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WO2007109844A1 - Complexes metalliques anti-inflammatoires - Google Patents

Complexes metalliques anti-inflammatoires Download PDF

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Publication number
WO2007109844A1
WO2007109844A1 PCT/AU2007/000376 AU2007000376W WO2007109844A1 WO 2007109844 A1 WO2007109844 A1 WO 2007109844A1 AU 2007000376 W AU2007000376 W AU 2007000376W WO 2007109844 A1 WO2007109844 A1 WO 2007109844A1
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Prior art keywords
alkyl
group
complex
ligand
alkynyl
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PCT/AU2007/000376
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English (en)
Inventor
Peter Lay
Trevor Hambley
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Anagenics Ltd
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Medical Therapies Ltd
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Publication date
Priority claimed from PCT/AU2006/000391 external-priority patent/WO2006099677A1/fr
Priority claimed from PCT/AU2006/000403 external-priority patent/WO2006099685A1/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 WO2007109844A1 publication Critical patent/WO2007109844A1/fr
Anticipated expiration legal-status Critical
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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 of inert oxidations states .
  • the compounds find application, in the prophylaxis and treatment of inflammation, cancer, pain, microbial and viral infections, and wound healing amongst others.
  • 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( ⁇ , ⁇ -dimethylformamide)tetrakis- ⁇ -(O, O '- ⁇ ndo)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.
  • 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.
  • Cu-salicylate complexes ie., [Cu 2 (3,5-di- ⁇ 5 f o-propylsalicylate) 4 L 2 ]
  • Cu-salicylate complexes ie., [Cu 2 (3,5-di- ⁇ 5 f o-propylsalicylate) 4 L 2 ]
  • IndoH has been included in topical formulations, it has not been shown to have a significant effect on either melanomas or squamous cell carcinomas when applied topically, and high concentrations of NSAIDs such as IndoH, can induce significant systemic toxicity when applied topically.
  • 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, 251- 258).
  • COX-2 selective NSAIDs are 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, 251- 258 In recent years 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. et al, NEJM, 2005, 352, 1071-1080; "Complications of the
  • COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery", NEJM, 2005, 352, 1081-1091; "Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial", NEJM, 2005, 352, 1092-1102).
  • NEJM COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery
  • NEJM 2005, 352, 1081-1091
  • Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial NEJM, 2005, 352, 1092-1102.
  • the latest evaluation of all double blind clinical trials on non-selective NSAIDs showing some cardiovascular events has not been able to discern any significant differences between placebo controls and the NSAIDs (Salpeter, S. R.; Gregor, P.; Ormiston, T. M.; Whitlock, R.; Raina, P.
  • 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, 248-252) suggesting that they play a role in cardiovascular pathogenesis.
  • the present invention relates to inert metal complexes having anti- inflammatory activity and their use in the prophylaxis or treatment of cancer, pain, diseases and conditions associated with inflammation or which have an inflammatory component, microbial and viral infections, and other diseases and conditions.
  • a metal complex of the following formula (1) there is provided a metal complex of the following formula (1):
  • M is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent metal ion having an inert oxidation state; each L 1 is independently selected and is a monodentate or bidentate carboxylate or monodentate amide ligand (O or N bound), or a monodentate ligand linked to a NSAID by an ester or amide linkage, having anti -inflammatory activity, and at least one ligand L 1 is other than a salicylate or a derivative of a salicylate; each L 2 is independently selected and is a monodentate or a polydentate ligand; m is 1, 2, 3 , 4, 5, or 6; n is 1, 2, 3, 4 or 5; and p is the charge of the complex.
  • each M is independently selected from monovalent, divalent, trivalent, tetravalent, pentavalent and hexavalent metal ions, and has an inert oxidation state; each L 1 is independently selected and is a monodentate or bidentate carboxylate or monodentate amide ligand (O or N bound), or a monodentate ligand linked to a NSAID by an ester or amide linkage, having anti -inflammatory activity, and at least one ligand L 1 is other than a salicylate or a derivative of a salicylate; each L is independently selected and is a monodentate or a polydentate ligand, or an amide ligand (O or N bound), having anti-inflammatory activity; each L 3 is independently selected and is a bridging ligand, such as an oxo, hydroxo, carboxylate (eg., a NSAID), halide, or other
  • ligand L 2 of a complex of formula (2) can be a monodentate or polydentate ligand including a chelating derivative of a carboxylate.
  • the polydentate chelating derivative can be bidentate.
  • M is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent metal ion having an inert oxidation state
  • each L 1 is independently selected and is a monodentate or bidentate carboxylate or monodentate amide ligand (O or N bound), or a monodentate ligand linked to a NSAID by an ester or amide linkage, having anti -inflammatory activity, and at least one ligand L 1 is other than a salicylate or a derivative of a salicylate
  • each L 2 is independently selected and is a monodentate or a polydentate ligand
  • each L 4 is independently selected and is a chelating derivative of a carboxylate, or amide ligand (O or N bound), having anti-inflammatory activity
  • m is 1, 2, 3, 4 or 5
  • n is 0, 1, 2, 3 or 4
  • o is 1,
  • any suitable monodentate or bidentate carboxylate(s), R CO 2 " with antiinflammatory activity, non-chelating amide derivative R CONR 2 R 3 (or its deprotonated form thereof, R 1 CON(R 2 ) " ), or non-chelating ester derivative R 1 COOR 4 of a NSAID that forms a co-ordination bond of the complex through a functional group of R , (as described below) can be employed as ligand L 1 in metal complexes of formulae (1) to (3).
  • the carboxylate having anti-inflammatory activity is a non-steroidal antiinflammatory drug (NSAID).
  • NSAIDs non-steroidal antiinflammatory drug
  • Suprofen ((+)- ⁇ -methyl-4-(2-thienylcarbonyl)phenylacetic acid ("SupH”)); Tolmetin (l-methyl-5-(p-toluoyl)-lH-pyrrole-2-acetic acid (“Tol ⁇ ”)); Naproxen ( ⁇ -methoxy- ⁇ -methyl ⁇ -naphthaleneacetic acid (“NapH”));
  • Ibuprofen ((+)- ⁇ -methyl-4-(isopropylmethyl)benzeneacetic acid (“IbuH”));
  • Flufenamic Acid (( ⁇ f-trifluoromethylphenyl)anthranilic acid (“FlufenH”));
  • Niflumic Acid ((2-(3-trifluoromethyl)phenylamino)-3-pyridinecarboxylic acid (“NifH”));
  • Diclofenac (2-[(2,6-dichlorophenyl)amino]phenylacetic acid (“DicH”)
  • Indomethacin (l ⁇ chlorobenzoy ⁇ -S-methoxy ⁇ -methyl-lH-indole-S-acetic acid ("IndoH”));
  • Acemetacin 1 -(4-chlorobenzoyl)-5-methoxy-2-methylindole-3 -acetic acid carboxymethyl ester (“ACMH”).
  • Ketorolac (+)-5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxyric acid
  • NSAID 2-amino-2-(hydroxymethyl)-l,3-propanediol.
  • Other suitable NSAIDs include:
  • Carprofen (6-chloro- ⁇ -methyl-9H-carbazole-2-acetic acid); Etodolac (l,8-diethyl-l,3,4,9-tetrahydro-pyrano[3,4-b]indole-l-acetic 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
  • the carboxylate or amide with anti-inflammatory activity will be selected from the group consisting of indomethacin (IndoH), ibuprofen, naproxen, dichlofenac, acemetacin, ketorolac, or non-chelating amide or ester derivative thereof.
  • indomethacin IndoH
  • ibuprofen ibuprofen
  • naproxen ibuprofen
  • dichlofenac acemetacin
  • ketorolac acemetacin
  • non-chelating amide or ester derivative thereof non-chelating amide or ester derivative thereof.
  • Suitable amide ligands, L 2 include ligands of the formula R 1 CONR 2 R 3 formed by coupling the amino group NHR 2 R 3 to a carboxylic NSAID R 1 CO 2 H (or its deprotonated form) having anti- inflammatory activity, wherein R 2 is H, an alkyl, or an aryl group wherein the alkyl or aryl group is optionally substituted, and R 3 is H, an alkyl, an aryl, or a heterocycle and the alkyl or aryl group is optionally substituted by one or more functional groups such as an amine or heterocycle that acts as a monodentate ligand to a metal ion of the complex.
  • R is H.
  • ligands in the above metal complexes can also independently have antiinflammatory and/or anti-cancer, and/or anti-diabetic, and/or anti-microbial activities . These ligands may also assist or alternatively, have wound healing and/or angiogenic activity, or offer protection from radiation damage (solar or ionising radiation).
  • the metal ion of a metal complex of the invention will typically be a transition metal ion (preferably, ruthenium(II), chromium (III), platinum(IV), ruthenium(III), rhodium(III), cobalt (III), ruthenium(IV) ions).
  • a transition metal ion preferably, ruthenium(II), chromium (III), platinum(IV), ruthenium(III), rhodium(III), cobalt (III), ruthenium(IV) ions).
  • H 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 amide is used to refer to the uncharged form of the carboxylate or amide.
  • “IndoH” refers to the uncharged form of indomethacin
  • “Indo” is used to refer to the deprotonated anionic form of indomethacin
  • ACMH refers to the uncharged form of acemetacin
  • ACM refers to the deprotonated anionic form.
  • Acemetacin, l-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid carboxymethyl ester is a glycolic acid ester of indomethacin.
  • the structure of ACMH is shown below, as is the structure of Keterolac.
  • a pharmaceutical composition comprising a metal complex of formula (1), (2) or (3) 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 a mammal in need thereof an effective amount of a metal complex of formula (1), (2) or (3).
  • Diseases or conditions mediated by inflammation or having an inflammatory component include diabetes and cardiovascular diseases, neurodegenerative diseases, and other conditions involving inflammation.
  • a method for prophylaxis or treatment of a cancer in a mammal comprising administering to the mammal an effective amount of a metal complex of formula (1), (2) or (3).
  • 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), (2) or (3).
  • a method for protecting against ionising radiation induced skin or organ damage in a mammal comprising administering to the mammal an effective amount of a metal complex of formula (1), (2) or (3).
  • an analgesic method for prophylaxis or treatment of pain in a mammal comprising administering to the mammal an effective amount of a metal complex of formula (1), (2) or (3).
  • a method for promoting wound healing or inhibiting skin or tissue aging including the prophylaxis or treatment of wounds caused by trauma or surgery, burns, sunburn, or ionising radiation, comprising administering to a mammal an effective amount of a metal complex of formula (1), (2) or (3).
  • 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), (2) or (3).
  • a method for treating damaged skin comprising administering to a mammal an effective amount of a metal complex of formula (1), (2) or (3).
  • a metal complex of formula (1), (2) or (3) in the manufacture of a medicament for prophylaxis or treatment of inflammation in a mammal or a disease or condition in the mammal having an inflammatory component.
  • a metal complex of formula (1), (2) or (3) in the manufacture of a medicament for prophylaxis or treatment of a cancer in a mammal.
  • a metal complex of formula (1), (2) or (3) in the manufacture of a medicament for prophylaxis or treatment of a microbial or a viral infection in a mammal.
  • a metal complex of formula (1), (2) or (3) in the manufacture of an analgesic medicament for prophylaxis or treatment of pain in a mammal.
  • a metal complex of formula (1), (2) or (3) in the manufacture of a medicament for wound healing, or inhibition of skin or tissue aging, or damage from solar or ionising radiation in a mammal.
  • a metal complex of formula (1), (2) or (3) in the manufacture of an analgesic medicament for prophylaxis or treatment of pain in a mammal.
  • Metal complexes as described herein can be administered for prophylaxis or treatment of a disease, condition, infection or the like alone, or in combination with other chemotherapeutic agents or treatments for the particular disease or condition being treated.
  • Metal complexes as described herein can be administered for the simultaneous prophylaxis or treatment of more than one disease, condition, infection or the like alone, or in combination with other chemotherapeutic agents or treatments for the particular diseases or conditions being treated.
  • One of the issues associated with the use of non-selective NSAIDs, such as indomethacin and their derivatives and complexes is GI and renal toxicity.
  • Metal complexes embodied by the invention can be incorporated into formulations that minimize their decomposition by biological fluids, such as gastric acid, or 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 efficiency of the complexes
  • biological fluids such as gastric acid
  • metal complexes of the invention can also have reduced toxicity and/or increased efficacy from slow release mechanisms, and/or target diseases and conditions characterized by hypoxia.
  • inert metal complexes of NSAIDs or amide derivatives of NSAIDs can have enhanced stability. This can result in one or more of:
  • Complexing the NSAID with a metal as described herein can also change the absorption profile of the NSAID.
  • the release of the NSAID from the ligand may be induced by hydrolysis of the ligand by cleaving the metal ligand bonds, and/or the ester or amide bonds; ligand substitution reactions; and/or redox catalysed substitution reactions inside cells or in regions of hypoxia.
  • the NSAID derivative, the NSAID, and the metal may provide synergistic activities.
  • the reductive release of the NSAID from a metal like Ru(III) can have multiple effects.
  • a Ru complex can exert its anti-cancer and/or anti-inflammatory activity by a combination of independent COX-2 inhibition (by both the parent NSAID and its derivatives, e.g., Indo hydrolysis product from ACM) and the anti-cancer effects of Ru once the complex decomposes at the site of a tumour.
  • the function of the Ru in this case, is not only to provide additional biological activity but to target the organic drugs to tumours by using its hypoxia selectivity properties .
  • the higher metabolic activity of certain tissues or cells can also be employed to increase the rate of ester and amide hydrolysis of the metal complexes of ester, amide derivatives of NSAIDs as a way of targeting disease states.
  • the positively charged inert oxidation states of metals e.g., Pt(IV), Ru(III), Co(III)
  • Pt(IV), Ru(III), Co(III) can also be employed to selectively target mitochodria as a way of treating disease states, and all such methods are expressly encompassed by the present invention.
  • the inert metal ions, co-ligands and metal oxidation states of one or more compounds embodied by the invention may also optimise the rate of release and/or hydrolysis of the NSAID-derivative as indicated above, reduce side -effects such as GI and renal toxicities, and/or provide sufficient stability to target the disease site before the bioactives of the complex are released.
  • 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 include methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, amyl, iso-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 include cyclic alkyl
  • 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 -methyl vinyl, butenyl, zso-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,
  • alkynyl refers to a straight chain, branched or cyclic alkynyl with one or more triple bonds, preferably a C 2 to C20 alkynyl, more preferably a C 2 to CO 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. Examples of 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 application 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, and microbial and viral infections, and the treatment of wounds, burns and skin damage, and the prophylaxis or treatment of damage induced in skin and other organs by solar or ionising radiation.
  • diseases and conditions characterised, mediated or involving inflammatory components such as cardiovascular, neurodegenerative, and diabetic conditions, pain, cancer, and microbial and viral infections
  • the treatment of wounds, burns and skin damage and the prophylaxis or treatment of damage induced in skin and other organs by solar or ionising radiation.
  • inert metal complexes of the invention having anti-inflammatory activity have application in preventing or treating cancers including carcinomas and other cancers, and may 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 indomethacin are more effective in preventing or treating carcinomas, in terms of efficacy and/or safety, than indomethacin itself, even in cases when IndoH is completely inactive.
  • carboxylic acids having anti-inflammatory activity that may be utilised in metal complexes embodied by the invention include the following.
  • Metronidazole 2-methyl-5-nitrobenzimidazole
  • Flufenamic Acid ( ⁇ f-trifluoromethylphenyl)anthranilic acid (Flufen ⁇ );
  • Niflumic Acid 2-((3-trifluoromethyl)phenylamino)-3-pyridinecarboxylic acid
  • Indomethacin l-(4-chlorobenzoyl)-5-methoxy-2-methyl-l ⁇ -indole-3-acetic acid
  • Diclofenac 2-[(2,6-dichlorophenyl)amino]phenylacetic acid (DicH).
  • Acemetacin 1 -(4-chlorobenzoyl)-5-methoxy-2-methylindole-3 -acetic acid carboxymethyl ester (“ACMH”)
  • Ketorolac (+)-5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxyric acid
  • NSAID 2-amino-2-(hydroxymethyl)-l,3-propanediol.
  • Other suitable NSAIDs include:
  • Carprofen (6-chloro- ⁇ -methyl-9H-carbazole-2-acetic acid);
  • Etodolac (l,8-diethyl-l,3,4,9-tetrahydro-pyrano[3,4-b]indole-l-acetic 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);
  • the monodentate carboxylate ligand or chelating carboxylate, R 1 CO 2 " thereof having anti-inflammatory activity in a metal complex of formulae (1) to (3) can also be:
  • R 5 is H or halo (i.e. Cl, F, Br or I);
  • R R i iss HH;; aa CCii ttoo CCOO aallkkyyll,, aann aallkkeennjyl or an alkynyl, where the Ci to CO alkyl, alkenyl or alkynyl may be optionally substituted; or
  • each R 6A is independently selected from the group consisting of H, C 1 to Ce alkyl, alkenyl, alkynyl, aryl, cycloalkyl and arylalkyl, where the Ci to C 6 alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be optionally substituted;
  • R is H or halo; each R 8 is independently selected from the group consisting of halo, -CH 3 , -CN, -OCH 3 , -SCH 3 and -CHCH 3 , where the -CH 3 , -OCH 3 , -SCH 3 or -CH 2 CH 3 may be optionally substituted; and r is 1, 2, 3, 4 or 5.
  • the monodentate carboxylate ligand or chelating carboxylate derivative, R CO 2 " , thereof having anti-inflammatory activity in a metal complex of formula (1) to (3) can be:
  • R 5 is H or halo (i.e. Cl, F, Br or I);
  • R is H; a C 1 to CO alkyl, an alkenyl or an alkynyl, where the C 1 to Ce alkyl, alkenyl or alkynyl may be optionally substituted; or
  • each R is independently selected from the group consisting of H, C 1 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 7 is H or halo; each R 8 is independently selected from the group consisting of halo, -CH 3 , -CN, -OCH 3 , -SCH 3 and -CHCH 3 , where the -CH 3 , -OCH 3 , -SCH 3 or -CH 2 CH 3 may be optionally substituted; and r is 1, 2, 3, 4 or 5.
  • R is a C 1 to Ce alkyl, an alkenyl or an alkynyl
  • the C 1 to Ce 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 A is a C 1 to C 6 alkyl, an alkenyl, an alkynyl, an aryl, a cycloalkyl or an arylalkyl
  • the C 1 to C 6 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 8 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, 5 -COOH and -NH 2 .
  • Metal complexes incorporating carboxylate ligands having inflammatory activity can be prepared by methods known in the art, or as described below. Such reactions include the substitution of a leaving group in an inert metal complex with a carboxylate group of an NSAID, or an amide group in a NSAID or an amide derivative 0 of a NSAID. This is exemplified by Example 1 in the preparation of [Co(NH 3 ) 5 (Indo)]X 2 , a complex metal of formula (1), as follows:
  • such complexes can be prepared by substitution of a weakly O coordinated, trifluoromethanesulfonato, or solvent, or other such ligands, as described for example in, Introduction to Trifluoromethanesulfonates and Trifluoromethanesulfonato- O Complexes.
  • metal complexes of the invention can be prepared by oxidation of a lower oxidation state containing L 1 or in the presence of L 1 , as exemplified by the preparation of [Pt ⁇ (Cn) 2 (O 2 CR) 2 (OH) 2 ] (see Example 1).
  • embodiments of metal complexes of the invention can be prepared by reaction of a derivative of R 1 COZ with a hydroxo or deprotonated amine ligand on O the metal, for example:
  • metal complexes embodied by the invention can be prepared by other methods including substitution reactions of the non-NSAID ligands to give new complexes.
  • esters of carboxylates having antiinflammatory activity also include esters of carboxylates having antiinflammatory activity, and amide derivatives of carboxylates that bind in a monodentate fashion to the metal.
  • esters and amides can contain heterocyclic groups or aliphatic or aromatic groups that contain other functional groups that bind to the inert metal in a monodentate fashion.
  • a monodentate amide ligand can bind via O to the metal ion or deprotonate and bind via N to a metal ion in the complex, as described in: Fairlie, D. P.; Ilan, Y.; Taube, H. Oxygen versus Nitrogen Bonding of Carboxamides to Pentaammineruthenium(II/III) Inorg. Chem. (1997), 36, 1029-1037. Oxygen and nitrogen-bound forms of the amide complexes can be interconverted by a change pH or other means of protonation/deprotonation reactions, for example:
  • X is a conjugate base of a strong or a weak acid (eg., X can be a halide, oxyanion, carboxylate, sulfonate, etc.);
  • X is a conjugate base of a weak acid, examples of which include oxyanions, carboxylates, amines, and N- heterocycles;
  • Y is a leaving group, examples of which include halo, alkylsulfonato, O- bound sulfoxides, O-bound amides, aldehydes, ketones, and nitrato ligands; and
  • R COZ is an acyl halide, anhydride or ester derivative of a NSAID.
  • Amide derivatives of carboxylic acids having anti-inflammatory activities can be prepared as described in International Patent Application No. WO 95/04030, or modifications thereof. See, for instance, indomethacin in the following example below (Scheme X).
  • R 3 can be a proton, alkyl, alkenyl, alkynyl, aryl or arylalkyl group, in which case the ligand would be a monodentate O or N donor to the metal, or R 3 can be a heterocycle or a substituted alkyl or aryl group that forms a monodentate bond to an inert metal ion.
  • R 2 or R 3 in these ligands can be independently chosen from H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, or heterocylic groups that do not include groups that compete with the amide ligand for coordination.
  • 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 will be an alkyl, alkenyl, alkynyl, aryl, or arylalkyl group containing a substituent, which can act as a monodentate or bidentate ligand, e.g., a carboxylate group as in ACM, an amino group (prepared from an aminoalcohol or amino acid, such as serine or tyrosine), a heterocycle, or other substituent that bind to the metal in a monodentate fashion.
  • agent will be an alkyl, alkenyl, alkynyl, aryl, or arylalkyl group containing a substituent, which can act as a monodentate or bidentate ligand, e.g., a carboxylate group as in ACM, an amino group (prepared from an
  • Metal complexes embodied by the invention can also be prepared by methods outlined in Example 1 below.
  • the complexes contain Indo,
  • any of the R 2 or R 3 groups of amide derivatives can also contain another donor group that can act as a monodentate ligand to the metal.
  • R 2 and R 3 groups can be, or contain, a large variety of functional groups that would be suitable as monodentate ligands to the metal ions of formulae (1), (2) or (3).
  • any of the R 4 groups of an ester derivative of a NSAID will contain a donor group that can act as a monodentate ligand.
  • a donor group that can act as a monodentate ligand.
  • These may, for instance, be a terminal amine group from amino acid or peptide derivatives of NSAIDs, or a RS " , thioether, phenol, carboxylate, or ⁇ -heterocyclic side-chain of such an amino acid or peptide derivative.
  • the R group of these ligands can be, or contain, any of a large variety of functional groups that would be suitable as monodentate ligands to the metal ions of formulae (1), (2) or (3).
  • Metal complexes in at least one form embodied by the invention are complexes of the following formula ( 1 ) : [M(L 1 ) m (L 2 ) n ] p (1) wherein
  • metal complexes embodied by the invention are complexes of the following formula (2): [M q (L 1 ) m (L 2 ) n (L 3 ) r ] p (2) wherein
  • M is independently selected from a monovalent, divalent, trivalent, tetravalent, pentavalent and hexavalent metal ions, and has an inert oxidation state; each L is independently selected and is a monodentate or bidentate carboxylate or monodentate amide ligand (O or N bound), or a monodentate ligand linked to a NSAID by an ester or amide linkage, having anti -inflammatory activity; each L 2 is independently selected and is a monodentate (for example, aqua, hydroxo, oxo, halo CO, NO, amine, amide, sulfoxide, alchol, heterocycle) or a polydentate ligand, (for example, an amine, amino acid, hydroxyacid, peptide, heterocycle, and combinations thereof); each L is independently selected and is a bridging ligand, for example an oxo, hydroxo, carboxylate (eg., an NSAID), halide, or other bridging
  • One or more of the ligands L 1 to L 4 of a complex of formula (3) in any combination can also form dimeric, trimeric, tetrameric, oligomeric or polymeric 0 complexes with one or more metal ions.
  • ligand L 1 which can be used in metal complexes of formulae (1) to (3) include: include, but are not limited to the conjugate base, R CO 2 " , of the NSAIDs, suprofen, tolmetin, naproxen, ibuprofen, flufenamic acid, niflumic acid, diclofenac, indomethacin, acemetacin, and ketorolac, which can be variethacin, acemetacin, and ketorolac, which can be trintate or bidentate ligands; 5 R 1A C ⁇ 2 ⁇ derivatives formed, for instance, from linkages to the above NSAIDs by ester coupling of amino acids (such as serine or tyrosine), amide coupling of amino acids, ester coupling of hydroxyacids; R 1 CONR 2 R 3 and R 1 CON(R 3 ) " formed by the coupling of amino groups NHR 2 R 3 to the above NSAIDs wherein R 2 is H, an al
  • Examples of ligands L 2 which can be used in metal complexes of formulae (1) to (3) include; monodentate ligands, for instance, halo, amine, heterocyclic, aqua, hydroxo, oxo, carbonyl, and nitrosyl ligands; polydentate ligands, for instance, include; amine, heterocyclic, amino acid, and peptide ligands.
  • Examples of bridging ligands L 3 that can be used in metal complexes of formulae (2) include: .O 2 ⁇ , OH " , halo, carboxylate, and other anionic acido ligands that are the conjugate bases of inorganic or organic acids.
  • ligands L which can be used in metal complexes of formula (3) include chelating derivatives of carboxylates and amide ligands as described herein. Further suitable ligands are for instance described in the Applicant's co-pending
  • Examples of aliphatic and aromatic groups of ligands that can be used in complexes embodied by the invention include substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, arylalkyl and heterocyclic groups.
  • Examples of heterocyclic groups include heterocyclic bases comprising one or more N atoms. In some embodiments, the heterocyclic base is optionally substituted.
  • the heterocyclic base may for example be selected from the group consisting of isoquinolyl, quinolyl, piperidinyl, pyridinyl, 2- methylpyridinyl, imadazoyl, pyranyl, pyrrolyl, pyrimidinyl, indolyl, purinyl and quinolizinyl.
  • the metal ion M of a metal complex embodied by the invention is a trivalent or tetravalent transition metal.
  • L 1 is NH 3 or a monodentate, polydentate, or macrocyclic amine ligand.
  • Preferred complexes of formula (1) include: [M(L ) m (NR R R ) n ] p where: L is independently chosen from an NSAID, R 1 CO 2 " , R 1 CON(R 3 ) " or an amide (R 1 CONR 2 R 3 ) or ester derivative 5 (R 1 COOR 4 ) of an NSAID; (NR 9 R 10 R 1 ⁇ is individually selected from monodentate or polydentate amine ligands; and M is selected from Ru(II), Co(III), Cr(III), Ir(III), Os(III), Rh(III), Ru(III) or Pt(IV) and more preferably, Ru(II), Co(III), Ru(III) or Pt(IV); [M(L 1 ) m (0H s ) n ] p where: L 1 is independently chosen from an NSAID
  • Suitable methods for the synthesis of metal complexes embodied by the invention are for instance described in: (Romakh, V. B.; Therrien, B.; Labat, G; Stoekli- Evans, H.; Shul'pin, G. B.; Suess-Fink, G. Dinuclear iron, ruthenium and cobalt complexes containing l,4-dimethyl-l,4,7-triazacyclononane ligands as well as carboxylato and oxo or hydroxo bridges.
  • Ru-CO complexes for promoting angiogenesis could be prepared for example by using methods similar to (Li Volti, G.; Sacerdoti, D.; Sangras, B.; Vanella, A.; Mezentsev, A.;
  • Inflammatory diseases and conditions that can be treated in accordance with one 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, and
  • 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.
  • the use of ruthenium complexes has for instance been described in United States Patent Application No.
  • 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 maturity-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 result
  • 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, hemangiosarcom
  • 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. Many infections are also associated with hypoxia. Hence, complexes that release the active under conditions of hypoxia can deliver the ligand/metal 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,
  • 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 antibacterial 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.
  • Viral infections that may be treated by one or more embodiments of metal complexes of the invention include retroviruses such as Human Immunodeficiency virus (eg., HIV-I, HIV-2), 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.
  • retroviruses such as Human Immuno
  • 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 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.
  • 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 (eg., hydroximate/hydroxamate ligands in complexes of formula (3), for instance, can add extra therapeutic benefits, in addition to the parent NSAID that inhibits COX-2).
  • COX-2 and 5-LO lipoxygenase
  • 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. Revue De Medecine Veterinaire 2006, 157, 185-192).
  • 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.
  • 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. PCT/IB2006/002423 the contents of which is incorporated herein by reference in its entirety.
  • 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, 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.
  • 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 in their entirety.
  • the metal complex can be dissolved in the composition or may be present in the composition as a solid.
  • the solid complex can 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.
  • a composition embodied by the invention will 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. Formation of the colloidal structure can for instance occur when the composition contacts an aqueous biological fluid in the human or animal body, for example, on contact with an aqueous fluid in the digestive tract.
  • 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 that 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 at the point at which it is administered, e.g. strong chelators, such as peptides, or reductants, such as thiol-containing biomolecules, are able to interact with the complex to cause the complex to dissociate. While such interactions can be important at the site of acitivity after the pro-drug is administered, they should preferably be minimized at the point of delivery in order to maximize efficacy and minimize side-effects.
  • 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 most preferably more than 95%, of the total amount of the carboxylate, amide or ester derivative of the carboxylate having anti-inflammatory activity, as part of a metal complex.
  • Preferably, also less than 10% of the carboxylate, or amide or ester derivative of the carboxylate complexed with the metal dissociates from the metal when the composition is stored for 12 months in the absence of light at room temperature (18°C to 25°C), unless for instance the formulation is prepared immediately before it is administered (as is the case for some injectable forms).
  • the amount of the carboxylate, or amide or ester derivative of the carboxylate 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, NMR spectroscopy, UV/Vis spectroscopy, HPLC, or using more specialized experiments involving X-ray absorption spectroscopy (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 complex can be dissolved in isotonic saline solution immediately before it is injected.
  • 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.
  • 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.
  • suitable routes are via injection into blood vessels which supply a tumour, tissues or particular organs to be treated. Agents may also be delivered into cavities such as for example the pleural or peritoneal cavity, or be injected directly into tumour tissue.
  • 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 for instance, 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 complex, one or more flavours, 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 can 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: cetomacrogol emulsifying wax 15 g liquid paraffin 1O g white soft paraffin 1O g chlorocresol 0.1 g propylene glycol 5 mL purified and cooled water to 100 g
  • 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 chemotherapeutic and anti-cancer agents such as those identified above.
  • the metal complex constitutes about 0.001% to about 20% by weight of the composition, preferably about 0.01% to about 20% by weight of the composition, more preferably about 0.01% to about 6% by weight of the composition and most preferably, the complex constitutes about 0.025% to about 10% by weight of the composition.
  • a topically acceptable composition for application to the skin will typically 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 typically be administered at a dosage 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 complex administered. 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; for topical doses for sunscreens and the prophylaxis of skin damage and aging, the complex will typically be dosed in 0.01-0.05% w/w topical carriers, but for more localised topical applications for lesions, wound healing and the treatment of pain and inflammation, topical formulations can be administered as more concentrated 0.25-2% w/w formulations, such that the maximum doses 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, Perissodactyla and Artiodactyla.
  • the subject will be a horse, dog, or primate and more usually, a human being.
  • [Pt(en)(Indo) 2 ] was prepared by the method described by Dendrinou-Samara, C; Tsotsou, G.; Ekateriniadou, L. V.; Kortsaris, A. H.; Raptopoulou, C. P.; Terzis, A.; Kyriakidis, D. A.; Kessissoglou, D. P. J. Inorg. Biochem. 1998, 71, 171-179.
  • [Pt ⁇ (Cn)(MdO) 2 (OH) 2 ] was prepared by an oxidation reaction as follows.
  • Inert metals such as Ru(III), Co(III), and Pt(IV) offer the potential of systemic delivery of even higher concentrations of NSAIDs through oral, injectable, and topical delivery and to incorporate them into slow release patches.
  • the complexes still exhibit significant anti-inflammatory activities.
  • the complexes can also have systemic anti-cancer and other activities, but may essentially eliminate gastric side-effects by being absorbed in the GI tract before release of the drug.
  • NSAID drug(s) and in some cases the active metal ion
  • hydrolysis of the metal- NSAID bond(s) in inert oxidation states, compared with labile oxidation states, such as Cu(II) and Zn(II)
  • the active drug concentration in the blood stream, or at the point application may be maintained for longer periods of time, or the drug can more readily reach the target tissue or cells before it is released.
  • Ru(III) and Co(III) also have the potential to act as hypoxia selective agents for the treatment of various conditions involving hypoxia as they are reduced to the M(II) oxidation state, which can release the active ligand, and in the case of Ru(II) produce a metal ion that will readily bind to target biomolecules to bring about a range of biological activities.
  • 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).
  • 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
  • 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 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 (IxIO 4 cells/well/ 100 ⁇ L for A549). 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 (50-400 ⁇ 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 the plates, 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 ⁇ Lper well).
  • 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.
  • the LC 50 value was 100 ⁇ M in the presence of the reductant glutathione.
  • the metal complex is not cytotoxic, cell viability in the presence of glutathione as a reductant reduces substantially, confirming that the activity is established during reduction of the complex.
  • the IC50 value is not low, it is still only a factor of two greater than for the Culndo complex, which is not cytotoxic in this in vitro model, but is very active in vivo .
  • cytotoxicity is unlikely to be the sole reason for the anti-cancer activity observed in vivo and other mechanisms are likely to be involved.
  • the other advantage for anti-cancer activity is the water solubility of the complex (see Example 4).
  • Sprague-Dawley rats (weighing 200-250 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 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.
  • 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.
  • 24 h- fasted animals were euthanased and the stomach was excised and opened by incision along the greater curvature. The stomach was rinsed and examined to determine the extent of macroscopic gastric toxicity, which is reported as the summation of the area of macroscopic ulcerations (mm 2 ).
  • the breakdown was intestinal ulceration, 150 mm , and duodenal ulceration 10 mm .
  • the latter is not typically seen in the rat model. It is noted, however, that at the higher concentration the organogel was not clear indicating incomplete dissolution of the drug. Thus the undis solved proportion of the drug would have less protection from the organogel against stomach acid and this may explain the much greater toxicity at this concentration.
  • Nil mortality was observed for the study period. Severe listlessness, disorientation and apnoea were observed within one minute post treatment at the higher concentration. The animal recovered without overt adverse clinical effects after approximately 5 - 10 minutes. Nil gastric ulceration was observed at necropsy (4 hours post treatment) and no adverse effects were observed at the lower dose.
  • a typical IndoH oral dose is 1 to 3 mg kg " bw while that administered to infants for closure of the ductus aorta is 0.1 to 0.2 mg kg "1 bw.
  • High doses of IndoH have adverse effect on central nervous system (CNS). Such effects include malaise and listlessness, drowsiness, hearing disturbances and in rare cases convulsions and coma. This was consistent with the reversible effects observed in the rat at a high dose (10-30 times higher than the therapeutic dose).
  • NOAEL No Observed Adverse Effect Level
  • Nil small intestine (0, 0, 0, 0 mm ) ulceration was observed in the control and all the treatment groups.
  • Mean inhibition of paw edema was 39 ( ⁇ 6) % for the 0.8 mg/kg bw treatment group. Surprisingly, no anti-inflammatory effect was observed in the 1.6 mg/kg bw treatment group.
  • a typical i.v. dose of IndoH administered to infants for closure of the ductus aorta is 0.1 to 0.2 mg kg "1 bw.
  • Higher doses of IndoH have adverse effect on Central Nervous System (CNS).
  • CNS Central Nervous System
  • Such effects include malaise and listlessness, drowsiness, hearing disturbances and in rare cases convulsions and coma.
  • Nil abnormal clinical observations for [Co(NH 3 ) 5 (Indo)]Cl 2 were recorded at an i.v.i treatment dose of 0.8 mg/kg bw.
  • the Co complex is both efficacious and has no toxicity at these concentrations.
  • the Co complex was extremely soluble in water, allowing a 100 ⁇ g/10 ⁇ L solution to be prepared.
  • the following zones of inhibition were recorded for the respective bacterial strains: E. coli, 12-mm diameter; S. aureus, 15-mm, Ps. aeruginosa, 30-mm.
  • Indomethacin delivered at the same concentration in N, N- dimethylformamide (DMF) to maintain solubility resulted in no zone of inhibition.
  • Co complex may provide a broad spectrum anti- microbial activity against both gram-positive and gram-negative bacteria.
  • metal complexes of anti-inflammatory drugs have activity against diabetes.
  • metal complexes of anti -inflammatory drugs have also been shown to be efficacious in terms of cardiovascular inflammation (similar processes to which occur in the early stages of neurodegenerative diseases) and in prophylaxis for the reduction of radiation-induced skin damage that leads to skin cancers (http://www.medicaltherapies.com.au).
  • these effects arise from a combination of the release of the anti- inflammatory ligand and the metal, these slow release complexes are likely to have similar activities.
  • UV radiation will release carboxylate and other ligands from Co(III) amine ligands and this can act as a light-induced, slow-release mechanism for the drug in sunscreens and skin lotions, especially since this photochemistry is selective for the UV wavelengths responsible for photodamage (Sarkar, S. K.; Tarafdar, P. K.; Roy, A.; Aditya, S. Photochemistry of cobalt(III)-pentaammine oxalate and cobalt(III)-tetraammine oxalate complexes). J. Ind. Chem. Soc. (1983), 60, 1142-6. Kantrowitz, E. R.; Endicott, J. F.; Hoffman, M. Z.

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Abstract

L'invention concerne des complexes métalliques de ligands anti-inflammatoires utiles pour le traitement d'une ou de plusieurs maladies parmi l'inflammation, le cancer, le diabète, les maladies cardiovasculaires et autres.
PCT/AU2007/000376 2006-03-24 2007-03-26 Complexes metalliques anti-inflammatoires Ceased WO2007109844A1 (fr)

Applications Claiming Priority (30)

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

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WO2004000215A2 (fr) * 2002-06-21 2003-12-31 Medinox, Inc. Derives hydroxamate de medicaments anti-inflammatoires non steroidiens
WO2005002293A2 (fr) * 2003-06-25 2005-01-06 Vanderbilt University Agents d'imagerie a cible de cox-2
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CINI: "Anti-inflammatory compounds as ligands in metal complexes as revealed in x-ray structural studies", COMMENTS ON MODERN CHEMISTRY, vol. 22, no. 3-4, 2000, pages 151 - 186 *
DENDRINOU-SAMARA ET AL.: "Anti-inflammatory drugs interacting with Zn(II), Cd(II) and Pt(II) metal irons", JOURNAL OF INORGANIC CHEMISTRY, vol. 71, 1998, pages 171 - 179 *
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Publication number Priority date Publication date Assignee Title
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