WO2007109844A1

WO2007109844A1 - Anti-inflammatory metal complexes

Info

Publication number: WO2007109844A1
Application number: PCT/AU2007/000376
Authority: WO
Inventors: Peter Lay; Trevor Hambley
Original assignee: Medical Therapies Limited
Priority date: 2006-03-24
Filing date: 2007-03-26
Publication date: 2007-10-04
Also published as: WO2007109843A1

Abstract

There are described metal complexes of anti- inflammatory ligands useful in the treatment of one or more of inflammation, cancer, diabetes, cardiovascular and other conditions.

Description

ANTI-INFLAMMATORY METAL COMPLEXES

FIELD OF THE INVENTION

The invention relates to metal complexes of inert oxidations states . The compounds find application, in the prophylaxis and treatment of inflammation, cancer, pain, microbial and viral infections, and wound healing amongst others.

BACKGROUND

Non-steroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of a variety of inflammatory conditions in humans and animals. NSAIDs are, for example, used to treat inflammatory conditions such as rheumatoid arthritis, osteoarthritis, acute musculoskeletal disorders (such as tendonitis, sprains and strains), lower back pain (commonly referred to as lumbago), and inflammation, pain and oedema following surgical or non-surgical procedures. However, many NSAIDs cause adverse effects in humans and animals, particularly adverse gastrointestinal (GI) effects.

Indomethacin (IndoH) is a NSAID and is effective in treating inflammatory conditions in humans and animals. The structure of indomethacin is as follows:

However, indomethacin can cause severe adverse gastrointestinal effects in humans and animals, particularly when administered orally. In humans, oral administration of indomethacin can cause ulcerations in the oesophagus, stomach, duodenum and intestines, and some fatalities have been reported. 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) cardiovascular effects (fluid retention and peripheral oedema), (c) ocular effects (corneal deposits and retinal disturbances), (d) central nervous system effects (headaches and dizziness), (e) masking of infections due to antipyretic properties, (f) renal effects (as with other NSAIDs, there have been reports of acute interstitial nephritis with hematuria, proteinuria and, occasionally, nephrotic syndrome in patients receiving long-term administration of indomethacin). Studies have also shown that administration of indomethacin by other routes, e.g. as a suppository or by topical application (e.g. Amico-Roxas, M.; Matera, M.; Caruso, A.; Puglisi, G.; Bernardi, R.; Rinaldo, G. Rivista Europea per Ie Scienze Mediche e Farmacologiche 1982, 4, 199-204), results in adverse effects.

These adverse effects have limited the use of indomethacin in the treatment of inflammation in humans and animals.

It has been reported that dinuclear metal complexes of indomethacin (i.e. complexes containing two metal coordination centres) cause less adverse gastrointestinal effects, and result in improved uptake of the drug, compared to the free indomethacin. For example, the oral administration of the dinuclear copper(II) complex of indomethacin, bis(Λ^,Λ^-dimethylformamide)tetrakis-μ-(O, O '-Ιndo)dicopper(II) ([Cu₂(Indo)₄(DMF)₂], Indo is the deprotonated form of indomethacin), has been found to cause less gastrointestinal toxicity than indomethacin. The mechanism of the reduced gastrointestinal toxicity has not been elucidated, but is believed to be due to reduced interaction of the indomethacin with the COX- 1 enzyme in the gastrointestinal tract. Compositions containing this complex sold under the name Cu-Algesic have been used in veterinary practice in Australia, New Zealand, South Africa and other countries. These compositions are in the form of a tablet or a paste.

Complexes of copper and dithiocarbamate have previously been studied for the treatment of melanoma. The mechanism proposed for the anti-melanoma effect of such complexes is that both the copper and the ligand affect the intracellular redox status, which makes melanoma cells more susceptible to these drugs because of the susceptibility of melanoma cells to apoptosis induced by reactive oxygen species.

However, it appears that copper is not essential for the anti -melanoma effect as complexes of the redox-inactive Zn(II) and dithiocarbamate were also found to be effective (Cen, D.; Gonzalez, R. L; Buckmeier, J. A.; Kahlon, R. S.; Tohidian, N. B.; Meyskens, F. L., Jr. MoI. Cancer Ther. 2002, 1, 197-204). It therefore seems that the presence of the dithiocarbamate ligand is necessary for the complex to exhibit anti- melanoma effects. In mouse models of melanoma no response to indomethacin was observed (Indomethacin and telomerase activity in tumor growth retardation. Lonnroth, C; Andersson, M.; Lundholm, K. Int. J. Oncology 2001, 18, 929-937). A minimal effect of indomethacin on human melanoma lung metastases in nude mice models has been reported, although a combination of interleukin-2 (IL-2) with indomethacin led to a cure of the metastases in some cases (Cure of human melanoma lung metastases in nude mice with chronic indomethacin therapy combined with multiple rounds of IL-2: characteristics of killer cells generated in situ. LaIa, P. K.; Elkashab, M.; Kerbel, R. S.; Parhar, R. S. Int. Immunol. 1990, 2, 1149-1158).

A range of human clinical trials have been conducted on the effects of indomethacin in combination therapy for the treatment of cancer (IL-1/indomethacin, IL-2/indomethacin, or IL-2/ranitidine/ indomethacin). While there is some conflict as to whether there is any benefit of indomethacin in these clinical trials, the majority of the trials conclude that the benefit is marginal and that it contributes to adverse side effects such as renal toxicity (Phase II trial of interleukin-1 alpha and indomethacin in treatment of metastatic melanoma. Janik, J. E.; Miller, L. L.; Longo, D. L.; Powers, G. C; Urba, W. J.; Kopp, W. C; Gause, B. L.; Curti, B. D.; Fenton, R. G.; Oppenheim, J. J.; Conlon, K. C; Holmlund, J. T.; Sznol, M.; Sharfman, W. H.; Steis, R. G.; Creekmore, S. P.;

Alvord, W. G.; Beauchamp, A. E.; Smith, J. W., 2nd. /. Natl. Cancer Inst. 1996, 88, 44- 49; Sustained indomethacin and ranitidine with intermittent continuous infusion of interleukin-2 in advanced malignant melanoma: a phase II study. Mertens, W. C; Bramwell, V. H.; Banerjee, D.; Gwadry-Sridhar, F.; LaIa, P. K. Clin. Oncol. (Roy. College Radiol. (Gt Brit.)) 1993, 5, 107- 113; Indomethacin, ranitidine, and interleukin-2 in melanoma. Hamblin, T. J. Lancet 1992, 340, 8826; Marginal effect and interfered with treatment. Randomized trial of recombinant alpha 2b-interferon with or without indomethacin in patients with metastatic malignant melanoma. Miller, R. L.; Steis, R. G.; Clark, J. W.; Smith, J. W. 2nd; Cram, E.; McKnight, J. E.; Hawkins, M. J.; Jones, M. J.; Longo, D. L.; Urba, W. J. Cancer Res. 1989, 49, 1871-1876; Repetitive weekly cycles of interleukin-2. II. Clinical and immunologic effects of dose, schedule, and addition of indomethacin. Sosman, J. A.; Kohler, P. C; Hank, J. A.; Moore, K. H.; Bechhofer, R.; Storer, B.; Sondel, P. M. /. Natl. Cancer Inst. 1988, 80, 1451-1461). NSAIDs, including indomethacin and related NSAIDs, have been reported to have a chemoprotective effect against colorectal and other cancers although results from epidemiological studies have been variable (Turchanowa, L. , Dauletbaev, N., Milovic, V., Stein, J. Eur. J. Clin. Invest. 2001, 31, 887-893; Collet, J.-P.; Sharpe, C; BeIzUe, E.; Boivin, J.-F.; Hanley, J.; Abenhaim, L. Brit. J. Cancer 1999, 81, 62-68). It has also been reported that NSAIDs may enhance the anti-cancer activities of known anti-cancer drugs (Touhey, S.; O'Connor, R.; Plunkett, S.; Maguire, A.; Clynes, M. Eur. J. Cancer 2002, 38, 1661-1670). However, in some models of colorectal cancer, indomethacin was reported to increase mortality and metastases compared to control animals (Danzi, M.; Ferulano, G. P.; Abate, S.; Califano, G. Carcinogenesis 1984, 5, 287-289). Moreover, although other studies have reported anti-cancer activity in chemically induced colorectal cancers in rats, no such effect was found when a cultured cell line was injected into rats (Olsson, N. O.; Caignard, A.; Martin, M. S.; Martin, F. Int. J. Immunopharmac. 1984, 6, 329-334). More recent research has indicated that advanced solid tumour patients treated with indomethacin survive twice as long as do such patients who receive supportive care alone (Blanke, C. D. Oncology (Williston Park, N.Y.) 2002, 16 (4 Suppl 3)).

Cu-salicylate complexes (ie., [Cu₂(3,5-di-ϊ5^fo-propylsalicylate)₄L₂]) have been shown to have a limited effect (no-statistically significant difference) in tumorogenisis in female C3H/HeNCR mice models of mammary cancer (Crispins, Jr., C. G.;

Sorenson, J. R. J. Anti-Cancer Res. 1992, 12, 1271-1273). Although these complexes had anti-cancer activity against reticulum cell sarcoma in SJL/J mice if injected subcutaneously, they were toxic if injected via the i.p route (Crispins, Jr., C. G.; Sorenson, J. R. J. Anti-Cancer Res. 1988, 8, 77-79). In addition, the level of Cu in Cu- salicylate complexes required to have a therapeutic or strong prophylaxic effect is not appropriate for daily use in terms of potential Cu toxicity. Similarly, while IndoH has been included in topical formulations, it has not been shown to have a significant effect on either melanomas or squamous cell carcinomas when applied topically, and high concentrations of NSAIDs such as IndoH, can induce significant systemic toxicity when applied topically.

The NSAID aspirin (acetylsalicylic acid) is widely used in low dosages to prevent cardiovascular events and is generally prescribed as a standard treatment for prophylaxis of cardiac disease in high-risk patients. However, 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). In recent years there have also been reports of increased risk of significant adverse side-effects associated with the long term use use of COX-2 selective NSAIDs. Data, for example, has suggested that COX-2 inhibitors such as rofecoxib, celecoxib, valecoxib and parecoxib may be associated with an increased risk of thrombotic events ("Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention", Scott, D. et al, NEJM, 2005, 352, 1071-1080; "Complications of the

COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery", NEJM, 2005, 352, 1081-1091; "Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial", NEJM, 2005, 352, 1092-1102). By contrast, the latest evaluation of all double blind clinical trials on non-selective NSAIDs showing some cardiovascular events has not been able to discern any significant differences between placebo controls and the NSAIDs (Salpeter, S. R.; Gregor, P.; Ormiston, T. M.; Whitlock, R.; Raina, P.; Thabane, L.; Topol, E. L Am. J. Med. 2006, 119, 552-559).

The literature further indicates that at least some transition metals may have a role in the development of cardiovascular disease at the molecular level. In particular, both copper and zinc have been shown to accumulate in atherosclerotic plaque at a higher rate than in surrounding vascular tissue ("Relationship of calcium, magnesium, zinc and copper concentrations in the arterial wall and serum in atherosclerosis obliterans and aneurysm", Iskra, M., Patelski, J., Majewski, W., J. Trace Elem. Med. Biol., 1997, 11, 248-252) suggesting that they play a role in cardiovascular pathogenesis.

SUMMARY OF THE INVENTION

The present invention relates to inert metal complexes having anti- inflammatory activity and their use in the prophylaxis or treatment of cancer, pain, diseases and conditions associated with inflammation or which have an inflammatory component, microbial and viral infections, and other diseases and conditions. In a first aspect of the invention there is provided a metal complex of the following formula (1):

wherein

M is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent metal ion having an inert oxidation state; each L¹ is independently selected and is a monodentate or bidentate carboxylate or monodentate amide ligand (O or N bound), or a monodentate ligand linked to a NSAID by an ester or amide linkage, having anti -inflammatory activity, and at least one ligand L¹ is other than a salicylate or a derivative of a salicylate; each L² is independently selected and is a monodentate or a polydentate ligand; m is 1, 2, 3 , 4, 5, or 6; n is 1, 2, 3, 4 or 5; and p is the charge of the complex.

In another aspect of the invention there is provided a metal complex of the following formula (2):

[M_q(L^l)_m(L\(L\f (2) wherein each M is independently selected from monovalent, divalent, trivalent, tetravalent, pentavalent and hexavalent metal ions, and has an inert oxidation state; each L¹ is independently selected and is a monodentate or bidentate carboxylate or monodentate amide ligand (O or N bound), or a monodentate ligand linked to a NSAID by an ester or amide linkage, having anti -inflammatory activity, and at least one ligand L¹ is other than a salicylate or a derivative of a salicylate; each L is independently selected and is a monodentate or a polydentate ligand, or an amide ligand (O or N bound), having anti-inflammatory activity; each L³ is independently selected and is a bridging ligand, such as an oxo, hydroxo, carboxylate (eg., a NSAID), halide, or other bridging group. m is an integer from 0 to 5q; n is an integer from 1 to 5q; p is the charge of the complex; q is an integer between 2 and 20 inclusive; r is a integer from 1 to 60.

In at least some embodiments, ligand L² of a complex of formula (2) can be a monodentate or polydentate ligand including a chelating derivative of a carboxylate. The polydentate chelating derivative can be bidentate. In another aspect of the invention there is provided a metal complex of the following formula (3):

[M(L¹)_m(L²)_n(L⁴)_o]^p (3) wherein M is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent metal ion having an inert oxidation state; each L¹ is independently selected and is a monodentate or bidentate carboxylate or monodentate amide ligand (O or N bound), or a monodentate ligand linked to a NSAID by an ester or amide linkage, having anti -inflammatory activity, and at least one ligand L¹ is other than a salicylate or a derivative of a salicylate; each L² is independently selected and is a monodentate or a polydentate ligand; each L⁴ is independently selected and is a chelating derivative of a carboxylate, or amide ligand (O or N bound), having anti-inflammatory activity; m is 1, 2, 3, 4 or 5; n is 0, 1, 2, 3 or 4; o is 1, 2, or 3; and p is the charge of the complex.

Any suitable monodentate or bidentate carboxylate(s), R CO₂ ^" with antiinflammatory activity, non-chelating amide derivative R CONR²R³ (or its deprotonated form thereof, R¹CON(R²)^"), or non-chelating ester derivative R¹COOR⁴ of a NSAID that forms a co-ordination bond of the complex through a functional group of R , (as described below) can be employed as ligand L¹ in metal complexes of formulae (1) to (3). Typically, the carboxylate having anti-inflammatory activity is a non-steroidal antiinflammatory drug (NSAID). Particularly preferred examples of carboxylate NSAIDs include the deprotonated anionic forms of the following compounds:

Suprofen ((+)-α-methyl-4-(2-thienylcarbonyl)phenylacetic acid ("SupH")); Tolmetin (l-methyl-5-(p-toluoyl)-lH-pyrrole-2-acetic acid ("TolΗ")); Naproxen (β-methoxy-α-methyl^-naphthaleneacetic acid ("NapH"));

Ibuprofen ((+)-α-methyl-4-(isopropylmethyl)benzeneacetic acid ("IbuH"));

Flufenamic Acid ((Λf-trifluoromethylphenyl)anthranilic acid ("FlufenH"));

Niflumic Acid ((2-(3-trifluoromethyl)phenylamino)-3-pyridinecarboxylic acid ("NifH"));

Diclofenac (2-[(2,6-dichlorophenyl)amino]phenylacetic acid ("DicH"));

Indomethacin (l^Φchlorobenzoy^-S-methoxy^-methyl-lH-indole-S-acetic acid ("IndoH"));

Acemetacin ( 1 -(4-chlorobenzoyl)-5-methoxy-2-methylindole-3 -acetic acid carboxymethyl ester ("ACMH")); and

Ketorolac ((+)-5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxyric acid,

("KetH") 2-amino-2-(hydroxymethyl)-l,3-propanediol). Other suitable NSAIDs include:

Carprofen (6-chloro-α-methyl-9H-carbazole-2-acetic acid); Etodolac (l,8-diethyl-l,3,4,9-tetrahydro-pyrano[3,4-b]indole-l-acetic acid);

Fentiazac (4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetic acid);

Flurbiprofen (2-fluoro-α-methyl-[l,l'-biphenyl]-4-acetic acid);

Ketoprofen (3-benzoyl-α-methylbenzeneacetic acid);

Oxaprozin (4,5-diphenyl-2-oxazolepropanoic acid); Pranoprofen (α-methyl-5H-[l]benzopyrano[2,3-b]pyridine-7-acetic acid);

Sulindac ( ( 1 Z)- 5 -fluoro -2-methyl- 1 - [ [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). Any suitable chelating derivative of these carboxylates can be employed as ligand L⁴ in a metal complex of formula (3).

Preferably, the carboxylate or amide with anti-inflammatory activity will be selected from the group consisting of indomethacin (IndoH), ibuprofen, naproxen, dichlofenac, acemetacin, ketorolac, or non-chelating amide or ester derivative thereof. Suitable amide ligands, L², include ligands of the formula R¹CONR²R³ formed by coupling the amino group NHR²R³ to a carboxylic NSAID R¹CO₂H (or its deprotonated form) having anti- inflammatory activity, wherein R² is H, an alkyl, or an aryl group wherein the alkyl or aryl group is optionally substituted, and R³ is H, an alkyl, an aryl, or a heterocycle and the alkyl or aryl group is optionally substituted by one or more functional groups such as an amine or heterocycle that acts as a monodentate ligand to a metal ion of the complex. In one or more forms, R is H.

Other ligands (eg., L² of formulae (1), L³ of formulae (2) and ligand L³ of formulae (3)) in the above metal complexes can also independently have antiinflammatory and/or anti-cancer, and/or anti-diabetic, and/or anti-microbial activities . These ligands may also assist or alternatively, have wound healing and/or angiogenic activity, or offer protection from radiation damage (solar or ionising radiation)..

The metal ion of a metal complex of the invention will typically be a transition metal ion (preferably, ruthenium(II), chromium (III), platinum(IV), ruthenium(III), rhodium(III), cobalt (III), ruthenium(IV) ions).

In this specification, the inclusion of the "H" at the end of an abbreviation for a carboxylate (e.g., any one of the carboxylic acid listed above) or amide is used to refer to the uncharged form of the carboxylate or amide. For example, "IndoH" refers to the uncharged form of indomethacin, and "Indo" is used to refer to the deprotonated anionic form of indomethacin. Similarly, "ACMH" refers to the uncharged form of acemetacin and "ACM" refers to the deprotonated anionic form.

Acemetacin, l-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid carboxymethyl ester, is a glycolic acid ester of indomethacin. The structure of ACMH is shown below, as is the structure of Keterolac.

Acemetacin Indomethacin

Ketorolac

In another aspect of the invention there is provided a pharmaceutical composition comprising a metal complex of formula (1), (2) or (3) together with a pharmaceutically acceptable carrier or diluent.

In another aspect of the invention there is provided a method for prophylaxis or treatment of inflammation or a disease or condition mediated by inflammation or having an inflammatory component, comprising administering to a mammal in need thereof an effective amount of a metal complex of formula (1), (2) or (3).

Diseases or conditions mediated by inflammation or having an inflammatory component include diabetes and cardiovascular diseases, neurodegenerative diseases, and other conditions involving inflammation.

In another aspect of the invention there is provided a method for prophylaxis or treatment of a cancer in a mammal, comprising administering to the mammal an effective amount of a metal complex of formula (1), (2) or (3).

In another aspect of the invention there is provided a method for prophylaxis or treatment of a microbial or viral infection in a mammal, comprising administering to the mammal an effective amount of a metal complex of formula (1), (2) or (3). In another aspect of the invention there is provided a method for protecting against ionising radiation induced skin or organ damage in a mammal, comprising administering to the mammal an effective amount of a metal complex of formula (1), (2) or (3).

In another aspect of the invention there is provided an analgesic method for prophylaxis or treatment of pain in a mammal, comprising administering to the mammal an effective amount of a metal complex of formula (1), (2) or (3).

In another aspect of the invention there is provided a method for promoting wound healing or inhibiting skin or tissue aging, including the prophylaxis or treatment of wounds caused by trauma or surgery, burns, sunburn, or ionising radiation, comprising administering to a mammal an effective amount of a metal complex of formula (1), (2) or (3).

In another aspect of the invention there is provided a method for enhancing the efficacy of radiotherapy in cancer treatment, comprising administering to a mammal an effective amount of a metal complex of formula (1), (2) or (3).

In another aspect of the present invention there is provided a method for treating damaged skin, the method comprising administering to a mammal an effective amount of a metal complex of formula (1), (2) or (3).

In another aspect of the invention there is provided use of a metal complex of formula (1), (2) or (3) in the manufacture of a medicament for prophylaxis or treatment of inflammation in a mammal or a disease or condition in the mammal having an inflammatory component.

In another aspect of the invention there is provided use of a metal complex of formula (1), (2) or (3) in the manufacture of a medicament for prophylaxis or treatment of a cancer in a mammal.

In another aspect of the invention there is provided use of a metal complex of formula (1), (2) or (3) in the manufacture of a medicament for prophylaxis or treatment of a microbial or a viral infection in a mammal.

In another aspect of the invention there is provided use of a metal complex of formula (1), (2) or (3) in the manufacture of an analgesic medicament for prophylaxis or treatment of pain in a mammal.

In another aspect of the invention there is provided use of a metal complex of formula (1), (2) or (3) in the manufacture of a medicament for wound healing, or inhibition of skin or tissue aging, or damage from solar or ionising radiation in a mammal.

Metal complexes as described herein can be administered for prophylaxis or treatment of a disease, condition, infection or the like alone, or in combination with other chemotherapeutic agents or treatments for the particular disease or condition being treated. Metal complexes as described herein can be administered for the simultaneous prophylaxis or treatment of more than one disease, condition, infection or the like alone, or in combination with other chemotherapeutic agents or treatments for the particular diseases or conditions being treated. One of the issues associated with the use of non-selective NSAIDs, such as indomethacin and their derivatives and complexes is GI and renal toxicity. Metal complexes embodied by the invention can be incorporated into formulations that minimize their decomposition by biological fluids, such as gastric acid, or change the profile of absorption of the bioactives as exemplified in International Patent Application No. PCT/AU2005/000442, to reduce GI and/or renal toxicity while substantially maintaining or enhancing efficiency of the complexes The use of all such formulations in methods of the invention is expressly encompassed.

One or more embodiments of metal complexes of the invention can also have reduced toxicity and/or increased efficacy from slow release mechanisms, and/or target diseases and conditions characterized by hypoxia. In particular, inert metal complexes of NSAIDs or amide derivatives of NSAIDs can have enhanced stability. This can result in one or more of:

(i) a reduction in GI toxicity by increasing the stability of the drugs in the

GI tract; (ii) slow release forms of the NSAIDs to improve efficacy and safety profiles;

(iii) water-soluble, slow release forms of the NSAIDs for intravenous use; (iv) hypoxia selectivity of the metal -ions for targeting/treating certain diseases or conditions; (v) sensitivity to photoreduction for protecting against damage induced by solar and ionizing radiation and/or to enhance the efficacy of radiotherapy; and/or

(vi) the provision of chelates for delivery of metal ions and other groups that are synergistic and/or provide enhanced efficacy of the parent NSAID in its mode of action.

Complexing the NSAID with a metal as described herein can also change the absorption profile of the NSAID. The release of the NSAID from the ligand may be induced by hydrolysis of the ligand by cleaving the metal ligand bonds, and/or the ester or amide bonds; ligand substitution reactions; and/or redox catalysed substitution reactions inside cells or in regions of hypoxia. Once released, the NSAID derivative, the NSAID, and the metal may provide synergistic activities.

As an example, the reductive release of the NSAID from a metal like Ru(III) can have multiple effects. For instance, a Ru complex can exert its anti-cancer and/or anti-inflammatory activity by a combination of independent COX-2 inhibition (by both the parent NSAID and its derivatives, e.g., Indo hydrolysis product from ACM) and the anti-cancer effects of Ru once the complex decomposes at the site of a tumour. The function of the Ru, in this case, is not only to provide additional biological activity but to target the organic drugs to tumours by using its hypoxia selectivity properties .

The higher metabolic activity of certain tissues or cells can also be employed to increase the rate of ester and amide hydrolysis of the metal complexes of ester, amide derivatives of NSAIDs as a way of targeting disease states. Moreover, the positively charged inert oxidation states of metals (e.g., Pt(IV), Ru(III), Co(III)) can also be employed to selectively target mitochodria as a way of treating disease states, and all such methods are expressly encompassed by the present invention.

Moreoever, the inert metal ions, co-ligands and metal oxidation states of one or more compounds embodied by the invention may also optimise the rate of release and/or hydrolysis of the NSAID-derivative as indicated above, reduce side -effects such as GI and renal toxicities, and/or provide sufficient stability to target the disease site before the bioactives of the complex are released.

All publications mentioned in this specification are herein incorporated by reference. Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed anywhere in the world before the priority date of this application.

Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers, or steps.

The features and advantages of the present invention will become further apparent from the following detailed description of preferred embodiments.

DEFINITIONS

In this specification the term "halo" refers to fluoro, chloro, bromo or iodo.

In this specification the term "alkyl" used either alone or in a compound word such as "arylalkyl", refers to a straight chain, branched or mono- or polycyclic alkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, wo-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, amyl, iso-amyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, hexyl, 4-methylpentyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2-trimethylpropyl. Examples of cyclic alkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In this specification, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic alkyl having 3 to 12 carbons.

In this specification, the term "alkenyl" refers to a straight chain, branched or cyclic alkenyl with one or more double bonds. Preferably, the alkenyl is a C₂ to C20 alkenyl, more preferably C₂ to C₆ alkenyl. Examples of alkenyl include vinyl, allyl, 1 -methyl vinyl, butenyl, zso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methylcyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl,

1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl.

In this specification, the term "alkynyl" refers to a straight chain, branched or cyclic alkynyl with one or more triple bonds, preferably a C₂ to C20 alkynyl, more preferably a C₂ to CO alkynyl. In this specification, the term "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. When the aryl comprises a heterocyclic aromatic ring system, 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.

In this specification, the term "arylalkyl" refers to an alkyl substituted with an aryl group. An example of arylalkyl is benzyl.

In this specification, the term "bidentate ligand" refers to a ligand having two co-ordination bonds to a metal atom. Bidentate ligands include unsymmetric bidentate ligands with one weaker and one relatively stronger bond to the metal atom. In this specification, the term "monodentate ligand" refers to a ligand having a single co-ordination bond with a metal atom.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE

INVENTION

Metal complexes in one or more embodiments of the invention application find application in the prophylaxis or treatment of various diseases and conditions including inflammation, diseases and disorders characterised, mediated or involving inflammatory components such as cardiovascular, neurodegenerative, and diabetic conditions, pain, cancer, and microbial and viral infections, and the treatment of wounds, burns and skin damage, and the prophylaxis or treatment of damage induced in skin and other organs by solar or ionising radiation.

The present inventors have also surprisingly found that inert metal complexes of the invention having anti-inflammatory activity have application in preventing or treating cancers including carcinomas and other cancers, and may be more effective in preventing or treating the cancers in terms of efficacy and/or safety than the anti- inflammatory ligand(s) in the complex alone. For example, the present inventors have found that complexes of a metal and indomethacin are more effective in preventing or treating carcinomas, in terms of efficacy and/or safety, than indomethacin itself, even in cases when IndoH is completely inactive.

Examples of carboxylic acids having anti-inflammatory activity that may be utilised in metal complexes embodied by the invention include the following.

Suprofen = (+)-α-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (SupH); Tolmentin = l-methyl-5-(p-toluoyl)-lH-pyrrole-2-acetic acid (TolΗ); Naproxen = β-methoxy-α-methyl^-naphthaleneacetic acid (NapΗ); Ibuprofen = (+)-α-methyl4-(isopropylmethyl)benzeneacetic acid (IbuΗ);

Metronidazole = 2-methyl-5-nitrobenzimidazole Flufenamic Acid = (Λf-trifluoromethylphenyl)anthranilic acid (FlufenΗ);

Niflumic Acid = 2-((3-trifluoromethyl)phenylamino)-3-pyridinecarboxylic acid

(NifΗ);

Indomethacin = l-(4-chlorobenzoyl)-5-methoxy-2-methyl-lΗ-indole-3-acetic acid

(IndoH); and Diclofenac = 2-[(2,6-dichlorophenyl)amino]phenylacetic acid (DicH).

Acemetacin ( 1 -(4-chlorobenzoyl)-5-methoxy-2-methylindole-3 -acetic acid carboxymethyl ester ("ACMH")) ; and

Ketorolac ((+)-5-benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxyric acid,

Carprofen (6-chloro-α-methyl-9H-carbazole-2-acetic acid);

Etodolac (l,8-diethyl-l,3,4,9-tetrahydro-pyrano[3,4-b]indole-l-acetic acid);

Fentiazac (4-(4-chlorophenyl)-2-phenyl-5-thiazoleacetic acid);

Flurbiprofen (2-fluoro-α-methyl-[l,l'-biphenyl]-4-acetic acid); Ketoprofen (3-benzoyl-α-methylbenzeneacetic acid);

Oxaprozin (4,5-diphenyl-2-oxazolepropanoic acid);

Pranoprofen (α-methyl-5H-[l]benzopyrano[2,3-b]pyridine-7-acetic acid);

Sulindac ((I Z)-5 -fluoro -2-methyl- 1 - [ [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)

The monodentate carboxylate ligand or chelating carboxylate, R¹CO₂ ^" thereof having anti-inflammatory activity in a metal complex of formulae (1) to (3) can also be:

wherein:

R⁵ is H or halo (i.e. Cl, F, Br or I);

R R iiss HH;; aa CCii ttoo CCOO aallkkyyll,, aann aallkkeennjyl or an alkynyl, where the Ci to CO alkyl, alkenyl or alkynyl may be optionally substituted; or

wherein each R^6A is independently selected from the group consisting of H, C₁ to Ce alkyl, alkenyl, alkynyl, aryl, cycloalkyl and arylalkyl, where the Ci to C₆ alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be optionally substituted;

R is H or halo; each R⁸ is independently selected from the group consisting of halo, -CH₃, -CN, -OCH₃, -SCH₃ and -CHCH₃, where the -CH₃, -OCH₃, -SCH₃ or -CH₂CH₃ may be optionally substituted; and r is 1, 2, 3, 4 or 5.

In another embodiment, the monodentate carboxylate ligand or chelating carboxylate derivative, R CO₂ ^", thereof having anti-inflammatory activity in a metal complex of formula (1) to (3) can be:

wherein:

R⁵ is H or halo (i.e. Cl, F, Br or I);

R is H; a C₁ to CO alkyl, an alkenyl or an alkynyl, where the C₁ to Ce alkyl, alkenyl or alkynyl may be optionally substituted; or

wherein each R is independently selected from the group consisting of H, C₁ to C₆ alkyl, alkenyl, alkynyl, aryl, cycloalkyl and arylalkyl, where the C₁ to C₆ alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be optionally substituted;

R⁷ is H or halo; each R⁸ is independently selected from the group consisting of halo, -CH₃, -CN, -OCH₃, -SCH₃ and -CHCH₃, where the -CH₃, -OCH₃, -SCH₃ or -CH₂CH₃ may be optionally substituted; and r is 1, 2, 3, 4 or 5.

When R is a C₁ to Ce alkyl, an alkenyl or an alkynyl, the C₁ to Ce alkyl, alkenyl or alkynyl may be substituted with one or more substituents. The one or more substituents may, for example, be independently selected from the group consisting of halo, -OH, -COOH and -NH₂.

When R ^A is a C₁ to C₆ alkyl, an alkenyl, an alkynyl, an aryl, a cycloalkyl or an arylalkyl, the C₁ to C₆ 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 -NH₂.

When R⁸ is -CH₃, -OCH_3, -SCH₃ or -CH₂CH₃, the -CH₃, -OCH_3, -SCH₃ or - CH₂CH₃ may be substituted with one or more substituents. The one or more substituents may, for example, be independently selected from the group consisting of halo, -OH, 5 -COOH and -NH₂.

Metal complexes incorporating carboxylate ligands having inflammatory activity can be prepared by methods known in the art, or as described below. Such reactions include the substitution of a leaving group in an inert metal complex with a carboxylate group of an NSAID, or an amide group in a NSAID or an amide derivative 0 of a NSAID. This is exemplified by Example 1 in the preparation of [Co(NH₃)₅(Indo)]X₂, a complex metal of formula (1), as follows:

[M(Y)_m(L²)_n]^p + InR¹CO₂(H) → [M(L ¹MhXf + mY(H),

5 [M(Y)_m(L²)_n]^p + InR¹CONR²R³ → [M(L¹U(L²),^ + mY,

where R¹CO₂ ^" = L¹, M = Co(III), Cr(III), Ir(III), Os(III), Rh(III), Ru(III), Pt(IV).

In general, such complexes can be prepared by substitution of a weakly O coordinated, trifluoromethanesulfonato, or solvent, or other such ligands, as described for example in, Introduction to Trifluoromethanesulfonates and Trifluoromethanesulfonato- O Complexes. Dixon, N. E.; Lawrance, G. A.; Lay, P. A.; Sargeson, A. M.; Taube, H. "Inorganic Synthesis" Schreeve, J. M.; Ed.; Wiley: New York, NY, 1986; Vol. 24, 243-250. 5 Some embodiments of metal complexes of the invention can be prepared by oxidation of a lower oxidation state containing L¹ or in the presence of L¹, as exemplified by the preparation of [Pt^(Cn)₂(O₂CR)₂(OH)₂] (see Example 1).

In addition, embodiments of metal complexes of the invention can be prepared by reaction of a derivative of R¹COZ with a hydroxo or deprotonated amine ligand on O the metal, for example:

[M(0H)_m(L²)_n]^p + HiR¹COZ → [M(L¹UhW + mZ [M(NR²R³)_m(L²)_n]^P + UiR¹COZ → [M(L¹)_m(L²)_n]^P + mZ.

An example of these synthetic routes is described in: Song, R.; Kim, Kwan M.; Lee, S, S.; Sohn, Y. S. Electrophilic Substitution of (Diamine)tetrahydroxo- platinum(IV) with Carboxylic Anhydrides. Synthesis and Characterization of

(Diamine)platinum(IV) Complexes of Mixed Carboxylates. Inorg. Chem. (2000), 39, 3567-3571.

It will also be understood that metal complexes embodied by the invention can be prepared by other methods including substitution reactions of the 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. These 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:

[M(OC(R)NHR³)_m(L²)_n]^p + mX² → [M(NR³(COR))_m(L²)_n]^p"m + mHX²

In the above chemical equations, X is a conjugate base of a strong or a weak acid (eg., X can be a halide, oxyanion, carboxylate, sulfonate, etc.); X is a conjugate base of a weak acid, examples of which include oxyanions, carboxylates, amines, and N- heterocycles; Y is a leaving group, examples of which include halo, alkylsulfonato, O- bound sulfoxides, O-bound amides, aldehydes, ketones, and nitrato ligands; and R COZ is an acyl halide, anhydride or ester derivative of a NSAID..

Amide derivatives of carboxylic acids having anti-inflammatory activities can be prepared as described in International Patent Application No. WO 95/04030, or modifications thereof. See, for instance, indomethacin in the following example below (Scheme X). In this instance, R³ can be a proton, alkyl, alkenyl, alkynyl, aryl or arylalkyl group, in which case the ligand would be a monodentate O or N donor to the metal, or R³ can be a heterocycle or a substituted alkyl or aryl group that forms a monodentate bond to an inert metal ion.

water

Scheme 2

R² or R³ in these ligands can be independently chosen from H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, or heterocylic groups that do not include groups that compete with the amide ligand for coordination.

Ester derivatives of carboxylic acids having anti-inflammatory activites can be prepared by a variety of ester coupling reactions. See, for instance, the indomethacin example shown below (Scheme 3). In this example, R will be an alkyl, alkenyl, alkynyl, aryl, or arylalkyl group containing a substituent, which can act as a monodentate or bidentate ligand, e.g., a carboxylate group as in ACM, an amino group (prepared from an aminoalcohol or amino acid, such as serine or tyrosine), a heterocycle, or other substituent that bind to the metal in a monodentate fashion. agent

Scheme 3

Metal complexes embodied by the invention can also be prepared by methods outlined in Example 1 below. In at least some forms, 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 NSAIDs. In metal complexes of the invention the functional groups of the ligands may themselves bind to the metal ion, and/or other ligating groups that are linked by these functionalities can bind to the metal. In some embodiments, any of the R² or R³ groups of amide derivatives can also contain another donor group that can act as a monodentate ligand to the metal. These may, for instance, be a carboxylate group from amino acid or peptide derivatives of NSAIDs, or a RS^", thioether, phenol, amine, orjV-heterocyclic side-chain of such an amino acid or peptide derivative. It will also be understood that the R² and R³ groups can be, or contain, a large variety of functional groups that would be suitable as monodentate ligands to the metal ions of formulae (1), (2) or (3).

In some embodiments, any of the R⁴ groups of an ester derivative of a NSAID will contain a donor group that can act as a monodentate ligand. These may, for instance, be a terminal amine group from amino acid or peptide derivatives of NSAIDs, or a RS^", thioether, phenol, carboxylate, or ^-heterocyclic side-chain of such an amino acid or peptide derivative. In addition, it will be understood that the R group of these ligands can be, or contain, any of a large variety of functional groups that would be suitable as monodentate ligands to the metal ions of formulae (1), (2) or (3).

Metal complexes in at least one form embodied by the invention are complexes of the following formula ( 1 ) : [M(L¹)_m(L²)_n]^p (1) wherein

M is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent transition metal ion having an inert oxidatioin state; each L is independently selected and is a monodentate or bidentate carboxylate or monodentate amide ligand (O or N bound), or a monodentate ligand linked to a NSAID by an ester or amide linkage, having anti -inflammatory activity; each L² is independently selected and is a monodentate or a polydentate ligand; m is 1, 2, 3, 4, 5, or 6; n is 1, 2, 3, 4 or 5; and p is the charge of the complex.

In another aspect, metal complexes embodied by the invention are complexes of the following formula (2): [M_q(L¹)_m(L²)_n(L³)_r]^p (2) wherein

M is independently selected from a monovalent, divalent, trivalent, tetravalent, pentavalent and hexavalent metal ions, and has an inert oxidation state; each L is independently selected and is a monodentate or bidentate carboxylate or monodentate amide ligand (O or N bound), or a monodentate ligand linked to a NSAID by an ester or amide linkage, having anti -inflammatory activity; each L² is independently selected and is a monodentate (for example, aqua, hydroxo, oxo, halo CO, NO, amine, amide, sulfoxide, alchol, heterocycle) or a polydentate ligand, (for example, an amine, amino acid, hydroxyacid, peptide, heterocycle, and combinations thereof); each L is independently selected and is a bridging ligand, for example an oxo, hydroxo, carboxylate (eg., an NSAID), halide, or other bridging group; m is a number from 0 to 5q; n is a number from 1 to 5q; p is the charge of the complex; q is typically a number between 2 and 20 inclusive; and r is a number from 1 to 60. In some embodiments, metal complexes of the invention in at least one form are complexes of the following formula (3):

[M(L¹)_m(L²)_n(L⁴)_o]^p (3)

5 wherein

M is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent transition metal ion having an inert oxidation state; each L¹ is independently selected and is a monodentate or bidentate carboxylate or monodentate amide ligand (O or N bound), or a monodentate ligand linked to a ester a 0 NSAID by an ester or amide linkage, having anti -inflammatory activity; each L² is independently selected and is a monodentate or a polydentate ligand; each L⁴ is independently selected and is a chelating derivative of a carboxylate, or amide ligand (O or N bound), having anti-inflammatory activity; m is 1, 2, 3, 4 or 5; 5 n is 0, 1, 2, 3 or 4; o is 1, 2, or 3; and p is the charge of the complex.

One or more of the ligands L¹ to L⁴ of a complex of formula (3) in any combination can also form dimeric, trimeric, tetrameric, oligomeric or polymeric 0 complexes with one or more metal ions.

Examples of ligand L¹ which can be used in metal complexes of formulae (1) to (3) include: include, but are not limited to the conjugate base, R CO₂ ^", of the NSAIDs, suprofen, tolmetin, naproxen, ibuprofen, flufenamic acid, niflumic acid, diclofenac, indomethacin, acemetacin, and ketorolac, which can be mondentate or bidentate ligands; 5 R^1ACθ₂ ^~ derivatives formed, for instance, from linkages to the above NSAIDs by ester coupling of amino acids (such as serine or tyrosine), amide coupling of amino acids, ester coupling of hydroxyacids; R¹CONR²R³ and R¹CON(R³)^" formed by the coupling of amino groups NHR²R³ to the above NSAIDs wherein R² is H, an alkyl, or an aryl group, and R³ is H, an alkyl, an aryl, or a heterocycle, and the alkyl or aryl group can be O optionally substituted by a functional group such as an amine or heterocycle that can act as a monodentate ligand to the metal ion; R¹CO₂R⁴ derivatives of the above NSAIDs, where R⁴ can be, but is not limited to, an alkyl or aryl amine, a monodentate heterocylic group, or an aryl or alkyl group containing a monodentate heterocyle. Examples of ligands L² which can be used in metal complexes of formulae (1) to (3) include; monodentate ligands, for instance, halo, amine, heterocyclic, aqua, hydroxo, oxo, carbonyl, and nitrosyl ligands; polydentate ligands, for instance, include; amine, heterocyclic, amino acid, and peptide ligands. Examples of bridging ligands L³ that can be used in metal complexes of formulae (2) include: .O^2~, OH^", halo, carboxylate, and other anionic acido ligands that are the conjugate bases of inorganic or organic acids.

Examples of ligands L which can be used in metal complexes of formula (3) include chelating derivatives of carboxylates and amide ligands as described herein. Further suitable ligands are for instance described in the Applicant's co-pending

International Patent Application entitled "Metal complexes having anti-inflammatory activity" filed 26 March 2007, the contents of which is incorporated herein by cross- reference in its entirety.

Examples of aliphatic and aromatic groups of ligands that can be used in complexes embodied by the invention include substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, arylalkyl and heterocyclic groups. Examples of heterocyclic groups include heterocyclic bases comprising one or more N atoms. In some embodiments, the heterocyclic base is optionally substituted. The heterocyclic base may for example be selected from the group consisting of isoquinolyl, quinolyl, piperidinyl, pyridinyl, 2- methylpyridinyl, imadazoyl, pyranyl, pyrrolyl, pyrimidinyl, indolyl, purinyl and quinolizinyl.

Typically, the metal ion M of a metal complex embodied by the invention is a trivalent or tetravalent transition metal.

In some embodiments of the complex of formula (1), L¹ is NH₃ or a monodentate, polydentate, or macrocyclic amine ligand. Preferred complexes of formula (1) include: [M(L )_m(NR R R )_n]^p where: L is independently chosen from an NSAID, R¹CO₂ ^", R¹CON(R³)^" or an amide (R¹CONR²R³) or ester derivative 5 (R¹COOR⁴) of an NSAID; (NR⁹R¹⁰R¹ \ is individually selected from monodentate or polydentate amine ligands; and M is selected from Ru(II), Co(III), Cr(III), Ir(III), Os(III), Rh(III), Ru(III) or Pt(IV) and more preferably, Ru(II), Co(III), Ru(III) or Pt(IV); [M(L¹)_m(0H_s)_n]^p where: L¹ is independently chosen from an NSAID, R¹CO₂ ^", R¹CON(R³)^" or an amide (R¹CONR²R³) or ester derivative (R¹COOR⁴) of a NSAID; s 0 is independently selected from 1 or 2; and and M is selected from Co(III), Cr(III), Ir(III), Os(III), Rh(III), Ru(III) or Pt(IV) and more preferably, Co(III), Ru(III) or Pt(IV); [M(L¹)_m(L₂)_n] where L¹ is independently selected from a NSAID, with formula R⁶CO₂ ^", R¹CON(R³)^" or an amide (R¹CONR²R³) or ester derivative (R¹COOR⁴) of a NSAID; L² is independently selected from a halo, aqua, hydroxo, carboxylato, N- 5 heterocycle, sulfoxide, amine, amide, amino acid, peptide or macrocyclic ligand; and R⁹, R¹⁰ and R¹¹ are independently selected from H, aliphatic, aromatic and heterocyclic substituents that may be optionally substituted with one or more amine groups that form co-ordination bond(s) of the metal complex.

Examples of complexes for formula (2) include [Ru₂(Indo)₄Cl] , O [Ru₂(Indo)₄(O₂CR^1A)] and [M₃ ^III(O)(μ-O₂CR^1A)₅(μ-L³)(L²)₃]⁺,(where, M is independently selected from Cr(III), Co(III), Co(IV), Ru(III), Ru(IV) and preferably Co or Ru; R^1A is R¹ or an ester-linked derivative of an amino acid ( e.g., serine or tyrosine), or a hydroxy acid derivative Of R¹CO₂H (i.e., R¹COOR⁴), L³ = OH^", 0(R¹¹)^", or O₂C(R¹¹)^", L² is a iV-heterocycle or aqua ligand, and R¹¹ is a H, alkyl or aryl substituent; 5 and [(L²)_mM(μ-OCOR^1A)_r(μ-L³)_r>M(L²)_m]^p, where r = 1, 2, or 3, L³ = O^2" or OH^" and r'

= 0, I, or 2.

Examples of metal complexes of formula (3) for instance, include: [M(O₂CR^1A)(L²)_n(L⁴)o]^p where, n = O, 1, 2, or 3; o = 1 or 2, R^1AC0₂ ^" is an NSAID, R CO₂ , or an ester derivative of an R CO₂ ^" NSAID having a terminal carboxylate; at O least one of L is independently chosen from a hydroxamate or hydroximate derivative of a NSAID; an amino acid derivative of a NSAID, a peptide derivative of a NSAID, an amine derivative of a NSAID and M = Co(III), Rh(III), Ir(III), Cr(III), Ru(III), Pt(IV), and preferably Co(III), Ru(III) or Pt(IV), [M(O₂CR^1A)₂(L²)_n(L⁴)_o]^p where, n = 0, 1 or 2; o = 1 or 2, R ^ACO₂ ^~ is independently chosen from an NSAID, or an ester or amino acid derivative of an R CO₂ ^" NSAID having a terminal carboxylate; at least one of L⁴ is independently chosen from a hydroxamate or hydroximate derivative of a NSAID; an amino acid derivative of a NSAID, a peptide derivative of a NSAID, or an amine derivative of a NSAID and M = Co(III), Rh(III), Ir(III), Cr(III), Ru(III), Pt(IV), and preferably Co(III), Ru(III) or Pt(IV),, or [M(O₂CR^1A)₂(L⁴)]^P, where L⁴ in a peptide derivative of a NSAID or an amide derivative of an NSAID.

Suitable methods for the synthesis of metal complexes embodied by the invention are for instance described in: (Romakh, V. B.; Therrien, B.; Labat, G; Stoekli- Evans, H.; Shul'pin, G. B.; Suess-Fink, G. Dinuclear iron, ruthenium and cobalt complexes containing l,4-dimethyl-l,4,7-triazacyclononane ligands as well as carboxylato and oxo or hydroxo bridges. Inorg. Chim. Acta (2006), 359, 3297-3305; Eberlin, M. N.; Tomazela, D. M.; Araki, K.; Alexiou, A. D. P.; Formiga, A. L. B.; Toma, H. E.; Nikolaou, S. Electrospray Ionization Tandem Mass Spectrometry of Polymetallic μ-Oxo- and Carboxylate-Bridged [Ru₃O(CH₃COO)₆(Py) ₂(L)]⁺ Complexes: Intrinsic Ligand (L) Affinities with Direct Access to Steric Effects. Organometallics (2006), 25, 3245-3250; Eremin, A. V.; Belyaev, A. N.; Simanova, S. A. Binuclear Ruthenium(III) μ-Oxocarboxylates of the Nonelectrolyte Type. Molecular Structure of the Complex [Ru^III ₂(μ-O)(μ-O₂CCF₃)₂Py₄(O₂CCF₃)₂].(CH₃)₂CO. Rus. J. Coord. Chem. (2005), 31, 761-767); Belyaev, A. N.; Simanova, S. A. Ru, Rh, and Ir Trinuclear Mixed- Valence Oxygen-Bridged Carboxylate Complexes. Rus. J. Coord. Chem. (2004), 30, 184-193) for carboxylate bridged complexes of formulae (1) or (2); Ru-CO complexes for promoting angiogenesis could be prepared for example by using methods similar to (Li Volti, G.; Sacerdoti, D.; Sangras, B.; Vanella, A.; Mezentsev, A.;

Scapagnini, G.; Falck, J. R.; Abraham, N. G. Carbon monoxide signaling in promoting angiogenesis in human micro vessel endothelial cells. Antioxidants & Redox Signaling (2005), 7, 704-710)

Inflammatory diseases and conditions that can be treated in accordance with one or more embodiments of the invention include primary arthritis (osteoarthritis, rheumatoid arthritis, septic arthritis, gout and pseudogout, juvenile arthritis, Still's disease, ankylosing spondylitis), secondary arthritis caused by other diseases (systemic lupus erythematosus, Henoch-Schδnlein purpura, psoriatic arthritis, reactive arthritis (Reiter's syndrome), hemochromatosis, hepatitis, Wegener's granulomatosis (and many other vasculitis syndromes), familial Mediterranean fever, hyperimmunoglobulinemia D and periodic fever syndrome, and TNF- alpha receptor associated periodic fever syndrome), bronchitis, bursitis, scoliosis, muscle and joint injury, colitis (ulcerative colitis, Crohn's colitis, diversion colitis, ischemic colitis, infectious colitis, chemical colitis and atypical colitis, and pseudomembranous colitis), conjunctivitis, dermatitis, epicondylitis, tendonitis.

Diseases and conditions with an inflammatory component that can be treated in accordance with one or more embodiments of the invention include psoriasis, rosacea, and neurodegenerative, cardiovascular and diabetes related diseases and conditions.

Inflammation is an important component of the formation of arterial plaques and acute inflammation follows strokes and heart attacks, due to the involvement of reactive oxygen species. Similar oxidative damage is associated with the onset and progression of neurodegenerative diseases and diabetes. See for example, Dragomir, E.; Simionescu, M.. Monocyte Chemoattractant Protein- 1 - a major contributor to the inflammatory process associated with diabetes. Arch. Physiol. Biochem. (2006), 112, 239-244; Kadiu, L; Glanzer, J. G.; Kipnis, J.; Gendelman, H. E.; Thomas, M. P. Mononuclear phagocytes in the pathogenesis of neurodegenerative diseases. Neurotoxicity Res. (2005), 8, 25-50. Cardiovascular diseases and conditions that can be treated in accordance with one or more embodiments of the invention include acute and chronic cardiovascular inflammation including as a result of surgery or other trauma, cardiovascular disease, angina pectoris, arteritis, atheroma, atherosclerosis, arteriosclerosis, congestive heart failure, coronary heart disease, cardiomyopathy, myocardial infarction, stroke, ischeamic conditions, ischaemic cardiomyopathy, patent ductus arteriosus, high blood pressure, pulmonary hypertension peripheral artery disease, coronary artery disease, coronary artery spasm, pericarditis and strokes. The use of ruthenium complexes has for instance been described in United States Patent Application No. 20020193363 (CIP of US 6,417,182) (Bridger, Gary J.; Fricker, Simon P.; Abrams, Michael J.; Mayers, Irvin. Use of ruthenium complexes as nitric oxide scavengers to modulate inflammation and matrix metalloproteinase activity).

Diabetes related diseases and conditions that can be treated include Type I diabetes mellitus, Type II diabetes mellitus, gestational diabetes mellitus (GDM), insulin-dependent diabetes, non-insulin dependent diabetes, juvenile onset diabetes, late onset diabetes, maturity-onset diabetes of the young (MODY), insulin sensitive diabetes, insulin deficient diabetes, carbohydrate intolerance, and diabetes associated with another disease or condition ( eg., such as polycystic ovary disease or acanthosis nigricans), and non-resistant forms of diabetes observed following pancreatic surgery and for instance, following trauma to the pancreas (eg., as a result of injury).

Neurodegenerative conditions that can be treated include dementia, Lewy body disease, Parkinsons diseases, Alzheimers disease, amyloid plaque deposition diseases, multiple sclerosis, demyelination diseases, and motor neurone diseases. Carcinomas that can be treated include lesions and tumours of the epithelium.

The lesion can, for example, be a skin lesion such as basal cell carcinoma, squamous cell carcinoma or melanoma. The carcinoma can be selected from other cancers of the epithelium, such as lung cancer, cancer of the oesophagus, colon cancer, colorectal cancer, breast cancer, lung cancer, and other cancers of the epithelial tissues such as epithelial cancers of the tongue, salivary glands, gums and other areas of the mouth, oropharynx, nasopharynx, hypopharynx, oesophagus, pancreas, stomach, small intestine, duodenum, gall bladder, pancreas, larynx, trachea, uterus, cervix, ovary, vagina, vulva, prostate, testes, penis, bladder, kidney, thyroid, eye, and mestastic cancers thereof. However, it will be understood that use of metal complexes embodied by the invention is not limited to epithelial cancers and metal complexes of formula (1), (2) or (3) also have application in the prophylaxis or treatment of non -epithelial cancers. The application of metal complexes in the treatment of carcinoma is further described in Applicant's co-pending International Patent Application No. PCT/AU2006/000403 the contents of which is incorporated herein by cross-reference in its entirety. Examples of non -carcinoma cancers which can be treated in accordance with one or more embodiments of the invention include leukemias (chronic myeloid, acute myeloid, chronic lymphocytic, acute lymphoblastic and hairy cell), Non-Hodgkin lymphoma, Hodgkin lymphoma, multiple myeloma, sarcomas, lymphomas, Kaposi's sarcomas (classic, endemic or African, AIDS -related, transplant-related), primary bone cancers (osteosarcoma, Ewing's sarcoma, chondrosarcoma, spindle cell sarcoma, chordoma, angiosarcoma), soft tissue sarcomas (dermatofibrosarcoma, desmoid tumor, desmoplastic small round cell tumor, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, hemangiopericytoma, hemangiosarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, malignant fibrous histiocytoma, neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma), Askin's Tumor, malignant hemangioendothelioma, malignant schwannoma, mesothelioma, gliomas (ependymomas, astrocytomas, oligodendrogliomas, and mixed gliomas, such as oligoastrocytomas), choriocarcinoma, germ cell tumours (dysgerminoma and nondysgerminomatous ovarian tumours, teratoma or seminoma testicular cancers), sex cord-stromal tumours (granulosa stromal cell tumours, Sertoli- or Sertoli-Leydig cell tumours, lipid cell tumors and gynandroblastomas). The treatment of cancers with metal complexes incorporating ligands having anti-inflammatory activity is further described in the Applicant' s co-pending International Patent Application filed 26 March 2007 entitled "Combination therapy for treatment of cancer" the contents of which are incorporated herein by cross-reference in its entirety.

Analgesic applications of embodiments of metal complexes of the invention include treatment of post-operative pain, pain caused by bone cancer, arthritic pain, muscle pain, period pain, severe headaches, and pain associated with inflammatory diseases and conditions, trauma and infection.

Metal complexes as described herein can be taken orally, intraveneously (as many are water soluble) or by direct application to the site of infection. Many infections are also associated with hypoxia. Hence, complexes that release the active under conditions of hypoxia can deliver the ligand/metal selectively to the site of infection. Microbial pathogens that can be treated by one or more embodiments of the invention include bacterial, fungal and yeast pathogens which cause systemic, mucosal, oral, nasal, oropharyngeal, nasalpharyngeal, pharyngeal, digestive tract, vaginal, respiratory tract, urinary tract, kidney, eye and skin infections, including Chlamydia species, Haemophilus influenzae species, Non-typable Haemophilus influenzae (NTHi) species, Pseudomonas species, Streptococcus species, Staphylococcus species, E. coli species, Mycoplasma species and Helicobacter species amongst others. Examples of bacterial pathogens include P. aeruginosa, Non-typeable H. influenzae (NTHi), Streptococcus pneumoniae and Pseudomonas aeruginosa, Helicobacter pylori, Haemophilus influenzae type b (Hib), Staphylococcus aureus, Staphylococcus albus,

Chlamydia pneumoniae, Chlamydia trachomatis, Moraxella catarrhalis, Streptococcus pyrogenes, Chlostridium diptheriae, M. tuberculosis and M. genitalium. Fungal pathogens include Aspergillus species. Yeast pathogens include for instance Saccharomyces species and the candidiasis causing agent Candida albicans.

Indomethacin for instance has been reported to have an anti-microbial effect on H. pylori. These bacteria have been identified as a causative agent of at least some gastric cancers. Observations by the present inventors indicate that metal complexes embodied by the invention such as copper indomethacin can have a stronger antibacterial effect on gut bacteria than indomethacin alone and it will be understood that one or more methods embodied by the invention extend to combination therapy with other chemotherapeutic agents and drugs for the prophylaxis of H. pylori infections and gastric cancers involving a microbial component, as well as other microbial infections such as those exemplified above. Any conventionally known agents or drugs commonly used for the prophylaxis or treatment of such bacterial, fungal and other microbial infections can be used in such combination therapy.

Viral infections that may be treated by one or more embodiments of metal complexes of the invention include retroviruses such as Human Immunodeficiency virus (eg., HIV-I, HIV-2), DNA viruses such as Epstein-Barr virus (EBV), Human papillomavirus (HPV), Hepatitis B virus and Hepatitis C virus, Human T-cell lymphotropic virus, Kaposi's sarcoma associated herpes virus, herpes simplex viruses (HSV-I, HSV-2), varicella-zoster virus, vaccinia virus, SV40 virus, respiratory syncytial virus (RSV), parainfluenza viruses (PIV), human metapneumovirus, positive- stranded RNA viruses such as rhinoviruses, polioviruse, rubella virus and equine encephalitis viruses, and further RNA viruses including influenza virus, (eg influenza A and influenza B viruses), measles virus and mumps virus.

Treatment with type -2 selective and non- selective cyclooxygenase inhibitors for instance improves T-cell proliferation in HIV-infected patients on anti -retro vral therapy (Johansson CC, et al., AIDS 18(6): 951-952 Apr. 2004). Hence, the invention further extends to combination therapy of metal complexes embodied by the present invention with anti- viral drugs and/or treatments. Any conventionally known anti-viral drug may be employed including Acyclovir (acylguanosine), Arildone and WIN drugs which inhibit viral uncoating, Pleconaril, Amantadine, Rimantadine, nucleoside analogue drugs, further DNA polymerase inhibitors such as Ganciclovir, Azidothymidine (AZT), and adenosine arabinoside, dideoxyinosine, iodo-deoxyuridine, trifluorothymidine, Nevirapine, pyridinone derivatives, Efavirenz, RNA synthesis inhibitors, RNA cleavage enzymes and protease inhibitors.

Surprisingly, embodiments of metal complexes described herein may also promote angiogenesis and so have application in wound healing, treating tissue damage, inhibiting skin aging, and promoting angiogenesis in skin and other tissues, including hypoxic and ischemic tissues. For instance, Ru and amino acid complexes containing Co can strongly promote angiogenesis by the release of Co, such that any of the complexes of formulae (l)-(3) with at least one L² = Co can promote angiogenesis, as can Co complexes, when they are reduced to Co(II) under hypoxic conditions that will also release the NSAID or NSAID derivative (Li Volti, G.; Sacerdoti, D. ; Sangras, B.; Vanella, A.; Mezentsev, A.; Scapagnini, G.; Falck, J. R.; Abraham, N. G. Carbon monoxide signaling in promoting angiogenesis in human micro vessel endothelial cells. Antioxidants & Redox Signaling (2005), 7, 704-710; Tanaka, T.; Kojima, L; Ohse, T.; Ingelfinger, J. R.; Adler, S.; Fujita, T.; Nangaku, M. Cobalt promotes angiogenesis via hypoxia-inducible factor and protects tubulointerstitium in the remnant kidney model. Lab. Invest. (2005), 85, 1292-1307).

Moreover, the anti-microbial action of embodiments of metal complexes of the invention can promote healing of wounds and have application in the treatment and prevention of skin conditions that have a microbial component. Further to this, metal complexes described herein may provide a means of improved delivery and release of ligands that inhibit COX-2 and 5-LO (lipoxygenase) enzymes, which have synergistic effects on reducing skin damage, such as that arising from sunburn and other burns (eg., hydroximate/hydroxamate ligands in complexes of formula (3), for instance, can add extra therapeutic benefits, in addition to the parent NSAID that inhibits COX-2). Thus, metal complexes embodied by the invention can be used to deliver NSAIDs with beneficial effects in wound and tissue repair as well as the metal of the complex to areas of hypoxia, particularly in areas of bacterial infection often associated with slow healing wounds that are difficult to treat systemically and topically because of poor vascularisation. Metal complexes of Co(III) and Ru(III) are particularly preferred for wound healing, tissue repair and anti-skin aging applications.

While studies have indicated that IndoH itself has some anti-cancer activity in carcinomas believed to be due to a range of effects including inhibition of the COX enzymes which are upregulated in cancer cells (Vane, J. R.; Bakhle, Y. S.; Botting, R. M.Annu. Rev. Pharmacol. Toxicol. 1998, 38, 97-120) and a reduction of angiogenesis, the inventors have surprising found that metal complexes of indomethacin (Indo) can be much more effective in preventing or treating carcinomas than indomethacin as a result of the promotion of angiogenesis. Without wishing to be bound by theory, promotion of angiogenesis is believed to contribute to inhibition of skin aging by facilitating the regeneration and neovascularization of tissue, facilitating the transport of nutrients and oxygen to tissue, and/or generally promoting blood flow to tissue, particularly after tissue inflammation, or exposure of skin tissue to injury or insult. The inhibition of skin aging can manifest itself in one or more of increased or maintenance or vascularity of the skin, the maintenance or enhancement of elasticity of the skin, delayed deterioration of elasticity of the skin, decreased or delayed formation of creases or fine or deep wrinkles in the skin, decreased or delayed thinning of skin, the inhibition of loss of underlying fat from the skin, the inhibition of the development of transparency of skin, and inhibition of other visual markers associated with skin aging such as the formation or keratosis, dryness, and cracking of the skin.

Angiogenesis in wound healing can be assessed by measuring the extent of vessel growth at the site of wounds as described in Erpek, S.; Kilic, N.; Kozaci, D.; Dikicioglu, E.; Kavak, T. Revue De Medecine Veterinaire 2006, 157, 185-192). Any suitable conventionally known protocol for assessing aging of the skin can be used to score the efficacy of metal complexes described herein. Skin damage that leads to aging effects can for example be assessed by examination of the erythema reducing capacity of a metal complex as described herein in animals or humans exposed to the complex, Grundmann, J. U.; Bockelmann, R.; Bonnekoh, B.; Gollnick, H. P. M, Photochem. Photobiol. 2001, 74, 587-592). In particular, examination of the skin for biochemical markers of aging such as the induction of heme oxygenase, and the depletion of IFN-γ and IL- 12 from the epidermis can provide short term information. Aging and skin damage from UV exposure in hairless mice can for instance be assessed histologically by examining changes in epidermal hyperplasia and dermal mast cell numbers, pronounced focal elastotic deposits, degraded dermal collagen and deposition of glycosaminoglycans in the lower dermis (Tyrell, R. M.; Reeve, V. E. Prog. Biophys. MoI. Biol. 2006, 92, 86-91; Reeve, V. E.; Widyarini, S.; Domanski, D.; Chew, E.; Barnes, K. Photochem. Photobiol. 2005, 81, 1548-1553). The treatment of skin damage is to be taken in the broadest sense to encompass the treatment of any skin damage responsive to the application of a metal complex as described herein and is not limited to skin damage arising from inflammation and microbial infections (or having a microbial component), trauma, burns (including radiation burns) and skin conditions.

Wound or tissue repair encompassed by one or more methods embodied by the invention include repair following cuts and abrasions, photodamage or tissue insult resulting from exposure to ultraviolet radiation including erythema, burns, non-healing skin ulcers including diabetic, venous stasis, and pressure ulcers, and tissue damage caused by surgery or as a result of injury or trauma. The treatment of burns includes burns arising from exposure of tissue to excessive heat as well as from ultra-violet radiation (eg., sunburn) , and ionizing radiation as may result from cancer radiation therapy for the treatment of cancer, neoplastic disease or other disease or condition. For wound healing, treating burns, inhibiting skin aging and the like, metal complexes embodied by the invention can be applied topically to the tissue to be treated although for internal treatment, the metal complexes can be administered systemically. For general use in inhibiting skin aging, the metal complex can be topically applied on a daily basis to areas of the skin exposed to ultraviolet radiation such as the face, neck, arms, shoulders and legs while undertaking normal daily or leisure activities such as sunbaking. This also applies to methods of the invention for prophylaxis or treatment of carcinomas and other cancers. In either instance, the metal complex can be formulated in a sunscreen or cosmetic composition. Suitable sunscreen and cosmetic formulations are for example described in the Applicant' s co-pending Interntaional Patent Application No. PCT/IB2006/002423 the contents of which is incorporated herein by reference in its entirety.

As used herein, the term "effective amount" means an amount to treat or provide a prophylactic, therapeutic or chemopreventative effect. The specific "effective amount" will vary with factors such as the disease or condition for which the metal complex is being administered, the composition in which the metal complex is being administered, the route of administration, the age and physical condition of the human or animal, the type of animal being treated and the duration of the treatment, the nature of concurrent therapy (if any). The dosage administered and route of administration will be at the discretion of the attending, clinician or veterinarian and will be determined in accordance with accepted medical or veterinary principles. For instance, a low dosage may initially be administered which is subsequently increased at each administration following evaluation of the response of the subject. Likewise, the frequency of administration may be determined in the same way, that is, by continuously monitoring the response of the subject and modifying the interval between dosages.

The metal complex can be co-administered in combination with one or more chemotherapeutic agents conventionally used in the treatment of the particular disease, condition, infection at hand. By "co-administered" is meant simultaneous administration in the same formulation or a plurality of formulations by the same or different routes, or sequential administration by the same or different routes. By "sequential" administration is meant one is administered one after the other. The interval between the administration of the metal complex may be relatively short and can for instance be seconds or minutes, or longer periods of times such as hours or even a day or more. The metal complex may be administered before or following the chemotherapeutic agent. A composition embodied by the invention will typically further comprise a pharmaceutically acceptable carrier and be formulated to minimise dissociation of the metal complex to enhance the stability of the complex and shelf life of the formulation. Carrier formulations for enhancing stability of the complex are for instance described in the co-pending International Patent Application No. PCT/AU2005/000442 and co- pending International Patent Application No. PCT/AU2006/000403 of the Applicant, the contents of both of which are incorporated herein in their entirety.

The metal complex can be dissolved in the composition or may be present in the composition as a solid. The solid complex can be in the form of a crystal containing solvents of crystallisation and/or waters of crystallisation. When the complex is charged, the complex will be associated with a counter ion.

The complex will generally be administered in the form of a composition comprising the complex together with a pharmaceutically acceptable carrier.

As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering the complex to a human or animal. The carrier may be liquid or solid and is selected with the intended manner of administration in mind. The carrier is "pharmaceutically acceptable" in the sense of being not biologically or otherwise undesirable, i.e., the carrier may be administered to a human or animal along with the complex without causing any or a substantial adverse reaction. For instance, the carrier may be a solvent or dispersion medium containing one or more of physiological saline, ethanol, polyol (e.g. glycerol, propylene glycol, liquid polyethylene glycol and the like), vegetable oils and mixtures thereof.

In at least some instances, a composition embodied by the invention will be formulated as described in International Application No. PCT/AU2005/000442 filed 30 March 2005, the contents of which is incorporated herein by cross-reference in its entirety. As described in PCT/AU2005/000442, a formulation having a colloidal structure or which forms a colloidal structure post administration is particularly desirable for administration of metal complexes. Examples of suitable compositions having a colloidal structure or which form a colloidal structure upon, or following administration, are exemplified in PCT/AU2005/00042 and any suitable such formulations for the selected mode of administration may be utilised in methods embodied by the present invention. Formation of the colloidal structure can for instance occur when the composition contacts an aqueous biological fluid in the human or animal body, for example, on contact with an aqueous fluid in the digestive tract.

A composition has a colloidal structure if it comprises a colloidal system. A colloidal system is a system in which particles of a colloidal size of any nature (eg., solid as liquid or gas) are dispersed in a colloidal phase of a different composition or state. In particularly preferred embodiments, 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.

Without wishing to be bound by theory, it is believed the colloidal structure protects the metal complex from interaction with acids or other compounds that would otherwise interact with the complex to cause the complex to dissociate. It is also believed the colloidal structure reduces the extent to which some compounds present in the composition are able to interact with the complex, e.g. during storage of the composition, that may cause the complex to dissociate. Similarly, when such a composition is administered to a subject, the colloidal structure may limit the extent to which some compounds that come into contact with the composition after it is administered are able to interact with the complex and which cause the complex to dissociate before it is absorbed. For example, for compositions administered orally, the colloidal structure may limit the extent to which compounds present in stomach acid are able to interact with the complex to cause the complex to dissociate before it is absorbed through the gastrointestinal tract.

Similarly, for compositions administered by other routes, the colloidal structure may limit the extent to which compounds that come into contact with the composition at the point at which it is administered, e.g. strong chelators, such as peptides, or reductants, such as thiol-containing biomolecules, are able to interact with the complex to cause the complex to dissociate. While such interactions can be important at the site of acitivity after the pro-drug is administered, they should preferably be minimized at the point of delivery in order to maximize efficacy and minimize side-effects. As indicated above, 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. For example, in some embodiments, the composition is immiscible with water, and is thus immiscible with aqueous biological fluids whereby a colloidal system is thereby formed.

Preferably, the colloidal structure is maintained for a sufficient time after administration of the composition for the majority, for example more than 70%, 80% or 90%, of the metal complex, to be absorbed by the body as a metal complex.

Oils that may be utilized in compositions include pharmaceutically acceptable vegetable or mineral oils. Suitable oils include, but are not limited to: triglycerides, particularly medium chain triglycerides, combinations of medium chain and long-chain triglycerides, combinations of triglycerides with fish oil; vegetable oils, such as, soya oil, safflower oil and sunflower oils; isopropyl myristate; and paraffins. Such oils are suitable for use in compositions for oral, injectable, or topical administration.

When the composition comprises micelles in an aqueous carrier, the composition will typically further comprise one or more surfactants for formation of the micelles. Any surfactants may be used that are capable of forming micelles in the aqueous carrier, are pharmaceutically acceptable when administered by the intended route of administration, and which substantially do not interact with the metal carboxylate complex to cause dissociation from the metal when the composition is stored in the absence of light. Suitable surfactants for use in compositions for oral or topical administration include, but are not limited to, the sorbitan fatty acid ester group of surfactants. Such surfactants comprise mono-, tri-, or partial esters of fatty acids such as oleic, lauric, palmic and stearic acids, and include sorbitan trioleate (Span 85), sorbitan monooleate (Span 80), sorbitan tristearate (Span 65), sorbitan monostearate (Span 60), sorbitan monopalmitate (Span 40), and sorbitan monolaurate (Span 20).

Other 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 surfactants in this class include the Polyoxyethylene Sorbitan Fatty Acid Esters group of surfactants, including polyoxyethylene (20) sorbitan monolaurate (Tween 20), polyoxyethylene (4) sorbitan monolaurate(Tween 21), and polyoxyethylene (20) sorbitan monooleate (Tween 80).

A composition as described herein may can optionally further comprise one or more solvents or solubilising components for increasing the solubility of the metal carboxylate complex in the composition. The solvent may, for example, be tetraglycol (IUPAC name: 2-[2-[(tetrahydro-2-furanyl)methoxy]ethoxy]ethanol; other names: 2-[2- (tetrahydrofurfuryloxy)ethoxy]ethanol; tetrahydrofurfuryldiethyleneglycol ether) or other glycofurols (also known as tetrahydrofurfurylpolyethyleneglycol ethers), polyethylene glycols, glycerol, propylene glycol, or other pharmaceutically acceptable glycol. An example of a solubilising component is a polyvinylacohol/povidone mixture. The composition may also further comprise a thickener such as Aerosil 200, clay or another inorganic filler.

Preferably, such compositions contain more than 80%, preferably more than 90%, and most preferably more than 95%, of the total amount of the carboxylate, amide or ester derivative of the carboxylate having anti-inflammatory activity, as part of a metal complex. Preferably, also less than 10% of the carboxylate, or amide or ester derivative of the carboxylate complexed with the metal dissociates from the metal when the composition is stored for 12 months in the absence of light at room temperature (18°C to 25°C), unless for instance the formulation is prepared immediately before it is administered (as is the case for some injectable forms). The amount of the carboxylate, or amide or ester derivative of the carboxylate remaining bound to the metal complex can be readily determined by a person skilled in the art using known methods such as EPR spectroscopy for complexes that give EPR signals, NMR spectroscopy, UV/Vis spectroscopy, HPLC, or using more specialized experiments involving X-ray absorption spectroscopy (e.g., XAFS Studies of Anti-inflammatory Dinuclear and Mononuclear Zn(II) Complexes of Indomethacin. Zhou, Q.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A. Inorg. Chem. 2003, 42, 8557-8566; Determination of the Structures of Antiinflammatory Copper(II) Dimers of Indomethacin by Multiple- Scattering Analyses of X-ray Absorption Fine Structure Weder, J. E.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A.; Foran, G. J.; Rich, A. M. Inorg. Chem. 2001, 40, 1295-1302; Three-Dimensional Structure Determination using Multiple-Scattering Analysis of XAFS: Applications to Metalloproteins and Coordination Chemistry. Levina, A.; Armstrong, R. S.; Lay, P. A. Coord. Chem. Rev. 2005, 249, 141-160).

In other embodiments, such as compositions for intraveneous injections, the complex can be dissolved in isotonic saline solution immediately before it is injected.

More generally, the metal complex may be dissolved in the composition or may be present in the composition as a solid. The solid complex may be in the form of a crystal containing solvents of crystallisation and/or waters of crystallisation. When the complex is charged, the complex will be associated with a counter ion.

The composition for use in the method of the invention may be suitable for oral, rectal, nasal, topical (including buccal and sublingual), ophthalmological, vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration, or for administration respiratoraly, intratrachaely, nasopharanyngealy, intraoccularly, intrathecally, intranasally, by infusion, or via IV group patch and by implant. With respect to intravenous administration, particularly suitable routes are via injection into blood vessels which supply a tumour, tissues or particular organs to be treated. Agents may also be delivered into cavities such as for example the pleural or peritoneal cavity, or be injected directly into tumour tissue. The composition may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy. Such methods include the step of bringing into association the complex with the carrier. Typically, the carrier comprises two or more ingredients. In general, the composition of the present invention is prepared by uniformly and intimately bringing into association the complex with the carrier, and then, if necessary, shaping the product. The complex and the one or more components making up the carrier may be mixed in any order. However, it is preferred that the components are mixed in a manner that minimises the amount of the complex that dissociates during the preparation of the composition.

A composition for oral administration can be in the form of a viscous paste, a tablet, a capsule, a chewable composition, or any other form suitable for oral administration. The composition can also be encapsulated in a hard or soft capsule (e.g. gelatine) by techniques known in the art. Moreover, the metal complex may be provided in the form of ingestible tablets, buccal tablets, troches, elixirs, suspensions or syrups. Slow release formulations and formulations for facilitating passage through the environment of the stomach to the small intestines are also well known to the skilled addressee and are expressly encompassed by the invention.

A composition for oral use can for instance, also comprise one or more agents selected from the group of sweetening agents such as sucrose, lactose or saccharin, disintegrating agents such as corn starch, potato starch or alginic acid, lubricants such as magnesium stearate, flavouring agents, colouring agents and preserving agents e.g. such as sorbic acid, in order to produce pharmaceutically elegant and palatable preparations. A chewable composition can, for example, comprise the complex, one or more flavours, a base formulation, one or more preservatives, one or more pH modifiers, one or more desiccants and one or more fillers. As an example, for a chewable composition the base may comprise pre-gel starch, gelatine, flour and water. The composition can also comprise other components including phosphoric acid, salt, sugar, sorbitol and/or glycerol, sorbic acid and/or potassium sorbate, benzoic acid, propionic acid and maltodextrin. A chewable composition for an animal such as a dog for example, can comprise the complex, meat emulsion, an acidulate (e.g. phosphoric acid), one or more antifungal agents (e.g. benzoic acid and sorbic acid), sugar or sugar alcohol, and salt. A composition for topical application can comprise the complex in a conventional oil-in-water emulsion, water-in-oil emulsion, or water-immiscible pharmaceutical carrier suitable for topical application. Such carriers include for example, lacrilube, cetomacrogol cream BP, wool fat ointment BP or emulsifying ointment BP. Such carriers are typically in the form of an emulsion or are immiscible with water. An example of a composition for topical application to skin is a composition comprising 0.5-2% w/w of the complex in an emulsifying cream with chlorocresol (4- chloro-3-methylphenol) as a preservative, the emulsifying cream comprising: cetomacrogol emulsifying wax 15 g liquid paraffin 1O g white soft paraffin 1O g chlorocresol 0.1 g propylene glycol 5 mL purified and cooled water to 100 g

Another example of a topical composition for application to skin is a composition comprising 2% w/w of the complex in wool fat. This composition is immiscible with water.

Compositions for parenteral administration include compositions in the form of sterile aqueous or non- aqueous suspensions and emulsions. A composition embodied by the invention can also include one or more pharmaceutically active components in addition to the complex that have anti-cancer activity or other therapeutic activity. Such active components include conventionally used anti- inflammatory drugs, and conventionally used metal and non-metal based chemotherapeutic and anti-cancer agents such as those identified above.

Typically, the metal complex constitutes about 0.001% to about 20% by weight of the composition, preferably about 0.01% to about 20% by weight of the composition, more preferably about 0.01% to about 6% by weight of the composition and most preferably, the complex constitutes about 0.025% to about 10% by weight of the composition. For prophylaxis of skin carcinoma or topical administration of a metal complex, a topically acceptable composition for application to the skin will typically comprise the metal complex in an amount of about 0.1% by weight of the composition or less.

The dosage of a metal complex embodied by the invention will depend on a number of factors including whether the complex is to be administered for prophylactic or therapeutic use, the disease or condition for which the active is intended to be administered, the severity of the condition, the age of the individual, and related factors including weight and general health of the individual as may be determined in accordance with accepted medical principles. For instance, a low dosage may initially be given which is subsequently increased or descreased at each administration following evaluation of the individual's response. Similarly, the frequency of administration can be determined in the same way that is, by continuously monitoring the individual's response between each dosage and if necessary, increasing the frequency of administration or alternatively, reducing the frequency of administration.

For oral, intravenous injection or other form of systemic administration, a metal complex as described herein will typically be administered at a dosage in a range of from about 0.1 mg/kg to about 10 mg/kg body weight per day, depending on the condition being treated and the complex administered. More preferably, the metal complex will be administered at a dosage in a range of from 0.5 mg/kg to about 4 mg/kg body weight, and most preferably, in a range of from 1 mg/kg to about 3 mg/kg body weight. Typical oral or suppository doses will be in the range of 1 mg/kg to 4 mg/kg; for topical doses for sunscreens and the prophylaxis of skin damage and aging, the complex will typically be dosed in 0.01-0.05% w/w topical carriers, but for more localised topical applications for lesions, wound healing and the treatment of pain and inflammation, topical formulations can be administered as more concentrated 0.25-2% w/w formulations, such that the maximum doses fall with the ranges indicated above. Injection directly into cancerous lesions can have concentrations as high as 30% w/w, whereby a volume of the formulation equivalent to the volume of the lesion is injected.

Suitable pharmaceutically acceptable carriers and formulations useful in the present invention may for instance be found in handbooks and texts well known to the skilled addressee, such as "Remington: The Science and Practice of Pharmacy (Mack Publishing Co., 1995)" and subsequent update versions thereof, the contents of which is incorporated herein in its entirety by reference.

The mammalian subject may be a human or an animal. The animal can, for example, be a companion animal such as a dog or cat, or a domestic animal such as a horse, pony, donkey, mule, camel, llama, alpaca, pig, cow or sheep, or a zoo animal.

Suitable animals include members of the Orders Primates, Rodentia, Lagomorpha, Cetacea, Carnivora, Perissodactyla and Artiodactyla. Typically, the subject will be a horse, dog, or primate and more usually, a human being.

A number of embodiments of the present invention will now be described below by reference to the following non-limiting examples. EXAMPLE 1: Preparation of compounds

1.1.1 Inert metal ions with bridging ligands (Formula (2)). [Ru₂Cl(Indo)-j] complex [RuCl (O₂CCH₃ )₄] was prepared as previously reported (R. W. Mitchell, A.

Spencer and G. Wilkinson, J. Chem. Soc, Dalton Trans) 1973, 846-854). The [Ru₂Cl(O₂CCH₃)₄] (0.25 g, 0.48 mmol) was dissolved in methanol (70 niL) under N₂, a solution of IndoH (0.82 g, 2.3 mmol) in methanol (30 mL) was added, and the mixture was refluxed for 4 h under N₂. After cooling, the brown microcrystals were filtered off, washed with methanol, and dried in air at room temperature. [Ru₂Cl(Indo)₄], Anal. CaIc for C₇₆H₆₀Cl₅N₄O₁₆Ru₂: C, 54.83; H, 3.63, N, 3.37, Cl, 10.65, Ru, 12.14. Found: C, 53.70; H, 3.76, N, 3.26, Cl, 11.01, Ru, 12.06.

1.1.2 Metal amine complexes with mononuclear ligands (Formula 1)

[Co(NH3)₅(Indo)](CF₃SO₃)2

[Co(NH₃)_S(OSO₂CF₃)] (CF₃SO₃)₂ (0.5 g, 0.84 mmol) was slowly added to excess IndoH (1.0 g, 2.8 mmol) and triethylamine (0.283 g, 2.8 mmol), after stirring for 3 h at 80 ⁰C, the solution was cooled and then added to ice-cooled diethyl ether (400 mL) with vigorous stirring, the oily compounds solidified after decantation, stirring and sonication, alternatively. The solid was filtered off and washed twice with diethyl ether and an orange powder was obtained. The solid was then dissolved in a large amount of warm water, filtered, and the filtrate was evaporated on the rota-evaporator to a small volume and then left to crystallize. The crystals obtained were dried in a vacuum desiccator over P₂O₅. Anal. Calcd for C₃H₁₅N₅F₉O₉S₃Co: C, 5.67; H, 2.38; N, 11.03; S, 15.14. Found: C, 5.6; H, 2.5; N, 11.3; S, 14.9%. ¹H NMR (DMSaJ₆): 57.71-6.64 (m, Ph-H), 4.04 (s), 3.79(s), 3.65(s), 3.10 (s), 2.62(s), 2.24 (s). ¹³C NMR (DMSO-J₆): 14.20, 34.67, 56.42, 103.48, 112.15, 115.88, 116.79, 119.90, 124.14, 130.28, 132.16, 132.44, 132.93, 136.15, 136.22, 139.46, 157.38, 169.34, 183.11. [Co(NH₃)₅(Indo)]Cb.0.5Et₂O.0.5H₂O

[Co(NH₃)₅(Indo)] (CF₃SO₃)₂ was dissolved in minimum volume of acetone (HPLC grade), and to the resultant solution was added to two equivalents of Et₄NCl-SH₂O with stirring. After stirring for 10 min, an orange coloured solid precipitated from the solution. After filtration, the solid was re-dissolved in the minimum volume of water, filtered again and the filtrate was then slowly added to ice- cold diethyl ether with vigorous stirring. The precipitate was filtered, washed with diethyl ether, dried in desiccator in vacuo (yield 63.7%). Anal. Calcd for C₂₁H₃₆N₆Cl₃O₅Co: C, 40.82; H, 5.87; N, 13.60; Cl, 17.21, Co, 9.54%. Found: C, 40.85; H, 5.68; N, 13.42; Cl, 16.92, Co, 9.56%. ¹³C NMR (D₂O): 13.18, 30.68, 33.48, 39.25, 56.18, 102.53, 110.89, 115.16, 115.53, 129.18, 130.98, 131.30, 131.66, 13.63, 136.36, 139.06, 155.66, 169.64, 183.71.

Similar reactions were used to prepare [Ru(NH₃)₅(Indo)]X₂ complexes and [Co(en)₂(Indo)₂] (CF₃SO₃), where en = 1,2-ethanediamine.

([Co(NH₃)₅(ACM)](SO₃CF₃)₂.2(CH₃)₂SO)

The [Co(NH₃)5(ACM)](SO₃CF₃)₂ complex was prepared using the general method described in Ion Association and the Reactions of Cobalt(III)-Acido complexes. 4. Origin of the Products in the Base Hydrolysis of [Co(NH₃₎₅X]^(3~n) Complexes.

Brasch, N. E.; Buckingham, D.A.; Clark, C.R.; Finnie, K.S. Inorg. Chem. 1989, 238, 4567-4574. Briefly, 1^"CO(NHOS(OSO₉CFOI (CF^SOO₉, (0.84 mmol, 0.5 g) was slowly added to excess acemetacin (2.8 mmol, 1.16 g) in triethylamine (2.8 mmol, 0.38 ml) and DMSO (5 ml), and the mixture was stirred over an oil bath for 3 hr at 50 ⁰C. The solution was then heated to 80 ⁰C for 2 hr. It was cooled and slowly added to diethyl ether (800 ml) with brisk stirring. The oily residue was stirred for an hour, the cloudy diethyl ether was replaced with fresh diethyl ether and the mixture was refrigerated overnight. It was sonicated for 10 minutes resulting in formation of a red solid, which was filtered and dried under vacuum. Anal. Found: C, 31.9; H, 4.16; N, 8.26; CaIc. for CoC₂₇H₄₄ClN₆O₁₄S₄F₆: C, 32.00; H, 4.38; N, 8.30. [Pt(en)(Indo)₂(OH)₂]

[Pt(en)(Indo)₂] was prepared by the method described by Dendrinou-Samara, C; Tsotsou, G.; Ekateriniadou, L. V.; Kortsaris, A. H.; Raptopoulou, C. P.; Terzis, A.; Kyriakidis, D. A.; Kessissoglou, D. P. J. Inorg. Biochem. 1998, 71, 171-179. [Pt^(Cn)(MdO)₂(OH)₂] was prepared by an oxidation reaction as follows.

Addition of 30% H₂O₂ (10 ml) to an aqueous suspension of partially dissolved [Pt(en)(Indo)₂] (2 mmol) produced a clear solution initially, which was then followed by the appearance of a white precipitate of the Pt(IV) complex. After stirring at room temperature overnight, the resulting precipitate was filtered, washed with water, acetone and diethyl ether, and dried in vacuum. [Pt(en)(Indo)₂(OH)₂] was obtained as a off- white solid. As expected it had a very similar IR spectrum to the Pt(II) precursor except bands were shifted, especially the carbonyl stretch of the carboxylate ligand.

1.2.1 Results and discussion Inert metals, such as Ru(III), Co(III), and Pt(IV) offer the potential of systemic delivery of even higher concentrations of NSAIDs through oral, injectable, and topical delivery and to incorporate them into slow release patches. The complexes still exhibit significant anti-inflammatory activities. Hence, the complexes can also have systemic anti-cancer and other activities, but may essentially eliminate gastric side-effects by being absorbed in the GI tract before release of the drug. The slow release of the

NSAID drug(s) (and in some cases the active metal ion) by hydrolysis of the metal- NSAID bond(s) (which can also be acid or base catalysed) in inert oxidation states, compared with labile oxidation states, such as Cu(II) and Zn(II), means that the active drug concentration in the blood stream, or at the point application, may be maintained for longer periods of time, or the drug can more readily reach the target tissue or cells before it is released. Ru(III) and Co(III) also have the potential to act as hypoxia selective agents for the treatment of various conditions involving hypoxia as they are reduced to the M(II) oxidation state, which can release the active ligand, and in the case of Ru(II) produce a metal ion that will readily bind to target biomolecules to bring about a range of biological activities. (Ware DC, Sum BG, Robinson KG, Denny WA,

Brothers PJ, and Clark GR (1991) Inorg Chem 30:3750-3757; Ware DC, Palmer BD, Wilson WR, and Denny WA (1993) J Med Chem 36:1839-1846; Ware DC, Palmer HR, Brothers PJ, Rickard CEF, Wilson WR, and Denny WA (1997) J Inorg Biochem 68:215- 224; Ware DC, Brothers PJ, Clark GR, Denny WA, Palmer BD, and Wilson WR (2000) J Chem Soc, Dalton Trans: 925-932). These complexes can also release other ligands such as CO and NO or control the concentration of NO, which is important in many diseases.

EXAMPLE 2 Cytotoxicity studies of [Co(NH₃)₅(Indo)]Cl₂.0.5Et₂O.0.5H₂O on A549 (non -small lung) cancer cells

2.1 Experimental The cytotoxicity of the complexes on cancer cell line A549 was assessed using an MTT assay.

2.1.1 Medium Preparation for A549 cell lines

Advanced DMEM medium was used in all the cell culture work. The medium did not contain certain components needed to facilitate cell growth. Therefore, antibiotics-actimycotic (0.5 mL), (100 U m^" penicillin, 100 μg mL^" streptomycin and 0.25 μg mL^" amphotericin B), 200 mM glutamine solution (0.5 mL) and fetal calf serum (2 %, 0.8 mL) were added to the medium (40 mL) before proceeding with any cell work. All of the above components were obtained from Gibco Industries Inc. (Langley, OK, USA). All other reagents used in the cell work were obtained from Sigma (St. Louis, MO, USA).

2.1.2 Thawing of frozen A549 cancer cells

Frozen cells were stored in liquid nitrogen. The cells were rapidly warmed in a 37 ⁰C water bath for approximately 5 min. The cell suspension was then transferred to a

10- mL centrifuge tube with 9 mL of medium and centrifuged for 3 min at 2000 rpm. The medium was removed from the resultant pellet and fresh medium (1 mL) was added to resuspend the cells, then transfer the cells to a 10-cm plate with fresh medium (10 mL) added to it. Cells were incubated at 37 ⁰C in a humidified atmosphere containing 5 % CO₂ for 3 days. 2.1.3 Subculturing of A549 cells

The medium was removed from the cells and the cell layer was washed with phosphate buffer solution (PBS, 10 mL) prior to trypsination with 0.25 % trypsin EDTA solution (4 mL). Cells were then incubated for 6 min at 37 ⁰C, after which medium with serum (5 mL) was added to inactivate the trypsin. The cell suspension was then collected into a centrifuge tube and the mixture was centrifuged at 2000 rpm for 3 min. The medium was subsequently removed from the cell pellet and fresh medium (1 mL) was added to resuspend the cells. The cell suspension (0.58 mL) was transferred from the total cell suspension to a centrifuge tube. Further, medium (3 mL) was added to the centrifuge tube and the cells were counted using a haemocytometer.

2.1.4 Seeding of A549 cells for cytotoxicity experiments

The cell suspension (100 μL per well) was transferred to four sets of ninety six- well plates with each well having approximately the same amount of cells (IxIO⁴ cells/well/ 100 μL for A549). The plates were incubated overnight at 37 ⁰C prior to the addition of the test compound.

2.2 Sample preparation for [Co(NH₃)₅(Indo)]Cl₂.0.5Et₂O.0.5H₂O

[Co(NH3)5(Indo)]Ci2.0.5Et₂0.0.5H₂O was tested over a range of concentrations (50-400 μM) in the presence and absence of glutathione as a reductant.

2.2.1 Treatment of A549 cells with [Co(NH₃)₅(Indo)]Cl₂.0.5Et₂O.0.5H₂O

The medium was removed from all the wells via a vacuum pump. A number of wells were left without addition of the test compound and were used as control wells. Appropriate concentrations of the test compound (50-400 μM) in complete medium were added to the remainder of the wells. After treatment, the plates were incubated at 37 ⁰C for 3 days.

2.2.2 Quantification of A549 cancer cells

For the MTT assay, the medium was removed from the plates, MTT (1 mg/mL) was added to all the wells and the cells were further incubated for approximately 4 h at 37 ⁰C to allow sufficient time for it to interact with the cells. The medium was then carefully discarded and the cellular contents were extracted using DMSO (100 μLper well).

Absorption at 595 nm was determined using an ELISA plate reader. The percent survival was determined by the intensity of the absorbance obtained, which correlated to the amount of cells present in each well. The negative control wells were arbitrarily assigned as 100% survival. The MTT assay provides a measure only for viable cells.

Statistical analysis of data of all the cell work after quantification with the plate reader was achieved using Origin 6.1 software (Microcal Inc., 1999).

2.3 Cytotoxicity results

While the complex was inactive over the concentration range in the absence of glutathione, the LC₅₀ value was 100 μM in the presence of the reductant glutathione.

2.4 Discussion

While the metal complex is not cytotoxic, cell viability in the presence of glutathione as a reductant reduces substantially, confirming that the activity is established during reduction of the complex. Although the IC50 value is not low, it is still only a factor of two greater than for the Culndo complex, which is not cytotoxic in this in vitro model, but is very active in vivo . Hence, cytotoxicity is unlikely to be the sole reason for the anti-cancer activity observed in vivo and other mechanisms are likely to be involved. The other advantage for anti-cancer activity is the water solubility of the complex (see Example 4). These factors combined are likely to make such complexes useful anti-cancer slow-release agents and/or hypoxia- selective agents either by themselves or in combination therapy with other chemotherapeutic agents as described in the Applicant's co-pending International Patent Applications entitled "Combination therapy for treatment of cancer" and "Metal complexes having anti-inflammatory activity" both filed 26 March 2007, the contents of which are incorporated herein by cross-reference in their entirety. EXAMPLE 3 Treatment of inflammation by oral administration.

3.1 Methodology 3.1.1 Test compositions The compounds ( [Co(NH₃ )₅(Indo)] (SO₃CF₃ )₂ (Formula (1) and

([Ru2Cl(Indo)₄]) (Formula (2)) were examined for their anti-inflammatory action following oral delivery by gavage as medium chain triglyceride (MCT) organogels as described in as described in International Patent Application No. PCT/AU2005/000442.

3.1.2 Animals

Sprague-Dawley rats (weighing 200-250 g) used for these studies were supplied by the laboratory animal services at The University of Sydney. 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.

3.1.3 In Vivo anti-inflammatory activity and gastric toxicity Groups of four rats were used for all studies. All doses were calculated as equivalent concentrations of Indo. Rats were allowed free access to food and water except for gastric toxicity studies, when they were fasted for 24 h but with free access to water. Inflammation was induced 1 h after dosing by injection of the formulation by an injection of carrageenan (0.1 mL, 1% w/v in isotonic saline) into the plantar region of the hind paw.

Paw volume was measured prior to dosing and at 3 h after carrageenan injection by immersing the left hind paw (to the lateral malleus) into a vessel filled with water and measuring the volume of water displaced as decribed in International Patent Application No. PCT/AU2005/000442 filed 30 March 2005, the contents of which is incorporated herein by cross-reference in its entirety. Immediately after paw volume measurements, 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 (mm²).

3.1.4 In Vivo small intestinal toxicity Groups of four rats were used for all studies and were treated similarly as described in Example 3.1.3, except that they were allowed free access to food and water during the assay. At 24 h after dosing, the entire small intestine was excised and flushed with water to expel the intestinal contents. The intestine was examined from 10 cm distal to the ligament of Treitz to the ileocecal junction, and the toxicity is reported as the summation of the area of macroscopic ulcerations (mm ).

The Student t test was used to compare mean values between two groups and repeated measures ANOVA followed by Bonferroni correction for comparisons was used to compare mean values between more than two groups. Data are expressed as the mean + SEM. AH reported P values are two-sided, and P<0,05 was considered statistically significant.

3.2 Results The results are summarised below in Tables 1 and 2 below.

3.2.1 [Co(NH₃)₅(Indo)](SO₃CF₃)₂

Oral administration with IndoH and [Co(NH₃ )₅(Indo)] (SO₃CF₃)I in the MCT organogel composition at an IE of 10 and 3 mg kg^{" 1} bw, respectively, was significantly anti-inflammatory at a level of (P<0.01 (**)) and (P<0.05 (*)), respectively, compared to the control cohort. No statistical (P>0.05) difference, however, was found between the control cohort and treatment with [Co(NH₃ )₅(Indo)] (SO₃CF₃^ in MCT organogel at an IE of 10 mg kg^"1.

No statistically significant (P>0.05) difference in mean gastric ulceration (mm ) was found between the control cohort and oral treatment with

[Co(NH₃)₅(Indo)](SO₃CF₃)₂ in the MCT organogel at IE of 3 and 10 mg kg^"1 bw. However, oral administration of IndoH at IE of 10 mg kg^"1 bw resulted in significant (P<0.05 (*)) gastric ulceration compared to the control cohort.

No statistically significant (P>0.05) difference in mean small intestine ulceration (mm²) was found between the control cohort and oral treatment at IE of 3 and 10 mg kg^"1 bw of [Co(NH₃)₅(Indo)](SO₃CF₃)₂ in the MCT organogel. However, oral administration of IndoH at IE of 10 mg kg^"1 bw resulted in significant (P<0.01 (**)) small intestine ulceration in the test group (n = 4) with small intestine ulceration scores in the individual animals of 45, 38, 135, 50 mm compared to nil small intestine ulceration observed in the control cohort animals. Whilst there was no significant (P>0.05) difference in mean small intestine ulceration (mm²) between the

[Co(NH₃)₅(Indo)](SO₃CF₃)₂ treatments at IEs of 3 and 10 mg kg^"1 bw, all animals (n = 4) in the [Co(NH₃)₅(Indo)(SO₃CF₃)₂] group treated at IE of 10 mg kg^"1 bw presented with small intestine ulceration (35, 54, 40 and 22 mm ) compared to nil ulceration in animals treated at an IE of 3 mg kg^"1 bw. By exclusion the IndoH treatment group from the study cohort, significant (P<0.001 (***)) small intestine ulceration was found in the [Co(NH₃)₅(Indo)](SO₃CF₃)₂ group treated at IE of 10 mg kg^" bw compared to controls and compared to [Co(NH₃)s(Indo)] (SO₃CF₃ )i at 3 mg kg^" bw. At 10 mg/kg^" bw IE for the Co(III) complex, the small intestine ulceration included duodenal ulceration. Duodenal ulcerations have not to date been observed in the rat model. The observered ulcerations are as follows: intestinal ulceration (25, 50, 40, 22 mm²); duodenal ulceration (10, 4, 0, 0 mm²).

.At necropsy, one animal dosed with [Co(NH₃)s(Indo)](SO₃CF₃)2 at 3 mg kg^" bw presented with an engorged (bile-stained fluid) small intestine and oedematous and haemorrhagic spotted lungs. Respiratory rales were noted in the animal approximately 30 minutes post treatment. An intubation error, i.e. administration of the oral gavage dose directly into the lungs, was discounted as the cause of the adverse lung affect as the gavage tube was cleanly and fully inserted.

3.2.2 [Ru₂Cl(IiIdO)₄] Oral administration at an Indomethacin Equivalence (IE) treatment of 3 and 10 mg kg^"1 bw of [Ru₂Cl(Indo)₄] in organogel composition resulted in no statistically significant (P>0.05) difference in mean gastric and small intestine ulceration compared to the control cohort. Individual rats (n = 4) dosed at A.I. of 3 and 10 mg kg bw presented with gastric ulcerations of (0, 0, 0, 0 mm²) and (30, 5, 5, and 75 mm²), respectively. Individual rats (n = 4) dosed at A.I. of 3 and 10 mg kg^" bw presented with small intestine ulcerations of (0, 0, 0, 2 mm²) and (0, 160, 28, and 3 mm²), respectively. The lack of statistical difference in the gastric and small intestine ulceration for the treatments compared to controls results is attributed to the wide individual variability in the ulceration observed at 10 mg kg^"1 bw. By excluding the two animals with only 5 mm² of gastric ulceration, significant (P<0.01 (**)) gastric ulceration was observed in the treatment group compared to controls. Likewise, by excluding the two animals with only 0 and 3 mm² of small intestine ulceration, significant (P<0.05 (*)) small intestine ulceration was observed in the treatment group compared to controls. For the animal with 160 mm of ulceration in the small intestine, the breakdown was intestinal ulceration, 150 mm , and duodenal ulceration 10 mm . The latter is not typically seen in the rat model. It is noted, however, that at the higher concentration the organogel was not clear indicating incomplete dissolution of the drug. Thus the undis solved proportion of the drug would have less protection from the organogel against stomach acid and this may explain the much greater toxicity at this concentration.

Treatment at IE of 3 and 10 mg kg^" bw of [Ru₂Cl(MdO )₄] in organogel was significantly anti-inflammatory at a level of (P<0.05 (*)) and (P<0.01 (**)), respectively, compared to the control cohort. No statistical (P>0.05 (*)) difference, however, was found between the IE treatments of 3 and 10 mg kg^" bw of [Ru₂Cl(Indo)₄] in the organogel.

Table 1: Data of mean acute gastric and small intestine ulceration ±sem (mm²) and individual rat (n = 4) gastric and small intestine ulceration (mm²) for the Active Ingredient (A.I.) [Co(NH₃)₅(Indo)](SO₃CF₃)₂ and [Ru₂Cl(Indo)₄] in MCT organogel dosed at IE of 3 and 10 mg kg^" bw.

Table 2: Percent (%) mean inhibition in rat hind-paw volume compared to a control cohort 3 hr post intraplantar injection of carrageenan (0.1 mL of 1% solution) post treatment with the A.I. by means of oral gavage (n = 4). The greater the antiinflammatory response of the treatment, the greater is the value of the % mean inhibition compared to the control cohort.

3.3 Discussion Oral administration at an Indomethacin Equivalence (IE) treatment dose of 3 and 10 mg kg^"1 bw of [Co(NH₃)5(Indo)] (SO₃CF₃)I in MCT organogel resulted in an effective and -inflammatory response compared to controls at 3 mg kg^" bw but not at 10 mg kg^" bw. The results show that coordination of the parent NSAID (IndoH) with Co(III) was protective of the stomach and small intestine with respect to ulceration compared to IndoH. It is unclear why the small anti-inflammatory response compared to controls is not significant at an IE of 10 mg kg^{" 1} bw of [Co(NH₃)₅(Indo)](SO₃CF₃)₂ but it may indicate a narrow anti-inflammatory therapeutic window for oral absorption of the cobalt complex compared to the parent NSAID (IndoH). The results, however, do demonstrate that the inert nature of the Co(III) complex reduces both acute GI toxicity and efficacy compared to Indo, which is consistent with the slow-release nature of the drug.

The cause of the oedematous lungs and small intestine in one animal treated with [Co(NH₃ )₅(Indo)] (SO₃CF₃ )₂ at IE of 3 mg kg^"1 bw is uncertain. However, it is noted that both cobalt and the parent NSAID have the potential to cause a rare hypersensitivity reaction. The effect may also be due to the CF₃SO₃ ^" counterion since no such effect was observed on intraveneous injection with the chloride salt (Example 4), where the acute dose of complex reaching the lungs is much higher.

Oral administration at an IE dose of 3 and 10 mg kg^" bw of [Ru2Cl(Indo)₄] in organogel resulted in an effective anti-inflammatory response. The individual variability in the animals results with respect to gastric and small intestine ulceration, indicates the ruthenium complex was not necessarily protective of the stomach and small intestine. Whilst the results indicate the ruthenium complex to be efficacious, evaluation of the dosage of the complex for optimum protective effects of the gastric acid and small intestine mucosa is desirable.

EXAMPLE 4: Intravenous injection toxicity of [Co(NH₃)₅(Indo)]Cl₂

4.1 Introduction

This study was conducted to demonstrate the efficacy and safety of the water- soluble complex [Co(NH₃)₅(Indo)]Cl₂ of formula (1) for intraveneous injection. Indomethacin is normally dosed intravenously at 0.1 to 0.2 mg/kg bw per day in humans. The high solubility of the Co complex allowed its intraveneous toxicity to be examined at much higher levels.

4.2 Experimental Freshly prepared solutions containing the cobalt complex (active ingredient) in sterile saline was prepared by dissolving the cobalt complex (without heat) in the saline. The resultant clear solution was filtered with a sterile 0.22 micron filter and used immediately. The i.v push was given over approximately 10 s. All other experimental procedures are as described in Example 3. One rat only was used for this study at each concentration 0.8 and 3 mg/kg. A single 0.5 rnL i.v. injection of the complex in normal saline was administered by means of the tail vein. The animal was observed for up to 30 min and 4 hr post treatment, respectively.

4.3 Results

Nil mortality was observed for the study period. Severe listlessness, disorientation and apnoea were observed within one minute post treatment at the higher concentration. The animal recovered without overt adverse clinical effects after approximately 5 - 10 minutes. Nil gastric ulceration was observed at necropsy (4 hours post treatment) and no adverse effects were observed at the lower dose.

4.4 Discussion

At 0.8 kg^"1 bw IE i.v. in normal saline nil mortality and overt morbidity was observed for the study period (a 30 minutes post treatment observation time). A typical IndoH oral dose is 1 to 3 mg kg^" bw while that administered to infants for closure of the ductus aorta is 0.1 to 0.2 mg kg^"1 bw. High doses of IndoH have adverse effect on central nervous system (CNS). Such effects include malaise and listlessness, drowsiness, hearing disturbances and in rare cases convulsions and coma. This was consistent with the reversible effects observed in the rat at a high dose (10-30 times higher than the therapeutic dose).

Based on the limited pilot investigations, a No Observed Adverse Effect Level (NOAEL) of ~1 mg kg^" bw is proposed for i.v. administration of [Co(NH3)s(Indo)]Cl2 and this was used to assess efficacy and GI toxicity in Example 5.

EXAMPLE 5: Efficacy and GI toxicity of [Co(NH₃)₅(Indo)]Cl₂

5.1 Experimental

Procedures for the evaluation of efficacy and safety of [Co(NH3)s(Indo)]Cl2 intravenous injections are given in Examples 3 and 4, using intravenous doses of 0.8 rng/kg bw and 1.6 mg/kg bw indomethacin equivalents. The treatment doses of 0.8 mg/kg bw and 1.6 mg/kg bw corresponded to injection solutions of 0.8 mg/mL and 1.6 mg/mL, respectively. One of the 4 rats in the 0.8 mg/kg bw treatment group was unsuccessfully injected and was excluded from the study. 5.2 Results

5.2.1 Small Intestine Toxicity

Nil small intestine (0, 0, 0, 0 mm ) ulceration was observed in the control and all the treatment groups.

5.2.2 Inhibition of Carrageenan-Induced Paw Edema

Mean inhibition of paw edema was 39 (±6) % for the 0.8 mg/kg bw treatment group. Surprisingly, no anti-inflammatory effect was observed in the 1.6 mg/kg bw treatment group.

5.3 Discussion

An anti-inflammatory effect with nil small intestine ulceration was observed in the 0.8 mg/kg bw i.v.i treatment group. The lack of a dose-response effect observed in this study is unexplained but the weaker effect at the higher dose mirrors the behavior observed on oral dosing.

As indicated in Example 4, a typical i.v. dose of IndoH administered to infants for closure of the ductus aorta is 0.1 to 0.2 mg kg^"1 bw. Higher doses of IndoH have adverse effect on Central Nervous System (CNS). Such effects include malaise and listlessness, drowsiness, hearing disturbances and in rare cases convulsions and coma. Nil abnormal clinical observations for [Co(NH₃)₅(Indo)]Cl₂ were recorded at an i.v.i treatment dose of 0.8 mg/kg bw. Thus the Co complex is both efficacious and has no toxicity at these concentrations. These results further indicate the Co complex has application in the safe intravenous treatment of a range of conditions without problems associated with solubility. The above results demonstrate that [Co(NH₃)5(Indo)]Cl2 has low GI and intravenous toxicity, which is consistent with the slow release nature of such complexes. The cytotoxicity results also show the complex is activated on reduction, which is consistent with potential of such complexes to be used for hypoxia selectivity.

EXAMPLE 6 Antimicrobial activity of [Co(NH₃)₅(Indo)]Cl₂.0.5Et₂O.0.5H₂O

The anti-microbrial activities of the cobalt complex [Co(NH₃)₅(Indo)]Cl₂.0.5Et₂0.0.5H₂O and the parent indomethacin were compared against the human pathogenic bacterial strains: Escherichia coli (Gram -ve), Staphylococcus aureus (Gram +ve) and Pseudomonas aeruginosa.

6.1 Experimental Solutions (100 μg/10 μL) of the test compounds were placed onto a sterile filter paper disk positioned on the surface of nutrient agar plates which had been evenly streaked with the respective bacterial strains to produce a confluent bacterial lawn. Plates were incubated overnight at 37 ⁰C. The next day, the plates were inspected for the presence of a zone of inhibition around the filter paper disk.

6.2 Results

The Co complex was extremely soluble in water, allowing a 100 μg/10 μL solution to be prepared. The following zones of inhibition were recorded for the respective bacterial strains: E. coli, 12-mm diameter; S. aureus, 15-mm, Ps. aeruginosa, 30-mm. Indomethacin delivered at the same concentration in N, N- dimethylformamide (DMF) to maintain solubility resulted in no zone of inhibition.

6.3 Discussion

The results indicate the Co complex may provide a broad spectrum anti- microbial activity against both gram-positive and gram-negative bacteria.

As described in Applicants co-pending Australian Provisional Patent Application No. 2006901583, metal complexes of anti-inflammatory drugs have activity against diabetes. Recently, metal complexes of anti -inflammatory drugs have also been shown to be efficacious in terms of cardiovascular inflammation (similar processes to which occur in the early stages of neurodegenerative diseases) and in prophylaxis for the reduction of radiation-induced skin damage that leads to skin cancers (http://www.medicaltherapies.com.au). As these effects arise from a combination of the release of the anti- inflammatory ligand and the metal, these slow release complexes are likely to have similar activities. Moreover, UV radiation will release carboxylate and other ligands from Co(III) amine ligands and this can act as a light-induced, slow-release mechanism for the drug in sunscreens and skin lotions, especially since this photochemistry is selective for the UV wavelengths responsible for photodamage (Sarkar, S. K.; Tarafdar, P. K.; Roy, A.; Aditya, S. Photochemistry of cobalt(III)-pentaammine oxalate and cobalt(III)-tetraammine oxalate complexes). J. Ind. Chem. Soc. (1983), 60, 1142-6. Kantrowitz, E. R.; Endicott, J. F.; Hoffman, M. Z. Excited states in the ultraviolet photochemistry of cobalt(III) complexes. Evidence from chemical scavenger studies Of Co(NH₃)_SO₂CCH₃ ²⁺ at 254 nm. J. Am. Chem. Soc. (1970), 92, 1776-7. Wells. W. L.; Endicott, J. F. Ultraviolet photochemistry of ruthenium(III) ammine complexes. J. Phys. Chem. (1971), 75, 3075-80) and can also be used to protect the skin and organs from radiation damage from patients receiving radiation therapy for cancer (since such effects are often dose limiting) (see for instance Anderson, RF; Denny, WA; Ware, DC; Wilson, WR. Pulse radiolysis studies on the hypoxia- selective toxicity of a cobalt -mustard complex. Brit. J. Cancer, Suppl. (1996), 74, S48-S51. Cohen, H.; Meyerstein, D. Aliphatic radicals as reducing agents of cobalt(III) and ruthenium(III) complexes: a pulse - radiolytic study. J. Chem. Soc, Dalton Trans. (1977), 1056-62.). The sentivity of the complexes to radiation-induced reduction and release of the NSAID and a active metal ion, such as Ru(II), can also be used to enhance the effectiveness of radiotherapy.

Although the invention has been described with reference to particular examples, it will be appreciated by those skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

1. A metal complex of the following formula (1):

wherein:

M is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent metal ion having an inert oxidation state; each L is independently selected and is a monodentate or bidentate carboxylate or monodentate amide ligand (O or N bound), or a monodentate ligand linked to a

NSAID by an ester or amide linkage, having anti -inflammatory activity; and at least one ligand L¹ is other than a salicylate or a derivative of a salicylate. each L is independently selected and is a monodentate or a polydentate ligand; m is 1, 2, 3 , 4, 5, or 6; and p is the charge of the complex.

2. A complex according to claim 1 wherein at least one L ligand is a monodentate amide ligand (O or N bound).

3. A complex according to claim 1 wherein at least one L¹ ligand is a monodentate or bidentate carboxylate and the carboxylate is a NSAID .

4. A complex according to claim 1 wherein at least one L ligand is a monodentate ester or amide derivative of a NSAID, which can be bound by a functional group on the amide or ester substituent.

5. A complex according to claim 4 wherein at least one L is an amide derivative of a carboxylate NSAID.

6. A complex according to claim 1 wherein at least one L¹ ligand is a ligand of the formula R¹CONR²R³ or R¹CON(R³)^" comprising an amino group NHR²R³ coupled to a NSAID, wherein R¹CO₂H is a NSAID, R² is H, an alkyl, alkenyl, alkynyl, an aryl or an arylalkyl group, and R is H, alkenyl, alkynyl, an aryl, an arylalkyl group or a heterocycle, and wherein when R3 is an alkyl or aryl group, the alkyl or aryl group can be optionally substituted by a functional group that forms a co-ordination bond with the metal ion.

7. A complex according to any one of claims 3 to 6 wherein the NSAID is selected from the group consisting suprofen, tolmetin, naproxen, ibuprofen, flufenamic acid, niflumic acid, diclofenac, indomethacin, acemetacin, and ketorolac.

8. A complex according to any one of claims 3 to 6 wherein the NSAID is selected from the group consisting of carprofen, etodolac, fentiazac, flurbiprofen, ketoprofen, oxaprozin, pranoprofen, sulindac, or suxibuzone.

9. A complex according to claim 1 wherein L is a ligand of the formula:

wherein: R⁵ is H or halo;

R⁶ is H; a C₁ to C₆ alkyl, an alkenyl or an alkynyl, where the C₁ to C₆ alkyl, alkenyl or alkynyl may be optionally substituted; or

wherein each R , 6A i •s independently selected from the group consisting of H, C₁ to Ce alkyl, alkenyl, alkynyl, aryl, cycloalkyl and arylalkyl, where the C₁ to C₆ alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be optionally substituted;

R is H or halo; each R⁸ is independently selected from the group consisting of halo, -CH₃, -CN, -OCH₃, -SCH₃ and -CH₂CH₃, where the -CH₃, -OCH_3, -SCH₃ or -CH₂CH₃ may be optionally substituted. r is 1, 2, 3, 4 or 5.

10. A complex according to claim 1 wherein L i i .s a ligand of the formula:

wherein: R is H or halo;

R is H; a Ci to CO alkyl, an alkenyl or an alkynyl, where the Ci to CO alkyl, alkenyl or alkynyl may be optionally substituted; or

wherein each R is independently selected from the group consisting of H, Ci to CO alkyl, alkenyl, alkynyl, aryl, cycloalkyl and arylalkyl, where the Ci to CO alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be optionally substituted;

11. A complex according to claims 9 or 10 wherein when R is a Ci to Ce alkyl, an alkenyl or an alkynyl, the Ci to C₆ alkyl, alkenyl or alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, -COOH and -NH₂.

12. A complex according to any one of claims 9 to 11 wherein when R ^A is a Ci to Ce alkyl, an alkenyl, an alkynyl, an aryl, a cycloalkyl or an arylalkyl, the Ci to C₆ alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, -COOH and -NH₂.

13. A complex according to any one of claims 9 to 12 wherein when R⁸ is -CH₃, -OCH₃, -SCH₃ Or -CH₂CH₃, the -CH₃, -OCH₃, -SCH₃ Or -CH₂CH₃ is optionally substituted with one or more substituents is independently selected from the group consisting of halo, -OH, -COOH and -NH₂.

14. A complex according to any one of claims 1 to 13 wherein ligand L also has anti-inflammatory, and/or, anti-cancer and or anti-diabetic activity.

15. A complex according to any one of claims 1 to 14 wherein the metal ion is selected selected from the group consisting of Co, Cr, Ir, Os, Rh, Ru and Pt.

16. A complex according to claim 1 wherein the complex is a complex of the formula:

[M(L¹)_m(NR⁹R¹⁰R¹¹)J^p

wherein each L¹ is independently a NSAID, R¹CO₂ ^", an amide or ester derivative of an NSAID, each (NR⁹R ⁰R ) is independently a monodentate amine ligand or polydentate amine ligand, and M is selected from the group consisting of Co(III), Cr(III), Ir(III), Os(III), Rh(III), Ru(III) or Pt(IV).

17. A complex according to claim 1 wherein the complex is a complex of formula the formula:

[M(L¹UOHJ_nF

wherein each L¹ is independently a NSAID, RCO₂ ^", or an amide or ester derivative of an NSAID, M is selected from Co(III), Cr(III), Ir(III), Os(III), Rh(III), Ru(III) and Pt(IV), and s is independently 1 or 2.

18. A complex according to claim 16 or 17 wherein M is selected from the group consisting of Co(III), Ru(III) and Pt(IV).

19. A metal complex of the following formula (2):

[M_q(L¹)_m(L²)n(L³)_r]^p (2) wherein

M is independently selected from a monovalent, divalent, trivalent, tetravalent, pentavalent and hexavalent metal ions having an inert oxidation state; each L is independently selected and is a monodentate or bidentate carboxylate or monodentate amide ligand (O or N bound), or a monodentate ligand linked to a

NSAID by an ester or amide linkage, having anti -inflammatory activity; and at least one ligand L is other than a salicylate or a derivative of a salicylate. each L is independently selected and is a monodentate or a polydentate ligand, or an amide ligand (O or N bound), having anti-inflammatory activity; each L³ is independently selected and is a bridging ligand: m is an integer from 0 to 5q; n is an integer from 1 to 5q; p is the charge of the complex; q is an integer between 2 and 20 inclusive; and r is a integer from 1 to 60.

20. A complex according to claim 19 wherein L¹ is a monodentate amide ligand (O or N bound).

21. A complex according to claim 19 wherein at least one L is a monodentate or bidentate carboxylate NSAID.

22. A complex according to claim 19 wherein at least one L¹ ligand is a monodentate ester or amide derivative of a NSAID.

23. A complex according to claim 22 wherein at least one L¹ is an amide derivative of a carboxylate NSAID.

24. A complex according to claim 19 wherein at least one L ligand is a ligand of the formula R¹CONR²R³ or R¹CON(R³)^" comprising an amino group NHR²R³ coupled to a NSAID, wherein R¹CO₂H is a NSAID, R² is H, an alkyl, alkenyl, alkynyl, an aryl or arylalkyl group, and R³ is H, an alkyl, an aryl, or a heterocycle, and wherein when R³ is an alkyl, alkenyl, alkynyl, an aryl or arylalkyl group, the alkyl alkenyl, alkynyl, an aryl or arylalkyl group can be optionally substituted by a functional group that forms a co- ordination bond with the metal ion.

25. A complex according to claim any one of claims 21 to 24 wherein the NSAID is selected from the group consisting of the deprotonated anionic forms suprofen, tolmetin, naproxen, ibuprofen, flufenamic acid, niflumic acid, diclofenac, indomethacin, acemetacin, and ketorolac.

26. A complex according to any one of claims 21 to 24 wherein the NSAID is selected from the group consisting of carprofen, etodolac, fentiazac, flurbiprofen, ketoprofen, oxaprozin, pranoprofen, sulindac, or suxibuzone.

27. A complex according to claim 19 wherein L is a ligand of the formula:

wherein:

R i 5 is H or halo (i.e. Cl, F, Br or I);

wherein each R is independently selected from the group consisting of H, C₁ to CO alkyl, alkenyl, alkynyl, aryl, cycloalkyl and arylalkyl, where the C₁ to Ce alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be optionally substituted;

R⁷ is H or halo; each R is independently selected from the group consisting of halo, -CH₃, -CN, -OCH₃, -SCH₃ and -CH₂CH₃, where the -CH₃, -OCH_3, -SCH₃ or -CH₂CH₃ may be optionally substituted. r is 1, 2, 3, 4 or 5.

28. A complex according to claim 19 wherein L i i .s a ligand of the formula:

wherein: R is H or halo;

29. A complex according to claim 27 or 28 wherein when R is a Ci to Ce alkyl, an alkenyl or an alkynyl, the Ci to C₆ alkyl, alkenyl or alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, -COOH and -NH₂.

30. A complex according to any one of claims 27 to 29 wherein when R ^A is a Ci to Ce alkyl, an alkenyl, an alkynyl, an aryl, a cycloalkyl or an arylalkyl, the Ci to C₆ alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, -COOH and -NH₂.

31. A complex according to any one of claims 27 to 30 wherein when R⁸ is -CH₃, -OCH₃, -SCH₃ Or -CH₂CH₃, the -CH₃, -OCH₃, -SCH₃ Or -CH₂CH₃ is optionally

5 substituted with one or more substituents is independently selected from the group consisting of halo, -OH, -COOH and -NH₂.

32. A complex according to any one of claims 19 to 31 wherein ligand L has antiinflammatory activity.

33. A complex according to any one of claims 19 to 31 wherein L³ is selected from 0 the group consisting of oxo, hydroxo, carboxylate, NSAIDs and halide bridging groups.

34. A complex according to any one of claims 19 to 33 wherein the metal ion is selected from the group consisting of Co, Cr, Ir, Os, Rh, Ru and Pt.

35. A complex according to claim 19 wherein the complex is a complex selected from the group consisting of [Ru₂(Indo)₄Cl] , [Ru₂(MdO)₄(O₂CR)] and 5 [Co₃ ^iπ(O)(O₂CR)₅(L³)(L²)]⁺, wherein L³ is OH^", OR^", or O₂CR^", and L² is an N- heterocycle.

36. A metal complex of the following formula (3):

O wherein

M is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent metal ion having an inert oxidation state; each L¹ is independently selected and is a monodentate or bidentate carboxylate or monodentate amide ligand (O or N bound), or a monodentate ligand linked to a 5 NSAID by an ester or amide linkage, having anti -inflammatory activity; and at least one ligand L¹ is other than a salicylate or a derivative of a salicylate. each L² is independently selected and is a monodentate or a polydentate ligand; each L⁴ is independently selected and is a chelating derivative of a carboxylate, or amide ligand (O or N bound), having anti-inflammatory activity; 0 m is 1, 2, 3, 4 or 5; n is O, 1, 2, 3 or 4; o is 1, 2, or 3; and p is the charge of the complex.

37. A complex according to claim 36 wherein L i i .s a monodentate amide ligand (O or N bound).

38. A complex according to claim 36 wherein at least one L¹ is a monodentate or bidentate carboxylate NSAID.

39. A complex according to claim 36 wherein at least one L ligand is a monodentate ester or amide derivative of a NSAID.

40. A complex according to claim 39 wherein at least one L is an amide derivative of a carboxylate NSAID.

41. A complex according to claim 36 wherein at least one L¹ ligand is a ligand of the formula R¹CONR²R³ or R¹CON(R³)^" comprising an amino group NHR²R³ coupled to a NSAID, wherein R¹CO₂H is a NSAID, R² is H, an alkyl, alkenyl, alkynyl, an aryl or arylalkyl group, and R is H, an alkyl, an aryl, or a heterocycle, and wherein when R is an alkyl, alkenyl, alkynyl, an aryl or arylalkyl group, the alkyl alkenyl, alkynyl, an aryl or arylalkyl group can be optionally substituted by a functional group that forms a co- ordination bond with the metal ion.

42. A complex according to claim any one of claims 38 to 41 wherein the NSAID is selected from the group consisting of the deprotonated anionic forms suprofen, tolmetin, naproxen, ibuprofen, flufenamic acid, niflumic acid, diclofenac, indomethacin, acemetacin, and ketorolac.

43. A complex according to any one of claims 38 to 41 wherein the NSAID is selected from the group consisting of carprofen, etodolac, fentiazac, flurbiprofen, ketoprofen, oxaprozin, pranoprofen, sulindac, or suxibuzone.

44. A complex according to 36 wherein at least one of L is a ligand of the formula:

wherein:

R i 5 is H or halo; R ,6 i •s H; a Ci to CO alkyl, an alkenyl or an alkynyl, where the Ci to CO alkyl, alkenyl or alkynyl may be optionally substituted; or

wherein each R is independently selected from the group consisting of H, Ci to Ce alkyl, alkenyl, alkynyl, aryl, cycloalkyl and arylalkyl, where the Ci to C₆ alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be optionally substituted;

R⁷ is H or halo; each R⁸ is independently selected from the group consisting of halo, -CH₃, -CN, -OCH₃, -SCH₃ and -CH^CH₃, where the -CH₃, -OCH₃, -SCH₃ or -CH₂CH₃ may be optionally substituted. r is 1, 2, 3, 4 or 5.

45. A method according to claim 36 wherein L is a ligand of the formula:

wherein:

R⁵ is H or halo (i.e. Cl, F, Br or I);

R is H; a Ci to CO alkyl, an alkenyl or an alkynyl, where the Ci to Ce alkyl, alkenyl or alkynyl may be optionally substituted; or

wherein each R is independently selected from the group consisting of H, Ci to CO alkyl, alkenyl, alkynyl, aryl, cycloalkyl and arylalkyl, where the Ci to CO alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be optionally substituted; R⁷ is H or halo; each R is independently selected from the group consisting of halo, -CH3, -CN, 5 -OCH₃, -SCH₃ and -CH₂CH₃, where the -CH₃, -OCH₃, -SCH₃ or -CH₂CH₃ may be optionally substituted; and r is 1, 2, 3, 4 or 5.

46. A complex according to claim 44 or 45 wherein when R is a Ci to CO alkyl, an alkenyl or an alkynyl, the Ci to C₆ alkyl, alkenyl or alkynyl is optionally substituted with 0 one or more substituents independently selected from the group consisting of halo, -OH, -COOH and -NH₂.

47. A complex according to any one of claims 44 to 46 wherein when R^6A is a C₁ to Ce alkyl, an alkenyl, an alkynyl, an aryl, a cycloalkyl or an arylalkyl, the Ci to C₆ alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl is optionally substituted with one or more 5 substituents independently selected from the group consisting of halo, -OH, -COOH and -NH₂.

48. A complex according to any one of claims 44 to 47 wherein when R⁸ is -CH₃, -OCH₃, -SCH₃ Or -CH₂CH₃, the -CH₃, -OCH₃, -SCH₃ Or -CH₂CH₃ is optionally substituted with one or more substituents is independently selected from the group O consisting of halo, -OH, -COOH and -NH₂.

49. A complex according to any one of claims 36 to 48 wherein the complex has at least one L² ligand.

50. A complex according to claim 49 wherein ligand L² can also have antiinflammatory, anti-cancer or anti-diabetic activity. 5

51. A complex according to any one of claims 36 to 50 wherein at least one L is a chelating derivative of a carboxylate NSAID.

52. A complex according to any one of claims 36 to 51 wherein the metal ion is selected from the group consisting of Co, Cr, Ir, Os, Rh, Ru and Pt.

53. A complex according to claim 36 wherein the complex is a complex of formula O [M(O₂CR)₂(L⁴)₂]^P wherein RCO₂ ^" is a NSAID, L⁴ is a hydroxamate or hydroximate derivative of a NSAID, and M is Co or Cr.

54. A complex according to claim 36 wherein the complex is a complex of formula [M(O₂CR)₂(L⁴)]^P wherein L⁴ is a peptide derivative of a NSAID.

55. A pharmaceutical composition comprising a metal complex as defined in any one of claims 1 to 54 together with a pharmaceutically acceptable carrier or diluent.

56. A method for prophylaxis or treatment of inflammation or a disease or condition in a mammal mediated by inflammation or having an inflammatory component, comprising administering to the mammal an effective amount of a metal complex as defined in any one of claims 1 to 54.

57. A method for prophylaxis or treatment of a cancer in a mammal, comprising administering to the mammal an effective amount of a metal complex as defined in any one of claims 1 to 54.

58. A method for prophylaxis or treatment of a microbial or viral infection in a mammal, comprising administering to the mammal an effective amount of a metal complex as defined in any one of claims 1 to 54.

59. An analgesic method for prophylaxis or treatment of pain in a mammal, comprising administering to the mammal an effective amount of a metal complex as defined in any one of claims 1 to 54.

60. A method for promoting wound healing or inhibiting skin or tissue aging in a mammal, comprising administering to a mammal in need thereof an effective amount of a metal complex as defined in any one of claims 1 to 54.

61. A method for treating damaged tissue or skin of a mammal, the method comprising administering an effective amount of a metal complex as defined in any one of claims 1 to 54.

62. A method for promoting angiogenesis in a mammal, comprising administering to the mammal an effective amount of a metal complex as defined in any one of claims 1 to 54.

63. A method for protecting against ionising radiation induced skin or organ damage in a mammal, comprising administering to the mammal an effective amount of a metal complex as defined in any one of claims 1 to 54.

64. A method for enhancing the effectiveness of radiotherapy in cancer treatment, comprising administering to a mammal in need thereof an effective amount of a metal complex as defined in any one of claims 1 to 54.