting of:
Figure imgf000050_0002
R2 is hydrogen or methyl;
R3 is (1-4C)alkyl, (3-7C)cycloalkyl or heterocycloalkyl, each optionally substituted with one or more of NR7R8, hydroxy, (1-3C)alkyl, (1-4C)alkoxy, halo, (1-3C)fluoroalkyl, C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1-3C)alkylR11 , heterocycloalkyl, (3-7C)cycloalkyl, heteroaryl and aryl;
R4 is hydrogen or (1-4C)alkyl;
X is NR12, O, S or a bond;
R5 is hydrogen, (1-4C)alkyl, (3-7C)cycloalkyl, heterocycloalkyl, heteroaryl or aryl, wherein (1- 4C)alkyl, (3-7C)cycloalkyl, heterocycloalkyl, heteroaryl or aryl are optionally substituted with one or more of NR7R8, hydroxy, (1-3C)alkyl, (1-4C)alkoxy, halo, (1-3C)fluoroalkyl, C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1-3C)alkylR11 , heterocycloalkyl, (3-7C)cycloalkyl, heteroaryl and aryl;
R6 is hydrogen, (1-4C)alkyl, halo, hydroxy or (1-4C)alkoxy;
R7 is hydrogen, (1-4C)alkyl, SO(1-3C)alkyl, S02(1-3C)alkyl, S02NR13R14, aryl or CH=NR15;
R9 is hydrogen, (1-4C)alkyl or aryl, wherein (1-4C)alkyl or aryl are optionally substituted with one or more of hydroxy, (1-4C)alkoxy, halo, (1-3C)fluoroalkyl and C02R16;
R11 is hydroxy, (1-4C)alkoxy or NR17R18;
R17 is hydrogen, (1-4C)alkyl, SO(1-3C)alkyl, S02(1-3C)alkyl, S02NR19R2°, aryl or CH=NR21 ; and
R8, R10, R12, R13, R14, R15, R16, R18, R19, R20 and R21 are each independently selected from hydrogen or (1-3C)alkyl; or a pharmaceutically acceptable salt thereof.
2. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R2 is methyl.
3. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein R3 is (1-4C)alkyl or heterocycloalkyl, each optionally substituted with one or more of NR7R8, hydroxy, (1-3C)alkyl, (1-4C)alkoxy, halo, C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1-3C)alkylR11 , heterocycloalkyl, (3-7C)cycloalkyl, heteroaryl and aryl.
4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein R3 is (1-4C)alkyl or heterocycloalkyl, each optionally substituted with one or more of NR7R8, halo, C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1-3C)alkylR11and heterocycloalkyl.
5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein R4 is hydrogen.
6. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein R4 is methyl.
7. A compound of formula (IB):
Figure imgf000051_0001
wherein R1 and R3 to R21 are as defined in claim 1 , or a pharmaceutically acceptable salt thereof.
8. A compound of formula (IB), or a pharmaceutically acceptable salt thereof, according to claim 7, wherein R1 is:
Figure imgf000051_0002
9. A compound of formula (IB), or a pharmaceutically acceptable salt thereof, according to claim 7, wherein R1 is:
Figure imgf000052_0001
10. A compound of formula (IB), or a pharmaceutically acceptable salt thereof, according to claim 7, wherein R1 is:
Figure imgf000052_0002
1 1. A compound of formula (IB), or a pharmaceutically acceptable salt thereof, according to any one of claims 8 to 10, wherein R4 is methyl.
12. A compound of formula (IB), or a pharmaceutically acceptable salt thereof, according to any one of claims 8 to 10, wherein R4 is hydrogen.
13. A compound of formula (IB), or a pharmaceutically acceptable salt thereof, according to any one of claims 8 to 12, wherein R3 is (1-4C)alkyl or heterocycloalkyl, each optionally substituted with one or more of NR7R8, halo, C(=0)NR9R1°, C(=NH)(1-3C)alkyl, (1-3C)alkylR11 or heterocycloalkyl.
14. A compound of formula (IF):
Figure imgf000052_0003
wherein R2 to R21 and X are as defined in claim 1 , or a pharmaceutically acceptable salt thereof.
15. A compound of formula (I H):
Figure imgf000053_0001
wherein R4 to R21 and X are as defined in claim 1 , or a pharmaceutically acceptable salt thereof.
16. A compound of formula (I J):
Figure imgf000053_0002
wherein R2 to R21 and X are as defined in claim 1 , or a pharmaceutically acceptable salt thereof.
17. A compound of formula (IL):
Figure imgf000053_0003
wherein R4 to R21 and X are as defined in claim 1 , or a pharmaceutically acceptable salt thereof.
18. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 , selected from:
Figure imgf000054_0001
19. A compound as claimed in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use as a medicament.
20. A compound as claimed in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in the treatment of a bacterial infection in a warm-blooded animal, such as man.
21. A compound as claimed in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in the treatment of a bacterial infection in a warm-blooded animal, such as man, in combination with a b-lactam antibiotic.
22. A method of treating a bacterial infection, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound as claimed in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in combination with a b-lactam antibiotic.
23. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 18, and one or more pharmaceutically acceptable excipients.
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Citations (2)

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EP0481116A1 (en) * 1989-10-03 1992-04-22 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI & CO. LTD. A process for producing halomethylcarbapenems
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CHRISTOPHER T. LOHANS ET AL: "A New Mechanism for [beta]-Lactamases: Class D Enzymes Degrade 1[beta]-Methyl Carbapenems through Lactone Formation", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 57, no. 5, 26 January 2018 (2018-01-26), DE, pages 1282 - 1285, XP055543553, ISSN: 1433-7851, DOI: 10.1002/anie.201711308 *

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