WO2007110755A1 - Prophylaxie ou traitement d'une inflammation cardio-vasculaire - Google Patents

Prophylaxie ou traitement d'une inflammation cardio-vasculaire Download PDF

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WO2007110755A1
WO2007110755A1 PCT/IB2007/000778 IB2007000778W WO2007110755A1 WO 2007110755 A1 WO2007110755 A1 WO 2007110755A1 IB 2007000778 W IB2007000778 W IB 2007000778W WO 2007110755 A1 WO2007110755 A1 WO 2007110755A1
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complex
independently selected
ligand
indo
alkenyl
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PCT/IB2007/000778
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Peter Lay
Trevor Hambley
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Medical Therapies Limited
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Publication of WO2007110755A1 publication Critical patent/WO2007110755A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/30—Copper compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/315—Zinc compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to the prophylaxis or treatment of cardiovascular diseases and conditions.
  • the present invention relates to a method for the prophylaxis or treatment of cardiovascular inflammation comprising the administration of a metal complex having anti-inflammatory activity.
  • Non-steroidal anti-inflammatory drugs are used in the treatment of a variety of inflammatory conditions.
  • 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 edema following surgical or non-surgical procedures.
  • GI adverse gastrointestinal
  • Indomethacin is a NSAID effective in treating inflammatory conditions in both humans and animals.
  • the structure of indomethacin is as follows:
  • indomethacin can cause ulcerations in the oesophagus, stomach, duodenum and intestines. In dogs, oral administration of indomethacin causes fatal gastrointestinal haemorrhaging.
  • Other effects associated with oral administration of indomethacin include: (a) inhibition of platelet aggregation, (b) adverse 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, and (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).
  • indomethacin e.g. as a suppository or by topical application can have adverse effects.
  • Anti-inflammatory activity of Indomethacin following topical application Amico-Roxas, M., Mater, M., Caruso, A., Puglisi, G., Bernadini, R., Rinaldo, G., Eur. Rev. Med. Pharmacol. Sd., 1982, IV, 1999, 204.
  • adverse effects have limited the use of indomethacin in the treatment of inflammation in humans and animals.
  • dinuclear metal complexes of indomethacin i.e. complexes containing two metal coordination centres
  • DMF N,iV-dimethylformamide
  • the NSAID aspirin acetylsalicylic acid
  • 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.
  • the effect of aspirin is not consistent with a significant proportion of the population (up to 45%) being aspirin resistant ("Aspirin resistance: Definitions, mechanisms, prevalence, and clinical significance", Macchi, L., Sorel, N., Christiaens, L., Curr. Pharm. Des., 2006, 12, 251- 258).
  • Indomethacin has recently been studied in the treatment of strokes and heart attacks ("Neurogenesis in Rats After Focal Cerebral Ischemia is Enhanced by Indomethacin", Hoehn, B.D., Palmer, T.D., Steinberg, G.K., Stroke, 2005, 36, 2718- 2724), and is approved for use worldwide for the treatment of a number of neonatal cardiac conditions. For example, it is used for the prophylaxis of intraventricular haemorrhage in premature infants ("Prophylactic indomethacin for prevention of intraventricular haemorrhage in premature infants", Bandstra, E.S., Montalvo, B.
  • indomethacin may be useful for preventing certain abdominal aortic aneurysms in rats ("Indomethacin prevents elastase-induced abdominal aortic aneurysms", J Surg Res, 1996, 63, 305-9), other studies have found that indomethacin does not limit aneurysm in a rat model of abdominal aortic aneurysm ("Suppression of experimental aortic aneurysms: comparison of inducible nitric oxide synthase and cyclooxygenase inhibitors", Armstrong, PJ., Franklin, D.P., Carey, DJ., Elmore, J.R., Ann. Vase.
  • non-specific NSAID naproxen may be cardio-protective ("Nonsteroidal anti-inflammatory drug use and acute myocardial infarction", Rahme, E., Pilote, L., LeLorier, J., Arch Intern Med., 2002, 162, 1111-1115), other studies have found no cardio-protective effect of naproxen ("Non-steroidal anti-inflammatory drugs and risks of serious coronary heart disease: an observational cohort study", Ray, W.A., Stein, CM., Hall, K., Daugherty, J.R., Griffin, M.R., The Lancet, 2002, 359, 118-123).
  • 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, hi particular, both copper and zinc have been shown to accumulate in atherosclerotic plaques 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.
  • 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, MJ., Pasterkamp, G., de Kleijn, D.P., Strauss, B.H., Curr. Pharm. Des., 2003, 9, 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. More efficacious drugs and unproved delivery modes are needed for the treatment of cardiovascular diseases and conditions.
  • a method for the prophylaxis or treatment of a cardiovascular inflammation in a mammalian subject comprising treating the subject with a therapeutically effective amount of a complex of a metal and a carboxylate, or derivative of a carboxylate, having anti-inflammatory activity, wherein the carboxylate or derivative is other than salicylate or a derivative of salicylate.
  • the carboxylate or the derivative of the carboxylate having anti-inflammatory activity will generally have such activity when administered to a human or animal.
  • the derivative of the carboxylate can be hydrolysed in vivo, and the hydrolysed compound may have anti-inflammatory activity.
  • the derivative of the carboxylate can be selected from the group consisting of a hydroxamate, hydroximate, amide or ester. These derivatives have functional groups that bind to one or more metal(s) as a monodentate ligand, a chelate and/or a bridging ligand.
  • a method for the prophylaxis or treatment of cardiovascular inflammation in a mammalian subject comprising treating the subject with a therapeutically effective amount of a complex of a metal and a carboxylate, or a hydroxamate, hydroximate, amide or ester, having anti-inflammatory activity.
  • the carboxylate having anti-inflammatory activity can be any deprotonated carboxylic acid compound having anti-inflammatory activity.
  • the carboxylate having anti-inflammatory activity may, for example, be the deprotonated anionic form of any one of the following carboxylic acids NSAIDs:
  • ToIH l-memyl-5-(p-toluoyl)-lH-pyrrole-2-acetic acid
  • Naproxen (6-me ⁇ oxy- ⁇ -methyl-2-naphthaleneacetic acid (“NapH”)); Ibuprofen ((+)- ⁇ -methyl-4-(isopropyhnethyl)benzeneacetic acid (“IbuH”)); Flufenamic Acid ((N-trifluoromethylphenyl)anthranilic acid (“FlufenH”)); Niflumic Acid ((2-(3-trifluoromethyl)phenylamino)-3-pyridinecarboxylic acid
  • Diclofenac (2-[(2,6-dichlorophenyl)amino]phenylacetic acid (“DicH”)
  • Indomethacin (l-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH-indole-3-acetic acid ("IndoH”)); Acemetacin (l-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid carboxymethyl ester (“ACMH”))
  • Ketorolac ( ⁇ )-5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylic acid, ("KetH") 2-amino-2-(hydroxymethyl)- 1,3 -propanediol); and Indobufen (4-(l ,3-dihydro-l-oxo-2H-isoindol-2-yl)-a-ethylbenzeneacetic acid (“Indob”)) Indobufen, in addition to its anti-inflammatory effects, is used to prevent thrombosis in much the same way as aspirin, but suffers from the same problems as the other anti-inflammatory drugs in terms of GI toxicity at therapeutic doses, although the effects are not as severe as aspirin. (Endoscopic evaluation of the effects of indobufen and aspirin in healthy volunteers. Marzo A; Crestani S; Fumagalli I; Giusti A; Lowenthal D T, Am. J. Therapeutics (2004),
  • the inclusion of the "H" at the end of an abbreviation for a carboxylate e.g., any one of the carboxylic acids listed above
  • 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.
  • 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.
  • the carboxylate, or hydroxamate, hydroximate, ester or amide derivative having anti-inflammatory activity can be any non-steroidal anti-inflammatory drug (NSAID).
  • the NSAID can be indomethacin (IndoH), or an ester derivative of indomethacin, such as acemetacin, ibuprofen, indobufen, diclofenac, vaproxen, or ketorolac, or a hydroxamate, hydroximate, or amide derivative of indomethacin or acemetacin or other NSAID.
  • the terms hydroxamate or hydroximate are to be taken to mean the deprotonated and doubly deprotonated forms of the ligands.
  • Further NSAIDs that can be utilized in the metal complexes (as can their derivatives) as described herein include: Carprofen (6-chloro-a-methyl-9H-carbazole-2-acetic acid);
  • Etodolac (1 ,8-diethyl-l ,3,4,9-tetrahydro-pyrano[3,4-b]indole-l -acetic acid);
  • Flurbiprofen (2-fluoro-a-methyl-[l,r-biphenyl]-4-acetic acid);
  • Ketoprofen (3-benzoyl-a-methylbenzeneacetic acid); Oxaprozin (4,5-diphenyl-2-oxazolepropanoic acid);
  • Pranoprofen (a-methyl-5H-[l]benzopyrano[2,3-b]pyridine-7-acetic acid); Sulindac ((lZ)-5-fluoro-2-methyl-l-[[4-(niethylsulfinyl)phenyl]methylene]- lH-indene-3 -acetic acid); and
  • Acemetacin 1 -(4-chlorobenzoyl)-5-methoxy-2-methylindole-3 -acetic acid carboxymethyl ester, is a glycolic acid ester of indomethacin.
  • the structure of acemetacin is shown below as is the structure for ketorolac.
  • the metal complex used in a method embodied by the invention may be any complex comprising at least one metal ion and at least one carboxylate, or hydroxamate, hydroximate, ester or amide derivative having anti-inflammatory activity.
  • the carboxylate or hydroximate, hydroxamate, ester or amide derivative can be coordinated with the metal ion via the carboxylate, hydroximate, hydroxamate, amide and other groups attached to the amide or ester linkages, such as sugars, amino acids, peptides, chelates containing heterocycles, and other chelating ligands.
  • the metal complex may be a mononuclear, dinuclear, or trinuclear metal complex, or a metal complex having higher nuclearity, or an oligomeric or polymeric complex containing one or more metal centres and one or more carboxylates, or derivatives of a carboxylate (eg., hydroxamate, hydroximate, ester, and amide ligands) having anti-inflammatory activity.
  • a carboxylate eg., hydroxamate, hydroximate, ester, and amide ligands
  • the complex includes other ligands in addition to the carboxylate or carboxylate derivative(s) having anti-inflammatory activity.
  • these other ligands can also have anti-inflammatory and/or anti-cancer activities.
  • the complex is one of the following complexes (eg., see Copper Complexes of Non-steroidal Anti-inflammatory Drugs: An Opportunity yet to be Realized Weder, J. E.; Dillon, C. T.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A.; Biffin, J. R.; Regtop, H. L.; Davies, N. M. Coord. Chem. Rev. 2002, 232, 95-126).
  • complexes see Copper Complexes of Non-steroidal Anti-inflammatory Drugs: An Opportunity yet to be Realized Weder, J. E.; Dillon, C. T.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A.; Biffin, J. R.; Regtop, H. L.; Davies, N. M. Coord. Chem. Rev. 2002, 232, 95-126).
  • Suprofen (+)- ⁇ -methyl-4-(2-thienyl-carbonyl)phenylacetic acid (SupH);
  • Tolmentin l-methyl-5-(/?-toluoyl)-lH-pyrrole-2-acetic acid (ToIH);
  • DMSO dimethylsulfoxide
  • Naproxen 6-methoxy- ⁇ -methyl-2-naphthaleneacetic acid (NapH)
  • Ibuprofen (+)- ⁇ -methyl-4-(isopropylmethyl)benzeneacetic acid (IbuH);
  • Indomethacin l-(4-chlorobenzoyl)-5-methoxy-2-mefhyl-lH-indole-3-acetic acid (IndoH);
  • M a is a metal ion and in at least some enbodiments, a transition metal ion.
  • M a can, for example, be a copper ion.
  • the complex can be any one of the complexes referred to in the table above in which the metal ion is a transition metal ion other than copper (eg zinc, nickel, ruthenium, iron, cobalt ions, and preferably zinc or ruthenium). See for instance, Copper and Zinc Complexes as Anti- Inflammatory Drugs. Dillon, C. T.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A.; Weder, J. E.; Zhou, Q.
  • the complex is a mononuclear, dinuclear, trinuclear or polynuclear complex of a metal (where each metal of the complex is independently selected) and a ligand of the formula L 2 :
  • R 1 is H or halo (i.e. Cl, F, Br or I);
  • R 2 is H; a C 1 to C 6 alkyl, an alkenyl or an alkynyl, where the C 1 to C 6 alkyl, alkenyl or alkynyl may be optionally substituted; or wherein each R 2A 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 3 is H or halo;
  • 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 3
  • R 2 is a C 1 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 2A 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 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 .
  • the complex may be a complex of formula (1), (2) or (3):
  • M is a divalent or trivalent metal ion
  • L is a ligand as defined above: each L is independently selected and is a monodentate ligand; m is 1 or 2; and p is the charge of the complex;
  • each M is independently selected and is a divalent or trivalent metal ion
  • L 2 is a ligand as defined above: each L is independently selected and is a monodentate ligand; m is 0, 1 or 2; and p is the charge of the complex;
  • each M' is independently selected and is a trivalent or tetravalent metal ion
  • L 2 is a ligand as defined above: each L is independently selected and is a monodentate ligand; and p is the charge of the complex.
  • R 2 is a C 1 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 2A 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 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 1 is typically H.
  • R 3 is typically H.
  • R 2 is typically CH 3 .
  • L 2 is ACM.
  • M may be any divalent or trivalent metal ion.
  • M is preferably copper ion, zinc ion, cobalt ion, nickel ion, chromium ion, molybdenum ion, tungsten ion or ruthenium ion. More preferably, M is copper ion.
  • M' may be any trivalent or tetravalent metal ion.
  • M' is preferably iron ion, vanadium ion, manganese ion, chromium ion or ruthenium ion, and more preferably iron ion or ruthenium ion.
  • the ligand L may be any monodentate ligand.
  • L may be a charged or uncharged ligand.
  • L may for example be water, an alcohol, ⁇ iV-dimethylformamide (DMF), iV-methylpyrrolidone, dimethylsulfoxide or ⁇ yV-dimethylacetamide (DMA).
  • DMF ⁇ iV-dimethylformamide
  • DMA iV-methylpyrrolidone
  • DMA ⁇ yV-dimethylacetamide
  • the complexes of formula (1), (2) or (3) may be dissolved in a solvent, or may be in the form of a solid. Crystals of a complex of formula (1), (2) or (3) may include solvents of crystallisation. Crystals of a complex of formula (1), (2) or (3) may also include waters of crystallisation.
  • the complex is a mononuclear complex of the following fo ⁇ nula (4):
  • M is a divalent or trivalent metal ion
  • L 1 is a ligand of the formula:
  • R 1 is H or halo (i.e. Cl, F, Br or I);
  • R 2 is H; a C 1 to C 6 alkyl, an alkenyl or an alkynyl, where the C 1 to C 6 alkyl, alkenyl or alkynyl may be optionally substituted; or
  • each R 2A 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 3 is H or halo;
  • 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 3 , -SCH 3 or -CH 2 CH 3 may be optionally substituted; and n is i, 2, 3, 4 or 5; each L is independently selected and is a monodentate ligand; m is 1 or 2; and p is the charge of the complex;
  • the mononuclear complex of formula (4) is a complex of formula (4A):
  • M is a divalent or trivalent metal ion
  • R 1 is H or halo (i.e. Cl, F, Br or I);
  • R 2 is H; a C 1 to C 6 alkyl, an alkenyl or an alkynyl, where the C 1 to C 6 alkyl, alkenyl or alkynyl may be optionally substituted; or
  • each R ,2A 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 3 is H or halo; 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 3, -SCH 3 or -CH 2 CH 3 may be optionally substituted; n is 1, 2, 3, 4 or 5; each L is independently selected and is a monodentate ligand; and p is the charge of the complex.
  • R is a C 1 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 2A 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 5 when 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 1 is typically H.
  • R 3 is typically H.
  • R 2 is typically CH 3 .
  • each R 5 is typically halo (i.e. F, Cl, Br or I), and n is typically 1, 2 or 3.
  • L 1 may for example be Indo.
  • M may be any divalent or trivalent metal ion.
  • M is preferably copper ion, zinc ion, cobalt ion, nickel ion, chromium ion, molybdenum ion, tungsten ion or ruthenium ion. More preferably, M is copper ion or zinc ion.
  • the complex is a dinuclear complex of the formula (5):
  • each M is independently selected and is a divalent or trivalent metal ion
  • ⁇ -L 1 is a ligand of the formula L 1 :
  • R 1 is H or halo (i.e. Cl, F, Br or I);
  • R 2 is H; a C 1 to C 6 alkyl, an alkenyl or an alkynyl, where the C 1 to C 6 alkyl, alkenyl or alkynyl may be optionally substituted; or
  • each R 2A 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 3 is H or halo; each R 5 is independently selected from the group consisting of halo, -CH 3 , -CN,
  • R 2 is a C 1 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 2A 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 5 when 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 1 is typically H.
  • R 3 is typically H.
  • R 2 is typically CH 3 .
  • L 1 may for example be Indo.
  • M is any divalent or trivalent metal ion. M is typically selected from copper ion, zinc ion, cobalt ion, nickel ion, chromium ion, molybdenum ion, tungsten ion and ruthenium ion. Preferably, M is copper ion.
  • the ligand L may be any monodentate ligand.
  • L may, for example, be water (OH 2 ), an alcohol, dimethylsulfoxide (DMSO), tetrahydrofuran (THF), or L may be a ligand containing a tertiary amide or cyclic tertiary amide.
  • the complex is a trinuclear complex of the following formula (6):
  • each M' is independently selected and is a trivalent or tetravalent metal ion; and ⁇ -L 1 , L and p are as defined above for formula (5).
  • the complex is a trinuclear complex of the following formula (7):
  • M is a divalent metal ion
  • L 3 is a carboxylate having anti-inflammatory activity
  • L 4 is an optionally substituted heterocyclic base comprising one or two heterocyclic rings independently having 5 or 6 ring members and 1 to 3 heteroatoms independently selected from N, O and S; wherein each L 3 is independently selected; and each L 4 is independently selected.
  • L 3 can be a monodentate, bidentate or bridging ligand of formula L 1 or L 2 as follows:
  • R 1 is H or halo (i.e. Cl, F, Br or I);
  • R is H; a C 1 to C 6 alkyl, an alkenyl or an alkynyl, where the C 1 to C 6 alkyl, alkenyl or alkynyl may be optionally substituted; or
  • each R >2 ⁇ A A 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 3 is H or halo; 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 3, -SCH 3 or -CH 2 CH 3 may be optionally substituted; and n is i, 2, 3, 4 or 5.
  • M can, for example, be selected from the group consisting of zinc ion, cobalt ion, nickel ion, magnesium ion, copper ion and calcium ion
  • the heterocyclic base comprises one or more N atoms.
  • 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 heterocyclic base is quinolyl.
  • the metal complex is a complex of formula (8) as follows:
  • the metal complex is a metal complex of formula (8 a) as follows:
  • the metal complex is a complex of formula (9) as follows:
  • the metal complex is a complex of formula (11) as follows:
  • the metal complex is a complex of formula (12) as follows:
  • One or more of the ligands L 5 and L 8 in any combination may also form dimeric, trimeric, tetrameric, oligomeric or polymeric complexes with one or more metal ions.
  • the ancilliary ligands can be chosen from ligands that exert a separate anti-inflammatory activity.
  • the metal complex may be administered to the mammalian subject alone or in combination with other anti- inflammatory drug(s) or treatments for cardiovascular inflammation. Such administration can be given to improve the response to the other anti-inflammatory drug(s) or treatment(s), or to reduce the dose of such other drug(s) to reduce toxic side- effects while maintaining a comparable efficacy.
  • the ligand(s) of the metal complex used in a method embodied by the invention may not have anti-inflammatory activity alone, the activity being provided by the combination of the metal and the ligand(s) in the complex.
  • Methods of the invention find broad application in the prophylaxis or treatment of cardiovascular diseases and conditions. Any cardiovascular disease or condition involving inflammation responsive to a metal-NSAID complex can be treated by a method as described herein.
  • a method for prophylaxis or treatment of a cardiovascular disease or condition in a mammalian subject comprising administering to the subject a therapeutically effective amount of a metal complex and a carboxylate, or derivative of a cafboxylate, having antiinflammatory activity, wherein the carboxylate or derivative is other than salicylate or a derivative of salicylate.
  • the present invention also provides the use of a complex of a metal and a carboxylate, or a derivative of a carboxylate, having anti-inflammatory activity in the manufacture of a medicament for the prophylaxis or treatment of cardiovascular inflammation in a mammalian subject, the carboxylate or derivative being other than salicylate or a derivative of salicylate.
  • cardiovascular diseases and conditions including, but not limited to, acute and chronic cardiovascular inflammation including as a result of surgery or other trauma, cardiovascular disease, angina pectoris, 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 and pericarditis.
  • acute and chronic cardiovascular inflammation including as a result of surgery or other trauma, cardiovascular disease, angina pectoris, 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 and pericarditis
  • GI gastrointestinal
  • Metal complexes as described herein can 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 all such formulations for administration of metal complexes as described herein is expressly encompassed.
  • chelating derivatives of NSAIDs can also enhance the stability of metal-NSAID complexes. This can result in one or more of:
  • the release of the NSAID from the ligand can 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.
  • 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 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 , 5 -lipoxygenase inhibition by the hydroxamic acid, and the effects of Cu once the complex decomposes at a target site.
  • inert oxidation states of metals e.g., Ru(III) or Co(III)
  • metal ions, co-ligands and metal oxidation states of the metal complexes can be utilized to optimise the rate of release and/or hydrolysis of the NSAID-derivative (eg. at sites of hypoxia) to enable sufficient stability to target the disease site before the anti-inflammatory ligands of the metal complex are released.
  • the use of metal NSAID complexes with a variety of different metal ions can allow allow a therapeutic regime to be tailored to the type of cardiovascular condition, its location, and for instance the severity of hypoxia at the intended site of action.
  • labile and lipophilic metal complexes are particularly suitable for applications in which the formulation is administered to, or in the vicinity of, the site of action.
  • NS AID-ligand chelating derivatives can be tailored to target the tissue type, or co-ligands can be added to improve targeting. These complexes can also be provided in water-soluble form for optimized systemic delivery by intravenous injection or infusion.
  • Metal complexes used in at least some embodiments of the invention will have reduced toxicity associated side effects compared to ligand(s) in the metal complex (eg carboxylates, hydroxamates, hydroximates, esters and amides).
  • the metal complex can have substantially less gastrointestinal and/or renal toxicity than the parent anti-inflammatory ligand.
  • the metal complexes can be administered more safely at normal therapeutic doses, or in higher dosages (eg., for acute conditions) and/or over longer periods of time resulting in increased efficacy in treatment.
  • one or more methods embodied by the invention can provide an alternative prophylactic or therapeutic treatment for the treatment of cardiovascular diseases and conditions which avoid or reduce the adverse cardiovascular side-effects associated with the use of selective COX-2 NSAIDs.
  • Figure 1 shows the chemical structure of [Cu2(Indo) 4 (DMF) 2 ]
  • Permeability was determined by dosing the rats with the drug or the vehicle, then 0.5 mL of sucrose solution (0.5 g/mL) two hours later. The amount of sucrose in the urine was then determined in urine collected from 0-24 h after sucrose administration;
  • Figure 11 is a graph showing the reduction in neutrophils (as a measure of reduction in acute coronary inflammation) compared to a saline control in a carotid arterial walls of a New Zealand White (NZW) rabbit model of arterial inflammation.
  • NZW New Zealand White
  • the rabbits were infused with saline only (as an untreated control), saline plus lipid-free Al (ApoA-1, 8 mg/kg) as a positive control for an anti-inflammatory effect; or an oral gavage of an MCT organogel formulation containing IndoH (3 mg/kg), [Cu 2 (Indo) 4 (OH 2 ) 2 ] (1 or 3 mg/kg Indo equivalents) or [Cu(ACM) 2 (OH 2 ) 2 ] (3 mg/kg Indo equivalents);
  • Figure 12 shows cross sections of arteries in the rabbit model of arterial inflammation showing neutrophil levels as the dark-stained regions following the treatment with drugs as outlined in Figure 11.
  • the 1 and 3 after Cu-indo refer to doses of 1 or 3 mg/kg Indo equivalents, respectively;
  • Figure 13 is a graph showing endothelial V-CAM expression in the carotid arterial walls of a New Zealand White (NZW) rabbit model of arterial inflammation following treatment with undomodif ⁇ ed indomethacin (Indo; 3 mg/kg),
  • Figure 14 is a graph showing endothelial I-CAM expression in the New Zealand White (NZW) rabbit model of arterial inflammation following the Indo, Cu-
  • a reference to “Ibup” is a reference to Ibuprofen; a reference to “Im” is a reference to imidazole; a reference to “2-MeIm” is a reference to 2-methylimidazole; a reference to “Py” is a reference to pyridine; a reference to “3-pic” is a reference to 3-picoline; a reference to “4-pic” is a reference to 4-picoline; a reference to “Bim” is a reference to benzimidazole; a reference to
  • IndoH is a reference to indomethacin; a reference to “AcSHAH 2 " is a reference to acetylsalicylhydroxamic acid; a reference to “SHAH 2 " is a reference to salicylhydroxamic acid; a reference to “IndoHAEb” is a reference to indomethacin hydroxamic acid; a reference to “EtOAc” is a reference to ethyl-acetate; and the abbreviation “THF” is a reference to tetrahydrofuran; “AN” refers to acetonitrile; “Pyrro” refers to pyrrolidine; “DMA” refers to ⁇ N-dimethylacetamide; “DMSO” refers to dimethylsulfoxide; “NMP” refers to iV-methylpyrrolidone; and “DMF” refers to ⁇ iV-dimethylformamide.
  • 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, is ⁇ -propyl, butyl, zs ⁇ -butyl, sec-butyl, tert-buiyl, 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 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 C 20 alkenyl, more preferably a C 2 to C 6 alkenyl.
  • alkenyl include vinyl, allyl,
  • 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 C 6 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 unsynimetric 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.
  • the present invention stems from the recognition that at least some metal complexes and in particular complexes of a metal and a carboxylate, hydroxamate, hydroximate, ester or amide having anti-inflammatory activity are effective in the prophylaxis or treatment of inflammation associated with cardiovascular diseases and conditions, and can be more effective in treating cardiovascular inflammation in terms of efficacy and/or safety than the carboxylate, hydroxamate, hydroximate, ester or amide having anti-inflammatory activity itself.
  • complexes of a metal and indomethacin may be more effective in the prophylaxis or treatment of cardiovascular inflammation, in terms of efficacy and/or safety, than indomethacin itself.
  • the metal complex used in the method of the invention may, for example, be any of the complexes set out in following Table 1. It will also be understood that copper ion may be substituted with another transition metal ion (eg zinc, nickel, or cobalt ions as described in Copper and Zinc Complexes as Anti-Inflammatory Drugs. Dillon, C. T.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A.; Weder, J. E.; Zhou, Q. in "Metal Ions and
  • Suprofen (+)- ⁇ -methyl-4-(2-thienyl-carbonyl)phenylacetic acid (SupH);
  • Tolmentin l-methyl-5-(p-toluoyl)-lH-pyrrole-2-acetic acid (ToIH);
  • c DMSO dimethylsulfoxide;
  • Naproxen ⁇ -methoxy- ⁇ -methyl-l-naphthaleneacetic acid (NapH);
  • Ibuprofen (+)- ⁇ -methyl-4-(isopropylmethyl)benzeneacetic acid (IbuH);
  • ⁇ Metronidazole 2-methyl-5-nitrobenzimidazole s
  • Flufenamic Acid (TV-trifluoromethylphenyl)anthranilic acid (FlufenH);
  • h Niflumic Acid 2-((3-trifluoromethyl)phenylamino)-3-pyridinecarboxylic acid (NifH);
  • Indomethacin l-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH-indole-3-acetic acid (IndoH);
  • Diclofenac 2-[(2,6-dichlorophenyl)amino]phenylacetic acid (DicH).
  • NSAIDs include: Carprofen (6-chloro-a-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-a-methyl-[l,r-biphenyl]-4-acetic acid);
  • Ketoprofen (3-benzoyl-a-methylbenzeneacetic acid); Oxaprozin (4,5-diphenyl-2-oxazolepropanoic acid);
  • Pranoprofen (a-methyl-5H-[l]benzopyrano[2,3-b]pyridine-7-acetic acid);
  • Sulindac (I Z)-5-fluoro-2-methyl-l -[[4-(methylsulfinyl)phenyl]methylene]- lH-indene-3 -acetic acid); and Suxibuzone (butanedioic acid, l-[(4-butyl-3,5-dioxo-l,2-diphenyl-4- pyrazolidinyl)methyl] ester).
  • Metal complexes useful in methods embodied by the invention can be prepared by methods known in the art, or prepared by methods described below. Methods known in the art are described in, for example, United States Patent No. 5,466,824 or the paper: Anti-inflammatory Dinuclear Copper(II) Complexes with Indomethacin. Synthesis, Magnetism and EPR Spectroscopy; Crystal Structure of the ⁇ iV-Dimethylformamide Adduct. Weder, J. E.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A.; MacLachlan, D.; Bramley, R.; Delfs, C. D.; Murray, K. S.; Moubaraki, B.; Warwick, B.; Biffin, J. R.; Regtop, H. L. Inorg. Chem. 1999, 38, 1736-1744.
  • the complex can be a complex comprising at least one metal ion and at least one hydroximate, hydroxamate, ester or amide derivative of a carboxylate NSAID having anti-inflammatory activity.
  • 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 for example, also form chelates of deprotonated amides or amide monodentate complexes with a metal ion in the complex.
  • Inert 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 of a NSAID. This is exemplified by Example 1 in the preparation of [Co(NH 3 ) 5 (Indo)]X 2 as follows:
  • M Co(III), Cr(III), Ir(III), Os(III), Rh(III), Ru(III), Pt(IV), preferably Co(III) or Ru(III).
  • such complexes can be prepared by substitution of a weakly coordinated, trifluoromethanesulfonato, or solvent, or other such ligands, as described for example in, Introduction to Trifluoromethanesulfonates and Trifluoromethanesulfonato-0 Complexes.
  • embodiments of metal complexes of the invention can be prepared by reaction of a derivative OfR 6 COZ with a hydroxo or deprotonated amine ligand on the metal, for example:
  • metal complexes embodied by the invention can be prepared by other methods including substitution reactions of non-NSAID ligands to give new complexes.
  • Further derivatives of carboxylic acids that can be employed in metal complexes embodied by the invention also include esters of carboxylates having antiinflammatory activity, and amide derivatives of carboxylates that bind in a monodentate fashion to the metal.
  • the 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 2 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 nitrate ligands; and
  • R COZ is an acyl halide, anhydride or ester derivative of a ⁇ SAID
  • Metal complexes embodied by the invention can also be prepared by methods outlined in Example 1 below.
  • the complexes contain Indo, ACM, ketorolac or derivatives of Indo, ACM or ketorolac ligands as described above, or amide or ester derivatives of these or other NS AIDs.
  • the functional groups of the ligands can themselves bind to the metal ion, and/or other ligating groups that are linked by these functionalities can bind to the metal.
  • any R group (eg., alkyl, aryl etc) of an amide derivative can also contain donor functional group(s) that form a co-ordination bond with a metal ion.
  • Such functional groups include, for instance, a carboxylate group of an amino acid or peptide derivative of a NSAID, or a RS " , thioether, phenol, amine, or N-heterocyclic side-chain of such an amino acid or peptide derivative. It will also be understood that a large variety of other functional groups would be suitable.
  • Hydroxamic acids having anti-inflammatory activity that may be utilised in the complexes used in the method of the invention include those of the type described in
  • R AIk or Ar hydroxamato hydroximato complex complex
  • Amide derivatives of carboxylic acids having anti-inflammatory activites can be prepared as described in International Patent Application No. WO 95/04030, or modifications thereof. See, for instance, the indomethacin example below (Scheme 2).
  • R may be a proton, alkyl or aryl group, in which case the ligand would be a monodentate O or N donor to the metal.
  • R may contain one or more functional groups that could 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 a stagentate or bidentate carboxylate donor only), or more complex donor bidentate sets with amino acids containing metal binding side-chains, e.g., cysteine, serine, methionine, histidine, tyrosine, etc.
  • Other suitable R groups include amino sugar derivatives and glycoproteins that target tumour cells.
  • the coupling reaction may also involve short chain peptides, which can act as chelating ligands, or other groups to give metal chelators with anti-inflammatory activities, as described in WO 95/04030.
  • Ester derivatives of carboxylic acids having anti-inflammatory activites may be prepared by a variety of ester coupling reactions. See, for instance, the indomethacin example shown below (Scheme 3).
  • R may be an alkyl or aryl group containing a substituent, which can act as a monodentate or polydentate ligand, e.g., a carboxylate group as in ACM, or an amino group (prepared from an aminoalcohol) with a monodentate or polydentate amine ligands or more complex donor bidentate sets with serine or short-chain peptides containing serine.
  • Other suitable chelating groups that may be coupled and may also target tumours, include sugars and glycoproteins.
  • the ligand having anti-inflammatory activity is an amide-containing NSAID that is not a carboxylate.
  • NSAIDs that are not carboxylates include for instance oxicam NSAIDs such as piroxicam (4-hydroxy-2-methyl-N-2- pyridyl-2H-l ,2-benzothiazine-3-carboxamide-l ,1 -dioxide), tenoxicam (4-hydroxy-2- methyl-iV-2-pyridinyl-2H-thieno(2,3 -e)- 1 ,2-thiazine-3 -carboxamide- 1 , 1 -dioxide) and meloxicam.
  • the complex is a complex of the formula (A):
  • M is a metal ion
  • L 4 is a hydroxamate or hydroximate having anti-inflammatory activity or a chelating amide (such as those containing an amino acid or peptide linkage as the chelate) having anti-inflammatory activity; each L is independently selected and is a monodentate or polydentate ligand; n is 1, 2 or 3; m is O, 1, 2, 3 or 4; and p is the charge of the complex.
  • M is a divalent, trivalent, tetravalent, pentavalent or hexavalent metal ion.
  • the complex used in the method of the present invention may be a mononuclear, dinuclear, trinuclear, oligomeric or polymeric complex containing the ligand L 2 as defined above.
  • the complex may be a complex of formula (1), (2), (3) or (8), as defined above.
  • Complexes of formula (1) or (2) can be prepared by mixing a stoichiometric amount of a compound L H (where L is as defined above) and a divalent or trivalent metal salt, preferably a basic salt such as M(OAc) 2 , in a solvent L (the solvent forming the ligand L in the resultant complex, or in the case of the aqua complex, adventitious water in the organic solvent).
  • the product is then heated until precipitation occurs and it is then cooled and the solid is filtered off.
  • the product may need to be recrystallised until elemental, spectroscopic and/or diffraction methods demonstrate that the complex is of the required purity.
  • a similar procedure may also be performed in which L 2 H, a divalent or trivalent metal salt and the ligand L are added to a solvent more weakly coordinating than L or in which L is added or is adventitious water.
  • the same procedures as discussed above may then be followed for the isolation and purification of the complex.
  • Complexes of formula (3) can be prepared by the same procedures as those described above for the preparation of complexes of formula (1) or (2) using a trivalent or tetravalent metal salt. Such complexes are obtained by mixing L 2 H and a suitable metal salt in aqueous/organic solvent mixtures under basic conditions. Additional ligands L may be added to these solutions to precipitate the complexes.
  • the complexes of formula (1), (2) or (3) may be charged or neutral.
  • Complexes of formula (1) and (2) are neutral in charge if M is a divalent metal ion and all the ligands L are neutral ligands.
  • a complex of formula (1) or (2) may have a charge, for example, p may be 1 " or 2 ⁇ .
  • Complexes of formula (3) have a charge of 1 if all the metal ions M' in the complex are trivalent metal ions and all the ligands L are neutral.
  • the complex of formula (3) may have a charge of 2 ⁇ , ⁇ ⁇ , 0, or 2 .
  • Examples of complexes of formula (1) include [Cu(ACM) 2 (DMF) 2 ], [Cu(ACM) 2 (OH 2 ) 2 ], [Zn(ACM) 2 (DMF) 2 ] and [Zn(ACM) 2 (OH 2 ) 2 ].
  • Examples of complexes of formula (2) include [Ru 2 (ACM) 4 L] p and
  • the complex of formula (2) is a complex of the formula (2A):
  • the complex is a mononuclear complex of the following formula (4):
  • the mononuclear complex of formula (4) is a complex of formula (4A):
  • the complex of formula (4) may be charged or neutral.
  • Preferred complexes include [Cu(Indo) 2 (Im) 2 ], [Cu(ACM) 2 (OH 2 ) 2 ], [Zn(Indo) 2 (OH 2 ) 2 ].nH 2 O and [Zn(ACM) 2 (OH 2 ) 2 ].
  • the complex of formula (4) may be in solution, or may be in the form of a solid. Crystals of a complex of formula (4) may include solvents of crystallisation. Crystals of a complex of formula (4) may also include waters of crystallisation.
  • the complex of formula (4) will be charged (e.g., p is 1 ⁇ or 2 ⁇ ) and a solid of the complex of formula (4) will include cations that are counter ions to the anionic complexes.
  • Such solids include solids having the following formulas: YtMC ⁇ '-L 1 ) ⁇ ] (4B) and
  • Y is a counter ion having a 2 charge and Y is a counter ion having a 1 charge.
  • Cu(II) complexes of formula (4) are formed when copper(II) indomethacin complexes are formed using strong donor ligands, as described in the Applicants a co-pending International Patent Application entitled “Copper complexes” filed 24 March 2006 and claiming priority from Australian Provisional Patent Application No. 2005901464, the contents of which are incorporated herein by cross-reference in its entirety.
  • Complexes of formula (4) where M is Cu(II) may, for example, be formed using the ligand pyrrolidine.
  • Other ligands having a similar donor strength to, or a greater donor strength than, pyrrolidine can also form complexes of formula (4).
  • L is a ligand containing an iV-heterocyclic group.
  • Ligands containing an JV-heterocyclic group include pyrrolidine, alkyl-substituted pyrrolidines, proline, proline derivatives, imidazole, imidazole derivatives such as substituted imidazoles or ligands containing an imidazole ring (e.g.
  • L is an amine, e.g. NH 3 or an organic amine (e.g. diethylamine), an alcohol or an amide (e.g. diethylacetamide), or another ligand that is a strong donor such as triethylphosphate.
  • L can be a solvent having a solvent donor number of about 30 or greater.
  • Complexes of formula (4) may, for example, be prepared by direct reaction of the appropriate ratios of a compound of the formula L 1 H where L 1 is as defined above and a copper salt such as copper(II) acetate in a solvent having a solvent donor number of about 30 or greater, the solvent forming the ligand L in the resulting complex.
  • Complexes of formula (4) may also be prepared by adding a solvent having a solvent donor number of about 30 or greater, or adding a ligand that is not a solvent but has a similar donor strength to a solvent having a solvent donor number of about 30 or greater, to a solution of the metal ion (e.g. Cu(II)) and L 1 in a weaker donor solvent.
  • a solvent having a solvent donor number of about 30 or greater or adding a ligand that is not a solvent but has a similar donor strength to a solvent having a solvent donor number of about 30 or greater, to a solution of the metal ion (e.g. Cu(II)) and L 1 in a weaker donor solvent.
  • complexes of formula (4) can be prepared by re-crystallisation of a dinuclear complex, such as [Cu 2 (Indo) 4 (DMF)2], in a solvent having a solvent donor number of about 30 or greater, such as pyrrolidine, or in a solvent containing a ligand that is a strong donor such as imidazole (Im).
  • a dinuclear complex such as [Cu 2 (Indo) 4 (DMF)2]
  • a solvent having a solvent donor number of about 30 or greater such as pyrrolidine
  • a solvent containing a ligand that is a strong donor such as imidazole (Im).
  • the complexes of formula (4) are more lipophilic than indomethacin or other compounds of the formula L 1 H and thus are more easily absorbed through membranes and taken up by tissues locally.
  • the complexes of formula (4) are, therefore, expected to be more readily absorbed into cells than free indomethacin or other compounds of the formula L H when administered topically.
  • the complex is a dinuclear complex of the formula (5):
  • Complexes of formula (5) may be charged or neutral in charge.
  • each M is a divalent metal ion and each L is a neutral ligand, the complex is not charged (i.e., p is 0).
  • the ligand L may be any monodentate ligand.
  • the ligand L may be charged or uncharged.
  • L may, for example, be water (OH 2 ), an alcohol, dimethylsulfoxide (DMSO), pyridine (Py), acetonitrile (AN), tetrahydrofuran (THF), or L may be a ligand containing a tertiary amide or cyclic tertiary amide.
  • L may be a molecule of a tertiary amide of the formula:
  • R 1 is an alkyl having from 1 to 4 carbon atoms, and each R 1 may be the same or different, and R 2 is a cycloalkyl having from 2 to 7 carbon atoms.
  • the tertiary amide or cyclic tertiary amide may be, for example, ⁇ JV-dimethylformamide, N, N-dimethylacetamide or 7V-methylpyrrolidone.
  • ⁇ -L 1 is a ligand of the formula L 1 :
  • M is Cu or Zn; each L is independently selected and is a monodentate ligand; and p is the charge of the complex.
  • L 1 may for example be Indo.
  • the complex is a dinuclear metal/indomethacin complex of the formula (5B):
  • M 2 ( ⁇ -Indo) 4 Y 2 [M 2 ( ⁇ -Indo) 4 Y 2 ] (5B) wherein M is Cu or Zn, Y is water (OH 2 ) or a ligand containing a tertiary amide or cyclic tertiary amide (such as DMF and DMA), or Y is selected from an alcohol, DMSO, pyridine, acetonitrile, or tetrahydrofuran.
  • Indomethacin is one of the most lipophilic NSAIDs and, again without being limited by theory, the present inventors believe that the binding of the ligand to a metal makes complexes of formula (5B) more lipophilic than IndoH and hence promotes the transport of M (i.e. Cu or Zn) and Indo into the vasculature (i.e. there is greater absorption of the complex than IndoH).
  • M i.e. Cu or Zn
  • Indo into the vasculature i.e. there is greater absorption of the complex than IndoH.
  • the greatly reduced adverse effects of the complex compared with free indomethacin such as gastrointestinal and particularly, the newly discovered reduction in renal effects on oral administration as described herein
  • Complexes of formula (5B) include, for example, [Cu 2 (Indo) 4 (DMF) 2 ], [Cu 2 (UIdO) 4 (DMA) 2 ], [Cu 2 (Indo) 4 (NMP) 2 ], [Cu 2 (Indo) 4 (DMSO) 2 ], [Cu 2 (Indo) 4 (THF) 2 ], [Cu 2 (Indo) 4 (Py) 2 ], [Cu 2 (Indo) 4 (AN) 2 ], [Cu 2 (Indo) 4 (OH 2 ) 2 ], [Cu 2 (Ket) 4 (OH 2 ) 2 ],
  • a preferred complex is [Cu 2 (Indo) 4 (OH 2 ) 2 ].nH2 ⁇ , wherein n is the number of waters of crystallisation.
  • the number of waters of crystallisation will vary depending on the technique used to prepare the complex, and is typically from 1 to 5.
  • Complexes of formula (5) may be prepared by methods known in the art.
  • copper(II) and zinc(II) complexes with indomethacin may be prepared as described in United States Patent No. 5,466,824 or as generally described in the paper: Anti-inflammatory Dinuclear Copper(II) Complexes with Indomethacin. Synthesis, Magnetism and EPR Spectroscopy; Crystal Structure of the iV,iV-Dimethylformamide Adduct. Weder, J. E.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A.; MacLachlan, D.; Bramley, R.; Delfs, C. D.; Murray, K.
  • Trinuclear metal complexes with the ligand L 1 Trinuclear metal complexes with the ligand L 1
  • the complex is a trinuclear complex of the following formula (6):
  • each M' is independently selected and is a trivalent or tetravalent metal ion; and ⁇ -L 1 , L and p are as defined above for formula (5).
  • Trinuclear metal complexes with the ligand L 3 and L 4 Trinuclear metal complexes with the ligand L 3 and L 4
  • the complex is a trinuclear complex of the following formula (7):
  • L 3 is a carboxylate having anti-inflammatory activity
  • L 4 is an optionally substituted heterocyclic base comprising one or two heterocyclic rings independently having 5 or 6 ring members and 1 to 3 heteroatoms independently selected from N, O and S; and wherein each L 3 is independently selected; and each L 4 is independently selected.
  • L 3 may be a monodentate, bidentate or bridging ligand of formula L 1 or L 2 as follows:
  • R 1 is H or halo (i.e. Cl, F, Br or I);
  • R 2 is H; a C 1 to C 6 alkyl, an alkenyl or an alkynyl, where the C 1 to C 6 alkyl, alkenyl or alkynyl may be optionally substituted; or
  • each R ,2A 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 3 is H or halo; 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 3, -SCH 3 or -CH 2 CH 3 may be optionally substituted, and n is 1, 2, 3, 4 or 5.
  • R 2 is a C 1 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 2A 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 5 when 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 0 consisting of halo, -OH, -COOH and -NH 2 .
  • R 1 is typically H.
  • R 3 is typically H.
  • R 2 is typically CH 3 .
  • L 2 is ACM. 5
  • M may be selected from the group consisting of zinc, cobalt, nickel, magnesium, copper and calcium.
  • the heterocyclic base comprises one or more N atoms.
  • the heterocyclic base is optionally substituted.
  • the heterocyclic base may be selected from the group consisting of isoquinolyl, O quinolyl, piperidinyl, pyridinyl, 2-methylpyridinyl, imadazoyl, pyranyl, pyrrolyl, pyrimidinyl, indolyl, purinyl and quinolizinyl.
  • the heterocyclic base is quinolyl.
  • the ligands of these complexes comprise carboxylate ligands, or derivatives of carboxylates, having anti-inflammatory activity such as hydroximate, hydroxamate, amide, or ester derivatives having anti-inflammatory activity.
  • Metal complexes of these formulae can for instance, be prepared by methods outlined in Example 1 of this application or by other suitable synthesis methods.
  • the metal O complexes can, for instance, include ligands L 1 and L 2 as described above, ketorolac or other NSAID as described herein, or their hydroximate, hydroxamate, hydrazine, amide, or ester derivatives.
  • the functional groups of the ligands can themselves bind to the metal ion, and/or other ligating groups that are linked by these functionalities can bind to the metal.
  • the metal comlexes can be inert or labile complexes.
  • the metal ion or metal ions of inert complexes have an inert oxidation state.
  • the metal complex is a complex of formula
  • M is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent metal ion; each L 5 is independently selected and is a monodentate carboxylate (preferably Indo, ACM or Keterolac) or an amide ligand (O or N bound) (preferably a derivative of Indo, ACM or Keterolac), having anti-inflammatory activity; each L 6 is independently selected and is NH 3 , a monodentate ligand, a polydentate ligand, or a macrocyclic ligand; m is 1, 2, 3 or 4 n is O, 1, 2, 3, 4 or 5; and p is the charge of the complex.
  • L 5 is NH 3 or a monodentate, polydentate, or macrocyclic amine ligand.
  • Preferred complexes of formula (8) include tM(O 2 CR 6 ) m (NR 9 R 10 R 11 )(6-m)] p where M is selected from Co(III), Cr(III), Ir(III), Os(III), Rh(III), Ru(III) or Pt(IV) and more preferably, Co(III) or Ru(III), and R 6 CO 2 " is an anti-inflammatory NSAID such as exemplified above, and R 9 , R 10 and R 11 can independently be H or an optionally substituted aliphatic or aromatic group.
  • L 5 is NH 3 or a monodentate, polydentate, or macrocyclic amine ligand.
  • Preferred complexes of formula (8) include: [M(L 1 ) m (NR 9 R 10 R 11 ) n ] p where L 5 is independently chosen from a NSAID, R 6 CO 2 " , R 6 CON(R 7 ) " or an amide (R 6 CONR 7 R 8 ) or ester derivative (R 1 COOR 4 ) of a NSAID, (NR 9 R 10 R 1 J ) 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) and Pt(IV) and more preferably, Ru(II), Co(III), and Ru(III); [M(L 5 ) m (OH s )n] p where L 5 is independently selected from a NSAID, R 6 CO 2 " ,
  • metal complexes of formula (8) include O [Co(NH 3 ) 5 (Indo)](CF 3 SO 3 ) 2 (see Example 1 below) and [Co(NH 3 ) 5 (ACM)](CF 3 SO 3 ) 2 .
  • the metal complex is a complex of formula (8 a):
  • M is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent metal ion; each L 5 is independently selected and is NH 3 , a monodentate ligand, a polydentate ligand, or a macrocyclic ligand; each L 6 is independently selected and is a chelating derivative of a carboxylate O such as a hydroximate, hydroxamate, hydrazine, ester, amino acid, peptide or sugar, or a amide chelating ligand (O or N bound), having anti-inflammatory activity; m is 0, 1, 2, 3, 4, or 5; n is 1, 2, 3 or 4; and p is the charge of the complex.
  • Complexes of formula (8a) include: [M(L 6 ) n (NR 9 R 10 R u )( 6- 2m)] p where each L 6 is independently a bidentate derivative of an NSAID, each (NR 9 R 10 R 11 ) is independently a monodentate amine ligand or a polydentate amine ligand, and M is selected from
  • L 6 is a tetradentate derivative of an NSAID
  • (NR 9 R 10 R ⁇ ) 2 is two independently selected monodentate amine ligands or a bidentate amine ligand
  • M is selected from Co(III), Cr(III), Ir(III), Os(III), Rh(III), Ru(III) and Pt(IV) and more preferably, Co(III) and Ru(III);
  • [M(L ⁇ (NR 9 R 10 R 1 x )f where L 6 is a pentadentate derivative of an NSAID, and M is 5 selected from Co(III), Cr(III), Ir(III), Os(III), Rh(III), Ru(III) and Pt(IV) and more preferably, Co(III) and Ru(III); [M(L 6 )(NR 9 R 10 R ⁇ ) 2 ] p where L 6 is a bidentate derivative of an NSAID, (NR 9 R 10 R 1 ⁇ 2 is two independently selected monodentate
  • complexes of formula (8a) include: [M(L 6 ) 3 ] P where L is a bidentate derivative of an NSAID, and M is selected from Cu(II), Zn(II), Co(III), Cr(III), Ga(III), Ir(III), Os(III), Rh(III), Ru(III) and Pt(IV) and more preferably, Cu(II), Zn(II), Co(III), 5 Ga(III) and Ru(III); [M(L 6 ) 2 ] P where L 6 is a tridentate derivative of an NSAID, and M is selected from Cu(II), Zn(II), Co(III), Cr(III), Ga(III), Ir(III), Os(III), Rh(III), Ru(III) and Pt(IV) and more preferably, Cu(II), Zn(II), Co(III), Ga(III), and Ru(III); [M(L 6 )] P where L 6 is a sexidentate derivative of an NSAID, and
  • Further complexes of formulae (8a) include: [M(L 6 ) n (OH t ) (6-2m )] p where L 6 is a bidentate derivative of an NSAID, t is independently selected from 0, 1 or 2, and M is selected from Fe(II), Mn(II), Cu(II), Zn(II), Co(III), Cr(III), Fe(III), Ga(III), Fe(III), Ir(III), Mn(III), Os(III), Rh(III), Ru(III), Mn(IV), Pt(IV), Ti(IV), V(IV), V(V), Mo(VI), and W(VI) and more preferably, Fe(II), Cu(II), Mn(II), Zn(II), Co(III), Ga(III), Ru(III), Mn(III), Mn(IV), V(IV), V(V), and Mo(VI); [M(L 6 )(OH t ) 3 ] p where L 6 is a tridentate derivative of an
  • the metal complex is a complex of the formula (9):
  • L is NH 3 or a monodentate, polydentate, or macrocyclic amine ligand.
  • Preferred complexes of formula (2) include [M(NR 9 R 10 R 1 ⁇ ( ⁇ f when L 8 is abidentate ligand, [M(NR 9 R 10 R 11 ML 8 )] 15 when L 8 is a tridentate ligand, and [M(NR 9 R 10 R 1 ⁇ 2 (L 8 )] 15 when L 8 is a tetradentate ligand, where M is selected from Co(III), Cr(III) 5 Ga(III), Ir(III), Os(III), Rh(III), Ru(III), Ru(II) and Pt(IV) and more preferably, Co(III), Ga(III), Ru(III) and Ru(II), and R 9 , R 10 , and ⁇ are as defined for formula (8 or 8a) above.
  • the metal complex of formula (9) can be [M(NR 9 R 10 R 1 ⁇ 2 (L 8 )] 15 where L 8 is a bidentate ligand, [M(NR 9 R 10 R 11 XL 8 )] 13 where L 8 is a tridentate ligand, and where M is Cu(II), Ni(II), Pd(II), Pt(II) or Au(III) and more preferably Cu(II), and R 9 , R 10 , R 11 and R 5 are as defined for formula (8 or 8a) above.
  • the metal complex is [M(L 8 ) n ] p .
  • L is a bidentate ligand n is 3, or when L is a tridentate ligand n is 2, and wherein M is preferably Co(III), Cu(II), Zn(II), Ga(III), Ru(III), or Ru(II); or when L 8 is a bidentate ligand n is 2, or when L 8 is a tetradentate ligand n is 1, wherein M is preferably Cu(II), Ni(II), Pd(II), Pt(II) or Au(III) and more preferably Cu(II).
  • R 9 , R 10 and R 11 of formulae (8 a) and (9) can for instance be selected from aliphatic and aromatic groups consisting of substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, arylalkyl and heterocyclic groups.
  • 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.
  • metal complexes of formula (9) include [Cu(IndoHAH)(OH)], [Co(en) 2 (IndoHA)]Cl 2 , [Co(en) 2 (IndoHA)](CF 3 SO 3 ) 2 , [V v O(IndoHAH)(IndoHA)] -2MeOH-1.5H 2 O, [Cr(IndoHA) 2 (OH 2 ) 2 ](NO 3 )-H 2 O,
  • a bridging ligand such as an oxo, hydroxo, carboxylate (including a NSAID), halide, or other bridging group.
  • the metal complex can be a complex of the following formula (11):
  • M is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent metal ion; each L 5 is independently selected and is a monodentate carboxylate or amide ligand (O or N bound), having anti-inflammatory activity; each L 7 is independently selected and is a monodentate or a polydentate ligand; each L 8 is independently selected and is a chelating derivative of a carboxylate, or amide ligand (O or N bound), having anti-inflammatory activity; o is 1, 2, 3, 4 or 5; m is 1, 2, 3 or 4; n is 1, 2, or 3; and p is the charge of the complex.
  • metal complexes of formula (11) for instance, include: [M(O 2 CR 6A )(L 7 ) m (L 8 ) n ] p where, m is 0, 1 , 2, or 3, n is 1 or 2, R 6A CO 2 ⁇ is a NSAID, R 6 CO 2 " , or an ester derivative of an R 6 CO 2 " NSAID having a terminal carboxylate, at least one of L 8 is independently selected from a hydroxamate or hydroximate derivative of a NSAID, an amino acid derivative of a NSAID, a peptide derivative of a NSAID, and an amine derivative of a NSAID, and M is Co(III), Rh(III), Ir(III), Cr(III), Ru(III) or Pt(IV), and preferably Co(III) or Ru(III); [M(O 2 CR 6A ) 2 (L 7 ) m (L 8 ) n f where, m is 0, 1 or 2, n is 1 or
  • the metal complex is a complex of the following formula (12): [M q (L 5 ) m (L 7 ) n (L 8 ) r ] p (12) wherein
  • One or more of the ligands L 5 to L 8 above in any combination may also form dimeric, trimeric, tetrameric, oligomeric or polymeric complexes with one or more metal ions.
  • Monodentate ligands which can be used in metal complexes described herein include monodentate ligand such as halo, aqua, hydroxo, oxo, CO, NO, amines, alcohols, amides, sulfoxides, JV-heterocylces, O-heterocycles, and iS-heterocycles.
  • Polydentate acyclic ligands include amines, amino acids, peptides, alcohol sugars, hydroxyacids, polycarboxylates, iV-heterocylces, O-heterocycles, and 5-heterocycles, and functional groups that can form co-ordinate bonds with a metal ion.
  • Polydentate macrocyclic ligands include amines, crown ethers, thioethers, macrocyclic peptides and amides, and ligands with combinations of these and other metal binding substituents.
  • bridging ligands that can be utilized in metal complexes as described herein include oxo, hydroxo, carboxylate (including carboxylate NSAIDs), halo and other bridging groups.
  • aliphatic and aromatic groups that can be employed 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 as described above.
  • the metal ion of metal complexes that can be utilized in methods embodied by the invention include d-block, f-block, p-block and s-block metal ions.
  • 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), or W(VI), or a trivalent or tetravalent ⁇ -block metal such as Ga(III), Bi(III) or Sn(IV).
  • Suitable methods for the synthesis of metal complexes are for instance, further 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 1,4- dimethyl-l,4,7-triazacyclononane ligands as well as carboxylato and oxo or hydroxo bridges.
  • one of the ancillary ligands can be CO, since Ru-CO complexes for promoting angiogenesis could be prepared for example by using methods similar to (Li Volti, G.; Sacerdoti, D.; Sangras,
  • Another desirable ligand is the NO ligand in complexes of Fe(II) or Ru(II) since these can release NO for vasodilation.
  • metal complexes of indomethacin, ibuprofen, naproxen, dichlofenec, ketorolac, and/or derivatives thereof having anti-inflammatory activity are utilised for the prophylaxis or the treatment of cancers as described herein.
  • any suitable such NSAID or derivative thereof can also be utilized.
  • the term "therapeutically effective amount” means an amount effective to yield a desired therapeutic response, eg prophylaxis or treatment of a cardiovascular inflammation or a cardiovascular disease or condition as described herein.
  • the metal can be administered alone or be co-administered in combination with one or more agents conventionally used in the treatment of cardiovascular asscociated diseases or conditions.
  • co-administered is meant simultaneous administration in the same formulation or a plurality of formulations by the same of different routes, or sequential administration by the same or different routes.
  • sequential administration is meant one is administered one after the other.
  • a metal complex in one or more methods embodied by the invention in combination with another anti-inflammatory agent may enhance the effectiveness of the other anti-inflammatory agent or allow the dosage of the other anti-inflammatory agent to be lowered to reduce toxic side effects of the other anti-inflammatory agent.
  • the specific "therapeutically effective amount" of the metal complex utilised in a method embodied by the present invention will vary with such factors as the particular condition being treated, the physical condition age and weight of the human or animal, the type of animal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific composition and complex employed.
  • 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.
  • a low dosage may initially be administered which is subsequently increased at each administration following evaluation of the response of the subject.
  • the frequency of administration can be determined in the same way, that is, by continuously monitoring the response of the subject and modifying the interval between dosages.
  • a plurality of different metal-NS AID complexes as described herein can be administered to the mammalian subject in the treatment of a cardiovascular disease or condition.
  • the metal complexes can be selected to provide different anti-inflammatory activies, have different rates of release of anti-inflammatory ligands, and/or for instance be targeted to different tissues to provide complimentary anti-inflammatory activity.
  • the complex(es) can be administered to the mammalian subject systemically and/or applied directly to the site of cardiovascular inflammation such as during surgery.
  • the complex can also be applied topically to the skin for diffusion into the body of the subject to the site of action, or by oral administration (including buccal or sublingual administration), or by suppository or any other mode of administration suitable for the particular disease or condition being treated.
  • the complex will generally be administered hi the form of a composition comprising the complex together with a pharmaceutically acceptable carrier.
  • the composition may be formulated as described in International Application No. PCT/AU2005/000442, 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 can 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 which would otherwise interact with the complex to cause the complex to dissociate.
  • 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.
  • 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.
  • 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 for use in the 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, pahnic 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).
  • sorbitan trioleate sorbitan monooleate
  • Span 65 sorbitan monooleate
  • Span 60 sorbitan monostearate
  • Span 40 sorbitan monopalmitate
  • sorbitan monolaurate sorbitan monolaurate
  • Suitable 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 suitable surfactants in this class include the Polyoxyethylene Sorbitan Fatty Acid Esters group of surfactants, including polyoxyethylene (20) sorbitan monolaurate (T ween 20), polyoxyethylene (4) sorbitan monolaurate (T ween 21), and polyoxyethylene (20) sorbitan monooleate (T ween 80).
  • surfactants that may be used include the block copolymers based on ethylene oxide and propylene oxide such Poloxamer 124 (Pluronic L44 NF), Poloxamer
  • Suitable surfactants also include the polyethylene glycol fatty acid esters (PEG esters) group of surfactants.
  • Such surfactants comprise mono-, tri-, or partial esters of fatty acids such as oleic, lauric, palmic, oleic, and stearic acids, including but not limited to PEG 200 monolaurate, PEG 300 dilaurate, ethylene glycol distearate, PEG 300 monooleate, PEG 400 monooleate, PEG 350 monostearate, PEG 300 monostearate, PEG 400 monostearate, PEG 600 monostearate, PEG 1000 monostearate, PEG 1800 monostearate, PEG 6500 monostearate, PEG 400 mono-iso stearate, PEG 600 mono-iso-stearate, PEG 200 dilaurate, PEG 600 distearate, PEG 6000 distearate, PEG 200 distearate, PEG 300 distearate, and PEG 400 distearate.
  • PEG 200 monolaurate PEG 300 dilaurate
  • PEG 300 monooleate PEG 400 mono
  • compositions have more than 80%, preferably more than 90%, and more preferably more than 95%, of the total amount of the carboxylate, or hydroxamate, hydroximate, ester, or amide derivative having anti-inflammatory activity present in the composition as part of a metal complex.
  • the amount of the carboxylate, or 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 compositions preferably do not comprise, or are substantially free of, peptides, carboxylate donors, reductants and thiolate groups, apart from those in the derivatives of the NSAID utilised.
  • the composition is also not strongly acidic or basic as strong acids and bases can cause metal carboxylate complexes to dissociate. More generally, the metal-NSAID complex can be dissolved in the composition or can 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.
  • a "pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering the complex to a human or animal.
  • the carrier can 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 can 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.
  • the composition for use in the method of the invention may be suitable for oral, rectal, nasal, topical (including buccal and sublingual), ophthahnological, vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration, or for administration respiratoraly, intratrachaely, nasopharanyngealy, intraoccularly, intrathecally, intranasally, by inhalation, infusion, or via IV group patch and by implant.
  • particularly suitable routes are via injection into blood vessels to be treated or which supply blood vessels or particular organs to be treated. Agents may also be delivered into cavities such as for example the pleural or peritoneal cavity.
  • compositions can also 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, an ingestible tablet, a capsule, a chewable composition, or any other form suitable for oral administration. If desired, the composition can be encapsulated in a hard or soft capsule
  • the metal complex can be provided in the form of 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 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, may 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 may 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.
  • 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 parenteral administration include compositions in the form of sterile aqueous or non-aqueous suspensions and emulsions.
  • the composition can also include one or more pharmaceutically active components in addition to the complex that have anti-inflammatory or other therapeutic activity.
  • active components include conventionally used anti-inflammatory drugs.
  • a metal complex will constitute about 0.025% to about 20% by weight of the composition, preferably about 0.025% to about 20% by weight of the composition, more preferably about 0.1% to about 20% by weight of the composition and most preferably, the complex constitutes about 0.1% to about 10% by weight of the composition.
  • a composition embodied by the invention may comprise the metal complex in an amount of about 1% by weight of the composition or less.
  • 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 can 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 Artiodacty Ia Typically, the subject will be a primate and more usually, a human being.
  • Metal complexes useful in one or more embodiments of methods of the invention were prepared as follows.
  • the crystal size and colour of the Cu-aqua complex was checked with a light microscope.
  • the crystals were found to be green in colour, with a star-like shape and 50-100 microns in diameter. This size was larger (by at least an order of magnitude) than crystals prepared by synthetic methods reported elsewhere.
  • Ibuprofen (1.03 g, 5 mmole) was allowed to dissolve in a solution of potassium bicarbonate (0.55 g, 5.5 mmole) in 80 ml of water. To this stirring solution was slowly added a solution of copper sulfate pentahydrate (0.625 g, 2.5 mmole) in 5 ml of water. The mixture was allowed to stir for 30 minutes. The aquamarine precipitate which formed was collected, washed with water and ethanol, and then recrystallized from ether/dichloromethane (80 mL). The product was air-dried. Anal. Calcd. for CuC 26 H 34 O 4 : C, 65.86; H, 7.24. Found: C, 65.37; H, 6.54%.
  • 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 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 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 NMR data indicate the formation of two Ga(III)-IndoHAH complexes (or geometric isomers) with singly deprotonated IndoHAH ligands.
  • 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 the formation of a bis-ligated Ga(III) hydroxamato complex, [Ga(LH) 2 (OH 2 ) 2 ] +
  • Rat paw oedema studies on this complex using the methodology described in Example 2 gave 30% reduction in inflammation and, remarkably, no gastric ulceration when dosed at 10 mg/kg Indo molar equivalent and dissolved into an MCT paste.
  • HBTU O-(Benzotriazol-l- yl)-N,N,iV,iV-tetramethyluronium hexafluorophosphate
  • ligands can be prepared by the following reaction schemes and can coordinate to metal ions via the diol functions.
  • Ketorolac tris salt (0.452 g, 1.20 mmol) was dissolved in water (5 mL).
  • Complexes such as the Co(III) complex described in Example 1.1.3 offer the potential of systemic delivery of even higher concentrations of NSAIDs through oral, injectable, and topical delivery and incorporation into slow release patches. As demonstrated by this example, the complex exhibits significant anti-inflammatory.
  • Animals were housed in polypropylene cages and allowed free access to standard laboratory rat chow (Purina Rat Chow, Ralston Purina, St Louis MO, USA) and tap water. Animals were housed in an animal care facility at ambient temperature and humidity with a 12-h light-dark cycle. The experimental animal protocols were approved by animal ethics committees at The University of Sydney, Australia and Washington State University, USA.
  • Rats (n 4 for each treatment) were deprived of food, but not water, for 18 h and fasted overnight.
  • the rats received either oral indomethacin at doses of 10 mg/kg or
  • Plasma was obtained by cardiac puncture using a 23 gauge (G) needle, attached to a 10 mL syringe, under halothane anaesthesia.
  • Haptoglobin concentration (milligrams per millilitre) was measured using a commercially available kit Dade Behring (Mannheim, Germany) by radial immunodiffusion using 5- ⁇ L samples in each well. Normal range values are a diffusion zone of approximately 6 mm of diameter (1.22 g/L). The diameter of the precipitin zone is directly proportional to the concentration of the relevant protein in the sample
  • Nabumetone an effective anti-inflammatory agent, lacks gastrointestinal irritancy in the rat when dosed orally for one month: comparison with tiaprofenic acid and etodolac. Melarange, R.; Gentry, C; Blower, P.R.; Toseland, CD.; Spangler, R. Eur. J. Rheumatol. Inflamm. 1994, 14, 15-22) (see Figure 4).
  • the rats received either oral indomethacin at doses of 10 mg/kg or [Cu 2 (Indo) 4 (DMF) 2 ] at doses of 13.3 mg/kg via gavage. Since [CU 2 (LKIO) 4 (DMF) 2 ] consists of a copper moiety and an indomethacin moiety, a higher dose of this compound was given so that an equivalent amount of the NSAID moiety was being delivered as in the indomethacin-treated rats.
  • the compounds were suspended in 2% carboxymethylcellulose. Rats were deprived of food, but not water, for 18 h and were administered indomethacin, [Cu 2 (Indo) 4 (DMF) 2 ] or vehicle.
  • Sucrose permeability changes were measured using a previously reported method (Sucrose urinary excretion in the rat using a simple assay: a model of gastroduodenal permeability. Davies, N.M.; Co ⁇ igan, B.W.; Jamali, F. Pharm. Res. 1995, 12, 1733-6).
  • Rats (n 4 for each treatment) were deprived of food, but not water, for 18 h and fasted overnight.
  • the rats received either oral indomethacin at doses of 10 mg/kg or [Cu 2 (Indo) 4 (DMF) 2 ] at doses of 13.3 mg/kg via gavage.
  • an aqueous solution (0.5 mL) containing 0.5 g/mL of sucrose was administered orally to each rat.
  • Urine was collected 0-24 h following the administration of the sucrose solution.
  • Relative permeability was determined by calculating the sucrose present in each urine sample as a percent of the administered dose (see Figure 3).
  • Rats (» 4 for each treatment) received either oral indomethacin at doses of 10 mg/kg or [Cu 2 (Indo) 4 (DMF) 2 ] at doses of 13.3 mg/kg via gavage.
  • oral indomethacin at doses of 10 mg/kg or [Cu 2 (Indo) 4 (DMF) 2 ] at doses of 13.3 mg/kg via gavage.
  • the animals were sacrificed 24 h after dosing and the intestines removed. A vertical mid-line abdominal incision was made, and the entire length of the small intestine was isolated, excised, and examined extending 10 cm distal to the ligament of Treitz to the ileocecal junction. A 26 G needle attached to 5-mL syringe was used to flush the intestine in order to avoid distension.
  • Intestinal ulceration was determined by measuring the length of lesions in millimetres using digital callipers and the lengths of all lesions observed in each intestine summed (NO-naproxen vs. naproxen: ulcerogenic, analgesic and antiinflammatory effects. Davies, N.M.; Roseth, A.G.; Appleyard, CB. ; et al. Aliment. Pharmacol. Ther. 1997, 11, 69-79) (see Figure 5).
  • tissue sections were obtained from damaged areas for histology. Tissue sections were embedded in plastic using a commercially available kit (JB-4 embedding kit, Polysciences. Inc. Warrington, PA). Embedded tissues were cut to thin sections (1-1.5 ⁇ m) and the sections were stained with Lee's methylene blue- basic fuchsin for 30 seconds. Sections were then examined by light microscopy.
  • Rats (n 4 for each treatment) received either oral indomethacin at doses of 10 mg/kg or [Cu 2 (Indo) 4 (DMF) 2 ] at doses of 13.3 mg/kg via gavage.
  • 0.5 rnL of a solution containing 10 ⁇ Ci/mL Of 51 Cr-EDTA was administered orally following the dose of placebo or NSAID.
  • Rats were housed in special metabolic cages where urine and faeces were collected separately. Urine was collected 0-24 h following the administration Of 51 Cr-EDTA. The urine was collected in cups and transferred to scintillation vials.
  • Urine samples were counted by a gamma counter Beckman Gamma 8000 (Irvine, California) for 1 min in a counting window scanning within a range of 0-2 MeV. At least two standards of 100 ⁇ L of the administered 51 Cr-EDTA solution were counted with every set of urine samples. Relative permeability was determined by calculating the activity present in each urine sample as a percent of the administered dose after correcting for background radiation (Anti-inflammatory drug-induced small intestinal permeability: the rat is a suitable model. Davies, N.M.; Wright, M.R.; Jamali, F. Pharm. Res. 1994, U(Il), 1652-6) (see Figure 6).
  • Rats (n 4 for each treatment) received either oral indomethacin at doses of
  • Quantitative polymerase chain reaction (QPCR) was used as previously described (Chemotherapy induced gastrointestinal toxicity in rats: involvement of mitochondrial DNA, gastrointestinal permeability and cyclooxygenase-2. Yanez, J.A.; Teng, X.W.; Roupe,
  • DNA was isolated from afflicted intestinal tissue using Qiagen® genomic tip and genomic DNA buffer set kit for mammalian DNA extractions (Valencia, CA, USA).
  • DNA quantitation utilized the PicoGreen® dsDNA Quantitation Kit (Molecular Probes, Eugene, OR, USA). Picogreen® was used to quantify dsDNA fragment.
  • QPCR involved the use of GeneAmp XL PCR kit (Applied Biosystems, Branchburg, NJ, USA) and dNTPs (Pharmacia, Peapack, NJ, USA). Primers were based on sequences already optimized by Van Houten (Analysis of gene-specific DNA damage and repair using quantitative polymerase chain reaction.
  • Rats (n 3-5 for each treatment) received either oral indomethacin at doses of 3 or 10 mg/kg or [Cu 2 (LIdO) 4 (DMF) 2 ] at doses of 3.8-13.3 mg/kg. Rats were housed in special metabolic cages where urine and faeces were collected separately 0-24 h after administration. Sodium, potassium, chloride and phosphate were assayed at the
  • indomethacin induced statistically significant gastric and intestinal damage in the rat at 10 mg/kg.
  • [Cu 2 (Indo) 4 (DMF) 2 ] administration at an equivalent dose of Indo, significantly attenuated the ulcerogenic properties and renal toxicity of the parent compound (see Figures 1-9).
  • Acute administration of ulcerogenic doses of indomethacin also resulted in decreased urinary excretion of Na , K + , and Cl and increased urinary excretion of NAG and phosphate (see Table 2, Figure 10).
  • Acute administration of [CU 2 (LKIO) 4 (DMF) 2 ] also decreased Na + , K + , and Cl but did not result in an increase in urinary NAG or phosphate excretion.
  • indomethacin indomethacin in a coordination complex with copper also modulates the gastrointestinal permeability. This, therefore, limits bacteria translocating across the intestinal mucosa through tight junctions of enterocytes and consequently, there is less ulceration and the sequelae of tissue damage in terms of up-regulated acute phase proteins such as haptoglobin and caecal haemoglobin and oxidative damage to the enterocytes.
  • composition comprising the [Cu 2 (Indo) 4 (OH 2 ) 2 ] complex in MCT oil was prepared for subcutaneous and intramuscular injections.
  • the composition comprised the following ingredients: Ingredient: Amount:
  • Tetraglycol is the solvent; Delios V MCT oil is a medium chain triglyceride oil.
  • the composition was prepared as follows:
  • the composition was a single-phase dark green oil immiscible in water.
  • the composition contained >95% of Indo in the composition as part of the dimer ([Cu 2 (Indo) 4 (OH 2 )2] as shown by EPR spectroscopy.
  • a similar composition containing IndoH in MCT oil was prepared by the same process using IndoH instead of ([Cu 2 (Indo) 4 (OH 2 ) 2 ].
  • 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 ).
  • composition containing IndoH alone resulted in small intestinal ulceration in all four rats at 7.5 mg/kg and greater ulceration than that observed at 10 mg/kg of Indo for the composition containing [Cu 2 (Indo) 4 (OH 2 ) 2 ].
  • AU gastric side-effects could be easily prevented, even at the very high dose of 20 mg/kg of Indo (administered using the composition containing [Cu 2 (Indo) 4 (OH 2 ) 2 ]) if the rats were not fasted, but at these high concentrations small intestinal ulceration was substantial.
  • composition containing [Cu 2 (Indo) 4 (OH 2 ) 2 ] in MCT oil has a similar efficacy and safety profile in rats as those observed following subcutaneous injections, although the efficacy for treatment of inflammation is higher in the plateau region of the dose-response curve.
  • compositions containing [Cu 2 (Indo) 4 (OH 2 ) 2 ] and IndoH have similar efficacy
  • the composition containing [Cu2(Indo) 4 (OH 2 )2] in MCT oil resulted hi less GI toxicity.
  • compositions containing the complex [Cu 2 (Indo) 4 (OH 2 ) 2 ] in MCT oil have considerable efficacy, with the latter mode of administration being more efficacious. If the composition was delivered as a physical mixture of a Cu salt and IndoH or the composition caused the complex to dissociate with the release of free Indo, then toxicity effects similar to those of IndoH are expected.
  • mice were pre-medicated with a sedative, administered in the form of subcutaneous acetylpromazine (2 mg/kg) and atropine sulfate (0.2 mg/kg). This occurred prior to venepuncture, surgery and sacrifice.
  • animals received an intramuscular injection of ketamine (7.5 mg/kg) and xylazine (3 mg/kg) and were then maintained with isofluorane (4-5% for induction and 1.5-2% for maintenance).
  • Analgesia was supplied by administration of buprenorphine IM shortly after induction of GA, and repeated 8 hourly until sacrifice if the animal appeared to have wound discomfort.
  • Local anaesthetic was applied at the wound site during the procedure and after wound closure topical antiseptic wound coverage was applied.
  • each animal was placed on soft bedding in a clean recovery cage with a heating lamp.
  • Analgesia was supplied by administration of buprenorphine IM shortly after induction of GA, and repeated 8 hourly until sacrifice if the animal appeared to have wound discomfort.
  • Local anaesthetic was applied at the wound site during the procedure and after wound closure topical antiseptic wound coverage was applied. Animals were given normal rabbit chow throughout the study. Food was withheld one hour prior to general anaesthesia and animals were individually housed in floor pens.
  • Heparin 100 U/kg was administered prior to sacrifice. An aliquot of 3 mL of blood was sampled from the marginal ear vein prior to entry in to the study (ie. before the commencement of drug treatment), at the time of collar implantation and immediately prior to sacrifice. Blood pressure was also recorded at these times for each animal.
  • the carotid arteries were removed from all animals following sacrifice. A proximal non-collared segment of artery was also removed from each to serve as a control. The arteries were placed in physiological buffer and the collar and fatty tissue surrounding the arteries was removed. The segments were divided into four rings. The first ring was assessed fresh for the presence of oxidative stress. The second ring was frozen in fixative solution for later analysis of inflammatory activity by immunohistochemistry. The third and fourth rings were snap frozen in liquid nitrogen for analyses at a later date for levels of mRNA and by vibrational and X-ray microprobe techniques for biochemical changes. Blood was assessed for drug concentrations, platelet aggregation and markers of renal toxicity.
  • the stomach and small intestine were also thoroughly examined postmortem for evidence of gastro-intestinal ulceration.
  • the stomach was excised and opened by incision along the greater curvature.
  • the stomach was then rinsed, submerged in 10% formaldehyde for 1 h and examined to determine the extent of macroscopic gastric damage. The damage was reported as the summation of the area of macroscopic ulcerations (mm 2 ).
  • the small intestine was examined at 24 h after dosing, with the entire small intestine excised and flushed with water to expel the intestinal contents.
  • the small intestine was examined from 10 cm distal to the ligament of Treitz to the ileocecal junction and damage was likewise reported as the summation of the area of macroscopic ulcerations (mm ).
  • metal-NSAIDs [Cu 2 (Indo) 4 (OH 2 ) 2 ] (Cu-Indo), [Cu(ACM) 2 (OH 2 ) 2 ] (Cu-ACM), [Zn(Indo) 2 (OH 2 ) 2 ] (Zn-Indo), [Zn(ACM) 2 (OH 2 ) 2 ] (Zn-ACM) were used in this study.
  • Example 5 Prior to carotid surgery the animals were sedated with subcutaneous acetylpromazine (0.5 mg/kg), then anesthetized with inhaled isofluorane (4-5% for induction and 1.5-2% for maintenance).
  • the left common carotid artery was exposed surgically and cleared of connective tissue along a 30-mm length.
  • the hollow, non-occlusive, silastic, peri-arterial collar (length, 20 mm; internal diameter along bore, 4mm; internal diameter at ends, lmm) was positioned around the artery and held in place with a nylon sleeve. The space inside the collar was again filled with sterile saline (0.9%, wiv).
  • VCAM-I and ICAM-I antibodies (gifts from Dr M. Cybulsky, University of Toronto) were used to assess endothelial expression of VCAM-I and ICAM-L.
  • the antibodies were diluted in TBS (0.01 M Tris, 0.15 M NaCl, 0.006% (w/v) NaN 3 and 0.005% (w/v) EDTA-Na 2 , pH 7.4) containing 10% (IA) heat-inactivated horse serum.
  • the diluted antibody was applied to the sections, which were then incubated for 1 hr at room temperature.
  • the sections were then washed twice with TBS, incubated with 300 ⁇ l of the Dalcocytometim Envision HRP system for 30 min at room temperature, then developed as instructed by the manufacturer for 3 min with DAB solution (DAKO Australia Pty, Ltd). The sections were lightly counterstained with haematoxylin. The specificity for anti-rabbit ICAM-I or VCAM-I antibody was determined by the use of an isotype control (irrelevant Ig).
  • Chronic treatment with the drugs is also likely to be beneficial in the prophylaxis of chronic cardiovascular conditions, since there is evidence that Cu supplementation at the levels used in these studies is advantageous in reducing cardiovascular and other degenerative diseases as many people have insufficient Cu hi their diet, which is a risk factor in such diseases.
  • Cu supplementation at the levels used in these studies is advantageous in reducing cardiovascular and other degenerative diseases as many people have insufficient Cu hi their diet, which is a risk factor in such diseases.
  • indobufen analogs of these complexes [Cu 2 (Indob) 4 L 2 ] and [Cu(Indob) 2 L 2 ] would have a three-fold remedial effect in the prophylaxis and treatment of cardiovascular conditions.
  • beneficial effects of Cu as described above; the anti-inflammatory effect of indobufen; and anti-thrombotic effect of indobufen, while simultaneously reducing the GI toxicity (Endoscopic evaluation of the effects of indobufen and aspirin in healthy volunteers. Marzo A; Crestani S; Fumagalli I; Giusti A; Lowenthal D T, Am. J. Therapeutics (2004), 11, 98-102.

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Abstract

L'invention concerne des méthodes de prophylaxie ou de traitement d'une inflammation cardio-vasculaire chez un mammifère, qui consistent à administrer une quantité thérapeutiquement efficace d'un complexe d'un métal et d'un carboxylate, ou d'un dérivé de carboxylate, présentant une activité anti-inflammatoire.
PCT/IB2007/000778 2006-03-27 2007-03-27 Prophylaxie ou traitement d'une inflammation cardio-vasculaire WO2007110755A1 (fr)

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AU2006901557A AU2006901557A0 (en) 2006-03-27 Method for prophylaxis or treatment of cardiovascular inflammation
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US60/830,203 2006-07-11
AU2006905170A AU2006905170A0 (en) 2006-09-19 Metal complexes having anti-inflammatory activity
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AU2006905265A AU2006905265A0 (en) 2006-09-22 Metal complexes having anti-inflammatory activity II
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AU2006905267A AU2006905267A0 (en) 2006-09-22 Metal complexes having anti-inflammatory activity
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