WO2007109843A1 - Complexes métalliques ayant une activité anti-inflammatoire - Google Patents

Complexes métalliques ayant une activité anti-inflammatoire Download PDF

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WO2007109843A1
WO2007109843A1 PCT/AU2007/000375 AU2007000375W WO2007109843A1 WO 2007109843 A1 WO2007109843 A1 WO 2007109843A1 AU 2007000375 W AU2007000375 W AU 2007000375W WO 2007109843 A1 WO2007109843 A1 WO 2007109843A1
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iii
complex
complex according
derivative
ligand
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Peter Lay
Trevor Hambley
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Anagenics Ltd
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Medical Therapies Ltd
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Priority claimed from PCT/AU2006/000403 external-priority patent/WO2006099685A1/fr
Priority claimed from PCT/AU2006/000391 external-priority patent/WO2006099677A1/fr
Priority claimed from AU2006901557A external-priority patent/AU2006901557A0/en
Priority claimed from PCT/IB2006/002423 external-priority patent/WO2007026240A1/fr
Application filed by Medical Therapies Ltd filed Critical Medical Therapies Ltd
Publication of WO2007109843A1 publication Critical patent/WO2007109843A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom

Definitions

  • the invention relates to metal complexes having anti-inflammatory activity.
  • the compounds find application in the prophylaxis and treatment of inflammation, cancer, pain, microbial infections including bacterial and viral infections, and other conditions in humans and animals.
  • Non-steroidal anti-inflammatory drugs are used in the treatment of a variety of inflammatory conditions in humans and animals.
  • NSAIDs are, for example, used to treat inflammatory conditions such as rheumatoid arthritis, osteoarthritis, acute musculoskeletal disorders (such as tendonitis, sprains and strains), lower back pain (commonly referred to as lumbago), and inflammation, pain and oedema following surgical or non-surgical procedures.
  • GI adverse gastrointestinal
  • Indomethacin is a NSAID and is effective in treating inflammatory conditions in humans and animals.
  • the structure of indomethacin is as follows:
  • indomethacin can cause severe adverse gastrointestinal effects in humans and animals, particularly when administered orally.
  • oral administration of indomethacin can cause ulcerations in the oesophagus, stomach, duodenum and intestines, and some fatalities have been reported.
  • oral administration of indomethacin causes fatal gastrointestinal haemorrhaging.
  • indomethacin effects associated with oral administration of indomethacin include: (a) inhibition of platelet aggregation, (b) cardiovascular effects (fluid retention and peripheral oedema), (c) ocular effects (corneal deposits and retinal disturbances), (d) central nervous system effects (headaches and dizziness), (e) masking of infections due to antipyretic properties, (f) renal effects (as with other NSAIDs, there have been reports of acute interstitial nephritis with hematuria, proteinuria and, occasionally, nephrotic syndrome in patients receiving long- term administration of indomethacin). Studies have also shown that administration of indomethacin by other routes, e.g.
  • dinuclear metal complexes of indomethacin i.e. complexes containing two metal coordination centres
  • indomethacin i.e. complexes containing two metal coordination centres
  • the oral administration of the dinuclear copper(II) complex of indomethacin, bis(N,N-dimethylformamide)tetrakis- ⁇ -(6>,6> -Indo)dicopper(II) [Cu 2 (Indo) 4 (DMF) 2 ]
  • Indo is the deprotonated form of indomethacin
  • compositions containing this complex sold under the name Cu -Algesic have been used in veterinary practice in Australia, New Zealand, South Africa and other countries. These compositions are in the form of a tablet or a paste. Complexes of copper and dithiocarbamate have previously been studied for the treatment of melanoma.
  • NSAIDs including indomethacin and related NSAIDs, have been reported to have a chemoprotective effect against colorectal and other cancers although results from epidemiological studies have been variable (Turchanowa, L., Dauletbaev, N., Milovic, V., Stein, J. Eur. J. Clin. Invest. 2001, 31, 887-893; Collet, J.-P.; Sharpe, C; Belzile, E.; Boivin, J. -F.; Hanley, J.; Abenhaim, L. Brit. J. Cancer 1999, Si, 62-68).
  • NSAIDs may enhance the anti-cancer activities of known anti -cancer drugs (Touhey, S.; O'Connor, R.; Plunkett, S.; Maguire, A.; Clynes, M. Eur. J. Cancer 2002, 38, 1661- 1670).
  • indomethacin was reported to increase mortality and metastases compared to control animals (Danzi, M.; Ferulano, G. P.; Abate, S.; Califano, G. Carcinogenesis 1984, 5, 287-289).
  • Cu-salicylate complexes ie., [Cu 2 (3,5-di-/sopropylsalicylate) 4 L 2 ]
  • Cu-salicylate complexes have been shown to have a limited effect (no -statistically significant difference) in tumorogenisis in female C3H/HeNCR mice models of mammary cancer (Crispins, Jr., C. G.; Sorenson, J. R. J. Anti-Cancer Res. 1992, 12, 1271-1273).
  • these complexes had anti-cancer activity against reticulum cell sarcoma in SJL/J mice if injected subcutaneously, they were toxic if injected via the i.p route (Crispins, Jr., C.
  • the NSAID aspirin (acetylsalicylic acid) is widely used in low dosages to prevent cardiovascular events and is generally prescribed as a standard treatment for prophylaxis of cardiac disease in high-risk patients.
  • Aspirin resistance Definitions, mechanisms, prevalence, and clinical significance", Macchi, L., Sorel, N., Christiaens, L., Curr. Pharm. Des., 2006, 12(2), 251-258.
  • COX-2 selective NSAIDs there have also been reports of increased risk of significant adverse side-effects associated with the long term use use of COX-2 selective NSAIDs.
  • COX-2 inhibitors such as rofecoxib, celecoxib, valecoxib and parecoxib may be associated with an increased risk of thrombotic events ("Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention", Scott, D.
  • the literature further indicates that at least some transition metals may have a role in the development of cardiovascular disease at the molecular level.
  • both copper and zinc have been shown to accumulate in atherosclerotic plaque at a higher rate than in surrounding vascular tissue ("Relationship of calcium, magnesium, zinc and copper concentrations in the arterial wall and serum in atherosclerosis obliterans and aneurysm", Iskra, M., Patelski, J., Majewski, W., J. Trace Elem. Med. Biol., 1997, 11(4), 248-252) suggesting that they play a role in cardiovascular pathogenesis.
  • Zinc has also been implicated as a potential contributor to cardiovascular disease through its role in metal -containing proteins such as the matrix metalloproteinases, the inhibition of which has become a recent goal for cardiovascular drug development ("Matrix metalloproteinases: a therapeutic target in cardiovascular disease", Sierevogel, M.J., Pasterkamp, G., de Kleijn, D.P., Strauss, B.H., Curr. Pharm. Des., 2003, 9(13), 1033-1044).
  • cardiovascular inflammatory related diseases have been treated by seeking to lower copper and zinc levels within the cardiovascular system or to reduce the risk of accumulation of these metals in the cardiovasculature.
  • the present invention relates to metal complexes having anti-inflammatory activity and their use in the prophylaxis or treatment of cancer, diseases and conditions associated with inflammation or which have an inflammatory component, pain, microbial and viral infections, and other conditions.
  • M is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent metal ion; each L 1 is independently selected and is NH 3 or other monodentate ligand, a polydentate ligand, or a macrocyclic ligand; each L is a chelating derivative of a carboxylate or chelating amide or hydroximate NSAID, having anti-inflammatory activity, and at least one ligand L 2 is other than a salicylate or a derivative of a salicylate; m is 0, 1, 2, 3, 4, or 5; n is 1, 2, 3 or 4; and p is the charge of the complex.
  • any suitable chelating derivative of a carboxylate with anti -inflammatory activity can be employed in the metal complexes of formulae (1) and (2).
  • the chelating derivative of a carboxylate having anti-inflammatory activity is a non-steroidal anti- inflammatory drug (NSAID).
  • NSAID non-steroidal anti- inflammatory drug
  • Particularly preferred examples of these chelating derivatives of carboxylate NSAIDs include derivatives of the following compounds:
  • Tolmetin (l-methyl-5-(/>toluoyl)-lH-pyrrole-2-acetic acid (“Tol ⁇ ")
  • Naproxen (6-methoxy- ⁇ -methyl-2-naphthaleneacetic acid (“Nap ⁇ ”));
  • Ibuprofen ((+)- ⁇ -methyl-4-(isopropylmethyl)benzeneacetic acid (“Ibu ⁇ ”)
  • Flufenamic Acid ((N-trifluoromethylphenyl)anthranilic acid (“Flufen ⁇ ”));
  • Acemetacin l-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid carboxymethyl ester
  • Ketorolac (+)-5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylic acid, ("Ket ⁇ ")
  • Carprofen (6-chloro- ⁇ -methyl-9 ⁇ -carbazole-2-acetic acid);
  • Etodolac (1,8-diethyl-l, 3,4,9 -tetrahydro-pyrano[3,4-b]indole-l -acetic acid); Fentiazac (4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetic acid);
  • Flurbiprofen (2-fluoro- ⁇ -methyl-[l,l'-biphenyl]-4-acetic acid);
  • Ketoprofen (3-benzoyl- ⁇ -methylbenzeneacetic acid);
  • Oxaprozin (4,5-diphenyl-2-oxazolepropanoic acid);
  • Pranoprofen ( ⁇ -methyl-5H-[l]benzopyrano[2,3-b]pyridine-7-acetic acid); Sulindac ((lZ)-5-fluoro-2-methyl-l-[[4-(methylsulfinyl)phenyl]methylene]-lH- indene-3-acetic acid); and
  • At least one ligand L of the metal complex of formula (1) or (2) can for instance, be independently be selected from the group consisting of hydroximates, hydroxamates, hydrazines, esters, amino acids, and peptide, sugar and amide NSAID chelating ligands (O or N bound), having anti-inflammatory activity by themselves or when hydrolysed to a carboxylic acid NSAID.
  • At least one ligand L will be an ester, hydroxamate, hydroximate or amide derivative of indomethacin, ibuprofen, naproxen, dichlofenac, acemetacin or ketorolac .
  • ligand L 2 will be non-carboxylate NSAIDs that can chelate to a metal ion via an amide and other functional group or via a hydroxamate or hydroximate group.
  • ligand L can be coordinated to the metal ion via the hydroximate, hydroxamate or hydrazine group, or for example, by other groups attached to an amide or ester linkage of ligand L 2 , such as sugar, amino acid, peptide, polyamine, heterocycle, and other chelate. It will also be understood that ligand L can be deprotonated at substituents that include, but are not limited to, amide, carboxylic acid, alcohol and thiol functional groups to strengthen the binding of the derivative to metal one or more metal ions of the complex of formulae (1) or (2).
  • all or at least most of ligands L2 will be other than salicylates or derivative(s) of salicylates.
  • one or more of the ancillary ligands (L 1 , L 3 ) in the metal complexes can have anti-inflammatory, anti-diabetic, anti -microbial or anti-cancer activity, and/ or be cardioprotective and/or protect against radiation -induced damage to tissues, neurodegenerative diseases and/or promote wound healing.
  • the metal ion of a metal complex of the invention can be copper ion or other d- block ion (e.g. zinc, titanium, vanadium, chromium, manganese, cobalt, iron, gold, platinum, ruthenium, rhodium, molybdenum and tungsten ions), or a p-block metal ion
  • an s-block metal ion or an f-block metal ion In one or more forms the metal ion will be a d-block or p-block metal ion.
  • the inclusion of the "H" at the end of an abbreviation for a carboxylate (e.g., any one of the carboxylic acid listed above) or a hydroxamate, hydroximate, or amide is used to refer to the uncharged form of the carboxylate or amide or the parent hydroxamic acid or its monodeprotonated hydroxamate form of the doubly deprotonated hydroximate. Accordingly, the abbreviation without the "H” is used to refer to the deprotonated anionic form.
  • IndoHAFb refers to the uncharged form of indomethacinhydroxamic acid
  • IndoHAH is used to refer to the monodeprotonated anionic form, indomethacinhydroxamate
  • IndoHA is used to refer to the doubly deprotonated anionic form, indomethacinhydroximate.
  • ACMHAH 2 refers to the uncharged form of acemetacinhydroxamic acid
  • ACMHAH is used to refer to the monodeprotonated anionic form, acemetacinhydroxamate
  • ACMHA is used to refer to the doubly deprotonated anionic form, acemetacinhydroximate.
  • Acemetacin, 1 -( ⁇ chlorobenzoy ⁇ -S-methoxy ⁇ -methylindole-S-acetic acid carboxymethyl ester, is a glycolic acid ester of indomethacin.
  • the structure of ACMH is shown below, as is the structure of Keterolac.
  • Ketorolac in another aspect of the invention there is provided a pharmaceutical composition
  • a pharmaceutical composition comprising a metal complex of formula (1) or formula (2), together with a pharmaceutically acceptable carrier or diluent.
  • a method for prophylaxis or treatment of inflammation or a disease or condition mediated by inflammation or having an inflammatory component comprising administering to the mammal an effective amount of a metal complex of formula (1) or formula (2).
  • Diseases or conditions mediated by inflammation or having an inflammatory component include diabetes, cardiovascular diseases, neurodegenerative diseases, and other conditions involving inflammation.
  • a method for prophylaxis or treatment of a cancer in a mammal comprising administering an effective amount of a metal complex of formula (1) or formula (2) to the mammal.
  • a method for prophylaxis or treatment of a microbial or viral infection in a mammal comprising administering to the mammal an effective amount of a metal complex of formula (1) or formula (2).
  • an analgesic method for prophylaxis or treatment of pain comprising administering to the mammal an effective amount of a metal complex of formula (1) or formula (2).
  • a method for promoting wound healing or inhibiting skin aging including the prevention or treatment of wounds caused by trauma or surgery, burns, or sunburn, or ionising radiation comprising administering to a mammal in need thereof an effective amount of a metal complex of formula (1) or formula (2).
  • a method for treating damaged skin comprising administering to the mammal an effective amount of a metal complex of formula (1) or formula (2).
  • a method for enhancing the efficacy of radiotherapy in cancer treatment comprising administering to a mammal an effective amount of a metal complex of formula (1) or formula (2).
  • a metal complex of formula (1) or (2) in the manufacture of a medicament for prophylaxis or treatment of inflammation or a disease or condition having an inflammatory component in a mammal.
  • a metal complex of formula (1) or (2) in the manufacture of a medicament for prophylaxis or treatment of a cancer in a mammal.
  • a metal complex of formula (1) or (2) in the manufacture of a medicament for prophylaxis or treatment of a microbial or viral infection in a mammal.
  • a metal complex of formula (1) or formula (2) in the manufacture of an analgesic medicament for prophylaxis or treatment of pain in a mammal.
  • a metal complex of formula (1) or formula (2) in the manufacture of a medicament for wound healing or inhibition and treatment of skin or tissue aging and radiation damage (both solar and ionising) in a mammal.
  • a metal complex of formula (1) or formula (2) in the manufacture of a medicament to enhance the efficacy of radiotherapy in cancer treatment in a mammal.
  • GI gastrointestinal
  • Metal complexes embodied by the invention may be incorporated into formulations that minimize their decomposition by biological fluids, such as gastric acid, or to change the profile of absorption of the bioactives as exemplified in International Patent Application No. PCT/AU2005/000442, to reduce GI and/or renal toxicity while substantially maintaining or enhancing efficacy of the complexes.
  • the use of such formulations in methods of the invention is expressly encompassed.
  • chelating derivatives of NSAIDs can enhance the stability of the complexes of NSAIDs. This may result in one or more of: (i) a reduction in GI toxicity by increasing the stability of the drugs in the GI tract;
  • Complexing a NSAID with a metal as described herein may also change the absorption profile of the NSAID.
  • the release of the parent carboxylate NSAID from the chelating ligand can be induced by hydrolysis of the ester, amide, hydroxamate/hydroximate or hydrazine bonds from either the complex or after the the chelating ligand has been released from the complex by: ligand substitution reactions; and/or redox catalysed substitution reactions.
  • the NSAID derivative, the NSAID, and the metal may provide synergistic activities. For instance, the decomposition of the metal hydroximates/hydroximates can have multiple effects.
  • a copper hydroxamate complex can exert anticancer, anti-inflammatory activity by a combination of independent COX-2 inhibition (by both the parent NSAID and the NSAIDHAH 2 ), the release of NO from the NSAIDHAH 2 , matrix metalloproteinase inhibition, 5 -lipoxygenase inhibition by the hydroxamic acid and apoptotic effects in cancer cells, and the effects of Cu once the complex decomposes at the site of a tumour or inflammation.
  • the function of the Cu in this case, is not only to provide additional biological activity but to target the organic drugs to tumours and sites of inflammation that concentrate the lipophilic complex.
  • the higher metabolic activity of certain tissues or cells can also be employed to increase the rate of ester and amide hydrolysis of metal complexes of ester, amino acids, peptide and sugar ligands and the like as described herein, as a way of targeting disease states.
  • inert oxidation states of metals e.g., Pt(IV), Ru(III), Co(III)
  • Pt(IV), Ru(III), Co(III) may selectively target hypoxic sites associated with certain solid tumours and ischemia associated with heart attacks, strokes and other cardiovascular conditions.
  • the metal ions, co-ligands and metal oxidation states can be utilized to optimise the rate of release and/or hydrolysis of the NSAID -derivative to minimise side- effects such as GI and renal toxicities, and/or to provide sufficient stability to target the disease site before the bioactives of the complex are released.
  • Figure 1 is a graph showing the effect of [V v O(IndoHAH)(IndoHA)] , [Cr m (IndoHAH) 3 ] and IndoHAH 2 suspended in MCT oil on the viability of A549 cells, where the concentration range refers to the equivalent concentration of IndoHA and not those of the vanadium or chromium complex.
  • Figure 2 is a graph of gastric damage (mm ) for active ingredients (Samples P, Q and R) dosed by means of oral gavage with a composition of MCT organogel and at Indomethacin Equivalence treat rate of 2 mg kg " bw.
  • Figure 3 is a graph of the anti -inflammatory effect on rat paw oedema (% ⁇ mm 3 ) of active ingredients (Samples P, Q and R) dosed by means of oral gavage with a composition of MCT organogel and at an Indomethacin Equivalence treat rate of 2 mg kg x bw.
  • Figure 4 is a graph showing the effect of ACM, CuACM and ZnACM suspended in MCT oil on the viability of A549 cancer cells, where the concentration range refers to the equivalent concentration of Indo and not the zinc or copper complexes.
  • Figure 5 is a graph showing the effect of [V v O(IndoHAH)(IndoHA)] .2MeOH and IndoHAH 2 suspended in MCT oil on the viability of A549 cells, where the concentration range refers to the equivalent concentration of IndoHA and not the copper complex;
  • Figure 6 is a graph showing the effect of [V v O(IndoHAH)(IndoHA)] .2MeOH and IndoHAH 2 suspended in MCT oil on the viability of A549 cells, where the concentration range refers to the equivalent concentration of IndoHA and not the copper complex
  • Figure 7 is a graph showing the ability of the vanadium(V) complex
  • halo refers to fluoro, chloro, bromo or iodo.
  • alkyl used either alone or in a compound word such as “arylalkyl”, refers to a straight chain, branched or mono- or polycyclic alkyl.
  • straight chain and branched alkyl examples include methyl, ethyl, propyl, /so-propyl, butyl, /s ⁇ -butyl, sec-butyl, tert-buty ⁇ , amyl, /so-amyl, sec-amyl, 1,2-dimethylpropyl, 1,1- dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl.
  • cyclic alkyl examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic alkyl having 3 to 12 carbons.
  • alkenyl refers to a straight chain, branched or cyclic alkenyl with one or more double bonds.
  • the alkenyl is a C 2 to C20 alkenyl, more preferably C 2 to C 6 alkenyl.
  • alkenyl examples include vinyl, allyl, 1-methylvinyl, butenyl, /so-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methylcyclopentenyl, 1 -hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloh
  • alkynyl refers to a straight chain, branched or cyclic alkynyl with one or more triple bonds, preferably a C 2 to C 2 o alkynyl, more preferably a C 2 to Ce alkynyl.
  • aryl used either alone or in compound words such as “arylalkyl”, refers to a radical of a single, polynuclear, conjugated or fused aromatic hydrocarbon or aromatic heterocyclic ring system.
  • aryl include phenyl, naphthyl and furyl.
  • the aromatic heterocyclic ring system may contain 1 to 4 heteroatoms independently selected from N, O and S and may contain up to 9 carbon atoms in the ring.
  • arylalkyl refers to an alkyl substituted with an aryl group.
  • An example of arylalkyl is benzyl.
  • the term “bidentate ligand” refers to a ligand having two co-ordination bonds to a metal atom. Bidentate ligands include unsymmetric bidentate ligands with one weaker and one relatively stronger bond to the metal atom. In this specification, the term “monodentate ligand” refers to a ligand having a single co-ordination bond with a metal atom.
  • Metal complexes in one or more embodiments of the invention find application in the prophylaxis or treatment of various diseases and conditions including inflammation, diseases and disorders characterised, mediated or involving inflammatory components such as cardiovascular, neurodegenerative and diabetic conditions, pain, cancer, microbial and viral infections, the treatment of wounds, burns, skin damage, radiation damage (eg., solar and ionising radiation damage), and slowing/inhibition of skin aging.
  • diseases and disorders characterised, mediated or involving inflammatory components such as cardiovascular, neurodegenerative and diabetic conditions, pain, cancer, microbial and viral infections, the treatment of wounds, burns, skin damage, radiation damage (eg., solar and ionising radiation damage), and slowing/inhibition of skin aging.
  • the present inventors have also surprisingly found that metal complexes of the invention having anti-inflammatory activity have application in preventing or treating cancers including carcinomas such as lung cancers, and may have fewer side -effects and/or be more effective in preventing or treating the cancers in terms of efficacy and/or safety than the anti-inflammatory ligand(s) in the complex alone.
  • the present inventors have found that complexes of a metal and derivatives of indomethacin (such as hydroximates or hydroxamates) may be more effective in preventing or treating carcinomas, than its derivative alone.
  • copper complexes formed in vivo from the chelation of copper by the copper chelators may themselves have a strong anti -cancer effect rather than the anti-cancer effect being due solely to the removal of copper in addition to the reduction in angiogenesis when Cu is sequestered. More particularly, the efficacy of the complexes is considered to be due to a combination of both the ligand (e.g, hydroximate, hydroxamate, ester or amide derivative) and the metal atom(s).
  • the ligand e.g, hydroximate, hydroxamate, ester or amide derivative
  • Complexes of a metal and a carboxylate, or hydroximate, hydroxamate, ester or amide derivatives thereof having anti-inflammatory activity have not previously been shown to be useful in the general prophylaxis or treatment of carcinomas.
  • the inventors have also surprisingly found that oral doses of inert complexes, such as Cr(III) complexes of NSAID hydroxamic acids may have low GI toxicity, but greater anti-inflammatory efficacy than the the parent NSAID hydroxamic acid.
  • carboxylic acids having anti- inflammatory activity that can be utilised as precursers of hydroxamate, hydroximate, hydrazine, ester and amide chelating ligands for metal complexes embodied by the invention include the following.
  • Tolmentin l-methyl-5-(/?-toluoyl)-lH-pyrrole-2-acetic acid (Tol ⁇ );
  • Naproxen 6-methoxy- ⁇ -methyl-2-naphthaleneacetic acid (Nap ⁇ );
  • Ibuprofen (+)- ⁇ -methyl4-(isopropylmethyl)benzeneacetic acid (Ibu ⁇ );
  • Flufenamic Acid (N-trifluoromethylphenyl)anthranilic acid (Flufen ⁇ );
  • ⁇ iflumic Acid 2-((3-trifluoromethyl)phenylamino)-3-pyridinecarboxylic acid
  • Diclofenac 2-[(2,6-dichlorophenyl)amino]phenylacetic acid (Dic ⁇ ).
  • Acemetacin l-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid carboxymethyl ester
  • Ketorolac (+)-5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylic acid, ("Ket ⁇ ")
  • Carprofen (6-chloro- ⁇ -methyl-9 ⁇ -carbazole-2-acetic acid);
  • Etodolac (1,8-diethyl-l, 3,4,9 -tetrahydro-pyrano[3,4-b]indole-l -acetic acid); Fentiazac (4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetic acid); Flurbiprofen (2-fluoro- ⁇ -methyl-[l,l'-biphenyl]-4-acetic acid); Ketoprofen (3-benzoyl- ⁇ -methylbenzeneacetic acid); Oxaprozin (4,5-diphenyl-2-oxazolepropanoic acid); Pranoprofen ( ⁇ -methyl-5H-[l]benzopyrano[2,3-b]pyridine-7-acetic acid); Sulindac ((lZ)-5-fluoro-2-methyl-l-[[4-(methylsulfinyl)phenyl]methylene]-lH- indene-3-acetic acid); and
  • the chelating derivative of a carboxylate having anti-inflammatory activity in a metal complex of formula (1) or (2) can also for instance be a ligand of formula (3) or (4)
  • R 1 is H or halo (i.e. Cl, F, Br or I);
  • each R 2A is independently selected from the group consisting of H, C i to C 6 alkyl, alkenyl, alkynyl, aryl, cycloalkyl and arylalkyl, where the C 1 to C 6 alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be optionally substituted;
  • R 3 is H or halo
  • COR is a carboxylate group or its deprotonated form
  • R ->4A is H, or an aliphatic, aryl or heterocyclic group optionally substituted with one or more functional groups forming a co-ordination bond of the metal complex;
  • R 4B is a substituent group optionally forming at least one co-ordination bond of the metal complex
  • R 4C is a substituent group forming at least two co-ordination bonds in the metal complex; and each R is independently selected from the group consisting of halo, -CH 3 , -CN, -OCH 3 , -SCH 3 and -CH 2 CH 3 , where the -CH 3 , -OCH 3 -SCH 3 or -CH 2 CH 3 may be optionally substituted; and s is 1, 2, 3,4 or 5.
  • R 1 is H or halo (i.e. Cl, F, Br or I);
  • R 2 is H; a Ci to C 6 alkyl, an alkenyl or an alkynyl, where the Ci to C 6 alkyl, alkenyl or alkynyl may be optionally substituted; or wherein each R is independently selected from the group consisting of H, Ci to CO alkyl, alkenyl, alkynyl, aryl, cycloalkyl and arylalkyl, where the Ci to Ce alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be optionally substituted; R 3 is H or halo;
  • COR 4 is a carboxylate group or its deprotonated form
  • R 4A is H, or an aliphatic or aryl group optionally substituted with one or more functional groups forming a co-ordination bond of the metal complex;
  • R is a substituent group optionally forming at least one co-ordination bond of the metal complex;
  • R 4C is a substituent group forming at least two co-ordination bonds in the metal complex; and each R 5 is independently selected from the group consisting of halo, -CH 3 , -CN, -OCH 3 , -SCH 3 and -CH 2 CH 3 , where the -CH 3 , -OCH 3i -SCH 3 or -CH 2 CH 3 may be optionally substituted; and s is 1, 2, 3, 4 or 5.
  • R of the ligand of formula (3) or (4) is a Ci to C 6 alkyl, an alkenyl or an alkynyl
  • the C 1 to C 6 alkyl, alkenyl or alkynyl may be substituted with one or more substituents.
  • the one or more substituents may, for example, be independently selected from the group consisting of halo, -OH, -COOH and -NH 2 .
  • R is a Ci to Ce alkyl, an alkenyl, an alkynyl, an aryl, a cycloalkyl or an arylalkyl
  • the Ci to Ce alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be substituted with one or more substituents.
  • the one or more substituents may, for example, be independently selected from the group consisting of halo, -OH, -COOH and -NH 2 .
  • R 5 is -CH 3 , -OCH 3, -SCH 3 or -CH 2 CH 3
  • the -CH 3 , -OCH 3, -SCH 3 or - CH 2 CH 3 may be substituted with one or more substituents.
  • the one or more substituents may, for example, be independently selected from the group consisting of halo, -OH, -COOH and -NH 2 .
  • R can be an aliphatic or aromatic group substituted with one or more heteroatoms or heterocyclic groups (eg., 1-6 heteroatoms selected from O, N and S).
  • R 4B can be a substituent derived from an amino acid, a peptide, a sugar, an acyclic aliphatic amine, or a cyclic amine, hydroxy acid, a polydentate heterocyclic or combinations thereof. It will also be understood that the derivative can contain one or more of a deprotonated at amide, carboxylic acid, alcohol, thiol group(s) or the like.
  • R can be a substituent derived from an amino acid, a peptide, a sugar, an acyclic aliphatic amine, or a cyclic amine, hydroxy acid, a polydentate heterocyclic or combinations thereof.
  • the derivative can contain one or more deprotonated amide, carboxylic acid, alcohol, thiol group(s) or the like.
  • Further derivatives of carboxylic acids that can be employed in metal complexes embodied by the invention include hydroxamic acid derivatives of carboxylates with antiinflammatory activity, which form hydroxamato or hydroximato complexes with the metal; hydrazine derivatives, esters of carboxylates having anti-inflammatory activity, such as sugar derivatives and those of amino acids and peptides; and amide derivatives of carboxylates having anti- inflammatory activity, such as amino acids, peptides amines, and sugars that form chelates of deprotonated amides with the metal.
  • a hydroxamic acid having anti-inflammatory activity can form hydroxamato or hydroximato complexes with a metal ion in the complex.
  • An amide having anti- inflammatory activity can form chelates of deprotonated amides or amide monodentate complexes with a metal ion in the complex.
  • Hydroxamic acids having anti-inflammatory activity that can be utilised in the complexes used in the method of the invention include carboxylates linked by a linker to a hydroxamate group (eg., International Patent Application No. PCT/US03/019228 (WO 04/000215)). Hydroxamic acid derivatives of carboxylates with anti-inflammatory activity, such as indomethacin, ibuprofen, naproxen, dichlofenac, acemetacin or ketorolac are particularly preferred.
  • hydroxamic acids can also be substituted on the N, in which case only the hydroxamato coordination mode is possible.
  • R can contain one or more functional groups that act as other donor groups to form a metal chelate.
  • Suitable coupling reactions include those with amino acids to form a mixed amide/carboxylate donor set, or more complex donor bidentate sets with amino acids containing metal binding side-chains, e.g., cysteine, serine, methionine, histidine, tyrosine, and the like.
  • Other suitable R groups include amino sugar derivatives and glycoproteins that can both target tumour cells and act as metal chelates.
  • the coupling reaction can also involve short chain peptides, which act as chelating ligands, or other groups to give metal chelators with anti -inflammatory activities, as described in WO 95/04030. water
  • the group forming the amide linkage can be an amino acid (natural or artificial), any natural or artificial peptide (including glycopeptides), a amino sugar derivative, a polydentate amine, amino alcohol, amino thiol, or other polydentate amine ligand containing one or more donor groups including heterocycles.
  • Ester derivatives of carboxylic acids having anti-inflammatory activites can be prepared by a variety of ester coupling reactions. See, for instance, the indomethacin example shown below (Scheme 3).
  • R can be an alkyl or aryl group containing a substituent which can act as a polydentate ligand, e.g., amino and alcohol groups (eg., prepared from a polydentate aminoalcohol) , with serine, tyrosine or short-chain peptides containing serine or tyrosine.
  • a polydentate ligand e.g., amino and alcohol groups (eg., prepared from a polydentate aminoalcohol)
  • Other suitable chelating groups that can be coupled and may also target tumours, include sugars and glycoproteins.
  • Metal complexes embodied by the invention may also be prepared by methods outlined in Example 1 below.
  • the complexes contain hydroximate, hydroxamate, amide, or ester derivatives of indomethacin, ibuprofen, naproxen, dichlofenac, acemetacin or ketorolac as ligands as described above.
  • the functional groups of the ligands may themselves bind to the metal ion, and/or other ligating groups that are linked by these functionalities can bind to the metal.
  • the metal complex may be a complex of the formula (1):
  • M is idependently chosen from a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent metal ion; each L 1 is independently selected and is NH 3 or other monodentate ligand, a polydentate ligand, or a macrocyclic ligand; each L 2 is independently a chelating derivative of a carboxylate such as a hydroximate, hydroxamate, hydrazine, ester, amino acid, or a peptide, sugar or amide NSAID chelating ligand (O or N bound), or a chelating amide or hydroximate NSAID, having anti-inflammatory activity, and at least one ligand L 2 is other than a salicylate or a derivative of a salicylate; m is 0, 1, 2, 3, 4, or 5; n is 1, 2, 3 or 4; and p is the charge of the complex.
  • a metal complex as described herein can be a metal complex of the following formula (2):
  • each M is independently selected from monovalent, divalent, trivalent, tetravalent, pentavalent and hexavalent metal ions ; each L 1 is independently selected and is NH 3 or other monodentate ligand, a polydentate ligand, or a macrocyclic ligand; each L is indendently a chelating derivative of a carboxylate such as hydroximate, hydroxamate, ester, amino acid, or peptide, sugar or amide NSAID chelating ligand (O or N bound), or a chelating amide or hydroximate NSAID, having anti-inflammatory activity, and at least one ligand L is other than a salicylate or a derivative of a salicylate; each L 3 is independently selected and is a bridging ligand; m is a number from 0 to 5q; n is a number from 1 to 2q; p is the charge of the complex; q is typically a number between 2 and 20 inclusive; and
  • q can be 2, 3, 4, 5, etc.
  • r can be 1, 2, 3, 4, 5, 6, etc.
  • q will be a number in a range from 2 to 15, more preferably in a range of from 2 to 10 and most preferably, in a range of from 2 to 4, and wherein r is in a range of from 1 to 20, more preferably in a range of from 1 to 15 and most preferably, in a range of from 1 to 10.
  • the metal ion of a metal complex embodied by the invention can be a d-block, f- block, p-block or s-block metal ion.
  • the metal M will be a divalent, trivalent, tetravalent, pentavalent or hexavalent d-block metal, preferably, Co(II), Cu(II), Fe(II), Mn(II), Ni(II), Pt(II), Ru(II), Zn(II), Au(III), Co(III), Cr(III), Fe(III), Mn(III), Ru(III), Mn(IV), Mo(IV), Pt(IV), Ru(IV), Ti(IV), V(IV), Mo(V), V(V), W(V), Mo(VI), W(VI) or a trivalent or tetravalent p-block metal such as Ga(III), Bi(III) or Sn(IV) .
  • L ligands useful in complexes of formulae (1) and (2) include: monodentate ligands such as halos, aqua, hydroxo, oxo, CO, NO, amines, alcohols, amides, sulfoxides, N-heterocylces, 0-heterocycles, and .S-heterocycles; polydentate acyclic ligands include amines, amino acids, peptides, alcohol sugars, hydroxyacids, polycarboxylates, N- heterocylces, O-heterocycles, and S-heterocycles, and other functional groups that can form co-ordinate bonds with a metal ion, and combinations thereof; polydentate macrocyclic ligands include amines, crown ethers, macrocyclic, thioethers, macrocyclic peptides and amides and ligands with combinations of these and other metal binding substituents.
  • monodentate ligands such as halos, aqua,
  • L 3 ligands useful in complexes of formula (2) include oxo, hydroxo, carboxylate (including carboxylate NSAIDs), halo and other bridging groups.
  • suitable aliphatic and aromatic groups include substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, arylalkyl and heterocyclic groups.
  • heterocyclic groups include heterocycles comprising one or more N, O and/or S atoms. In some embodiments, the heterocycle is optionally substituted.
  • the heterocycle can for example be selected from the group consisting of isoquinolyl, quinolyl, piperidinyl, pyridinyl, 2-methylpyridinyl, imadazoyl, pyranyl, pyrrolyl, pyrimidinyl, indolyl, purinyl and quinolizinyl.
  • Examples of complexes of formula (1) include: [M(L 2 ) n (NR 7 R 8 R 9 ) m) ] p wherein each L 2 is independently a bidentate derivative of a NSAID, each (NR 7 R 8 R 9 ) is independently a monodentate amine ligand or a polydentate amine ligand (eg., a cyclic amine), n is 1 or 2, m is 1, 2, 3, or 4, and M is selected from Ru(II), Co(III), Cr(III), Ir(III), Os(III), Rh(III), 5 Ru(III) and Pt(IV); [M(L 2 )(NR 7 R 8 R 9 )ta] p where L 2 is a tridentate derivative of a NSAID, each (NR 7 R 8 R 9 ) is independently a monodentate amine ligand or a polydentate amine ligand (eg., a cyclic amine), m is 1, 2 or 3 and M is selected from
  • L 2 is a tetradentate derivative of a NSAID, t is independently selected from O, 1 or 2, and M is selected from Fe(II), Mn(II), Cu(II), Zn(II), Co(III), Cr(III), Fe(III), Ga(III), Ir(III), Os(III), Rh(III), O Ru(III), Pt(IV), Ti(IV), V(IV), Mn(IV), V(V), Mo(V), W(V), Mo(VI) and W(VI); [M(L 2 XOH 1 )] p where L 2 is a pentadentate derivative of a NSAID, t is
  • M(L ) 2 ] p wherein L is a bidentate derivative of a NSAID, and M is selected from Cu(II), Ni(II), Pd(II), Pt(II) and Au(III) ; and five-coordinate, [V(O)(L 1 ) (m _ 1) (L 2 ) n ] p ; and wherein R 7 , R 8 and R 9 are independently H or an optionally substituted aliphatic , heterocyclic or aromatic group. 5 Specific examples of metal complexes of formula (1) include
  • each M is independently selected from Fe(II), Mn(II), Ru(II), Co(III), Cr(III), Fe(III), Ir(III), Os(III), Rh(III), Ru(III), Ru(IV), Os(IV) and Pt(IV).
  • Inflammatory diseases and conditions that can be treated in accordance with one 0 or more embodiments of the invention include primary arthritis (osteoarthritis, rheumatoid arthritis, septic arthritis, gout and pseudogout, juvenile arthritis, Still's disease, ankylosing spondylitis), secondary arthritis caused by other diseases (systemic lupus erythematosus, Henoch-Sch ⁇ nlein purpura, psoriatic arthritis, reactive arthritis (Reiter's syndrome), hemochromatosis, hepatitis, Wegener's granulomatosis (and many other vasculitis syndromes), familial Mediterranean fever, hyperimmunoglobulinemia D and periodic fever syndrome, and TNF-alpha receptor associated periodic fever syndrome), bronchitis, bursitis, scoliosis, muscle and joint injury, colitis (ulcerative colitis, Crohn's colitis, diversion colitis, ischemic colitis, infectious colitis, chemical colitis and atypical colitis
  • Diseases and conditions with an inflammatory component that can be treated in accordance with one or more embodiments of the invention include psoriasis, rosacea, and neurodegenerative, cardiovascular and diabetes related diseases and conditions.
  • Inflammation is an important component of the formation of arterial plaques and acute inflammation follows strokes and heart attacks, due to the involvement of reactive oxygen species. Similar oxidative damage is associated with the onset and progression of neurodegenerative diseases and diabetes. See for example, Dragomir, E.; Simionescu, M.. Monocyte Chemoattractant Protein- 1 - a major contributor to the inflammatory process associated with diabetes. Arch. Physiol. Biochem. (2006), 112, 239-244; Kadiu, L; Glanzer, J. G.; Kipnis, J.; Gendelman, H. E.; Thomas, M. P. Mononuclear phagocytes in the pathogenesis of neurodegenerative diseases. Neurotoxicity Res. (2005), 8, 25-50.
  • Cardiovascular diseases and conditions that can be treated in accordance with one or more embodiments of the invention include acute and chronic cardiovascular inflammation including as a result of surgery or other trauma, cardiovascular disease, angina pectoris, arteritis, atheroma, atherosclerosis, arteriosclerosis, congestive heart failure, coronary heart disease, cardiomyopathy, myocardial infarction, stroke, ischeamic conditions, ischaemic cardiomyopathy, patent ductus arteriosus, high blood pressure, pulmonary hypertension peripheral artery disease, coronary artery disease, coronary artery spasm, pericarditis and strokes.
  • Diabetes related diseases and conditions that can be treated include Type I diabetes mellitus, Type II diabetes mellitus, gestational diabetes mellitus (GDM), insulin-dependent diabetes, non-insulin dependent diabetes, juvenile onset diabetes, late onset diabetes, maturity -onset diabetes of the young (MODY), insulin sensitive diabetes, insulin deficient diabetes, carbohydrate intolerance, and diabetes associated with another disease or condition (eg., such as polycystic ovary disease or acanthosis nigricans), and non-resistant forms of diabetes observed following pancreatic surgery and for instance, following trauma to the pancreas (eg., as a result of injury).
  • GDM gestational diabetes mellitus
  • MODY early onset diabetes of the young
  • diabetes associated with another disease or condition eg., such as polycystic ovary disease or acanthosis nigricans
  • non-resistant forms of diabetes observed following pancreatic surgery and for instance, following trauma to the pancreas (eg., as a
  • Neurodegenerative conditions that can be treated include dementia, Lewy body disease, Parkinsons diseases, Alzheimers disease, amyloid plaque deposition diseases, multiple sclerosis, demyelination diseases, and motor neurone diseases.
  • Carcinomas that can be treated include lesions and tumours of the epithelium.
  • the lesion can, for example, be a skin lesion such as basal cell carcinoma, squamous cell carcinoma or melanoma.
  • the carcinoma can be selected from other cancers of the epithelium, such as lung cancer, cancer of the oesophagus, colon cancer, colorectal cancer, breast cancer, lung cancer, and other cancers of the epithelial tissues such as epithelial cancers of the tongue, salivary glands, gums and other areas of the mouth, oropharynx, nasopharynx, hypopharynx, oesophagus, pancreas, stomach, small intestine, duodenum, gall bladder, pancreas, larynx, trachea, uterus, cervix, ovary, vagina, vulva, prostate, testes, penis, bladder, kidney, thyroid, eye, and mestastic cancers thereof.
  • metal complexes embodied by the invention is not limited to epithelial cancers and metal complexes of formula (1), (2) or (3) also have application in the prophylaxis or treatment of non-epithelial cancers.
  • the application of metal complexes in the treatment of carcinoma is further described in Applicant's co -pending International Patent Application No. PCT/AU2006/000403 the contents of which is incorporated herein by cross-reference in its entirety.
  • non-carcinoma cancers which can be treated in accordance with one or more embodiments of the invention include leukemias (chronic myeloid, acute myeloid, chronic lymphocytic, acute lymphoblastic and hairy cell), Non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, sarcomas, lymphomas, Kaposi's sarcomas (classic, endemic or African, AIDS-related, transplant -related), primary bone cancers (osteosarcoma, Ewing's sarcoma, chondrosarcoma, spindle cell sarcoma, chordoma, angiosarcoma), soft tissue sarcomas (dermatofibrosarcoma, desmoid tumor, desmoplastic small round cell tumor, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, hemangiopericytoma, hemangiosarcoma
  • Analgesic applications of embodiments of metal complexes of the invention include treatment of post -operative pain, pain caused by bone cancer, arthritic pain, muscle pain, period pain, severe headaches, and pain associated with inflammatory diseases and conditions, trauma and infection.
  • Metal complexes as described herein can be taken orally, intraveneously (as many are water soluble) or by direct application to the site of infection (see example). Many infections are also associated with hypoxia. H and, hence, complexes that release the active under conditions of hypoxia can deliver the ligand/metaldrug selectively to the site of infection.
  • Microbial pathogens that can be treated by one or more embodiments of the invention include bacterial, fungal and yeast pathogens which cause systemic, mucosal, oral, nasal, oropharyngeal, nasalpharyngeal, pharyngeal, digestive tract, vaginal, respiratory tract, urinary tract, kidney, eye and skin infections, including Chlamydia species, Haemophilus influenzae species, Non-typable Haemophilus influenzae (NTHi) species, Pseudomonas species, Streptococcus species, Staphylococcus species, E. coli species, Mycoplasma species and Helicobacter species amongst others.
  • bacterial pathogens include P. aeruginosa, Non-typeable H.
  • influenzae (NTHi), Streptococcus pneumoniae and Pseudomonas aeruginosa, Helicobacter pylori, Haemophilus influenzae type b (Hib), Staphylococcus aureus, Staphylococcus albus, Chlamydia pneumoniae, Chlamydia trachomatis, Moraxella catarrhalis, Streptococcus pyrogenes, Chlostridium diptheriae , M. tuberculosis and M. genitalium.
  • Fungal pathogens include Aspergillus species.
  • Yeast pathogens include for instance Saccharomyces species and the candidiasis causing agent Candida albicans.
  • Indomethacin for instance has been reported to have an anti-microbial effect on H. pylori. These bacteria have been identified as a causative agent of at least some gastric cancers. Observations by the present inventors indicate that metal complexes embodied by the invention such as copper indomethacin can have a stronger anti-bacterial effect on gut bacteria than indomethacin alone and it will be understood that one or more methods embodied by the invention extend to combination therapy with other chemotherapeutic agents and drugs for the prophylaxis of H. pylori infections and gastric cancers involving a microbial component, as well as other microbial infections such as those exemplified above. Any conventionally known agents or drugs commonly used for the prophylaxis or treatment of such bacterial, fungal and other microbial infections can be used in such combination therapy.
  • DNA viruses such as Epstein-Barr virus (EBV), Human papillomavirus (HPV), Hepatitis B virus and Hepatitis C virus, Human T-cell lymphotropic virus, Kaposi's sarcoma associated herpes virus, herpes simplex viruses (HSV-I, HSV-2), varicella-zoster virus, vaccinia virus, SV40 virus, respiratory syncytial virus (RSV), parainfluenza viruses (PIV), human metapneumovirus, positive-stranded RNA viruses such as rhinoviruses, polioviruse, rubella virus and equine encephalitis viruses, and further RNA viruses including influenza virus, (eg influenza A and influenza B viruses), measles virus and mumps virus.
  • EBV Epstein-Barr virus
  • HPV Human papillomavirus
  • HPV Hepatitis B virus and Hepatitis C virus
  • Human T-cell lymphotropic virus Kaposi's sarcoma associated her
  • Any conventionally known anti-viral drug may be employed including Acyclovir (acylguanosine), Arildone and WIN drugs which inhibit viral uncoating, Pleconaril, Amantadine, Rimantadine, nucleoside analogue drugs, further DNA polymerase inhibitors such as Ganciclovir, Azidothymidine (AZT), and adenosine arabinoside, dideoxyinosine, iodo-deoxyuridine, trifluorothymidine, Nevirapine, pyridinone derivatives, Efavirenz, RNA synthesis inhibitors, RNA cleavage enzymes and protease inhibitors.
  • Acyclovir acylguanosine
  • Arildone WIN drugs which inhibit viral uncoating
  • Pleconaril Amantadine
  • Rimantadine nucleoside analogue drugs
  • further DNA polymerase inhibitors such as Ganciclovir, Azidothymidine (AZ
  • embodiments of metal complexes described herein including those with Cu may also promote angiogenesis and so have application in wound healing, treating tissue damage, inhibiting skin aging, and promoting angiogenesis in skin and other tissues, including hypoxic and ischemic tissues.
  • NSAID or NSAID derivative Li Volti, G.; Sacerdoti, D.; Sangras, B.; Vanella, A.; Mezentsev, A.; Scapagnini, G.; Falck, J. R.; Abraham, N. G. Carbon
  • metal complexes of the invention can promote healing of wounds and have application in the treatment and prevention of skin conditions that have a microbial component.
  • the presence of metal ions such as Zn in certain complexes can also promote skin repair.
  • metal complexes described herein may provide a means of improved delivery and release of ligands that inhibit COX-2 and 5-LO (lipoxygenase) enzymes which have synergistic effects on reducing skin damage, such as that arising from sunburn and other burns.
  • metal complexes embodied by the invention can be used to deliver NSAIDs with beneficial effects in wound and tissue repair as well as the metal of the complex to areas of hypoxia, particularly in areas of bacterial infection often associated with slow healing wounds that are difficult to treat systemically and topically because of poor vascularisation.
  • Metal complexes of Co(III) and Ru(III) are particularly preferred for wound healing, tissue repair and anti-skin aging applications.
  • IndoH itself has some anti-cancer activity in carcinomas believed to be due to a range of effects including inhibition of the COX enzymes which are upregulated in cancer cells (Vane, J. R.; Bakhle, Y. S.; Botting, R. M. Annu. Rev. Pharmacol. Toxicol. 1998, 38, 97-120) and a reduction of angiogenesis
  • the inventors have surprising found that metal complexes of indomethacin (Indo) can be much more effective in preventing or treating carcinomas than indomethacin as a result of the promotion of angiogenesis.
  • promotion of angiogenesis is believed to contribute to inhibition of skin aging by facilitating the regeneration and neovascularization of tissue, facilitating the transport of nutrients and oxygen to tissue, and/or generally promoting blood flow to tissue, particularly after tissue inflammation, or exposure of skin tissue to injury or insult.
  • the inhibition of skin aging can manifest itself in one or more of increased or maintenance or vascularity of the skin, the maintenance or enhancement of elasticity of the skin, delayed deterioration of elasticity of the skin, decreased or delayed formation of creases or fine or deep wrinkles in the skin, decreased or delayed thinning of skin, the inhibition of loss of underlying fat from the skin, the inhibition of the development of transparency of skin, and inhibition of other visual markers associated with skin aging such as the formation or keratosis, dryness, and cracking of the skin.
  • Angiogenesis in wound healing can be assessed by measuring the extent of vessel growth at the site of wounds as described in Erpek, S.; Kilic, N.; Kozaci, D.; Dikicioglu, E.; Kavak, T.
  • any suitable conventionally known protocol for assessing aging of the skin can be used to score the efficacy of metal complexes described herein.
  • Skin damage that leads to aging effects can for example be assessed by examination of the erythema reducing capacity of a metal complex as described herein in animals or humans exposed to the complex, Grundmann, J. U.; Bockelmann, R.; Bonnekoh, B.; Gollnick, H. P. M, Photochem. Photobiol. 2001, 74, 587-592).
  • the treatment of skin damage is to be taken in the broadest sense to encompass the treatment of any skin damage responsive to the application of a metal complex as described herein and is not limited to skin damage arising from inflammation and microbial infections (or having a microbial component), trauma, burns (including radiation burns) and skin conditions.
  • Wound or tissue repair encompassed by one or more methods embodied by the invention include repair following cuts and abrasions, photodamage or tissue insult resulting from exposure to ultraviolet radiation including erythema, burns, non-healing skin ulcers including diabetic, venous stasis, and pressure ulcers, and tissue damage caused by surgery or as a result of injury or trauma.
  • the treatment of burns includes burns arising from exposure of tissue to excessive heat as well as from ultra-violet radiation (eg., sunburn) , and ionizing radiation as may result from cancer radiation therapy for the treatment of cancer, neoplastic disease or other disease or condition.
  • metal complexes embodied by the invention can be applied topically to the tissue to be treated although for internal treatment, the metal complexes can be administered systemically.
  • the metal complex can be topically applied on a daily basis to areas of the skin exposed to ultraviolet radiation such as the face, neck, arms, shoulders and legs while undertaking normal daily or leisure activities such as sunbaking. This also applies to methods of the invention for prophylaxis or treatment of carcinomas and other cancers.
  • the metal complex can be formulated in a sunscreen or cosmetic composition. Suitable sunscreen and cosmetic formulations are for example described in the Applicant's co-pending Interntaional Patent Application No.
  • the term "effective amount” means an amount to treat or provide a prophylactic, therapeutic or chemopreventative effect.
  • the specific "effective amount” will vary with factors such as the disease or condition for which the metal complex is being administered, the composition in which the metal complex is being administered, the route of administration, the age and physical condition of the human or animal, the type of animal being treated and the duration of the treatment, the nature of concurrent therapy (if any) .
  • the dosage administered and route of administration will be at the discretion of the attending, clinician or veterinarian and will be determined in accordance with accepted medical or veterinary principles. For instance, a low dosage may initially be administered which is subsequently increased at each administration following evaluation of the response of the subject. Likewise, the frequency of administration may be determined in the same way, that is, by continuously monitoring the response of the subject and modifying the interval between dosages.
  • the metal complex can be co-administered in combination with one or more chemotherapeutic agents conventionally used in the treatment of the particular disease, condition, or infection at hand.
  • co -administered is meant simultaneous administration in the same formulation or a plurality of formulations by the same or different routes, or sequential administration by the same or different routes.
  • sequential administration is meant one is administered one after the other.
  • the interval between the administration of the metal complex may be relatively short and can for instance be seconds or minutes, or longer periods of times such as hours or even a day or more.
  • the metal complex may be administered before or following the chemotherapeutic agent(s).
  • a composition embodied by the invention will typically further comprise a pharmaceutically acceptable carrier and be formulated to minimise dissociation of the metal complex to enhance the stability of the complex and shelf life of the formulation.
  • Carrier formulations for enhancing stability of the complex are for instance described in the co-pending International Patent Application No. PCT/AU2005/000442 and co-pending International Patent Application No. PCT/AU2006/000403 of the Applicant, the contents of both of which are incorporated herein by cross-reference in their entirety.
  • the metal complex may be dissolved in the composition or may be present in the composition as a solid.
  • the solid complex may be in the form of a crystal containing solvents of crystallisation and/or waters of crystallisation. When the complex is charged, the complex will be associated with a counter ion.
  • the complex will generally be administered in the form of a composition comprising the complex together with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier is a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering the complex to a human or animal.
  • the carrier may be liquid or solid and is selected with the intended manner of administration in mind.
  • the carrier is "pharmaceutically acceptable” in the sense of being not biologically or otherwise undesirable, i.e., the carrier may be administered to a human or animal along with the complex without causing any or a substantial adverse reaction.
  • the carrier may be a solvent or dispersion medium containing one or more of physiological saline, ethanol, polyol (e.g. glycerol, propylene glycol, liquid polyethylene glycol and the like), vegetable oils and mixtures thereof.
  • compositions can be formulated as described in International Application No. PCT/AU2005/000442 filed 30 March 2005, the contents of which is incorporated herein by cross-reference in its entirety.
  • a formulation having a colloidal structure or which forms a colloidal structure post administration is particularly desirable for administration of metal complexes.
  • suitable compositions having a colloidal structure or which form a colloidal structure upon, or following administration are exemplified in PCT/AU2005/00042 and any suitable such formulations for the selected mode of administration may be utilised in methods embodied by the present invention.
  • a composition has a colloidal structure if it comprises a colloidal system.
  • a colloidal system is a system in which particles of a colloidal size of any nature (eg., solid as liquid or gas) are dispersed in a colloidal phase of a different composition or state.
  • the composition comprises micelles in an aqueous carrier or is an oil-in- water emulsion, or forms micelles or an oil-in- water emulsion when the composition is administered to a human or animal body.
  • the colloidal structure protects the metal complex from interaction with acids or other compounds which would otherwise interact with the complex to cause the complex to dissociate. It is also believed the colloidal structure reduces the extent to which some compounds present in the composition are able to interact with the complex, e.g. during storage of the composition, that may cause the complex to dissociate. Similarly, when such a composition is administered to a subject, the colloidal structure may limit the extent to which some compounds that come into contact with the composition after it is administered are able to interact with the complex and which cause the complex to dissociate before it is absorbed. For example, for compositions administered orally, the colloidal structure may limit the extent to which compounds present in stomach acid are able to interact with the complex to cause the complex to dissociate before it is absorbed through the gastrointestinal tract.
  • the colloidal structure may limit the extent to which compounds that come into contact with the composition after it is administered, e.g. strong chelators of Cu(II), such as peptides, or reductants of Cu(II), such as thiol -containing biomolecules, are able to interact with the complex to cause the complex to dissociate.
  • strong chelators of Cu(II) such as peptides
  • reductants of Cu(II) such as thiol -containing biomolecules
  • some compositions may not have a colloidal structure but will be formulated such that when administered to a human or animal body by the intended route of administration, a colloidal structure is formed.
  • the composition is immiscible with water, and is thus immiscible with aqueous biological fluids whereby a colloidal system is thereby formed.
  • the colloidal structure is maintained for a sufficient time after administration of the composition for the majority, for example more than 70%, 80% or 90%, of the metal complex, to be absorbed by the body as a metal complex.
  • Oils that may be utilized in compositions include pharmaceutically acceptable vegetable or mineral oils. Suitable oils include, but are not limited to: triglycerides, particularly medium chain triglycerides, combinations of medium chain and long-chain triglycerides, combinations of triglycerides with fish oil; vegetable oils, such as, soya oil, safflower oil and sunflower oils; isopropyl myristate; and paraffins. Such oils are suitable for use in compositions for oral, injectable, or topical administration.
  • the composition will typically further comprise one or more surfactants for formation of the micelles.
  • Any surfactants may be used that are capable of forming micelles in the aqueous carrier, are pharmaceutically acceptable when administered by the intended route of administration, and which substantially do not interact with the metal carboxylate complex to cause dissociation from the metal when the composition is stored in the absence of light.
  • Suitable surfactants for use in compositions for oral or topical administration include, but are not limited to, the sorbitan fatty acid ester group of surfactants.
  • Such surfactants comprise mono-, tri-, or partial esters of fatty acids such as oleic, lauric, palmic and stearic acids, and include sorbitan trioleate (Span 85), sorbitan monooleate (Span 80), sorbitan tristearate (Span 65), sorbitan monostearate (Span 60), sorbitan monopalmitate (Span 40), and sorbitan monolaurate (Span 20).
  • surfactants include the macrogol (polyoxyethylene) esters and ethers. These surfactants include, but are not limited to, the caster oil polyoxyethylene group of surfactants, such as Termul 1284 and caster oil ethoxylate. Additional surfactants in this class include the Polyoxyethylene Sorbitan Fatty Acid Esters group of surfactants, including polyoxyethylene (20) sorbitan monolaurate (Tween 20), polyoxyethylene (4) sorbitan monolaurate(Tween 21), and polyoxyethylene (20) sorbitan monooleate (Tween 80).
  • a composition as described herein may can optionally further comprise one or more solvents or solubilising components for increasing the solubility of the metal carboxylate complex in the composition.
  • the solvent may, for example, be tetraglycol (IUPAC name: 2-[2-[(tetrahydro-2-furanyl)methoxy]ethoxy]ethanol; other names: 2-[2- (tetrahydrofurfuryloxy)ethoxy]ethanol; tetrahydrofurfuryldiethyleneglycol ether) or other glycofurols (also known as tetrahydrofurfurylpolyethyleneglycol ethers), polyethylene glycols, glycerol, propylene glycol, or other pharmaceutically acceptable glycol.
  • An example of a solubilising component is a polyvinylacohol/povidone mixture.
  • the composition may also further comprise a thickener such as Aerosil 200, clay or another inorganic filler.
  • compositions contain more than 80%, preferably more than 90%, and more preferably more than 95%, of the total amount of hydroxamate, hydroximate, ester, or amide derivative having anti-inflammatory activity present in the composition as part of a metal complex.
  • the amount of the hydoxamate, hydroximate, ester or amide remaining bound to the metal complex can be readily determined by a person skilled in the art using known methods such as EPR spectroscopy for complexes that give EPR signals or using more specialized experiments involving X-ray absorption spectroscopy for all complexes (e.g., XAFS Studies of Anti -inflammatory Dinuclear and Mononuclear Zn(II) Complexes of Indomethacin. Zhou, Q.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A. Inorg. Chem.
  • the metal complex can be dissolved in the composition or can be present in the composition as a solid.
  • the solid complex may be in the form of a crystal containing solvents of crystallisation and/ or waters of crystallisation. When the complex is charged, the complex will be associated with a counter ion.
  • the composition for use in the method of the invention may be suitable for oral, rectal, nasal, topical (including buccal and sublingual), ophthalmological, vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration, or for administration respiratoraly, intratrachaely, nasopharanyngealy, intraoccularly, intrathecally, intranasally, by infusion, or via IV group patch and by implant.
  • compositions may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Such methods include the step of bringing into association the complex with the carrier.
  • the carrier comprises two or more ingredients.
  • the composition of the present invention is prepared by uniformly and intimately bringing into association the complex with the carrier, and then, if necessary, shaping the product.
  • the complex and the one or more components making up the carrier may be mixed in any order. However, it is preferred that the components are mixed in a manner that minimises the amount of the complex that dissociates during the preparation of the composition.
  • a composition for oral administration can be in the form of a viscous paste, a tablet, a capsule, a chewable composition, or any other form suitable for oral administration.
  • the composition can also be encapsulated in a hard or soft capsule (e.g. gelatine) by techniques known in the art.
  • the metal complex may be provided in the form of ingestible tablets, buccal tablets, troches, elixirs, suspensions or syrups. Slow release formulations and formulations for facilitating passage through the environment of the stomach to the small intestines are also well known to the skilled addressee and are expressly encompassed by the invention.
  • a composition for oral use can also comprise one or more agents selected from the group of sweetening agents such as sucrose, lactose or saccharin, disintegrating agents such as corn starch, potato starch or alginic acid, lubricants such as magnesium stearate, flavouring agents, colouring agents and preserving agents e.g. such as sorbic acid, in order to produce pharmaceutically elegant and palatable preparations.
  • a chewable composition can, for example, comprise the metal complex, one or more flavourants, a base formulation, one or more preservatives, one or more pH modifiers, one or more desiccants and one or more fillers.
  • the base may comprise pre-gel starch, gelatine, flour and water.
  • the composition may also comprise other components including phosphoric acid, salt, sugar, sorbitol and/or glycerol, sorbic acid and/or potassium sorbate, benzoic acid, propionic acid and maltodextrin.
  • a chewable composition for an animal such as a dog for example, can comprise the complex, meat emulsion, an acidulate (e.g. phosphoric acid), one or more antifungal agents (e.g. benzoic acid and sorbic acid), sugar or sugar alcohol, and salt.
  • a composition for topical application can comprise the complex in a conventional oil-in- water emulsion, water-in-oil emulsion, or water-immiscible pharmaceutical carrier suitable for topical application.
  • Such carriers include for example, lacrilube, cetomacrogol cream BP, wool fat ointment BP or emulsifying ointment BP.
  • Such carriers are typically in the form of an emulsion or are immiscible with water.
  • An example of a composition for topical application to skin is a composition comprising 0.5-2% w/w of the complex in an emulsifying cream with chlorocresol (4- chloro-3-methylphenol) as a preservative, the emulsifying cream comprising:
  • compositions for application to skin are a composition comprising 2% w/w of the complex in wool fat. This composition is immiscible with water.
  • compositions for parenteral administration include compositions in the form of sterile aqueous or non-aqueous suspensions and emulsions.
  • a composition embodied by the invention can also include one or more pharmaceutically active components in addition to the complex that have anti-cancer activity or other therapeutic activity.
  • Such active components include conventionally used anti-inflammatory drugs, and conventionally used metal and non-metal based chemo therapeutic and anti-cancer agents such as those identified above.
  • the metal complex constitutes about 0.005% to about 20% by weight of the composition, preferably about 0.005% to about 6% by weight of the composition, more preferably about 0.01% to about 3% by weight of the composition.
  • a topically acceptable composition of the invention can comprise the metal complex in an amount of about 0.1% by weight of the composition or less.
  • the dosage of a metal complex embodied by the invention will depend on a number of factors including whether the complex is to be administered for prophylactic or therapeutic use, the disease or condition for which the active is intended to be administered, the severity of the condition, the age of the individual, and related factors including weight and general health of the individual as may be determined in accordance with accepted medical principles. For instance, a low dosage may initially be given which is subsequently increased or descreased at each administration following evaluation of the individual's response. Similarly, the frequency of administration can be determined in the same way that is, by continuously monitoring the individual's response between each dosage and if necessary, increasing the frequency of administration or alternatively, reducing the frequency of administration.
  • a metal complex as described herein will normally be administered at a dosage up to about 0.5-4 mg/kg body weight and preferably, in a range of from about 0.1 mg/kg to about 10 mg/kg body weight per day, depending on the condition being treated and the nature of the complex. More preferably, the metal complex will be administered at a dosage in a range of from 0.5 mg/kg to about 4 mg/kg body weight, and most preferably, in a range of from 1 mg/kg to about 3 mg/kg body weight.
  • Typical oral or suppository doses will be in the range of 1 mg/kg to 4 mg/kg; sunscreen compositions and topical compositions for the prophylaxis of skin damage and aging, the metal complex will typically be dosed in a range of 0.01-0.05% w/w topical carriers, but for more localised topical application to skin carcinomas, for wound healing or the treatment of pain and inflammation, topical formulations will typically be administered as more concentrated 0.25-2% w/w formulations, such that the maximum dosage fall with the ranges indicated above.
  • Injection directly into cancerous lesions can have concentrations as high as 30% w/w, whereby a volume of the formulation equivalent to the volume of the lesion is injected.
  • Suitable pharmaceutically acceptable carriers and formulations useful in the present invention may for instance be found in handbooks and texts well known to the skilled addressee, such as "Remington: The Science and Practice of Pharmacy (Mack Publishing Co., 1995)” and subsequent update versions thereof, the contents of which is incorporated herein in its entirety by reference.
  • the mammalian subject may be a human or an animal.
  • the animal can, for example, be a companion animal such as a dog or cat, or a domestic animal such as a horse, pony, donkey, mule, camel, llama, alpaca, pig, cow or sheep, or a zoo animal.
  • Suitable animals include members of the Orders Primates, Rodentia, Lagomorpha, Cetacea,
  • Carnivora Carnivora, Perissodactyla and Artiodactyla.
  • the subject will be a primate and more usually, a human being.
  • Acetylsalicylhydroxamic Acid (AcSHAH 2 ) and its copper complex SHA AsSHAH,
  • Salicylhydroxamic acid (SHAH 2 ) (7.65 g, 50 mmol) was mixed with acetic anhydride (9.5 ml, 100 mmol). The solution was acidified with H3PO4 (1 ml) and was stirred in a water bath at 60 0 C for 30 min. Distilled water (5 ml) was added to the solution in order to decompose the unreacted acetic anhydride, and the resulting solution were stirred at room temperature until the vapor from the solution gave no acid reaction towards litmus paper. Finally, the reaction mixture was mixed with distilled water (50 ml) and AcSHAH 2 precipitated as a white powder solid (68.2%). Anal. Calcd.
  • AcSHA shows two bands centered at 3322 and 3272 cm “1 , ascribed to the m(OH) and m(NH) stretching vibrations, respectively.
  • the appearance of a sharp and strong peak located at ca. 1787 cm “ 1 in the spectrum of AcSHA clearly indicates the presence of the acetyl carbonyl, in addition to a peak due to the hydroxamic carbonyl at ca. 1640 cm “1 .
  • VOSO 4 SH 2 O (50.6 mg, 0.200 mmol) and IndoHAH 2 (149 mg, 0.400 mmol) were dissolved in methanol (MeOH, HPLC grade, 5.0 mL). The colour of the solution immediately turned dark-red. This solution was added to ice-cold H 2 O (Milli-Q grade, 50 mL), which led to the formation of a fine brown precipitate. The precipitate was isolated by centrifugation (5 min at 4000 g) and dissolved in a minimal volume of MeOH ( ⁇ 20 mL).
  • the resultant solution (which was slightly cloudy) was filtered through a small-pore (No. 4) glass filter under vacuum.
  • the volume of the filtrate was reduced by -2/3 under reduced pressure (at 40 0 C), which led to the formation of a red precipitate.
  • the precipitate was isolated on a glass filter (No. 4) under vacuum, and dried overnight under vacuum over silica gel. Yield, 48.9 mg (54.3% as calculated for [V v O(IndoHAH)(IndoHA)] -2MeOH- 1.5H 2 O.
  • the colour of the complex is strongly solvent-dependent: the solid compound is brown, solutions in methanol are orange-red, and solutions in tetrahydrofuran are dark- purple. Thus, it is most likely that the complex is six-coordinate, with a molecule of solvent as a ligand.
  • An acidic aqueous solution of Ga(III) (0.64 M) was prepared by partial dissolution of a piece of metallic Ga (99.99%, Fluka) in aqueous HCl ( ⁇ 5 M, ultra -pure, Merck), and the amount of dissolved Ga was determined by the mass difference. A portion of this solution (5.0 mM) was evaporated to dryness at 100 0 C, and the residue was dried under vacuum overnight and dissolved in anhydrous MeOH (5.0 mL), giving a solution of GaCl 3 (0.64 M) in MeOH.
  • the Ga content in the complex determined spectrophotometrically with 4- (2- pyridylazo)resorcine (PAR) after digestion of the complex with concentrated HNO 3 , was 8.0 and 8.7% (for two parallel samples,).
  • the data indicate the formation of a bis-ligated Ga(III) hydroxamato complex, [Ga(LH) 2 (OH 2 ) 2 ] +
  • Electrospray mass spectroscopy of [Cu(Indo- GIy) 2 (Im) 2 ] in DMF shows the presence of the [Cu(Indo-Gly)] + (475.9) and [Cu(Indo- Gly)(Imidazole)] + (544.0). From the IR spectra typical peaks of ligands of Indomethacin- glycine and imidazole are observed.
  • Vanadium and chromium complexes of this ligand are prepared by similar methods as those described for IndoHA, but electrospray mass spectrometry indicates that the complexes are polymeric rather than monomeric.
  • the aqueous had to be readjusted to pH 4 using dil. HCl (aq). This aqueous was then extracted with further EtOAc (25 ml). The aqueous was again adjusted to pH 3-4 using dil. HCl (aq) and extracted with EtOAc (25 ml). The combined EtOAc phases were washed with water (25 ml) then sat. brine (25 ml), then concentrated in vacuo to give a pale yellow foam (0.67 g obtained).
  • these peptide derivatives of NSAIDs can bind via combinations of the deprotonated amides, side-chains of the peptides and/or terminal carboxylates to produce a wide variety of complexes with virtually all of the metallic elements of the periodic table.
  • ligands can be prepared by the following reaction schemes and can coordinate to metal ions via the diol functions.
  • sugar groups and functionalised sugars bind to many different metal ions on mixing, usually via deprotoned alcohol groups of the sugars.
  • Advanced DMEM medium was used in all the cell culture work.
  • the medium did not contain certain components needed to facilitate cell growth. Therefore, antibiotics- actimycotic (0.5 mL), (100 U m " penicillin, 100 ⁇ g mL " streptomycin and 0.25 ⁇ g mL “ amphotericin B), 200 mM glutamine solution (0.5 mL) and fetal calf serum (2 %, 0.8 mL) were added to the medium (40 mL) before proceeding with any cell work. All of the above components were obtained from Gibco Industries Inc. (Langley, OK, USA). All other reagents used in the cell work were obtained from Sigma (St. Louis, MO, USA). 2.1.2 Thawing of frozen A549 cancer cells
  • Frozen cells were stored in liquid nitrogen. The cells were rapidly warmed in a 37 0 C water bath for approximately 5 min. The cell suspension was then transferred to a 10- mL centrifuge tube with 9 mL of medium and centrifuged for 3 min at 2000 rpm. The medium was removed from the resultant pellet and fresh medium (1 mL) was added to resuspend the cells, then transfer the cells to a 10-cm plate with fresh medium (10 mL) added to it. Cells were incubated at 37 0 C in a humidified atmosphere containing 5 % CO 2 for 3 days.
  • the medium was removed from the cells and the cell layer was washed with phosphate buffer solution (PBS, 10 mL) prior to trypsination with 0.25 % trypsin EDTA solution (4 mL). Cells were then incubated for 6 min at 37 0 C, after which medium with serum (5 mL) was added to inactivate the trypsin. The cell suspension was then collected into a centrifuge tube and the mixture was centrifuged at 2000 rpm for 3 min. The medium was subsequently removed from the cell pellet and fresh medium (1 mL) was added to resuspend the cells. The cell suspension (0.58 mL) was transferred from the total cell suspension to a centrifuge tube. Further, medium (3 mL) was added to the centrifuge tube and the cells were counted using a haemocytometer.
  • PBS phosphate buffer solution
  • the medium was removed from all the wells via a vacuum pump. The first and the last row of wells were left without addition of the test compound and were used as control wells. To the rest of the wells, appropriate concentrations of the test compound (20-400 ⁇ M) in complete medium were added into the wells. After treatment, the plates were incubated at 37 0 C for 3 days.
  • MTT MTT (1 mg/mL) was added to all the wells and the cells were further incubated for approximately 4 h at 37 0 C to allow sufficient time for it to interact with the cells. The medium was then carefully discarded and the cellular contents were extracted using DMSO (100 ⁇ L per well).
  • crystal violet blue assay the medium was removed from the plates and the cells were washed twice with saline (0.9% NaCl). To all the wells, crystal violet blue dye (1 mL in 5% PBS) was added and the mixture was left for ⁇ 1 min to stain the cells. The dye was then removed and the cells were extracted using a solution of propan-2-ol (1 mL).
  • Absorption at 595 nm was determined using an ELISA plate reader.
  • the percent survival was determined by the intensity of the absorbance obtained, which correlated to the amount of cells present in each well.
  • the negative control wells were arbitrarily assigned as 100% survival.
  • the MTT assay provides a measure only for viable cells.
  • V-IndoHA complex the relatively high activity of the V-IndoHA complex. It is considered that this lipophilic complex will transfer both the ligand and the metal inside the cells, where they are likely to exert their activities separately: the ligand by the many processes discussed above and the V by phosphatase activity.
  • composition containing the metal complexes in medium chain triglyceride (MCT) organogel paste and/ or an aqueous 2% w/w CMC solution were freshly prepared for each experiment.
  • MCT medium chain triglyceride
  • the organogel paste is described in PCT International Patent Application No. PCT/AU2005/000442. 3.1.2 Animals
  • Sprague-Dawley rats (weighing 200-250 g) used for these studies were supplied by the laboratory animal services at The University of Sydney, Sydney Australia. Animals were housed in polypropylene cages and allowed free access to standard laboratory rat chow (Purina Rat Chow, Ralston Purina, St Louis MO) and tap water. Animals were housed in the animal care facility of the Faculty of Pharmacy at ambient temperature and humidity with a 12-h light-dark cycle. The experimental animal protocols were approved by the Animal Ethics Committee of the University of Sydney.
  • Inflammation was induced (I h after dosing by gavage with an injection of carrageenan (0.1 mL, 1% w/v in isotonic saline) into the plantar region of the hind paw.
  • Paw volume was measured prior to dosing and at 3 h after carrageenan injection by immersing the left hind paw (to the lateral malleus) into a vessel filled with water and measuring the volume of water displaced as decribed in International Patent Application No. PCT/AU2005/000442 filed 30 March 2005, the contents of which is incorporated herein by cross-reference in its entirety.
  • the MCT organogel compositions of Oxametacin, Cr-Oxametacin and V-O-Oxametacin were non- irritating to the gastric mucosa with only the Cr-Oxametacin complex exhibiting significant anti-inflammatory activity. This demonstrates that a slow release oxametacin complex can have low GI with enhanced efficacy of the parent hydroamic acid.
  • ACM was significantly more anti-inflammatory than [Cu(AcSHAH)(OH)] (P ⁇ 0.05(*), [Cu(ACM) 2 (H 2 O) 2 ] and [Zn 2 (ACM) 4 (H 2 O) 2 ] were more anti -inflammatory (P ⁇ 0.05(*)) than either AcSAHA and [Cu(AcSHAH)(OH)], respectively.
  • [Zn 2 (ACM) 4 (H 2 O) 2 ] was significantly more anti-inflammatory (P ⁇ 0.01(**)) than [Cu(AcSAHA)(OH)].
  • Freshly prepared solutions containing the cobalt complex (active ingredient) in sterile saline was prepared by dissolving the cobalt complex (without heat) in the saline.
  • the resultant clear solution was filtered with a sterile 0.22 micron filter and used immediately.
  • the i.v push was given over approximately 10 s. All other experimental procedures are as described in Example 3. The animals were monitored for toxicity over 24 hr.
  • a typical i.v. dose of IndoH administered to infants for closure of the ductus aorta is 0.1 to 0.2 mg kg " bw.
  • High doses of IndoH have adverse effect on the central nervous system (CNS). Such effects include malaise and listlessness, drowsiness, hearing disturbances and in rare cases convulsions and coma.
  • a No Observed Adverse Effect Level (NOAEL) of ⁇ 1 mg kg " bw and LD50 of 3.3 mg/kg bw is proposed for i.v. administration of [Co(en) 2 (Oxametacin)]Cl 2 .
  • the recommended daily treatment dose of IndoH in humans is approximately 1 mg/kg bw administered in divided doses.
  • Oxametacin in typically dosed orally at 2-3 mg/kg.
  • the complex can be described in terms of indomethacin equivalence (IE) or equimolar amount of Indo.
  • IE indomethacin equivalence
  • the IE is the weight in mg of the Active Ingredient (A. L).
  • the IE can be calculated from the Molecular Weight (MW) of the A.I. and IndoH by the relationship:
  • n 2 for the Ga complex.
  • test formulations The efficacy and safety of the test formulations is described below in a series of in vivo studies for the assessment of the test composition as an anti-inflammatory agent and for its ability to induce acute gastric ulceration.
  • the test formulations transparent Medium Chain triglyceride (MCT) oily gels, were formulated at the University of Sydney, Australia.
  • MCT Medium Chain triglyceride
  • the test formulation was tested for the ability to inhibit inflammation in an inflammatory model, the carrageenan-induced paw oedema model, and were also tested in a gastric ulceration model as described below. 5.2.3 Animals
  • Sprague-Dawley rats (average weight 380-450 g) used for these studies were supplied by the laboratory animal services at The University of Sydney. Animals were housed in polypropylene cages and allowed free access to standard laboratory rat chow (Purina Rat Chow, Ralston Purina, St Louis MO) and tap water. Animals were housed in the animal care facility at The University of Sydney, at ambient temperature and humidity with a 12-h light -dark cycle. The experimental animal protocols were approved by the Animal Ethics Committee of The University of Sydney.
  • carrageenan 0.1 mL, 1% w/v in isotonic saline
  • Paw volume was measured prior to dosing and at 3 h after carrageenan injection by immersing the right hind paw (to the lateral malleus) into a vessel filled with water and sitting on a top pan balance tared to zero. According to Archimedes principle, the volume of water displaced by the paw was readily determined by reading the increased weight registered by the balance (i.e., submersing a paw of 1 c.c. volume registers an increase of 1 gm on the balance).
  • Nil gastric ulceration (0, 0, 0, 0 mm ) was observed in the control, Oxametacin (IndoHAFb) I.E. 4 mg/kg bw and [Cu 2 (Mo) 4 (0112)2] I.E. 1 mg/kg bw groups.
  • Minimal gastric ulceration (0, 0, 0, 2 mm ) was observed in the [Ga(IndoHA)2(OH2)2]Cl 3.6 mg/kg bw treatment group.
  • the cytotoxicity of metal complexes on cancer cell lines A549, A2780 and Hep-2 were assessed using MTT and crystal violet blue assays.
  • Advanced DMEM medium was used in all the cell culture work.
  • the medium did not contain certain components needed to facilitate cell growth. Therefore, for the A549 cells, antibiotics-actimycotic (0.5 mL), (100 U m " penicillin, 100 ⁇ g mL " streptomycin and 0.25 ⁇ g mL “ 1 amphotericin B), 200 mM glutamine solution (0.5 mL) and fetal calf serum (2 %, 0.8 mL) were added to the medium (40 mL) before proceeding with any cell work.
  • antibiotics-actimycotic 0.5 mL
  • penicillin 100 ⁇ g mL " streptomycin and 0.25 ⁇ g mL " 1 amphotericin B
  • 200 mM glutamine solution 0.5 mL
  • fetal calf serum 2 %, 0.8 mL
  • Advanced DMEM medium 40 mL was supplemented with antibiotics-actimycotic (0.5 mL), (100 U m "1 penicilin, 100 ⁇ g mL "1 streptomycin and 0.25 ⁇ g mL amphotericin B), 200 mM glutamine solution (1.0 mL) and fetal calf serum (5 %, 4 mL). All of the above components were obtained from Gibco Industries Inc. (Langley, OK, USA). All other reagents used in the cell work were obtained from Sigma (St. Louis, MO, USA). 6.1.2 Thawing of frozen A549, A2780 and Hep-2 cancer cells
  • Frozen cells were stored in liquid nitrogen. The cells were rapidly warmed in a 37 0 C water bath for approximately 5 min. The cell suspension was then transferred to a 10- mL centrifuge tube with 9 mL of medium and centrifuged for 3 min at 2000 rpm. The medium was removed from the resultant pellet and fresh medium (1 mL) was added to resuspend the cells, then transfer the cells to a 10-cm plate with fresh medium (10 mL) added to it. Cells were incubated at 37 0 C in a humidified atmosphere containing 5 % CO 2 for 3 days.
  • the medium was removed from the cells and the cell layer was washed with phosphate buffer solution (PBS, 10 mL) prior to trypsination with 0.25 % trypsin EDTA solution (4 mL). Cells were then incubated for 6 min at 37 0 C, after which medium with serum (5 mL) was added to inactivate the trypsin. The cell suspension was then collected into a centrifuge tube and the mixture was centrifuged at 2000 rpm for 3 min. The medium was subsequently removed from the cell pellet and fresh medium (1 mL, A549, and 1 mL Hep-2) was added to resuspend the cells.
  • PBS phosphate buffer solution
  • the cell suspension (0.58 mL, A549, 0.24 mL, A2780 and 1.6 mL, Hep-2) was transferred from the total cell suspension to a centrifuge tube. Further, medium (3 mL, for A549, A2780 and Hep-2) was added to the centrifuge tube and the cells were counted using a haemocytometer.
  • the cell suspension (100 ⁇ L per well) was transferred to four sets of ninety six- well plates with each well having approximately the same amount of cells (1x10 4 cells/well/100 ⁇ L for A549 and Hep-2 and IxIO 5 cells/well/100 ⁇ L for A2780). The plates were incubated overnight at 37 0 C prior to the addition of the test compound.
  • the medium was removed from all the wells via a vacuum pump. A number of wells were left without addition of the test compound and were used as control wells. Appropriate concentrations of the test compound (10-300 ⁇ M) in complete medium were added to the remainder of the wells. After treatment, the plates were incubated at 37 0 C for 3 days.
  • the medium was removed from all the wells via a vacuum pump. The first and the last row of wells were left without addition of the test compound and were used as control wells. To the remainder of the wells appropriate concentrations of the test compound (20- 400 ⁇ M) in complete medium were added into the wells. After treatment, the plates were incubated at 37 0 C for 3 days.
  • the medium was removed from all the wells via a vacuum pump. The first and the last row of wells were left without addition of the test compound and were used as control wells. To the rest of the wells, appropriate concentrations of the test compound (20-400 ⁇ M) in complete medium were added into the wells. After treatment, the plates were incubated at 37 0 C for 3 days.
  • MTT MTT (1 mg/mL) was added to all the wells and the cells were further incubated for approximately 4 h at 37 0 C to allow sufficient time for it to interact with the cells. The medium was then carefully discarded and the cellular contents were extracted using DMSO (100 ⁇ L per well).
  • crystal violet blue assays the medium was removed from the plates and the cells were washed twice with saline (0.9% NaCl). To all the wells, crystal violet blue dye (1 mL in 5% PBS) was added and the mixture was left for ⁇ 1 min to stain the cells. The dye was then removed and the cells were extracted using a solution of propan-2-ol (1 mL).
  • Absorption at 595 nm was determined using an ELISA plate reader.
  • the percent survival was determined by the intensity of the absorbance obtained, which correlated to the amount of cells present in each well.
  • the negative control wells were arbitrarily assigned as 100% survival.
  • the MTT assay provides a measure only for viable cells.
  • Table 2 LC50 values for IndoH and [Cu 2 (Indo) 4 (OH 2 )2] in A549 and A2780 cells
  • the Zn Indo complex was also compared against two cell lines Hep-2 and A549 and it was shown to have an equivalent effect on cell viability across the two cell lines (Figure 6). 6.4 Discussion
  • the V-IndoHA complex was found to have the highest activity. It is though that this lipophilic complex will effect transfer of both the ligand and the metal into cells, where they are likely to exert their activities separately: the ligand by Cox inhibition and the V by phosphatase activity. Given that the Culndo complexes are much more active as anti-cancer agents in vivo than in in vitro cell assays, it is likely that the V(V) complex is even more potent in vivo.
  • EXAMPLE 7 Cytotoxicity of NSAIDs and their metal complexes in Leukemia cell lines
  • HL-60 ATCC No. CCL-240, human acute promyelocytic leukemia
  • MOLT-3 ATCC No. CRL- 1552, human acute lymphoblastic leukemia
  • test NSAIDs and metal complexes were incubated with the applicable test NSAID or metal complex for 48 h, adjusted for non-adherent cells (e.g., the formed formazan crystal was solubilised by overnight incubation with a detergent solution. Stock solutions of all the compounds were prepared in DMSO.
  • the IC 50 for the Colndo complex is a factor of three lower than for IndoH for treatment of MOLT-3 cells (even though it is an inert metal complex).
  • the Co(III) oxamethacin complex (and related complexes) have high water solubility, high stability for intravenous use, and the active may be released on reduction once the complex is absorbed by the leukemia cells.
  • DP placebo groups
  • drug was administered as a single gavage dose (4 mg/kg of oxametacin equivalent, delivered as the vanadium complex in an MCT organogel) between 7 and 9 am in the morning.
  • tail vein blood was obtained immediately before administration and at 2, 4, 6, 8 and 18 hr following administration of the vanadium complex. Blood sugar level was measured by glucometer (Ames).
  • the BSL of diabetic animals treated with either drug (black circles) or placebo (open circles) are shown in Figure 7.
  • treatment of diabetic animals with the vanadium complex induced a 6-10-mmol/l decrease in blood glucose level when compared with the placebo treated group. This decrease was maintained for a further 6 hr and had returned to baseline levels by 24 hr.
  • Treatment of non-diabetic control animals had no blood sugar lowering effect over a similar time course (data not shown).
  • These data indicate that the drug has insulin-like action in that it can lower blood glucose levels in diabetic animals at much lower concentrations of vanadium than is normally administered to observe such effects.
  • the results also illustrate the potential role for the drug in simultaneously treating diabetes and inflammatory conditions in the one dose (either alone or in combination therapy with drug(s) conventionally used for the treatment of diabetes) for humans and animals suffering from this condition.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

L'invention porte sur des complexes métalliques de ligands anti-inflammatoires utiles dans le traitement des inflammations et/ou du cancer et/ou du diabète et/ou des troubles cardiovasculaires et/ou d'autres troubles.
PCT/AU2007/000375 2006-03-24 2007-03-26 Complexes métalliques ayant une activité anti-inflammatoire Ceased WO2007109843A1 (fr)

Applications Claiming Priority (30)

Application Number Priority Date Filing Date Title
AUPCT/AU2006/000391 2006-03-24
PCT/AU2006/000403 WO2006099685A1 (fr) 2005-03-24 2006-03-24 Methode de prevention ou de traitement de carcinomes
AUPCT/AU2006/000403 2006-03-24
PCT/AU2006/000391 WO2006099677A1 (fr) 2005-03-24 2006-03-24 Complexes metalliques
AU2006901557 2006-03-27
AU2006901557A AU2006901557A0 (en) 2006-03-27 Method for prophylaxis or treatment of cardiovascular inflammation
AU2006901583A AU2006901583A0 (en) 2006-03-28 Method for prophylaxis or treatment
AU2006901583 2006-03-28
US83020306P 2006-07-11 2006-07-11
US83029006P 2006-07-11 2006-07-11
US60/830,203 2006-07-11
US60/830,290 2006-07-11
IBPCT/IB2006/002423 2006-09-01
PCT/IB2006/002423 WO2007026240A1 (fr) 2005-09-01 2006-09-01 Écran solaire et compositions cosmétiques pour la prophylaxie ou pour le traitement des cancers de la peau
AU2006905170A AU2006905170A0 (en) 2006-09-19 Metal complexes having anti-inflammatory activity
AU2006905170 2006-09-19
AU2006905265 2006-09-22
AU2006905260 2006-09-22
AU2006905267 2006-09-22
AU2006905259 2006-09-22
AU2006905259A AU2006905259A0 (en) 2006-09-22 Prophylaxis or treatment of cancer
AU2006905265A AU2006905265A0 (en) 2006-09-22 Metal complexes having anti-inflammatory activity II
AU2006905260A AU2006905260A0 (en) 2006-09-22 Combination therapy for treatment of cancer
AU2006905267A AU2006905267A0 (en) 2006-09-22 Metal complexes having anti-inflammatory activity
AU2006905266A AU2006905266A0 (en) 2006-09-23 Skin treatment and wound repair
AU2006905266 2006-09-23
AU2006905378 2006-09-28
AU2006905377A AU2006905377A0 (en) 2006-09-28 Metal complexes having anti-inflammatory activity
AU2006905377 2006-09-28
AU2006905378A AU2006905378A0 (en) 2006-09-28 Metal complexes having anti-inflammatory activity II

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CN106928242A (zh) * 2017-03-29 2017-07-07 齐鲁工业大学 具有生物活性的钴配合物及其制备方法

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3242688B1 (fr) * 2015-01-09 2020-01-29 Reiley Pharmaceuticals, Inc. Conjugués contenant du platine et ciblant cox-2, et utilisation de ces derniers dans le traitement de tumeurs et de cancers

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