WO2014153624A1 - Composés antibactériens - Google Patents

Composés antibactériens Download PDF

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WO2014153624A1
WO2014153624A1 PCT/AU2014/050007 AU2014050007W WO2014153624A1 WO 2014153624 A1 WO2014153624 A1 WO 2014153624A1 AU 2014050007 W AU2014050007 W AU 2014050007W WO 2014153624 A1 WO2014153624 A1 WO 2014153624A1
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compound
formula
compounds
alkyl
heteroalkyi
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PCT/AU2014/050007
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English (en)
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Peter RUTLEDGE
Matthew Todd
James Anthony TRICCAS
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The University Of Sydney
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Priority claimed from AU2013901166A external-priority patent/AU2013901166A0/en
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Publication of WO2014153624A1 publication Critical patent/WO2014153624A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic 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
    • C07D405/14—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • the invention relates to synthesis of antibacterial compounds, to antibacterial compounds, to pharmaceutical compositions containing same and to methods of using same in antibacterial applications, particularly but not exclusively antimycobacterial applications.
  • Tuberculosis remains a major cause of mortality and morbidity worldwide.
  • M. tb Mycobacterium tuberculosis
  • This huge clinical load is a burden to struggling health services and has an enormous socioeconomic impact on a community.
  • M is a metal
  • X is selected from NR 10 , O or S, or combinations thereof;
  • R 10 is H, alkyl or heteroalkyi;
  • n is 0 or 1 ;
  • R 1 is selected from alkyl, heteroalkyi, alkenyl and alkynyl;
  • R 5 is selected from H, alkyl, heteroalkyi, alkenyl and alkynyl, wherein when R 5 is not H, R 5 may be linked to -R 6 -R 7 -R 8 ;
  • R 2 and R 6 are the same or different and are selected from alkyl, heteroalkyi, alkenyl, alkynyl, cycloalkyi, heterocycloalkyi, aryl and heteroaryl, which groups are optionally substituted;
  • R 3 and R 7 are the same or different and are selected from alkyl, heteroalkyi, alkenyl and alkynyl;
  • R 4 and R 8 are the same or different and are selected from alkyl, heteroalkyi, alkenyl, alkynyl, cycloalkyi, heterocycloalkyi, aryl, heteroaryl, aralkyi and heteroaralkyi, which groups are optionally substituted, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the present invention also relates to a compound of formula (II):
  • X is selected from NR 10 , O or S, or combinations thereof;
  • R 10 is H, alkyl or heteroalkyl;
  • n is 0 or 1 ;
  • R 1 is selected from alkyl, heteroalkyl, alkenyl and alkynyl;
  • R 5 is selected from H, alkyl, heteroalkyl, alkenyl and alkynyl, wherein when R 5 is not H, R 5 may be linked to -R 6 -R 7 -R 8 ;
  • R 2 and R 6 are the same or different and are selected from alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyi, heterocycloalkyi, aryl and heteroaryl, which groups are optionally substituted;
  • R 3 and R 7 are the same or different and are selected from alkyl, heteroalkyl, alkenyl and alkynyl;
  • R 4 and R 8 are the same or different and are selected from alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyi, heterocycloalkyi, aryl, heteroaryl, aralkyl and heteroaralkyl, which groups are optionally substituted, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • the metal is a /-block metal.
  • the metal may be Cu, Zn, Ni, Co, Fe, Mn or Cr (e.g. Cu(ll), Zn(ll), Ni(ll), Co(ll), Co(lll), Fe(ll), Fe(lll), Mn(ll) and Cr(lll)).
  • the following embodiments relate to compounds of formula (I) and (II).
  • Ri is a Ci -4 alkyl group (for example, Ci or C 2 alkyl).
  • Ri is a heteroalkyl group such as a polyether (e.g. polyethylene glycol), comprising from 1 to 4 carbon atoms.
  • R 3 and R 7 are not present.
  • R 5 is H.
  • R 1 and R 5 are the same. In other embodiments, R 1 and R 5 are different.
  • R 2 and R 6 are the same. In other embodiments, R 2 and R 6 are different. In one embodiment, R 3 and R 7 are the same. In other embodiments, R 3 and R 7 are different.
  • R 4 and R 8 are the same. In other embodiments, R 4 and R 8 are different. In one embodiment, the combination of R 1 , R 2 , R 3 and R 4 is the same as R 5 , R 6 , R 7 and R 8 . That is, the compound is symmetrical. In other embodiments, one or more of R 1 , R 2 , R 3 and R 4 are different to one or more of R 5 , R 6 , R 7 and R 8 . That is, the compound is not symmetrical.
  • R 4 is an aryl, heteroaryl, aralkyl or heteroaralkyl group.
  • R 4 may be selected from phenyl, naphthalene, pyridine, quinoline, anthracene, coumarin and napthalimide, such as a compound of formula (III):
  • Z is N or O; and when Z is O, R 9 is not present; and when Z is N, R 9 is H, alkyl, heteroalkyi, alkenyl, alkynyl, cycloalkyi, heterocycloalkyi, aryl, heteroaryl, aralkyl and heteroaralkyl.
  • R 8 may be the same or different to R 4 and may also be selected from aryl, heteroaryl, aralkyl or heteroaralkyl group.
  • R 8 may be selected from phenyl, naphthalene, pyridine, quinoline, anthracene, coumarin and compounds of formula (III).
  • the groups R 2 and/or R 6 include a moiety that is capable of coordinating to a metal ion complexed to the macrocycle.
  • R 2 may be a heteroaryl group, such as pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, triazole or tetrazole.
  • R 2 is a triazole group.
  • R 6 may be the same or different to R 2 and may also be selected from heteroaryl groups, such as pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, triazole and tetrazole. Preferably, R 6 is also a triazole group.
  • the present invention also relates to compositions including the above described compounds, and to uses of the compounds and compositions for treating mycobacterial infection, in particular M. tb infection.
  • Figure 1 Inhibition of mycobacterial growth by novel compounds. Lead inhibitors displayed potent inhibitory activity after 7 days incubation with BCG in culture media.
  • Figure 2 Structure of lead MCyC inhibitors. The zinc(ll) (C47) and copper(ll) (C48) MCyCs and the ammonium salt C53.
  • FIG. 4 Intracellular activity of inhibitors.
  • A THP1 cell were infected with M. avium, inhibitors or rifampicin (RIF) added (10 ⁇ ), and the number of surviving bacteria determined after 5 days. All inhibitors reduced bacterial load compared to untreated controls.
  • B Novel inhibitors display no toxicity against mammalian cells. THP1 cells were treated with inhibitors (50 ⁇ ) and the proportion of surviving cells compared to non-treated cells determined 7 days later.
  • Figure 5 Alternative pendant groups (R and R' in Figure 3 above) to be introduced as variants of the 2-ethyl-1 ,8-naphthalimide group of C47, C48 and C53.
  • FIG. 6 Novel compounds work in combination with existing TB drug.
  • M. tb was treated with suboptimal concentration of Rifampicin (RIF, 0.01 ⁇ ) or C47 (0.12 ⁇ ) or combination of the two drugs (RIF+C47). Significant inhibition of growth was only seen when drugs were used in combination.
  • Figure 7 Parent structure of lead compounds: the trifluoroacetate salt of the amine shown, plus the zinc(ll) and copper(ll) complexes of this ligand (as their perchlorate salts).
  • Figure 8 Alternative pendant groups incorporated into general AMC structure ( Figure 7) to generate new compounds for testing in this study.
  • the free amine (salt form) plus its zinc(ll) and copper(ll) complexes were prepared.
  • FIG. 9 Activity of AMCs against M. tuberculosis H37Rv. Selected AMCs were incubated with M. tuberculosis H37Rv cultures and 7 days later the indicator dye resazurin (0.05%) was added. Fluorescence was measured 24 hours later. Graphs represent the percentage survival of bacteria compared to non-treated cells. A compound was considered effective if it inhibited more than 50% growth of the test pathogen at the single concentration tested (less than 50% bacterial survival).
  • Figure 10 Activity of AMCs against gram-negative and gram positive-pathogens. Selected AMCs were incubated with the following strains: Panel A, E. coli EC958; Panel B, P.
  • aeruginosa PA01 Panel C, P. aeruginosa CJ2009; Panel D, methicillin-resistant Staphylococcus aureus (MRSA).
  • MRSA methicillin-resistant Staphylococcus aureus
  • Recited compounds are further intended to encompass compounds in which one or more atoms are replaced with an isotope, i.e., an atom having the same atomic number but a different mass number.
  • isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11 C, 13 C, and 14 C.
  • Compounds according to the formulae provided herein, which have one or more stereogenic centres, have an enantiomeric excess of at least 50%.
  • such compounds may have an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%.
  • Some embodiments of the compounds have an enantiomeric excess of at least 99%.
  • single enantiomers can be obtained by asymmetric synthesis, synthesis from optically pure precursors, biosynthesis (for example, using modified CYP102 such as CYP BM-3) or by resolution of the racemates, for example, enzymatic resolution or resolution by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral HPLC column.
  • Certain compounds are described herein using a general formula that includes variables such as R 1 , R 2 , R 3 , R 4 , A, Y and M.
  • each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. Therefore, for example, if a group is shown to be substituted with 0, 1 or 2 R * , the group may be unsubstituted or substituted with up to two R * groups and R * at each occurrence is selected independently from the definition of R * . Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds, i.e., compounds that can be isolated, characterized and tested for biological activity.
  • a “pharmaceutically acceptable salt” of a compound disclosed herein is an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication.
  • Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzenesulfonic, ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaieic, hydroiodic, phenylacetic, alkanoic (such as acetic, HOOC-(CH 2 ) n -COOH where n is any integer from 0 to 6, i.e.
  • acids such as hydrochloric, phosphoric, hydrobromic, malic,
  • a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, is preferred.
  • the compounds of formula (I) are metal complexes, and therefore are charged. Accordingly, the compound may be present in conjunction with a counterion (such as trifluoroacetate or perchlorate) to form a neutral salt.
  • a counterion such as trifluoroacetate or perchlorate
  • the compounds of formula (II) may exist in an ionised form. That is, where one or more Y groups are protonated. Accordingly, the compound may also be present in conjunction with a counterion (such as trifluoroacetate or perchlorate) to form a neutral salt.
  • a counterion such as trifluoroacetate or perchlorate
  • each compound of formulae (I) and (II) may, but need not, be present as a hydrate, solvate or non-covalent complex.
  • the various crystal forms and polymorphs are within the scope of the present invention, as are prodrugs of the compounds of formulae (I) and (II) provided herein.
  • a “prodrug” is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce a compound of formulae (I) or (II) provided herein.
  • a prodrug may be an acylated derivative of a compound as provided herein.
  • Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein.
  • Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to generate the parent compounds.
  • M is a metal.
  • the metal is a d- block metal.
  • the metal may be Cu, Zn, Ni, Co, Fe, Mn or Cr (e.g. Cu(ll), Zn(ll), Ni(ll), Co(ll), Co(lll), Fe(ll), Fe(lll), Mn(ll) and Cr(lll)).
  • the metal is one that is able to form an octahedral complex that consists of the macrocycle, R 1 and R 3 .
  • the metal may be one that is capable of forming an octahedral complex that consists of the macrocycle, either R 1 or R 3 , and another ligand (such as CI, H 2 O, and the like) that may be present in the composition containing the compound of the present invention.
  • a “ring substituent” may be a moiety such as a halogen, alkyl group, haloalkyl group or other substituent described herein that is covalently bonded to an atom, preferably a carbon or nitrogen atom, that is a ring member.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, i.e., a compound that can be isolated, characterized and tested for biological activity.
  • a pyridyl group substituted by oxo is a pyridone.
  • halogen for example, fluorine, chlorine, bromine or iodine atoms
  • alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 10 carbon atoms, for example a n-octyl group, especially from 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6, carbon atoms.
  • alkyl groups are methyl, ethyl, propyl, / ' so-propyl, n-butyl, / ' so-butyl, sec- butyl, terf-butyl, n-pentyl, / ' so-pentyl, n-hexyl and 2,2-dimethylbutyl.
  • heteroalkyl refers to an alkyl group as defined above that contains one or more heteroatoms selected from oxygen, nitrogen and sulphur (especially oxygen and nitrogen).
  • Specific examples of heteroalkyl groups are ethers (such as polyethylene glycol), methoxy, trifluoromethoxy, ethoxy, n-propyloxy, / ' so-propyloxy, butoxy, tert- butyloxy, methoxymethyl, ethoxymethyl, -CH 2 CH 2 OH, -CH 2 OH, methoxyethyl, 1 - methoxyethyl, 1 -ethoxyethyl, 2-methoxyethyl or 2-ethoxyethy1 , methylamino, ethylamino, propylamino, / ' so-propylamino, dimethylamino, diethylamino, / ' so-propyl- ethylamino, methylamin
  • heteroalkyl groups are nitrile, / ' so-nitrile, cyanate, thiocyanate, / ' so-cyanate, iso- thiocyanate and alkylnitrile groups, as well as groups that include one or more peptide bonds.
  • alkenyl refers to an at least partially unsaturated, straight-chain or branched hydrocarbon group that contains from 2 to 20 carbon atoms, preferably from 2 to 10 carbon atoms, especially from 2 to 6, i.e. 2, 3, 4, 5 or 6, carbon atoms.
  • alkenyl groups are ethenyl (vinyl), propenyl (allyl), / ' so-propenyl, butenyl, ethinyl, propinyl, butinyl, acetylenyl, propargyl, / ' so-prenyl and hex-2-enyl group.
  • alkenyl groups have one or two double bond(s).
  • alkynyl refers to a at least partially unsaturated, straight-chain or branched hydrocarbon group that contains from 2 to 20 carbon atoms, preferably from 2 to 10 carbon atoms, especially from 2 to 6, i.e. 2, 3, 4, 5 or 6, carbon atoms.
  • alkynyl groups are ethynyl, propynyl, butynyl, acetylenyl and propargyl groups.
  • alkynyl groups have one or two (especially preferably one) triple bond(s).
  • cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms.
  • cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetraline, adamantane (i.e. tricycle[3.3.1 .1 3,7 ]decane), cyclopentylcyclohexyl and cyclohex-2-enyl.
  • heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1 , 2 or 3) ring carbon atoms, each independently, have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom).
  • a heterocycloalkyl group has preferably 1 or 2 rings containing from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, O, N and S).
  • piperidyl is piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl and 2-pyrazolinyl group and also lactames, lactones, cyclic imides, cyclic anhydrides and biologically-active compounds, such as biotin (which includes a tetrahydroimidizalone ring fused with a tetrahydrothiophene ring).
  • biotin which includes a tetrahydroimidizalone ring fused with a tetrahydrothiophene ring.
  • aryl refers to an aromatic group that contains one or more rings containing from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms. Examples are phenyl, naphthyl and biphenyl groups.
  • heteroaryl refers to an aromatic group that contains one or more rings containing from 5 to 14 ring atoms, preferably from 5 to 10 (especially 5 or 6) ring atoms, and contains one or more (preferably 1 , 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N).
  • Examples are pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, triazole, tetrazole, pyridyl (for example, 4-pyridyl), imidazolyl (for example, 2-imidazolyl), phenylpyrrolyl (for example, 3-phenylpyrrolyl), thiazolyl, / ' so-thiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimi
  • aralkyi refers to a group containing both aryl and also alkyl, alkenyl, alkynyl and/or cycloalkyl groups in accordance with the above definitions, such as, for example, an arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, aryl-cycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl group.
  • the alkyl, alkenyl or alkynyl groups provide the means by which the alkyl group is joined to the compound of formula (I).
  • aralkyls are IH-indene, tetraline, dihydronaphthalene, indanone, phenylcyclopentyl, cyclohexylphenyl, fluorene and indane.
  • An aralkyi group preferably contains one, two or three aromatic ring systems (1 or 2 rings) containing from 6 to 10 carbon atoms and one alkyl, alkenyl and/or alkynyl group containing from 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing 5 or 6 ring carbon atoms.
  • heteroarylkyi refers to an aralkyi group as defined above in which one or more (preferably 1 , 2, 3 or 4) carbon atoms, each independently, have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atom (preferably oxygen, sulfur or nitrogen). That is, a group containing aryl or heteroaryl, respectively, and also alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cycloalkyl and/or heterocycloalkyl groups in accordance with the above definitions.
  • a heteroaralkyi group preferably contains one or two aromatic ring systems (1 or 2 rings) containing from 5 or 6 to 10 ring carbon atoms and one alkyl, alkenyl and/or alkynyl group containing 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing 5 or 6 ring carbon atoms, wherein 1 , 2, 3 or 4 of these carbon atoms have been replaced by oxygen, sulfur or nitrogen atoms. Examples include coumarin and naphthalimide groups.
  • halogen or "halogen atom” as preferably used herein means fluorine, chlorine, bromine, or iodine.
  • halogen for example, fluorine, chlorine, bromine or iodine atoms
  • This expression also refers to a group that is substituted by one, two, three or more (preferably unsubstituted) alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl groups.
  • a wording defining the limits of a range of length such as, for example, "from 1 to 5" means any integer from 1 to 5, i.e. 1 , 2, 3, 4 and 5.
  • any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.
  • preferred compounds are those where the metal is a /-block metal.
  • the metal may be Cu, Zn, Ni, Co, Fe, Mn or Cr.
  • Particulalry preferred compounds are those where the metal is Cu(ll), Zn(ll), Ni(ll), Co(ll), Co(lll), Fe(ll), Fe(lll), Mn(ll) or Cr(lll).
  • R 1 is a Ci -4 alkyl group (for example, Ci or C 2 alkyl).
  • R 1 may also be a heteroalkyl group such as a polyether (e.g. polyethylene glycol), comprising from 1 to 4 carbon atoms.
  • R 1 , R 2 , R 3 and R 4 are the same R 5 , R 6 , R 7 and R 8 . That is, the compound is symmetrical.
  • the present invention also includes compounds where one or more of R 1 , R 2 , R 3 and R 4 are different to one or more of R 5 , R 6 , R 7 and R 8 . That is, the compound is not symmetrical.
  • R 5 is H.
  • R 4 is an aryl, heteroaryl, aralkyl or heteroaralkyl group.
  • R 4 may be selected from phenyl, naphthalene, pyridine, quinoline, anthracene, coumarin and napthalimide, such as a compound of formula (III):
  • Z is N or O; and when Z is O, R 9 is not present; and when Z is N, R 9 is H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl.
  • R 2 is a dimer with another compound of formula (II).
  • Particularly preferred compounds of formula (I) are those where the groups R 2 and/or R 6 include a moiety that is capable of co-ordinating to a metal ion complexed to the macrocycle (for example, M in the compound of formula (I)).
  • R 2 may be a heteroaryl group, such as pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, triazole or tetrazole.
  • R 2 is a triazole group.
  • R 6 may be the same or different to R 2 and may also be selected from heteroaryl groups, such as pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, triazole and tetrazole. Preferably, R 6 is also a triazole group.
  • Particularly preferred compounds of the present invention are those where R 2 and/or R 6 are triazole groups. Accordingly, the compounds of the present invention can be synthesised in a simple manner using "click" chemistry. This allows each of the components (i.e. M, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 ) to be varied in turn to produce a large number of different compounds. This is discussed in the Examples section, below, in more detail.
  • R 4 and/or R 8 are biologically-active compounds, such as antibacterials, antibiotics, vitamins, and the like.
  • Di-te/t-butyl 4,1 1 -di(prop-2-yn-1 -yl)-1 ,4,8,1 1 -tetraazacyclotetradecane-1 ,8-dicarboxylate B1 , tri-tert-butyl 1 1 -prop-2-ynyl-1 ,4,8,1 1 -tetraazacyclotetradecane-1 ,4,8-tricarboxylic acid B2 and 6-azido-2-ethyl-benzo[de]isoquinoline-1 ,3-dione N1 were prepared according to literature methods. 14,15,25,29 2.
  • Alkyne B1 (1 .00 eq.) and azide (2.00eq.) were dissolved in either THF/H 2 O (7:3, 50 imM in alkyne) or f-BuOH/H 2 O (1 :1 , 50 imM in alkyne).
  • the reaction mixture was stirred under Ar at room temperature for 12 h, quenched with a saturated solution of NaHCO 3 (100 imL/mol copper) and extracted with DCM (3 x).
  • Boc-protected amine (1 .0 eq.) was mixed with a solution of 4M HCI in dioxane (5 imM in Boc-amine) was stirred at room temperature for 2-6 h. The solvent was removed under reduced pressure to give the desired hydrochloride salt of the parent amine.
  • Boc-protected amine (1 .0 eq.) was dissolved in a mixture of TFA/DCM/H2O (90:5:5, 5 imM in Boc-amine). The reaction mixture was stirred at room temperature for 2-6 h and concentrated under reduced pressure to give the desired trifluoroacetate salt of the parent amine.
  • Compound P5 (PBC20-1-51) Prepared from alkyne B1 and 2-(azidomethyl)naphthalene (CAS 164269-42-5) following Protocol 2 and then Protocol 5.
  • Protocol 2 Prepared from alkyne B1 and 3-(azidomethyl)pyridine (CAS 864528-33-6) following Protocol 2 and then Protocol 5.
  • Protocol 2 Prepared from alkyne B1 and 8-(azidomethyl)quinoline (CAS 131052-51 -2) following Protocol 2 and then Protocol 5.
  • Compound J4 (JTO-B-76-A) Prepared from alkyne B1 and 6-(azidomethyl)-2,3-dihydrobenzo[b][1 ,4]dioxine following Protocol 2 and then Protocol 4. (6-(Azidomethyl)-2,3-dihydrobenzo[b][1 ,4]dioxine prepared from 6-(bromomethyl)-2,3-dihydrobenzo[b][1 ,4]dioxine (CAS 79440-34-9) and sodium azide by adapting route to compound S2 in 5 ).
  • Protocol 4 Prepared from alkyne B1 and 2-(3-azidopropyl)isoindoline-1 ,3-dione (CAS 88192-21 -6) following Protocol 2 and then Protocol 4.
  • the resin was shaken for 2 h and washed with DMF (5 x), DCM (5 x) and DMF (5 x) .
  • Treatment of the resin with 1 0% piperidine/DMF (2 x 5 min) and measurement of the absorbance of the resulting piperidine-fulvene adduct at ⁇ 301 nm showed that the resin loading was quantitative.
  • Tri-ferf-butyl 1 ,4,8,11-tetraazacyclotetradecane-1 ,4,8-tricarboxylate (S7). 40 To a solution of cyclam (S5, 1 .51 g, 7.54 mmol) and triethylamine (5.20 mL, 37.3 mmol) in anhydrous DCM (300 mL) was added dropwise di-te/t-butyl dicarbonate (2.95 g, 13.5 mmol) in anhydrous DCM (90 mL) under N 2 .
  • the compound of formula (I) does not include a compound of formula (IV):
  • the compound of formula (I) does not include a compound of formula (V):
  • the compound of formula (I) does not include a compound of formula (VI):
  • the compound of formula (I) does not include a compound of formula (VII):
  • the compound of formula (I) does not include a compound of formula (VIII):
  • the compound of formula (I) does not include a compound of formula (IX):
  • the compound of formula (I) does not include a compound of formula (X):
  • the compound of formula (I) does not include a compound of formula (XI):
  • the compound of formula (I) does not include a compound of formula (XII):
  • the compound of formula (I) does not include a compound of formula (XIII):
  • the compound of formula (I) does not include a compound of formula (XIV):
  • the compound of formula (I) does not include a compound of formula (XV):
  • the compound of formula (I) does not include a compound of formula (XVI):
  • the compound of formula (I) does not include a compound of formula (XVII):
  • the compound of formula (I) does not include a compound of formula (XVIII):
  • the compound of formula (I) does not include a compound of formula (XIX):
  • the compound of formula (II) does not include a compound of formula (XXI):
  • the compound of formula (II) does not include a compound of formula (XXII):
  • the compound of formula (II) does not include a compound of formula (XXIII):
  • the compound of formula (II) does not include a compound of formula (XXIV):
  • the compound of formula (II) does not include a compound of formula (XXV):
  • the compound of formula (II) does not include a compound of formula (XXVI):
  • the compound of formula (II) does not include a compound of formula (XXVII):
  • the compound of formula (II) does not include a compound of formula (XXVIII):
  • the compound of formula (II) does not include a compound of formula (XXIX):
  • the compound of formula (II) does not include a compound of formula (XXX):
  • the compound of formula (II) does not include a compound of formula (XXXI):
  • the compound of formula (II) does not include a compound of formula (XXXII):
  • the compound of formula (II) does not include a compound of formula (XXXIII):
  • the compound of formula (II) does not include a compound of formula (XXXIV):
  • the compound of formula (II) does not include a compound of formula (XXXV):
  • the compound of formula (II) does not include a compound of formula (XXXVI):
  • the compound of formula (II) does not include a compound of formula (XXXVII):
  • the compound of formula (II) does not include a compound of formula (XXXVIII):
  • the compound of formula (I) does not include a compound of formula (XXXIX):
  • M Cu, Zn or Ni
  • R phenyl, isopropyl or indole
  • the compound of formula (I) does not include a compound of formula (XL):
  • the compound of formula (I) does not include a compound of formula (XLI):
  • the compound of formula (I) does not include a compound of formula (XLII):
  • the compound of formula (I) does not include a compound of formula (XLIII):
  • R phenyl, isopropyl or indole
  • the compound of formula (II) does not include a compound of formula (XLV):
  • the compound of formula (II) does not include a compound of formula (XLVI):
  • the compound of formula (II) does not include a compound of formula (XLVII):
  • compositions according to the present invention include at least one compound of formula (I) and/or formula (II) and, optionally, one or more carrier substances, for example, cyclodextrins such as hydroxypropyl ⁇ -cyclodextrin, micelles or liposomes, excipients and/or adjuvants.
  • the pharmaceutical compositions of the present invention include at least one compound of formula (IV) - (XLVII) and, optionally, one or more carrier substances, for example, cyclodextrins such as hydroxypropyl ⁇ -cyclodextrin, micelles or liposomes, excipients and/or adjuvants.
  • the pharmaceutical compositions of the present invention include at least one compound selected from compound 47, 48 and 53 from Table 1 and, optionally, one or more carrier substances, for example, cyclodextrins such as hydroxypropyl ⁇ -cyclodextrin, micelles or liposomes, excipients and/or adjuvants.
  • carrier substances for example, cyclodextrins such as hydroxypropyl ⁇ -cyclodextrin, micelles or liposomes, excipients and/or adjuvants.
  • compositions may additionally include, for example, one or more of water, buffers (for example, neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethylsulfoxide, carbohydrates (for example, glucose, mannose, sucrose and mannitol), proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives.
  • buffers for example, neutral buffered saline or phosphate buffered saline
  • ethanol for example, mineral oil, vegetable oil, dimethylsulfoxide
  • carbohydrates for example, glucose, mannose, sucrose and mannitol
  • proteins for example, glucose, mannose, sucrose and mannitol
  • proteins for example, glucose, mannose, sucrose and mannitol
  • proteins for example, glucose, mannose, sucrose and mannitol
  • proteins for example, glucose, mannose,
  • the compounds of the invention may advantageously be employed in combination with an antibiotic, antifungal, or antiviral agent, antihistamine, a non-steroidal anti-inflammatory drug, a disease modifying antirheumatic drug, a cytostatic drug, a drug with smooth muscle modulatory activity, an inhibitor of one or more of the enzymes that process the compounds of the present invention and lead to a decrease in their efficacy (for example, a cEH inhibitor), or mixtures of these.
  • an antibiotic, antifungal, or antiviral agent for example, antihistamine, a non-steroidal anti-inflammatory drug, a disease modifying antirheumatic drug, a cytostatic drug, a drug with smooth muscle modulatory activity, an inhibitor of one or more of the enzymes that process the compounds of the present invention and lead to a decrease in their efficacy (for example, a cEH inhibitor), or mixtures of these.
  • compositions may be formulated for any appropriate route of administration including, for example, topical (for example, transdermal or ocular), oral, buccal, nasal, vaginal, rectal or parenteral administration.
  • parenteral as used herein includes subcutaneous, intradermal, intravascular (for example, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, as well as any similar injection or infusion technique.
  • compositions in a form suitable for oral use or parenteral use are preferred.
  • compositions provided herein may be formulated as a lyophilizate.
  • Formulation for topical administration may be preferred for certain conditions such as in the treatment of skin conditions (for example, burns or itches).
  • Compositions intended for oral use may further comprise one or more components such as sweetening agents, flavoring agents, coloring agents and/or preserving agents in order to provide appealing and palatable preparations. Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binding agents such as starch, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearatc may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active ingredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as naturally-occurring phosphatides (for example, lecithin), condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate.
  • Aqueous suspensions may also comprise one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and/or flavouring agents may be added to provide palatable oral preparations.
  • Such suspensions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • compositions may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive oil or arachis oil, a mineral oil such as liquid paraffin, or a mixture thereof.
  • Suitable emulsifying agents include naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides such as sorbitan monoleate, and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide such as polyoxyethylene sorbitan monoleate.
  • An emulsion may also comprise one or more sweetening and/or flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavouring agents and/or colouring agents.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also comprise one or more demulcents, preservatives, flavouring agents and/or colouring agents.
  • Compounds may be formulated for local or topical administration, such as for topical application to the skin or mucous membranes, such as in the eye.
  • Formulations for topical administration typically comprise a topical vehicle combined with active agent(s), with or without additional optional components.
  • Suitable topical vehicles and additional components are well known in the art, and it will be apparent that the choice of a vehicle will depend on the particular physical form and mode of delivery.
  • Topical vehicles include organic solvents such as alcohols (for example, ethanol, / ' so-propyl alcohol or glycerin), glycols such as butylene, isoprene or propylene glycol, aliphatic alcohols such as lanolin, mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerin, lipid-based materials such as fatty acids, acylglycerols including oils such as mineral oil, and fats of natural or synthetic origin, phosphoglycerides, sphingolipids and waxes, protein-based materials such as collagen and gelatine, silicone-based materials (both nonvolatile and volatile), and hydrocarbon-based materials such as microsponges and polymer matrices.
  • organic solvents such as alcohols (for example, ethanol, / ' so-propyl alcohol or glycerin), glycols such as butylene, isoprene or propylene glycol, aliphatic alcohols such as
  • a composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials.
  • stabilizing agents such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.
  • a topical formulation may be prepared in a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids, emulsions, sprays and skin patches.
  • the physical appearance and viscosity of such forms can be governed by the presence and amount of emulsifier(s) and viscosity adjuster(s) present in the formulation.
  • Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form.
  • Solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Creams and lotions are often similar to one another, differing mainly in their viscosity. Both lotions and creams may be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity. These formulations, like those of lotions and creams, may also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Liquids are thinner than creams, lotions, or gels and often do not contain emulsifiers. Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, cetearyl alcohol, non-ionic emulsifiers like polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate and glyceryl stearate.
  • Suitable viscosity adjusting agents include, but are not limited to, protective colloids or nonionic gums such as hydroxyethylceilulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate.
  • a gel composition may be formed by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylceilulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate.
  • a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylceilulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate.
  • Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants.
  • dimethicone copolyol polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG-dimonium chloride, and ammonium laureth sulfate may be used within topical formulations.
  • Preservatives include, but are not limited to, antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and propyl gallate.
  • Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and butylene glycol.
  • Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils.
  • Suitable fragrances and colors include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5.
  • Suitable additional ingredients include, but are not limited to, abrasives, absorbents, anticaking agents, antifoaming agents, antistatic agents, astringents (such as witch hazel), alcohol and herbal extracts such as chamomile extract, binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters and protectants.
  • Typical modes of delivery for topical compositions include application using the fingers, application using a physical applicator such as a cloth, tissue, swab, stick or brush, spraying including mist, aerosol or foam spraying, dropper application, sprinkling, soaking, and rinsing.
  • Controlled release vehicles can also be used, and compositions may be formulated for transdermal administration (for example, as a transdermal patch).
  • a pharmaceutical composition may be formulated as inhaled formulations, including sprays, mists, or aerosols.
  • inhalation formulations the compounds provided herein may be delivered via any inhalation methods known to a person skilled in the art.
  • inhalation methods and devices include, but are not limited to, metered dose inhalers with propellants such as CFC or HFA or propellants that are physiologically and environmentally acceptable.
  • propellants such as CFC or HFA or propellants that are physiologically and environmentally acceptable.
  • Other suitable devices are breath operated inhalers, multidose dry powder inhalers and aerosol nebulizers.
  • Aerosol formulations for use in the subject method typically include propellants, surfactants and co-solvents and may be filled into conventional aerosol containers that are closed by a suitable metering valve.
  • Inhalant compositions may comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit dispensing metered doses.
  • Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent such as isotonic saline or bacteriostatic water.
  • the solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs.
  • Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • compositions may also be prepared in the form of suppositories such as for rectal administration.
  • Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • compositions may be formulated as sustained release formulations such as a capsule that creates a slow release of modulator following administration.
  • sustained release formulations such as a capsule that creates a slow release of modulator following administration.
  • Such formulations may generally be prepared using well-known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site.
  • Carriers for use within such formulations are biocompatible, and may also be biodegradable.
  • the formulation provides a relatively constant level of modulator release.
  • the amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.
  • the compounds of the present invention are considered to be particularly effective at treating infections caused by mycobacteria, and in particular, M. tb.
  • the dose of the biologically active compound according to the invention may vary within wide limits and may be adjusted to individual requirements.
  • Active compounds according to the present invention are generally administered in a therapeutically effective amount. Preferred doses range from about 0.1 mg to about 140 mg per kilogram of body weight per day, about 0.5 mg to about 7 g per patient per day.
  • the daily dose may be administered as a single dose or in a plurality of doses.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination (i.e. other drugs being used to treat the patient), and the severity of the particular disorder undergoing therapy.
  • terapéuticaally effective amount refers to an amount of the compound of formula (I) and/or (II) that results in an improvement or remediation of the symptoms of a mycobacterial infection.
  • Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, such that the preferred oral dosage forms discussed above can provide therapeutically effective levels of the compound in vivo.
  • the compounds of the present invention are preferably administered to a patient (for example, a human) orally or parenterally, and are present within at least one body fluid or tissue of the patient. Accordingly, the present invention further provides methods for treating patients suffering from mycobacterial infection (and in particular M. Tb infection).
  • treatment encompasses both disorder-modifying treatment and symptomatic treatment, either of which may be prophylactic, i.e. before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms, or therapeutic, i.e. after the onset of symptoms, in order to reduce the severity and/or duration of symptoms.
  • Patients may include but are not limited to primates, especially humans, domesticated companion animals such as dogs, cats, horses, and livestock such as cattle, pigs, sheep, with dosages as described herein.
  • the present invention also relates to a method of treating mycobacterial infection comprising administration to a patient of a therapeutically effective amount of a compound of formula (I) and/or (II).
  • the present invention also relates to the use of a therapeutically effective amount of a compound of formula (I) and/or (II) for treating mycobacterial infection.
  • the present invention also provides a pharmaceutical composition for use in treating mycobacterial infection, in any of the embodiments described in the specification.
  • the present invention also relates to the use of a therapeutically effective amount of a compound of formula (I) and/or (II) for the manufacture of a medicament for treating mycobacterial infection.
  • the present invention also relates to a compound of formula (I) and/or (II) when used in a method of treating mycobacterial infection.
  • the present invention also relates to a composition having an active ingredient for use in treating mycobacterial infection, wherein the active ingredient is a compound of formula (I) and/or (II).
  • the present invention also relates to the use of a compound of formula (I) and/or (II) in treating mycobacterial infection, such as described above.
  • the compound of formula (I) and/or (II) is essentially the only active ingredient of the composition.
  • the present invention also relates to a method of treating mycobacterial infection comprising administration to a patient of a therapeutically effective amount of one or more compounds of formulae (IV) - (XLVII).
  • the present invention also relates to the use of a therapeutically effective amount of one or more compounds of formulae (IV) - (XLVII) for treating mycobacterial infection.
  • the present invention also relates to the use of a therapeutically effective amount of one or more compounds of formulae (IV) - (XLVII) for the manufacture of a medicament for treating mycobacterial infection.
  • the present invention also relates to one or more compounds of formulae (IV) - (XLVII) when used in a method of treating mycobacterial infection.
  • the present invention also relates to a composition having an active ingredient for use in treating mycobacterial infection, wherein the active ingredient is one or more compounds of formulae (IV) - (XLVII).
  • the present invention also relates to the use of one or more compounds of formulae (IV) - (XLVII) in treating mycobacterial infection, such as described above.
  • the one or more compounds of formulae (IV) - (XLVII) are essentially the only active ingredient of the composition.
  • the present invention also relates to a method of treating mycobacterial infection comprising administration to a patient of a therapeutically effective amount of one or more compounds 47, 48 and 53 from Table 1 .
  • the present invention also relates to the use of a therapeutically effective amount of one or more compounds 47, 48 and 53 from Table 1 for treating mycobacterial infection.
  • the present invention also relates to the use of a therapeutically effective amount of one or more compounds 47, 48 and 53 from Table 1 for the manufacture of a medicament for treating mycobacterial infection.
  • the present invention also relates to one or more compounds 47, 48 and 53 from Table 1 when used in a method of treating mycobacterial infection.
  • the present invention also relates to a composition having an active ingredient for use in treating mycobacterial infection, wherein the active ingredient is one or more compounds 47, 48 and 53 from Table 1 .
  • the present invention also relates to the use of one or more compounds 47, 48 and 53 from Table 1 in treating mycobacterial infection, such as described above.
  • the one or more compounds 47, 48 and 53 from Table 1 are essentially the only active ingredient of the composition.
  • the invention provides a method for the treatment of an individual having, or at risk of having an infection with S. aureus, the method including providing an individual with a compound selected from the group consisting of P5, P6, P7 from Table 1 b, thereby treating the individual.
  • the S. aureus is methicillin-resistant S. aureus (MRSA).
  • MRSA methicillin-resistant S. aureus
  • the invention provides a method for the treatment of an individual having, or at risk of having an infection with P. aeruginosa, the method including providing an individual with a compound selected from the group consisting of P5, P6, P7 from Table 1 b thereby treating the individual.
  • a compound selected from the group consisting of P5, P6, P7 from Table 1 b thereby treating the individual.
  • the P. aeruginiosa is multiple resistant P. aeruginosa.
  • pathogenic bacteria to which the compounds of the invention may be applied include members of the Enterobacteriaceae, Staphylococcus spp., Streptococcus spp, Acinetobacter baumannii, Enterococcus faecium, Enterobacter spp. • Examples
  • Example 1 Selectivity and anti-mycobacterial efficacy of compounds of invention.
  • MMCs Lead metal cyclam complexes
  • the compounds identified display a number of properties that are attractive from a medicinal chemistry perspective. They are small and have low lipophilicity, allowing addition of functionality in the optimisation process. These compounds bear no resemblance to known drugs and are distinct from anti-TB compounds identified using small molecule libraries. 5 Furthermore, because of their high potency the ligand efficiency is high, they indicate specificity of target-ligand interactions and provide confidence that drug-like bulk properties are achievable following optimisation. For these reasons a number of variants of lead inhibitors were developed to test as antimycobacterial inhibitors.
  • the design of the lead inhibitors described above incorporates four key elements: a macrocycle (which may be a cyclam or other macrocycle), a linker (which may be a 'click'-derived triazole, or other linking moiety), a pendant group (one example being a naphthalimide, but with many other examples).
  • the compound may include a metal ion, although incorporation of the metal ion into the compound may occur after the compound has been administrated.
  • Compounds C47 and C48 are the zinc(ll) and copper(ll) complexes of the free amine form (perchlorate counterion); compound C53 is the ammonium salt (trifluoroacetate counterion; Figure 2).
  • each of the four structural components are varied in turn: the metal, the macrocycle, the linker and the pendant group.
  • the modular nature of the synthetic approach greatly simplifies library preparation ( Figure 3). For example: The metal: combining C53 with salts (perchlorate or trifluoroacetate) of Ni(ll), Co(ll),
  • Fe(ll), Mn(ll) and Cr(lll) will afford five new MCyCs each with a different metal centre; Co(lll) and Fe(lll) derivatives are accessed by oxidising the Co(ll) and Fe(ll) complexes.
  • the macrocycle replacing cyclam 1 (CioH 24 N 4 ) with the smaller azamacrocycle cyclen (C 8 H 2 oN 4 ) in each of C47, C48 and C53 will give 3 new targets.
  • the linker, the 'reversed click strategy' 6 uses the cyclam-azide building block 4 and changes the nature of the linker between the azamacrocycle and the pendant group.
  • the pendant group variations in this region modify the lipophilicity of target compounds and probe their ability to enter host cells.
  • Lead compounds (C47, C48 and C53) were tested to determine their activity against mycobacteria.
  • the inhibitor action of MCyCs against a panel of pathogenic and nonpathogenic mycobacterial species was examined as described. 7,8 These assays were performed using a micro-titre plate based assay of resazurin reduction to assess bacterial growth, according to standard procedures. 9"12
  • the analysis of anti-bacterial activity can be broadened to determine specificity of inhibitors for mycobacteria.
  • the absolute CFUs of bacteria either before or after treatment can be determined, thereby determine bacteriostatic activity (inhibition of bacterial growth) and bactericidal (killing of bacteria cells) of the compounds.
  • Example 5 MCyC derivatives with improved entry into host cells
  • aqueous solubility and partitioning studies are conducted under physiologically-relevant conditions, permeability properties are assessed using Caco-2 cell monolayers, and metabolic stability are investigated using hepatic microsomes from various species. All methods and procedures have been established and validated. 17
  • Example 7 in vivo effect of novel inhibitors against pathogenic mycobacteria
  • Example 8 Treatment of established M. tb infection.
  • a murine models of virulent M. tb infection 18"22 can be used to determine treatment of established infection with M. tb with MCyCs.
  • the models have been developed over a number of years. We select the lead compounds that display the best activity against intracellular M. tb and exhibit the required ADME properties.
  • mice are infected with aerosol M. tb and at acute stage of infection (day 14) or chronic stage (day 84) animals are left untreated or treated daily (i.p or orally) with 2 doses of each inhibitor. The doses are used based on in vitro efficacy results and ADMET.
  • the standard therapy of rifampicin plus isoniazid is used as a treatment control.
  • M. tb load lung, spleen, liver
  • lung pathology 18
  • M. avium considering the strong preliminary data with regards to inhibition of growth (Table 1 , Fig. 4).
  • Example 9 Use of MCyCs to shorten treatment time
  • Example 11 Efficacy against drug-resistant M.tb.
  • Example 12 Identifying the target of MCyCs.
  • MCyCs may be targeting a process that is unique to mycobacteria.
  • MCyC- resistant M. tb and M. avium clones as described. 7,8 MCyC-resistant mutants are isolated by plating 10 9 CFU on culture media containing 10 x MIC of inhibitors. Following incubation colonies are selected, grown in media and retested for susceptibility to MCyCs. Five resistant clones are sequenced by lllumina HiSeq and reads aligned to mycobacterial genomes to identify single-nucleotide polymorphism (SNPs).
  • SNPs single-nucleotide polymorphism
  • AMCs Azamacrocycle Conjugates
  • E. coil EC958 drug-resistant E. coli strain (gram-negative) that is a major cause of urinary tract infection
  • PA01 Pseudomonas aeruginosa is a common cause of healthcare- associated infections including pneumonia, bloodstream infections, urinary tract infections, and surgical site infections (gram-negative).
  • P. aeruginosa CJ2009 a highly drug-resistant strain of P. aeruginosa, particularly prevalent in patients with cystic fibrosis (gram-negative).
  • MIC 50 Minimal Inhibitory Concentration
  • MTC 50 Minimal Toxicity Concentration
  • J8 JTO-B-72-B-CU >100 >100 >100
  • T suchiya S. (1980) Establishment and characterization of human acute monocytic leukemia cell line (THP-1 ). Int J Cancer 26, 171 -176.

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  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne des composés antibactériens, leus procédés de synthèse et d'utilisation dans des applications antibactériennes.
PCT/AU2014/050007 2013-03-28 2014-03-28 Composés antibactériens WO2014153624A1 (fr)

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* Cited by examiner, † Cited by third party
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IT201600071723A1 (it) * 2016-07-08 2018-01-08 Eni Spa Complessi poliazamacrociclici di zinco comprendenti derivati xantenici

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT201600071723A1 (it) * 2016-07-08 2018-01-08 Eni Spa Complessi poliazamacrociclici di zinco comprendenti derivati xantenici

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