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WO2007109845A1 - Prophylaxie ou traitement du diabète - Google Patents

Prophylaxie ou traitement du diabète Download PDF

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Publication number
WO2007109845A1
WO2007109845A1 PCT/AU2007/000381 AU2007000381W WO2007109845A1 WO 2007109845 A1 WO2007109845 A1 WO 2007109845A1 AU 2007000381 W AU2007000381 W AU 2007000381W WO 2007109845 A1 WO2007109845 A1 WO 2007109845A1
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WIPO (PCT)
Prior art keywords
complex
independently selected
ligand
group
alkynyl
Prior art date
Application number
PCT/AU2007/000381
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English (en)
Inventor
Peter Lay
Trevor Hambley
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Medical Therapies Limited
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Publication date
Priority claimed from AU2006901583A external-priority patent/AU2006901583A0/en
Application filed by Medical Therapies Limited filed Critical Medical Therapies Limited
Publication of WO2007109845A1 publication Critical patent/WO2007109845A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention relates to the prophylaxis or treatment of diabetes.
  • the present invention relates to a method for the prophylaxis or treatment of diabetes comprising the administration of a metal complex having antiinflammatory activity.
  • Non-steroidal anti-ii ⁇ flammatory drugs are used in the treatment of a variety of inflammatory conditions.
  • NSAIDs are, for example, used to treat inflammatory conditions such as rheumatoid arthritis, osteoarthritis, acute musculoskeletal disorders (such as tendonitis, sprains and strains), lower back pain (commonly referred to as lumbago), and inflammation, pain and edema following surgical or non-surgical procedures.
  • GI adverse gastrointestinal
  • Indomethacin is a NSAID effective in treating inflammatory conditions in both humans and animals.
  • the structure of indomethacin is as follows:
  • indomethacin can cause ulcerations in the oesophagus, stomach, duodenum and intestines. In dogs, oral administration of indomethacin causes fatal gastrointestinal haemorrhaging.
  • Other effects associated with oral administration of indomethacin include: (a) inhibition of platelet aggregation, (b) adverse cardiovascular effects (fluid retention and peripheral oedema), (c) ocular effects (corneal deposits and retinal disturbances), (d) central nervous system effects (headaches and dizziness), (e) masking of infections due to antipyretic properties, and (f) renal effects (as with other NSAE)S, there have been reports of acute interstitial nephritis wifh hematuria, proteinuria and, occasionally, nephrotic syndrome in patients receiving long-term administration of indomethacin).
  • indomethacin e.g. as a suppository or by topical application can have adverse effects.
  • Anti-inflammatory activity of Indomethacin following topical application Amico-Roxas, M., Mater, M., Caruso, A., Puglisi, G., Bemadini, R., Rinaldo, G., European Review for Medical & Pharmacological Sciences, 1982, IV,
  • dinuclear metal complexes of indomethacin i.e. complexes containing two metal coordination centres
  • DMF N, ⁇ T-dimethylformamide
  • the NSATD aspirin acetylsalicy ⁇ ic acid
  • acetylsalicy ⁇ ic acid is widely used in low dosages to prevent cardiovascular events and is generally prescribed as a standard treatment for prophylaxis of cardiac disease in high-risk patients.
  • the effect of aspirin is not consistent with a significant proportion of the population (up to 45%) being aspirin resistant ("Aspirin resistance: Definitions, mechanisms, prevalence, and clinical significance", Macchi, L.. Scrrel, N., Christiaens, L., Curr. Pharm. Des., 2006, 12, 25J- 258).
  • COX-2 inhibitors such as rofecoxib, celccoxib, valecoxib and parecoxib may be associated with an increased ri$k of thrombotic events ("Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention", Scott, D.
  • NSAIDs are another class of drug that have been shown to have beneficial effects on the prevention and treatment of diabetes, including hydroxamic acid derivatives of NSAIDs.
  • hydroxamic acid derivatives of NSAIDs Wang, T.; Lai, C-S. United States Patent Publication No. 20040077691 (CIP of US 6,620,813) (2004).
  • hydroxamic acid complexes of vanadium have previously been shown to exhibit glucose lowering effects when delivered by intraperitoneal injection, but only show similar glucose lowering effects to the insulin mimetic complexes discussed above when administered at a similar concentration.
  • the present invention steins from the recognition that at least some metals have application in the treatment of diabetes and the condition commonly if not invariably has associated inflammatory components), and that metal complexes having antiinflammatory activity may be employed to therapeutically target one of both of these treatment pathways. While both metals and NSAIDs are known to separately exert anti-diabetic effects, the present i ⁇ ventots have surprisingly found that in at least some embodiments, metal complexes of NSAIDs can have an in-vivo glucose lowering effect that is comparable to the best vanadium drugs previously used for the treatment of diabetes but at significantly lower dose of up to orders of magnitude difference.
  • a method for the prophylaxis or treatment of a diabetes in a mammalian subject comprising treating the subject with a therapeutically effective amount of a complex of a metal and a carboxylate, or derivative of a carboxylate, having anti-inflammatory activity, wherein the carboxylate or derivative is other than salicylate or a derivative of salicylate,
  • the carboxylate or the derivative of the carboxylate having anti-inflammatory activity will generally have such activity when administered to a human or animal.
  • the derivative of the carboxylate can be hydrolysed in vivo, and the hydrolysed compound may have anti-inflammatory activity
  • the derivative of the carboxylate can be selected from the group consisting of ahydroxamate, hydroximate, amide or ester. These derivatives have functional groups that bind to one or more tnetal(s) as a monodentate ligand, a chelate and/or a bridging ligand.
  • a method for the prophylaxis or treatment of diabetes in a mammalian subject comprising treating the subject with a therapeutically effective amount of a complex of a metal and a carboxylate, or a hydroxamate, hydroxiraate, amide or ester, having anti- inflammatory activity.
  • the carboxylate having anti-inflammatory activity can be any deproto ⁇ ated carboxylic acid compound having anti-inflammatory activity.
  • the carboxylate having anti-inflammatory activity may, for example, be the dcprotonated anionic form of any one of the following carboxyiic acids NSAIDs: Suprofen ((+)- ⁇ -methyI-4-(2 ⁇ thienylcarbonyl) ⁇ henylacetic acid (“SupH”));
  • ToIH Tolmetin (1-methyl-5-(p-toluoyl)-lH-pyrrole-2-acetic acicl
  • Naproxen ⁇ -methoxy- ⁇ -methyl- ⁇ -naphthaleneacetic acid
  • IbuH Ibuprofen
  • Fhrfenamic Acid ( ⁇ trifluoromethylphenyljanthrati ⁇ ic acid (“FlufenH”)
  • Indomethacin (l-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH-indole-3-acctic acid (“IndoH”)); Acemetacin (l-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid carboxymethyl ester (“ACMH”))
  • Ketorolac ( ⁇ )-5-benzoyl-2,3-dihydro-lH-pyrro]izine-l-carboxylic acid
  • Indobufen in addition to its anti-inflammatory effects, i$ used to prevent thrombosis in much the same way as aspirin, but suffers from the same problems as the other anti-inflammatory drugs in terms of GI toxicity at therapeutic doses, although the effects are not a$ severe as aspirin.
  • the inclusion of the "H" at the end of an abbreviation for a carboxylate e.g., any one of the carboxylic acids listed above
  • a hydroxaraate, S hydroximate, or amide is used to refer to the uncharged form of the carboxylate or amide or the parent hydroxamic acid or its monodeproto ⁇ ated hydroxamate form of the doubly deprotonated hydroximate. Accordingly, the abbreviation without the "H” is used to refer to the deprotonated anionic form.
  • IndoH refers to the uncharged form of indomethacin
  • Indo is used to refer to the deprotonated o anionic form of indomethacin
  • ACMH refers to the uncharged form of acemetacin
  • ACM refers to the deprotonated anionic form.
  • the carboxylate, or hydroxamate, hydroxi ⁇ iate, hydrazide, ester or amide derivative having anti-inflammatory activity can be any non-steroidal anti-inflamniatory drug (NSAID).
  • the NSAID can be indomethacin (IndoH), or an ester 5 derivative of indomethacin, such as acemetacin, ibuprofen, indobufen, diclofenac, vaproxen, or ketorolac, or a hydroxamate, hydroximate, or amide derivative of ⁇ idomethacin or acemetacin or other NSAED.
  • hydroxamate or hydroximate are to be taken to mean the deprotonated and doubly deprotonated forms of the ligands.
  • NSAIDs that can be utilized in the metal complexes (as can their derivatives) as 0 described herein include;
  • Carprofen (6-chloro-a-methyl-9H-carbazole-2-acetic acid);
  • Etodolac (1 ,8-diethyl-1 5 3,4,9-tetrahydro-pyrano[3,4-b]indole-l-acetio a ⁇ id);
  • Flurbiprofen (2-fluoro-a-methyl-[l,r-biphcnyl]-4-acetic acid); 5 Ketoprofen (3-benzoyl-a-methylbcnzcneacctic acid);
  • Oxaprozin (4,5-diphenyl-2-oxazolepropanoic acid);
  • Pranoproftn (a-methyl-5H-[l]benzo ⁇ yrano[2,3-b]pyridine-7-acetic acid);
  • Sulindac (I Z)-5-fluoro-2-methyl-l -[[4-(methylsulfinyl)phenyl]methy]ene]- lH-indene-3 -acetic acid); and 0 Suxibuzone (butanedioic acid, l-[(4-butyl-3,5-dioxo-l,2-diphe ⁇ iyl-4- pyrazolidinyl) ⁇ iethyl] ester).
  • Acemetacin I -(4-chlorobenzoyl)-5-methoxy-2-methyIindole-3 -acetic acid carboxymethyl ester, is a glycolic acid ester of indometkacin. The structure of acemetacin is shown below as is the structure for ketorolac.
  • the metal complex used in a method embodied by the invention can be any complex comprising at least one metal ion and at least one carboxylate, or hydroxamate, hydroxirnate, hydrazide, ester or aaiide derivative having anti-inflammatory activity.
  • the carboxylate or hydroximate, hydroxamate, ester or amide derivative can be coordinated with the metal ion via the carboxylate, hydroximate, hydroxamate, amide and/or other groups attached to the amide or ester linkages, such as sugars, amino acids, peptides, chelates containing heterocycles, and other chelating ligands.
  • the metal complex may be a mononuclear, dinuclear, or trinuclear metal complex, or a metal complex having higher nuclearity, or an oligomeric or polymeric complex containing one or more metal centres and one or more carboxylates, or derivatives of a carboxyl&te (eg,, hydroxamate, hydroximate, hydrazide, ester, and amide ligands) having anti-inflammatory activity.
  • a carboxyl&te eg, hydroxamate, hydroximate, hydrazide, ester, and amide ligands
  • the complex includes other ligands in addition to the carboxylate or carboxylate derivative(s) having anti-inflammatory activity.
  • these other ligands can also have anti-inflammatory and/or anti-cancer activities.
  • the complex is one of the following complexes (eg., see Copper Complexes of Non-steroidal Anti-inflammatory Drugs; An Opportunity yet to be Realized Weder, J. E.; Dillon, C. T.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A.; Biffin, J. R.; Regtop, H. L.; Davies, N. M. Coord Chem. Rev, 2002, 232, 95-126).
  • complexes eg., see Copper Complexes of Non-steroidal Anti-inflammatory Drugs; An Opportunity yet to be Realized Weder, J. E.; Dillon, C. T.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A.; Biffin, J. R.; Regtop, H. L.; Davies, N. M. Coord Chem. Rev, 2002, 232, 95-126).
  • Ibuprofen (+-)- ⁇ -methyl-4-(i$op ⁇ pylmethyl)benzeneacetic acid (IbuH); ⁇ ⁇ Metronidazole - 2-methyl-5-nitrobe ⁇ zimidaz ⁇ le s
  • Flufenamic Acid (N-trifluoromethylphenyi)anthranilic acid (FlufenH);
  • a Niflumic Acid 2-(3-t ⁇ fl.uoromethyl)phenylamino)-3-pyridineoarb ⁇ ylic acid
  • Indotnethacin l-(4-chlorol>enzoyl)-S- ⁇ iethoxy-2-tnethyl-1H-indole-3-acetic acid (IndoH);
  • J Diclofenac 2-[(2,6-dichlorophenyl)araino]phenylacetiQ acid (DicH); and M a i$ a metal ion and in at least some enbodhents, a transition metal ion,
  • M a can, for example, be a copper ion.
  • the complex can be any one of the complexes referred to in the table above in which the metal ion is a transition metal ion other than copper (eg icinc, nickel, ruthenium, iron, cobalt ions, and preferably zinc or ruthenium). See for instance, Copper and Zinc Complexes as Anti- Inflammatory Drugs. Dillon, C, T.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A.; Weder, J, E.; Zhou, Q.
  • the complex is a mononuclear, dinuclear, trinuclear or poly ⁇ uclear complex of a metal (where each metal of the complex is independently selected) and a ligand of the formula L 2 :
  • R' is H or halo (i.e. Cl, F, Br or I);
  • R 2 is H; a Ci to Ce alkyl, an alkenyl or an alkynyl, where the Cj to C$ alkyl, alkenyl or alkynyl may be optionally substituted; or
  • each R 2A is independently selected from the group consisting of H, Ci to Ct alkyi, alkenyl., alkynyl, aryl, cycloalkyl and arylalkyl, where tiie Ci to Cs alkyl, alkenyl, alkynyi, aryl, cycloalkyl or arylalkyl may be optionally substituted;
  • R 3 is H or halo
  • each R 5 is independently selected from the group consisting of halo, -CH 3 ,
  • n 1 , 2, 3, 4 or 5.
  • R 2 is a C 1 to Ce alkyl, an alkenyl or an alkynyl
  • the Ci to C 6 alkyl, 0 alkenyl or alkynyl may be substituted with one or more substituents.
  • the one or mote substituents may, for example, be independently selected from the group consisting of halo, -OH, -COOH and -NH 2 .
  • R 2A is a Ci to C* alkyl, an alkenyl, an alkynyl, an aryl, a cycloalkyl or an arylalkyl
  • the Ci to Ce alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be 5 substituted with one or more substituents.
  • the one or more substituents may, for example, be independently selected from the group consisting of halo, -OH, -COOH and -NH 2 .
  • R 5 is -CH 3 , -OCH 3 , -SCH 3 Or-CH 2 CH 3
  • the -CH 3 , -OCH 3 , -SCH 3 or - CH 2 CH 3 may be substituted with one or more substituents.
  • the one or more O substituents may, for example, be independently selected from the group consisting of halo, -OH 5 -COOH and -NH 2 .
  • the complex can be a complex of formula (I), (2) or (3):
  • L 2 is a ligand as defined above: each L is independently selected and is amonodentate ligand; m is 1 or 2,' and 0 p is the charge of the complex;
  • each M is independently selected and is a divalent or bivalent metal ion
  • L 2 is a ligand as defined above:
  • each L is independently selected and is a monodentate ligand; • m is 0, 1 or 2; and p is the charge of the complex;
  • each M r is independently selected and is a trivale ⁇ t or tetravalent metal ion
  • L 2 is a ligand as defined above: each L is independently selected and is a monodentate ligand; and 5 p is the charge of the complex.
  • R 2 is a Ci to C 6 alkyl, an alkenyl or an alkynyl
  • the C 1 to Cg alkyl, alkenyl or alky ⁇ yl 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.
  • R 2A is a Ci to C 6 alkyl, an alkenyl, an alkynyl, an aryi, a cycloalkyl or an arylalkyl
  • the Ci to Ce alkyl, alkenyl, alky ⁇ yl, aryl, cycloalkyl or arylalkyl may be substituted with one or more substituents.
  • the one or more substituents may, for example, be independently selected from the group consisting of halo, -OH, -COOH and -NH 2 . 5
  • R 5 is -CH 3 , -OCH 3 , -SCH 3 or -CH 2 CH 3 , the
  • -CH 3 , -OCH 3 , -SCH 3 or -CH 2 CH 3 may be substituted with one or mote substituents.
  • the one or more substituents may, for example, be independently selected from the group consisting of halo, -OH, -COOH and -NH 2 .
  • R 1 is typically H.
  • 0 R 3 is typically H.
  • R 2 is typically CH 3 .
  • L 2 is ACM.
  • M may be any divalent or trivalent metal ion, M is preferably copper ion, zinc ion, cobalt ion, nickel ion, chromium ion, molybdenum ion, tungsten ion or ruthenium ion. More preferably, M is a copper or zinc ion.
  • M' may be any trivalent or tctravalent metal ion.
  • M' is preferably iron ion, vanadium ion, manganese ion, chromium ion or ruthenium ion, and more preferably iron ion or ruthenium ion.
  • the liga ⁇ d L may be any monodentate ligand.
  • L may be a charged or uncharged ligand, L may for example be water, an alcohol, jV,N-dimethylformamide (DMF), iV-methylpyrrolidone, dimethylsulfoxide or N ⁇ -dimethylacetamide (DMA).
  • DMF jV,N-dimethylformamide
  • iV-methylpyrrolidone dimethylsulfoxide or N ⁇ -dimethylacetamide
  • DMA N ⁇ -dimethylacetamide
  • the complexes of formula (1), (2) or (3) may be dissolved in a solvent, or may be in the form of a solid Crystals of a complex of formula (1), (2) or (3) may include solvents of crystallisation. Crystals of a complex of formula (1 ), (2) or (3) may also include waters of crystallisation.
  • the complex is a mononuclear complex of the following formula (4):
  • M is a divalent or trivalent metal ion
  • L 1 is a ligand of the formula
  • R 1 is H or halo (i.e. Cl, F, Br or I);
  • R 2 is H; a Ci to Q alkyl, an alkenyl or an alkynyl, where the C 1 to Ce alkyl, alkenyl or alkynyl may be optionally substituted; Of
  • each R 2A is independently selected from the group consisting of H, Ci to Ce alkyl, alkenyl, alkynyl, aryl, cycloalkyl and arylalkyl, where the Cj to Ce alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be optionally substituted;
  • R 3 is H or halo;
  • each R" 1 is independently selected from the group consisting of halo, -CHj, -CN, -OCH 3 , -SCH 3 and -CH 2 CH 3 , where the -CH 3 , -OCH 3 , -SCH 3 or -CH 2 CH 3 may be optionally substituted.
  • n is i, 2, 3, 4 or 5; each L is independently selected and is a monodentate ligand; m is 1 or 2; and p is the charge of the complex;
  • the mononuclear complex of formula (4) is a complex of formula (4A):
  • M is a divalent or divalent metal ion
  • ⁇ 2 -L' is a bidentate ligand of the formula L 1 ;
  • R 1 is H or halo (i.e. Cl, F, Br or I);
  • R 2 is H; a C 1 to Cs alkyl, an alkenyl or an alkynyl, where the Ci to Cs alkyl, alkeityl or alkynyl may be optionally substituted; or
  • each R 2A is independently selected from the group consisting of H, Ci to Cg alkyl, alkenyl, alkynyl, aryl, cycloalkyl and arylalkyl, where the Ci to Ce alkyl, 0 alketiyl, alkynyi, aryl, cycloalkyl or arylalkyl may be optionally substituted;
  • R 3 is H or halo; each R 5 is independently selected from the group consisting of halo, -CH 3 , -CN 3 -OCH 3 , -SCH 3 and -CH 2 CH 3 , where the -CH 3 , -OCH 3 , -SCH 3 or -CH 2 CH 3 may be optionally substituted; 5 n is 1, 2, 3, 4 or 5; each L is independently selected and is a monodentate ligand; and p is the charge of the complex.
  • R 3 is a Ci to Ce alkyl, an alkenyl or an alkynyl
  • the Ci to C(, alkyl, alkeny] or alkynyl may be substituted with one or more substituent$, O
  • the one or more siibstLtuents may, for example, be independently selected from the group coti$i$ting of halo, -OH, -COOH and -NH 2 .
  • R 2A is a Ci to Ce alkyl, an alkenyl, an alkynyl, an aryl, a cycloalkyl or an arylalkyl
  • the Ci to Ce alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be substituted with one or more substituents.
  • the one or more substituents may, for example, be independently selected from the group consisting of halo, -OH, -COOH and -NH 2 .
  • R 5 i$ -CH 3 , -OCH 3 , -SCH 3 or -CH 2 CH 3 when R 5 i$ -CH 3 , -OCH 3 , -SCH 3 or -CH 2 CH 3 , the - CH 3 , -OCH 3 , -SCH 3 or -CH 2 CH 3 may be substituted with one ot more substituents.
  • the 5 one or more substituents may, for example, be independently selected from the group consisting of halo, -OH, -COOH and -NH 2 .
  • R 1 is typically H
  • R 3 is typically H
  • R 2 is typically CH 3 , 0
  • T each R 5 is typically halo (i.e. F, Cl, Br or I) ? and n is typically I 1 2 or 3.
  • L 1 may for example be Indo.
  • M may be any divalent or trivalent metal ion.
  • M is preferably copper ion, zinc ion, cobalt ion, nickel ion, chromium ion, molybdenum ion, 5 tungsten ion or ruthenium ion. More preferably, M is copper ion or zinc ion.
  • the complex is a dinuclear complex of the formula (5);
  • each M is independently selected and is a divalent or trivalent metal ion
  • O ⁇ -L 1 is a ligand of the formula L 1 :
  • R 1 is H or halo (i.e. Cl, F, Br or I); 5 R 2 is H; a Cj to Co alkyl, an alkenyl or an alkynyl, where the Ci to Cs alkyl, alkenyl or alkynyl may be optionally substituted; or wherein each R 2A is independently selected from the group consisting of H, Ci to Ce alkyl, alkenyl, alkynyl, aryl, cycloalkyl and arylalkyl, where the Ci to Ce alkyl, alkenyl, aikynyl, aryl, cycloalkyl or arylalkyl maybe optionally substituted; 5 R 3 is H or halo; each R 5 is independently selected from the group consisting of halo, -CHj, -CN, -OCH 3 , -SCH 3 and -CH 2 CH 3 , where the -CH 3 , -OCH 3 , -SCH 3 Or-CH 2
  • R 2 is a Ci to C ⁇ alkyl, an alkenyl or an alkynyl
  • the Ci to Ce alkyl, alkenyl or alkynyl may be substituted with one or more sub$tituents.
  • the one 5 or more substituents may, for example, be independently selected from the group consisting of halo, -OH, -COOH and -NH 2 .
  • R 2A is a Ci to C 6 alkyl, an alkenyl, an alkynyl, an aryl, a Cycloalkyl or an arylalkyl
  • the Ci to C 6 alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be substituted with one or more substituents.
  • the one or more O substituents may, for example, be independently selected from the group consisting of halo, -OH, -COOH and -NH 2 .
  • R 5 when R 5 is -CH 3 , -OCH 3 , -SCH 3 or -CH 2 CH 3 , the -CH 3> -OCH 3 , -SCH 3 or -CHjCH 3 may be substituted with one or more substituents.
  • the one or more substituents may, for example, be independently selected from the group 5 consisting of halo, -OH, -COOH and -NH 2 .
  • R 1 is typically H.
  • R 3 is typically H.
  • R s is typically CH 3 .
  • L 1 may for example be Indo.
  • M is any divalent or trivalent metal ion. M is typically selected from copper ion, zinc ion, cobalt ion, nickel ion, chromium ion, molybdenum ion, tungsten ion and ruthenium ion. Preferably, M is copper ion.
  • the ligand L maybe any monodentate ligand, L may, for example, be water (OH 2 X an alcohol, dimethylsulfoxide (DMSO) 4 tetrahydrofuran (THF), or L may be a ligand containing a tertiary amide or cyclic tertiary amide.
  • DMSO dimethylsulfoxide
  • THF tetrahydrofuran
  • the complex is a trinuclear complex of the following formula (6):
  • each M' is independently selected and is a trivalent or tetravalent metal ion; and ⁇ -L 1 , L and p are as defined above for formula (5).
  • the complex is a trinuclear complex of the following formula (7):
  • M is a divalent metal ion
  • L 3 is a carboxylate having anti-inflammatory activity
  • L 4 is an optionally substituted heterocyclic base comprising one or two heterocyclic rings independently having 5 or 6 ring members and I to 3 heteroatoms independently selected from N, O and S; wherein each L 3 is independently selected; and each L 4 i$ independently selected.
  • L 3 can be a monodentate, bidentate or bridging ligand of formula L 1 or L 2 a$ follows;
  • R 1 i$ H or halo i.e. Cl, F, Br or I
  • R 2 i$ H a Ci to C 6 alkyl, an alkenyl or an alkynyl., where the Q to C$ alkyl, alkenyl or alkynyl may be optionally substituted; or
  • each R 2A is independently selected from the group consisting of H, Ci to C 6 alkyl, alkenyl, alkynyl, aryl, cydoalkyl and arylalkyl, where the Ci to C 6 alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl maybe optionally substituted;
  • R 3 is H or halo;
  • each R 5 is independently selected from the group consisting of halo, -CHs, -CN, -OCH 3 , -SCH 3 and -CH 2 CH 3 , where the -CH 3 , -OCHj, -SCH 3 Or-CH 2 CH 3 may be optionally substituted; and n is i, 2, 3, 4 or 5.
  • M can, for example, be selected from the group consisting of zinc ion, cobalt i ⁇ n, nickel ion, magnesium ion, copper ion and calcium ion.
  • the heterocyclic* base comprises one or more N atoms.
  • the heterocyclic base is optionally substituted.
  • the heterocyclic base may, for example, be selected from the group consisting of isoquinolyl, quinolyl, piperidinyl, pyridinyl, 2-r ⁇ ethylpyridinyl, imadazoyl, pyranyl, pyrrolyl, pyrimidinyl, indolyl, purinyl and quinolizinyl.
  • the heterocyclic base is quinolyl.
  • metal complex i$ a complex of formula (8) as follows:
  • M is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent metal ion; each L s is independently selected and is amonodentate carboxylate, (preferably Indo, ACM or Keterolac) or fl ⁇ amide ligand (O or N bound) (preferably a derivative of Indo, ACM or Keterolac), having anti-inflammatory activity; each L 6 is independently selected and is NH3, a monodentate ligand, a polydentate ligand, or a macrocyclic ligand; m is 1, 2, 3 or 4 n is O, l, 2 ? 3 ? 4 or 5; a ⁇ d p is the charge of the complex.
  • the metal complex is a metal complex of formula (8a) as follows: wherein
  • the metal complex is a complex of formula (9) a$ follows:
  • the metal complex is a complex of formula (11) as follows:
  • the metal complex is a complex of formula (12) as follows:
  • M is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent metal ion; each L s is independently selected and is a monodentate or bidentate carboxylate, or monodentate amide ligand (O or N bound), having anti-inflammatory activity; each L 7 is independently selected and is a monode ⁇ tate or a polydcntate ligand; each L 8 is independently selected and is a bridging ligand, such as an oxo, hydroxo, carboxylatc (including a N SAID), halide, or other bridging group.
  • One or more of the ligands L s and L 8 in any combination may also form dimeric, trimeric, tetrameric, oligomeric or polymeric complexes with one or more metal ions.
  • the ancilliary ligands can be chosen from ligands that exert a separate anti-inflammatory activity.
  • the metal complex may be administered to the mammalian subject alone or in combination with other antiinflammatory drug(s), or anti-diabetic drugs or treatments for diabetes.
  • Such administration can be given to improve the response to the other anti-inflammatory drug(s) » or anti-diabetic drugs or treatmei-t(s), or to reduce the dose of such other drug(s) to reduce toxic $ide-effect$ while maintaining a comparable efficacy.
  • the metal complex can be administered to the mammalian subject alone or in combination with other anti- inflammatory drug(s), or anti-diabetic drugs or treatments for the simultaneous treatment of diabetes and conditions associated with diabetes, such as cardiovascular disease and other inflammatory conditions as described in the Applicants co-pending International Patent Application entitled “Prophylaxis or treatment of cardiovascular inflammation” filed 27 March 2007, and co-pending International Patent Application entitled “Metal complexes having anti-inflammatory activity” filed 26 March 2007, the contents of both of which are incorporated herein by cross-reference in their entirety.
  • Such administration can be given to improve the response to the other anti-inflammatory drug(s) or anti-diabetic drugs or treatments), and/or to reduce the dose of such other drug(s) to reduce toxic side-effects while maintaining a comparable efficacy.
  • the ligand(s) of ⁇ c metal complex used in a method embodied by the invention may not have anti-inflammatory activity alone, the activity being provided by the combination of the metal and the ligand(s) in the complex,
  • Methods of the invention find broad application in the prophylaxis or treatment of diabetes.and pre-diabetic conditions,
  • the present invention also provides the use of a complex of a metal and a carboxylate, or a derivative of a carboxylate, having anti-inflammatory activity in the manufacture of a medicament for the prophylaxis or treatment of diabetes in a mammalian subject, the carboxylate or derivative being other than salicylate or a derivative of salicylate.
  • the diabetes treated by one or more methods embodied by the invention may be selected from the group including, but riot limited to, Type 1 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 a 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).
  • a disease or condition eg, such as polycystic ovary disease or acanthosis nigricans
  • non-resistant forms of diabetes observed following pancreatic surgery and for instance, following trauma to the pancreas (eg., as a result of injury).
  • chelating derivatives of NSAIDs can also enhance the stability of metal-NSAlD complexes. This can result in one or more of: (i) a reduction in GI toxicity by increasing the stability of the drugs in the
  • a copper hydroxamate complex can exert anti-inflammatory activity by a combination of independent COX-2 inhibition (by both the parent NSAID and the NSAlDHAH 2 ), the release of NO from the NSAlDHAH 2 , 5- lipoxyge ⁇ ase inhibition by the hydroxamic acid, and the effects of Cu once the complex decomposes at a target site.
  • metal ions, co-ligands and 0 metal oxidation states of the metal complexes can be utilized to optimise the rate of release and/or hydrolysis of the NSAID-derivative to enable sufficient stability before the anti-inflammatory Iigands of the metal complex are released.
  • metal-NSAID complexes with a variety of different metal ions can allow allow a therapeutic regime to be tailored to the type of diabetic condition being S treated.
  • Lipophilic formulations containing metal complexes are particularly beneficial fot delivery of lipophilic complexes as described herein.
  • Metal complexes can also be provided in water-soluble form for optimized systemic delivery by intravenous injection.
  • Metal complexes used in at least some embodiments of the invention will have 0 reduced toxicity associated side effects compared to ligand(s) in the metal complex (eg carbo ⁇ ylate$, hydroxamates, hydroximates, esters and amides).
  • the metal complex can have substantially less gastrointestinal and/or renal toxicity than the parent anti-inflammatory ligand.
  • the metal complexes can be administered more safely at normal therapeutic doses, or in higher dosages (eg., for acute conditions) and/or over longer periods of time resulting in increased efficacy in treatment.
  • one or more methods embodied by the invention can provide an alternative prophylactic or therapeutic treatment for the treatment of diabetes and pre-diabetic conditions which avoid or reduce the adverse cardiovascular side-effects associated with the use of selective COX-2 NSATDs.
  • metals used in complexes as described herein and particularly Cu and V can have beneficial cardiovascular effects.
  • Pre-diabetic conditions include, for example, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and gestational diabetes.
  • Figure 1 shows the chemical structure of [Cu ⁇ IndoMDMF ⁇ J
  • Figure 4 is a graph showing plasma haptoglobin following dosing of rats with equimolar Indo doses of IndoH and [Cu 2 (Indo)4(DMF)a] in 2% w/w CMC compared with control rats treated with CMC only ⁇ n - 4; Mean ⁇ SEM).
  • Plasma was obtained by cardiac puncture and the haptoglobin level was measured using a commercial kit (Bade Behring, Mannheim, Germany);
  • Figure 5 is a graph showing the extent of small intestinal ulceration following treatment of rats with equimolar Indo doses of IndoH or [Gu 2 (Indo) 4 (DMF) 2 ] in 2% w/w CMC compared with control rats treated with CMC only (n ⁇ 4; Mean ⁇ SEM). Ulceration was measured 24 h after dosing;
  • Figure 6 is a graph showing the extent of small intestine permeability as determined by the % 51 Cr-EDTA excretion in urine collected for 0-24 h after dosing of rats with equimolar Indo doses of IndoH or [Cu2(Indo>4(DMF)2] in 2% w/w CMC compared with control Tats treated with CMC only (n - 4; Mean ⁇ SEM);
  • Figure 9 is a graph showing the extent of mitochondrial DNA damage in rat intestinal tissue after administration of single doses equimolar Indo doses of IndoH or
  • Figure 11 is a graph of gastric damage (mm 2 ) for active ingredients (Samples S P, Q and R) dosed by means of oral gavage with a composition of MCT organogel and at Indomethaci ⁇ i Equivalence treat rate of 2 mg kg "1 bw.
  • Figure 12 is a graph of the anti-inflammatory effect on rat paw oedema (% ⁇ mm 3 ) of active ingredients (Samples P, Q and R) dosed by means of oral gavage with a composition of MCT organogel and at an Indomethacin Equivalence treat rate of 2 mg 0 kg "1 bw.
  • Figure 13 is a graph showing the ability of the vanadium (V) complex [V v O(IndoHAH) 2 (OMe)j (4 mg oxametacin equivalents per kg of body weight) to decrease blood sugar levels in diabetic rats,
  • a reference to “copper indomethacin” or “Culndo” is a reference to [Cu 2 (Ind ⁇ ) 4 (DMF) 2 ].
  • a reference to “Ibup” is a reference to Ibuprofen;
  • a reference to “Im” is a reference to imidazole;
  • a reference to “Py” is a reference to pyridine;
  • a reference to “3-pic” is a reference to 3-picoline;
  • a reference to “4-pic” is a reference XQ 4- ⁇ icoline;
  • a reference to “Bim” is a reference to benzimidazole;
  • a reference to "IndoH” is a reference to indomethacin;
  • a reference to "AcSHAHj” is a reference to aectylsalicylhydroxa
  • halo refers to fluoro, chloro, bromo or iodo.
  • alkyl used either alone or in a compound word such as “arylalkyi”, refers to a straight chain, branched or mono- or polycyclic aikyl.
  • straight chain and branched alkyl examples include methyl, ethyl, propyl, /s ⁇ -propyl, butyl, ⁇ o-butyi, sec-butyl, tert-butyl, amyl, tsoamyl, jec-amyl, 1,2-dimcthyl ⁇ ropyl, 1,1- dimethylpropyl, hexyl, 4-mcthylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpcntyl, 1,1-dimcthylbutyl, 2,2-dimethylbutyU 3,3-dimethyIbutyl,
  • cyclic alkyl examples include cyelopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic alkyl having 3 to 12 carbons.
  • alkenyl refers to a straight chain, branched or cyclic alkenyl with one or more double bonds.
  • the alkenyl is a Ch. to C20 alkenyl, more preferably a Ca to Q alkenyl.
  • alkenyl examples include vinyl, allyl, 1 -methyl vinyl, butenyl, ⁇ ro-but ⁇ yl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methylcyclo ⁇ entenyl, 1-hexenyl, 3-hexenyl ⁇ oyolohexenyl, 1-he ⁇ tenyl, 3-he ⁇ tenyl, 1-octcnyl, cyclooctcnyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl,
  • alkynyl refers to a straight chain, branched or cyclic alkynyl with one or more triple bonds, preferably a Cz to C2 0 alkynyl, more preferably a C 2 to C & alkynyl.
  • aryl used either alone or in compound words such as “arylalkyl”, refers to a radical of a single, polynuclear, conjugated or fused aromatic hydrocarbon or aromatic heterocyclic ring system.
  • aryl include phenyl, ⁇ aphthyl and fiiryl.
  • the aromatic heterocyclic ring system may contain 1 to 4 heteroatoms independently selected from N, O and S and may contain up to 9 carbon atoms in the ring.
  • arylalkyl refers to an alkyl substituted with an aryl group.
  • An example of arylalkyl is benzyl.
  • the term "bidentate ligand” refers to a ligand having two co-ordination bonds to a metal atom. Bidentate ligands include unsymmetric bidentate ligands with one weaker and one relatively stronger bond to the metal atom.
  • the terra "monodentate ligand” refers to a ligand having a single co-ordination bond with a metal atom.
  • the present invention steins from the recognition that at least some metal complexes and in particular complexes of a metal and a carboxylate, hydroxamate, hydroximate, ester or amide having anti-inflammatory activity are effective in the prophylaxis or treatment of diabetes, and can be more effective in treating diabetes in terms of efficacy and/or safety than the carboxylate, hydtoxamate, hydroximate, ester or amide having anti-inflammatory activity itself.
  • complexes of a metal and indomethacin may be more effective in the prophylaxis or treatment of cardiovascular inflammation, in terms of efficacy and/or safety, than i ⁇ domethacm itself.
  • the metal complex used in the method of the invention may, for example, be any of the complexes set out in following Table 1. It will also be understood that copper ion may be substituted with another transition metal ion (eg zinc, nickel, or cobalt ions as described in Copper and Zinc Complexes a$ Anti-Inflammatory Drugs. Dillon, C. T.; . Hambley, T. W.; Kennedy, B, J.; Lay, P. A.; Weder, J. E.; Zhou, Q. in "Metal I ⁇ n$ and Their Complexes in Medication", Vol. 41 of Metal Ions in Biological Systems'; Sigel, A 1 ; Sigel, H,, Eds.; M.
  • transition metal ion eg zinc, nickel, or cobalt ions as described in Copper and Zinc Complexes a$ Anti-Inflammatory Drugs. Dillon, C. T.; . Hambley, T. W.; Kennedy, B, J.; Lay, P. A.; We
  • Suprofen (+)- ⁇ - ⁇ iethy1-4-(2-thienyl-carbcaiyl) ⁇ henylacetic acid (SupH);
  • Tolmcntin l-methyl-5-(p-toluoylHH-py ⁇ role-2-acetic acid (ToIH);
  • c DMSO dimethylsulfoxide;
  • Naproxen 6- ⁇ )ethoxy- ⁇ - ⁇ nethyl-2-na ⁇ hthaleneaeetic add (NapH);
  • Ibuprofen (+)- ⁇ -methyI-4-(is ⁇ propylmet ⁇ yl)benzeneacetic acid (IbuH);
  • ⁇ Metronidazole * 2-methyl-5-oitfobenzimidazole s Rufenamic Add — (N-trifluoromefhyl ⁇ henyl)anthranilic acid (FlufenH);
  • ⁇ ⁇ iflumic Acid 2-((34rifluo ⁇ omethyl)phenylamino)-3-pyridinecarboxylio acid - ( ⁇ ifH);
  • Indomethadn l-(4-chlorobenzoyl)-5-mefhoxy-2-methyl-lH-indole-3-aceti ⁇ acid (IndoH);
  • ⁇ SAIDs include: Catprofen (6-chloro-a-methyl-9H-carbazole-2-acetic acid);
  • Etodolac (l,8-diethyl-l,3,4,9-tetrahydio-pyrano[3,4-b]indole-l -acetic aoid); Fentiazac (4-(4-chlo «)phenyl)-2-phe ⁇ yl-5-thiazoleaoetJc add); Flurbiprofen (2-fluoro-a-methyl-[l ] r-biphejiyl3-4-acetic acid); Ketoprofen (3-benzoyl-a-methylbenzeneacetic acid); Oxaprozin (4,5-di ⁇ henyl-2-oxazol ⁇ propanoic acid);
  • Pranoprofen (a-mcthyl-5H-[l]benzopyrano[2 t 3-b]pyridine-7-acetic add); Sulindac ((12)-5-fluoro-2-methyl-l-[[4-(inethylsulfinyl)phenyl]methylene]- lH-indene-3 -acetic acid); and
  • Metal complexes useful in methods embodied by the invention can be prepared by methods known in the art, or prepared by methods described below. Methods known in the art are described in, for example, United States Patent No, 5,466,824 or the paper: Anti-inflammatory Dinuclear Copper(II) Complexes with Tndomethacin. Synthesis, Magnetism and EPR Spectroscopy, Crystal Structure of the N,N-Dimethylformamide Adduct Weder, I E.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A.; MacLachlan, D.; Bramley, R 1 ; Delfs, C. D.; Murray, K, S,; Moubaraki, B.; Warwick, B.; Biffin, J.
  • the complex can be a complex comprising at least one metal ion and at least one hydroximate, hydroxamate, ester or amide derivative of a carboxylate NSAID having anti-inflammatory activity.
  • a hydroxamic acid having anti-inflammatory activity can form hydroxamato or hydroximato complexes with a metal ion in the complex.
  • An amide having anti-inflammatory activity can for example, also form chelates of deprotonated amides or amide monodentate complexes with a metal ion in the complex.
  • Inert metal complexes incorporating carboxylate ligands having inflammatory activity can be prepared by methods known in the art, or as described below. Such reactions include the substitution of a leaving group in an inert metal complex with a carboxylate group of an NSAID, or an amide group in a NS AID or an amide derivative of a NSAID, This i$ exemplified by Example 1 in the preparation of [Co(NH 3 )s(Indo)]X ? as follows:
  • M Co(IlD, Cr(IIT), Tr(ITT), Os(ITT), Rh(ITI),
  • such complexes can be prepared by substitution of a weakly coordinated, trifluoromethanesulfonato, or solvent, or other such ligands, as described for example in, Introduction to Trifluoromethanesulfonates and
  • m etal complexes of the invention can be prepared by reaction of a derivative of R 6 COZ with a hydroxo or deprotonated amine ligand on the metal, for example: [MCOHUL 6 ),/ + mR 6 C0Z ⁇ [M(L 5 ) ra (L 6 ) n ] p + mZ
  • esters of carboxylates having anti- 5 inflammatory activity and amide derivatives of carboxylates that bind in a m ⁇ n ⁇ dentate fashion to the metal.
  • the esters and amides can contain heterocyclic groups or aliphatic or aromatic groups that contain other functional groups that bind to the inert metal in a mo ⁇ odentate fashion,
  • a monodentate amide Iigand 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.; 0 Han, Y,; Taube, H, Oxygen versus Nitrogen Bonding of Carboxamides to
  • Oxygen and nitrogen-bownd forms of the amide complexes can be interconverted by a change pH or other means of pr ⁇ tonatio ⁇ /deprotonation reactions, for example:
  • X is a conjugate base of a strong or a weak acid (eg., X can be a halide, oxyanion, carboxylate, sulfonate, etc.);
  • X J is a conjugate base of a weak acid, examples of which include oxyanions, carboxylates, amines, and N- 0 heterocycles;
  • Y is a leaving group, examples of which include halo, alkylsulfonato, O- bound sulfoxides, 0-b ⁇ und amides, aldehydes, ketones, and nitrato ligands; and
  • R 6 COZ is an acyl halide, anhydride or ester derivative of a NSAID.
  • Metal complexes embodied by the invention can also be prepared by methods outlined in Example 1 below.
  • the complexes contain Indo, ACM, ketorolac or derivatives of Indo, ACM or ketorolac ligands as described above, or amide or ester derivatives of these or other NSAIDs.
  • the functional groups of the ligands can themselves bind to the metal ion, and/or other ligating groups that are linked by these functionalities can bind to the metal.
  • any R group (eg., alkyl, aryl etc) of an amide derivative can also contain donor functional group(s) that form a co-ordination bond with a metal ion.
  • Such functional groups include, for instance, a carboxylate group of an amino acid or peptide derivative of a NSAlD, or a RS " , thioether, phenol, amine, or iV-heterocyclic side-chain of such an amino acid or peptide derivative. It will also be understood that a large variety of other functional groups would be suitable.
  • Hydroxamic acids having anti-inflammatory activity that may be utilised in the complexes used in the method of the invention include those of the type described in International Patent Application No. WO 2004/000215 comprising a NSAID covalently linked by a linker to a hydroxamate.
  • Hydroxamic acid derivatives of carboxylates having anti-inflammatory activity such as Indo and esters of lndo (e.g. ACM), are particularly preferred.
  • R AIk or Ar hydroxamato hydroximato complex complex
  • Amide derivatives of carboxylic acids having anti-inflammatory activites can be prepared as described in International Patent Application No. WO 95/04030, or modifications thereof. See, for instance, the indomethacin example below (Scheme 2).
  • R may be a proton, alkyl or aryl group, in which case the liga ⁇ d would be a monodentate O or N donor to the metal.
  • R may contain one or more functional groups that could act as other donor groups to form a metal chelate.
  • Suitable coupling reactions include those with amino acids to form a mixed amide/carboxyiate donor set (or a stagentate or bidentate carboxylase donor only), or more complex donor bidentate sets with amino acids containing metal binding side-chains, e.g., cysteine, serine, methionine, histidine, tyrosine, etc.
  • Other suitable R groups include amino sugar derivatives and glycoproteins that target tumour cells *
  • the coupling reaction may also involve short chain peptides, which can act as chelating ligands, or other groups to give metal chelators with anti-inflammatory activities, as described in WO 95/04030.
  • R may be an alkyl or aryl group containing a substituent, which can act as a monodentate or polydentate Hgand, e.g., a carboxylate group as in ACM, Of an amino group (prepared from an aminoalcohol) with a monodentate or polydentate amine ligands Of more complex donor bidentate sets with serine or short-chain peptides containing serine.
  • chelating groups that may be coupled, include sugars and glycoproteins.
  • the ligand having anti-inflammatory activity is an amide-containing NSAID that i$ not a carboxylate.
  • NSAIDs that are not carboxylates include for instance ⁇ xicam NSAID$ such as piroxicam (4-hydroxy-2-methyl-N-2- pyridyl-2H- l ⁇ -ben ⁇ oihiazine-3-carboxamide- 1,1 -dioxide), tenoxicam (4-hydroxy-2- methyl-N-2-py ⁇ dinyl-2H ' iMeno(2,3-e)-l ⁇ -thiazine-3-carboxamide-l,l-dioxide) and meloxicatn.
  • the complex is a complex of the formula (A);
  • M is a metal ion
  • L 4 is a hydr ⁇ xamate or hydroximate having anti-inflammatory activity or a chelating amide (such as those containing an amino acid or peptide linkage as the chelate) having anti-inflammato ⁇ y activity; each L is independently selected and is a monode ⁇ tate or polydentate ligand; n is l, 2 or 3; m is 0, 1» 2, 3 or 4; and p is the charge of the complex,
  • M is a divalent, trivalent, tetravalent, pentavalent or hexavalent metal ion
  • NSAIDs and NSAlD ligands that may be utilised are described in for instance Wcdcr. J. E.; Dillon, C. T.; Hambley, T. W,; Kennedy, B. J.; Lay, P. A.; Biffin, J. R.; R ⁇ gtop, H. L., Davies.; N. M. Coord. Chem, Rev. 2005, 232, 95-126 and Dillon, G. T.; Hambley, T. W.; Kennedy, B. J.; Lay, P.
  • the complex used in the method of the present invention may be a mononuclear, dinuclear, trinuelear, oligomeric or polymeric complex containing the ligand L 2 as defined above.
  • the complex may be a complex of formula (1), (2), (3) or (8), as defined above.
  • Complexes of formula (1 ) or (2) can be prepared by mixing a stoichiometric amount of a compound L 2 H (where L 2 is as defined above) and a divalent or trivalent metal salt, preferably a ba$ic salt such as M(OAc) 2 , in a solvent L (the solvent forming the ligand L in the resultant complex, or in the case of the aqua complex, adventitious water in the organic solvent). The mixture is then heated until precipitation occurs and it is then cooled and the solid is filtered off.
  • a compound L 2 H where L 2 is as defined above
  • a divalent or trivalent metal salt preferably a ba$ic salt such as M(OAc) 2
  • the product may need to be recrystallised until elemental, spectroscopic and/or diffraction methods demonstrate that the complex is of the required purity
  • Complexes of formula (3) can be prepared by the same procedures as those described above for the preparation of complexes of formula (1) or (2) using a trivalent or tetravalent metal salt. Such complexes are obtained by mixing L 2 H and a suitable metal salt in aqueous/organic solvent mixtures under basic conditions. Additional ligands L may be added to these solutions to precipitate the complexes. Methods of preparation of complexes of formula (I) 1 (2) and (3) are discussed in the Applicants co-pending International Patent Application No. PCT/AU2006/000391, the contents of which arc incorporated herein by cross-reference in it$ entirety. The complexes of formulae (1), (2) or (3) may be charged or neutral.
  • Complexes of formula (1) and (2) are neutral in charge if M is a divalent metal ion and all the Hgands L are neutral Ugands.
  • a complex of formula (1) or (2) may have a charge, for example, p may be 1 " or 2 " .
  • Complexes of formula (3) have a charge of I + if all the metal ions M' in the complex are trivalent metal ions and all the ligands L are neutral. However, in some embodiments, the complex of formula (3) may have a charge of T, V, O 7 or 2 * .
  • Examples of complexes of formula (1) include [Cu(ACM) 2 (DMFh] * [Cu(ACM) 2 (OHa) 2 ], [Zn(ACM) 2 (DMF) 2 ] and [Zn(ACM) 2 (OH 2 ) 2 ].
  • Examples of complexes of formula (2) include [Cu 2 (ACM) 4 L 2 ], [Zn 2 (ACM) 4 L 2 ], [Ru 2 (ACM) 4 L] p and [Ru 2 (ACM) 4 L 2 ] p (where Ru is Ru(II)X and
  • the complex of formula (2) is a complex of the formula (2A):
  • the complex i$ a mononuclear complex of the following S formula (4):
  • the mononuclear complex of formula (4) is a complex of formula (4A):
  • the complex of formula (4) may be charged or neutral, Preferred complexes include [Cu(UIdO) 2 (Im) 2 ], [Cu(ACM) 2 (OH 2 ) 2 ], [ZnOndoMOrfek] ⁇ nH 2 O and [Z ⁇ (ACM) 2 (OH 2 ) 2 ].
  • the complex of formula (4) can be in solution, or may be in the form of a solid. 0 Crystals of a complex of formula (4) may include solvent$ of crystallisation. Crystals of a complex of formula (4) may also include waters of crystallisation. If L is an anionic ligand, the complex of formula (4) will be charged (e,g., p is 1 ⁇ or T) and a solid of the complex of formula (4) will include cations that are counter ions to the anionic complexes.
  • Such solids include solids having the following formulas: 5 YtMdf-L'fel ⁇ ] (4B) and wherein M, ⁇ 2 ⁇ lJ and L are as defined above for formula (4A), Y is a counter ion having a 2 + charge and Y ' is a counter ion having a I + charge.
  • Complexes of formula (4) where M is Cu(U) can, for example, be formed using the ligand pyrrolidine.
  • Other ligands having a similar donor strength to, or a greater donor strength than, pyrrolidine can also form complexes of formula (4).
  • L is a ligand containing an N-heterocyclic group.
  • Ligands containing an N-heterocyclic group include pyrrolidine, alkyl-substituted pyrrolidines, proline, proline derivatives, imidazole, imidazole derivatives $uch as substituted imidazoles or ligands containing an imidazole ring (eg.
  • L is an amine, e.g. NH 3 or an organic amine (e.g. diethylamine), an alcohol or an amide (e.g. diethylacetamide), or another ligand that is a strong donor such as ttiethylphosphate.
  • L can be a solvent having a solvent donor number of about 30 or greater.
  • Complexes of formula (4) may, for example, be prepared by direct reaction of the appropriate ratios of a compound of the formula L 1 H where L 1 is as defined above and a copper salt such as copper(H) acetate in a solvent having a solvent donor number of about 30 or greater, the solvent forming the ligaad L in the resulting complex.
  • Complexes of formula (4) may also be prepared by adding a solvent having a solvent donor number of about 30 or greater, or adding a ligand that is not a solvent but has a similar donor strength to a solvent having a solvent donor number of about 30 or greater, to a solution of the metal ion (e.g. Cu(D)) and L J in a weaker donor solvent.
  • complexes of formula (4) can be prepared by re-crystallisation of a dinuclear complex, $uch as [Cu 2 (ItIdO) 4 (DMF) Z ] * in a solvent having a solvent donor number of about 30 or greater, such as pyrrolidine, or in a solvent containing a ligeuid that is a strong donor such as imidazole (Im).
  • the complexes of formula (4) are. more lipophilic than indomethacin or other compounds of the formula L 1 H and thus are more easily absorbed through membranes and taken up by tissues locally.
  • the complexes of formula (4) are, therefore, expected to be more readily absorbed into cells than free indomethacin or other compounds of the formula L 1 H when administered topically.
  • the complex is a dinuclear complex of the formula (5):
  • Complexes of formula (5) may be charged or neutral in charge.
  • the ligand L may be any monodentate ligand.
  • the ligand L may be charged or uncharged.
  • L may, for example, be water (OH2), an alcohol, dimethylsulfoxide (DMSO), pyridine (Py), acetotiitrile (AN), tetrahydrofuran (THF), or L may be a ligand containing a tertiary amide or cyclic tertiary amide.
  • L may be a molecule of a tertiary amide of the formula
  • Ri i$ an alkyl having from 1 to 4 carbon atoms, and each Ri may be the same or different, and R 2 is a cycl ⁇ alkyl having from 2 to 7 carbon atoms.
  • the tertiary amide or cyclic tertiary amide may be, for example, JV.N-dimethylformainide, N,N-dimethylacetamide or N-methylpyrroIidone.
  • An example of a complex of formula (5) is a dimiclear complex of the formula (5A):
  • M is Cu or Zn; each L is independently selected and is a nio ⁇ odentate ligand; and p is the charge of the complex.
  • L 1 may for example be Indo.
  • the complex is a dinuclear metal/indomethadn complex of the formula (5B):
  • M 2 ( ⁇ -I ⁇ do)4Y 2 j 5B
  • M is Cu or Zn
  • Indomethacin is one of the most lipophilic NSATOs and, again without being 5 limited by theory, the present inventors believe that the binding of the ligand to a metal makes complexes of formula (5B) more lipophilic than IndoH and hence promotes the transport of M (i.e. Cu or Zn) and Indo into the vasculature (i.e. there is greater absorption of the complex than IndoH).
  • M i.e. Cu or Zn
  • Indo into the vasculature i.e. there is greater absorption of the complex than IndoH.
  • the greatly reduced adverse effects of the complex compared with free indomethacin such as gastrointestinal and 0 particularly, the newly discovered reduction in renal effects on oral administration as described herein
  • Complexes of formula (5B) include, for example, [Cu 2 (IUdO) 4 (DMFh], [Cu 2 (Indo) 4 (DMA) 2 ], [Cu 2 (UIdO) 4 (NIVlP) 2 ], [Cu 2 (LIdO) 4 (DMSO) 2 ], [Cu 2 (IiIdO) 4 (THF) 2 ], 5 [Cu 2 (LIdO) 4 (Py) 2 ], [Cu 2 (IBdO) 4 (AN) 2 ], [Cu 2 (Indo) 4 (OH 2 ) 2 ] ? [Cu 2 (Ket) 4 (OH 2 ) 2 ] s
  • NMP N-methylpyrrolidone
  • a preferred complex is [Cu 2 (Indo) 4 (OH 2 ) 2 ],nH 2 0, wherein n is the number of waters of crystallisation.
  • the number of waters of crystallisation will vary depending on O the technique used to prepare the complex, and is typically from 1 to 5.
  • Complexes of formula (5) may be prepared by methods known in the art.
  • copper(H) and zi ⁇ c ⁇ II) complexes with indomethacin may be prepared as described in United States Patent No. 5,466,824 or a$ generally described in the paper: Anti-inflammatory Dimiclear Copper(II) Complexes with Indomethacin. Synthesis, 5 Magnetism and EPR Spectroscopy; Crystal Structure of the ⁇ T,N-Dimethylformamide
  • the complex is a trinuclear complex of the following formula ( ⁇ ):
  • each M' is independently selected and is a trivalent or tetravalent metal ion; and ⁇ -L 1 , L and p are as defined above for formula (5).
  • Trinuclear metal complexes with the llgand L 3 and L 4 Trinuclear metal complexes with the llgand L 3 and L 4
  • the complex is a trinuclear complex of the following formula (7):
  • L 3 is a carboxylate having anti-inflammatory activity
  • L 4 is an optionally substituted heterocyclic base comprising one or two heterocyclic rings independently having 5 or 6 ring members and 1 to 3 heteroatoms independently selected from N, O and S; and wherein each L 3 is independently selected; and each L 4 is independently selected.
  • L 3 may be a mo ⁇ odentate, bidentate or bridging ligand of formula L 1 or L 2 as follows: wherein:
  • R 1 is H or halo (i.e. Cl, F, Br or 1);
  • R 2 is H; a C 1 to Ce alkyl, an alkenyl or an alkynyl, where the Cj to C ⁇ alkyl, alkenyl or alkynyl may be optionally substituted; or
  • each R 2 ⁇ is independently selected from the group consisting of H, Ci to Cs alkyl, alkenyl, alkynyl, aryl, cyclqalkyl and arylalkyl, where the Ci to Ce alkyl, alkenyl, alkynyl, aryl, cycloalkyl or arylalkyl may be optionally substituted;
  • R 3 is H or halo; each R s is independently selected.from the group consisting of halo, -CH3, -CN, -OCH 3 , -SCH 3 and -CH 2 CH 3 , where Hie -CH 3 , -OCH 3 , -SCH 3 or -CH 3 CH 3 may be optionally substituted, and n i$ 1 , 2, 3, 4 or 5.
  • R 2 is a Ci to C 6 alkyl, an alkenyl or an alkynyl, the Ci to
  • Co alkyl* alkenyl or alkynyl may be substituted with one or more sub$tituent$.
  • the one or more substituents may, for example, be independently selected from the group consisting of halo, -OH, -COOH and -NH 2 .
  • R 2A is a Ci to C 6 alkyl
  • the Ct to Ck alkyl, alkenyl, alkyayi, aryl, cycloalkyl or arylalkyl may be substituted with one or more substituents.
  • the one or more 5 substituents may, for example, be independently selected from the group consisting of halo, -OH, -COOH and -NH 2 ,
  • Tn formula (7) when R 5 i$ -CH 3 , -OCH 3 , -SCH 3 or -CH 2 CH 3 , the -CH 3 , -0CH3, -SCH 3 or -CH 2 CH 3 may be substituted with one or more substituents.
  • the one or more substituents may, for example, be independently selected from the group 0 consisting of halo, -OH, -COOH and -NH 2 .
  • R 1 i$ typically H.
  • R 3 i$ typically H.
  • R 2 is typically CH 3 .
  • L 2 is ACM. 5
  • M may be selected from the group consisting of zinc, cobalt, nickel, magnesium, copper and calcium.
  • the heterocyclic base comprises one or more N atoms. In some embodiments, the heterocyclic base is optionally substituted.
  • the heterocyclic base may be selected from the group consisting of isoqui ⁇ olyl, O quinolyl, piperidinyl, pyridinyl, 2-methylpyridinyl, imadazoyl, pyranyl, pyrrolyl, pyrimidinyl, fndolyl, purinyl and quinolizinyl.
  • the heterocyclic base is quinolyl.
  • the ligands of these complexes comprise carboxylate ligands, or derivatives of carboxylates, having anti-inflammatory activity such as hydroximate, hydroxamate, hydrazine, amide, or ester derivatives having anti-inflammatory activity.
  • Metal complexes of these formulae can for instance, be prepared by methods outlined in Example 1 of this application or by other suitable synthesis methods.
  • the metal O complexes can, for instance, include ligands L 1 and L 2 as described above, ketorolac or other NSAID as described herein, or their hydroximate, hydroxamate, hydrazine, amide, or ester derivatives.
  • the functional groups of the ligands can themselves bind to the metal ion, and/or other ligati ⁇ g groups that are linked by these functionalities can bind to the metal.
  • the metal comlexes can be inert or labile complexes.
  • the metal ion or metal ions of inert complexes have an inert oxidation state.
  • the metal complex is a complex of formula
  • each L 5 i$ independently selected and is a monodentate carboxylate (preferably T ⁇ do > ACM or Keterolac) or an amide ligand (O or N bound) (preferably a derivative of I ⁇ do, ACM or Keterolac), having anti-inflammatory activity; each L 6 is independently selected and is NHj, a monodentate ligand, a polydentate ligand, or a macrocyclic ligand; m i$ l 5 2 ⁇ 3 ⁇ r4 n is O, 1, 2, 3, 4 or 5; and p is the charge of the complex.
  • L 5 is NH3 or a monodentate, polydentate, or macrocyclic amine ligand.
  • Preferred complexes of formula (8) include [M(O 2 CR 1 O 1H (NR 9 R 111 R 1 Vm/ where M is selected from Co(III), Cr(IH) 5 Ir(III), Os(UI), Rh(III), Ru(IIl) or Pt(IV) and more preferably, Co(HI), Cr(III), or Ru(III), and R 6 CO 2 " is an anti-inflammatory NSAID such as exemplified above, and R 9 , R 10 and R 1 ' can independently be H or an optionally substituted aliphatic or aromatic group.
  • L 5 is NH 3 or a monodentate, polydentate, or macrocyclic amine ligand.
  • Preferred complexes of formula (S) include: [M(L 1 X n (NR 9 R 10 R 11 ), ⁇ where L 3 is independently chosen from a NSATD, R 6 CO 2 " , R 6 CON(RY or an amide (R 6 CONR 7 R*) or ester derivative 5 (R 6 COOR 8 ) of a NSAID, (KR 9 R 1 V x ) is individually selected from monodentate or polydentate amine tigands, and M is selected from Ru(II), Co(III), Cr(III) * MHI), Os(III), Rh(III), Ru(III) and Pt(IV) and more preferably, Ru(D), Co(III), Cr(IH), and Ru(III); (M(L s ) ra (0H s ) n f where L s is independently selected from a NSAJ
  • the metal complex is a complex of formula (8a): .
  • M is selected from Co(Hl), Cr(Ul), Ir(UI), Os(IIT), Rh(III), Ru(III) and Pt(IV) and more preferably, Co(IU), Cr(IIl), and Ru(III); [M(L ⁇ (NR 9 R 10 R 1 ') 3 ] p where L 6 is a tridentate 0 derivative of an N SAID, each (NR 9 R 10 R 1 ') is independently a monodentate amine ligand or polydentate amine Hgand, and M is selected from Co(III), Cr(III), Ir(III), Os(III), Rh(III), Ru(TII) and Pt(TV) and more preferably, Co(III), Cr(IH), and Ru(Hl); [M(L 6 )(NRV°R n ) 2 ] p where L 6 is a tetradentate derivative of an NSAJD, (NR 9 R 10 R 11 ⁇ is two independently selected monodentate amine ligands or a
  • S M is a monovalent, divalent, trivalent, tetravalent, pentavalent or hexavalent
  • each L 7 is independently selected and is NH 3 , a monodentate ligand, a polydentate ligand, or a macrocyclic ligand
  • each L 8 is independently selected and is a chelating derivative of a carboxylate 0 such as a hydroximate, hydroxamate, hydrazine, ester, amino acid, peptide or sugar, or amide chelating ligand (O or N bound), having anti-inflammatory activity, 5; n is 1, 2, 3 or 4; and p is the charge of the complex. 5
  • L is NH 3 or a monodentate, polydentate, or macrocyclic amine ligand.
  • Preferred complexes of formula (2) include [M(NR 9 R 10 R 1 ')( 6 - 2 ⁇ )(L 8 )J p when L s is a bidentate Hgand, [M(NR 9 R 10 R 1 ') 3 (L 8 )3 P when L 8 is a tridentate ligand, and [M(NR 9 R 10 R 1 ') 2 (L S )] P when L* is a tetradentate ligand, where M is selected from Co(III), Cr(III) J Ga(III), Ir(III), 0 Os(III), Rh(III), Ru(IlI), Ru(Il) and Pt(IV) and more preferably, Co(III), Cr(DI), Ga(III),
  • Ru(III) and Ru(Il), and R 9 , R 10 , and R 11 are as defined for formula (8 or 8a) above.
  • the metal complex of formula (9) can be [M(NR 9 R 10 R 11 J 2 (I/)] 11 where L 8 is a bidentate ligand, [M(NR 9 R l0 R u )(L 8 )] p where L 8 is a tridentate ligand, and where M is Cu(II), Ni(II), Pd(II), Pt(II) or Au(III) and more preferably Cu(II), and R 9 , 5 R 10 , R" and R 5 are as defined for formula (8 or 8a) above.
  • the metal complex is [M(L 8 )a] p .
  • L 8 is a bidentate ligand ri is 3, or when L s is a tridentate ligand n is 2, and wherein M is preferably Co(IH), Cu(II), Zn(II) 5 Ga(IH), Ru(HI), or Ru(II); or when L* is a bidentate ligand n is 2, or when L 8 is a tetradentate ligand n is 1, wherein M is O preferably Cu(Il), Ni(II), Pd(II), Pt(II) or Au(III) and more preferably Cu(II).
  • R 0 , R 10 and R ⁇ of formulae (8a) and (9) can for instance be selected from aliphatic and aromatic groups consisting of substituted or unsubstitutcd alkyl, alkenyl, alkynyl, aryl, ⁇ trylalkyl and heterocyclic groups.
  • heterocyclic groups include heterocyclic bases comprising ooe or more N atoms. In some embodiments, the heterocyclic base is optionally substituted.
  • the heterocyclic base may for example be selected from the group consisting of isoquinolyl, quinolyl, piperidinyl, pyridinyl, 2- methylpyridinyl, imadazoyl, pyranyl, pyrrolyl, pyrimidinyl, indolyl, purinyl and quinolizinyl.
  • metal complexes of formula (9) include [Cn(lndoHAH)(OH)], [Co(en) 2 (lndoHA)]Cl 2 , [Co(en) 2 (I ⁇ doHA)](CF 3 S ⁇ 3 ) 2 ,
  • metal complexes (hat can be used in methods embodied by the invention include complexes of formula (10):
  • each L 1 is independently selected and is NH 3 , another rno ⁇ dentate ligand, a polydentate ligand, or a macrocyclic ligand
  • the metal complex can be a complex of the following formula (11):
  • metal complexes of formula (11) for instance, include: [M(O 2 CR 6A )(L 7 ) m (L 8 ) D ] p where, m is 0, 1, 2, or 3, n is 1 or 2, R ⁇ COf is a NSAID, R 6 CO 2 " , or an ester derivative of an R 6 C ⁇ 2 ⁇ NSAID having a terminal carboxylate, at O least one of L 8 is independently selected from a hydroxamate or hydr ⁇ ximate derivative of a NSAlD, an amino acid derivative of a NSAID, a peptide derivative of a NSAID, and an amine derivative of a NSAID, and M is Co(III), Rh(III), Ir(III), Cr(ITI), Ru(III) or Pt(IV), and preferably Co(III), Cr(III), or Ru(III); where, m is O, 1 or 2, n is 1 of 2, R 6 ⁇ C ⁇ 2 ⁇ is independently a NSAID, or an ester or
  • each L 5 M is a monovalent, divalent, trivalem; tetravalent, pentavalent or hexavalent metal ion; each L 5 is independently selected and * is a roo ⁇ ode ⁇ tate of bidentate carboxylate, or monodentate amide ligand (O or N bound), having anti-inflammatory activity; 0 each L 7 is independently selected and is a mooodentate o ⁇ a polydentate Hgand; each L 8 is independently selected and is a bridging ligand, $uch as an oxo, hydroxo, carboxylate (including a NSAID), halide, or other bridging group, m is an integer from 0 to 5q; B is an integer from 1 to Sq; 5 p is the charge of the complex; q is typically an integer between 2 and 20 inclusive; and r is an integer from 1 to 60,
  • One or more of the ligands L 5 to L 8 above in any combination may also form dimeric, trimeric, tetr&meric, oligomei ⁇ c or polymeric complexes with one or more 0 metal ions,
  • L 7 is aN-heterocycle or aqua ligand
  • R 11 is a H, alkyl or aryl substituent
  • Monodentate ligands which can be used in metal complexes described herein o include monodentate ligand such as halo, aqua, hydroxo, oxo, CO, NO, amines, alcohols, amides, sulfoxides, W-heterocylces, 0-heterocycles, and 5-heterocycles.
  • Polydentate acyclic liga ⁇ ds include amines, amino acids, peptides,. alcohol sugars, hydroxyacids, polycarboxylates, N-heterocylces, 0-heterocycles, and S-heterocycles, and functional groups that can form co-ordinate bonds with a metal ion.
  • Polydentate macrocyclic ligands include amines, crown ethers, thi ⁇ ethers, macrocyclic peptides and amides, and ligands with, combinations of these and other metal binding substituents.
  • bridging ligands that can be utilized in metal complexes as described herein include oxo, hydroxo, carboxylate (including carboxylate NSAIDs), halo and other bridging groups.
  • aliphatic and aromatic groups that can be employed include substituted or unsubstitut ⁇ d alkyl, alkenyl, alkynyl, aryl, arylalkyl and heterocyclic 0 groups.
  • heterocyclic groups include heterocycles comprising one or more N, O and/or S atoms. In some embodiments, the heterocycle is optionally substituted.
  • the heterocycle can for example be selected from the group consisting of isoquinolyl, quinolyl, piperidinyl, pyrldinyl, 2-methyipyridinyI, imadazoyl, pyranyl, pyrrolyl, pyrimidinyl, indolyl, purinyl and quinolizinyl as described above.
  • the metal ion of metal complexes that can be utilized in methods embodied by the invention include d-block, f-block, p-block and s-block metal ions.
  • the metal M will be a divalent, bivalent, tetravalent, pentavalent or hexavale ⁇ t d-block metal, preferably, Co(II), Cu(II), Fe(II). Mn(II), Mi(Ir), Ru(TI), Zn(Il) 1 Co(IIl), Cr(IIIX Fe(IH), Mn(III) 9 Ru(III), Mn(IV). Mo(IV), Ru(IV), V(IV), 0 Mo(V), V(V), W(V), Mo(VI), or W(VI), or a trivalent or tetravalent p-block metal such as Ga(TH) 7 Bi(TTI) or Sn(TV).
  • a trivalent or tetravalent p-block metal such as Ga(TH) 7 Bi(TTI) or Sn(TV).
  • Suitable methods for the synthesis of metal complexes are for instance, further described in: (Romakh, V. B.; Therrien, B.; Labat, G; Stoekli-Eva ⁇ s, H,; Shul'pin, G- B.; Suess-Fink, G. Dinuclear iron, ruthenium and cobalt complexes containing 1,4- 5 dimethyl-1 ,4,7-triazacycIononanc ligands as well as carb ⁇ xylato and oxo or hydroxo bridges.
  • metal complexes of indomethacin, ibuprofen, naproxen, dichlofenec, ketorolac, and/or derivatives thereof having anti-inflammatory activity are utilised for the prophylaxis or the treatment of diabetes as described herein.
  • any suitable such NSAID or derivative thereof can also be utilized.
  • the term 'Hherapeutically effective amount means an amount effective to yield a desired therapeutic response, eg prophylaxis or treatment of diabetes or a diabetic condition as described herein.
  • the metal can be administered alone or be 0 co-administered in combination with one or more therapeutic agents conventionally used in the treatment of diabetes and pre-diabetic conditions.
  • co-administered is meant simultaneous administration in the same formulation or a plurality of formulations by the same of different routes, or sequential administration by the same or different routes.
  • sequential administration is meant one is administered one after 5 the other.
  • a metal complex in one or more methods embodied by the invention in combination with another anti-inflammatory or therapeutic agent conventionally used for the treatment of diabetes or pre-diabetic conditions may enhance the effectiveness of the other agents or allow the dosage of the other agents to be lowered to reduce toxic side effects of those agents.
  • the specific "therapeutically effective amount" of the metal complex utilised in a method embodied by the present invention will vary with such factors as the particular diabetic condition being treated, the physical condition age and weight of the human or animal, the type of animal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific composition and complex employed.
  • the dosage administered and route of administration will be at the discretion of the attending, clinician or veterinarian and will be determined in accordance with accepted 5 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. Similarly, the frequency of administration can be determined in the same way, that is, by continuously monitoring the response of the subject and modifying the interval between dosages.
  • Metal complexes as described herein will typically be administered at a dosage of the metal ion to body weight of the mammalian subject of about 0.1 mmol/kg or less, preferably at a dosage of 0.01 mmol/kg bodyweight or less, more preferably at a dosage of 0.005 mmol/kg bodyweight or less, and most preferably, in a dosage range of from 0.01 - 0.01 mmol/kg body weight. 5 It will also be understood that a plurality of different metal-NS AID complexes as described herein can be administered to the mammalian subject in the treatment of diabetes or pre-diabetic condition.
  • the metal complexes can be selected to provide different anti-inflammatory activies and/or have different rates of release of antiinflammatory ligands, 0
  • the roetal-NSAID complex(e$) can be administered to the mammalian subject systemicaUy.
  • the complex can also be applied topically to the skin for diffusion into the body of the subj ect to the site of action, by oral administration, or by suppository or any other mode of administration suitable for the particular diabetic condition being treated.
  • S The complex will generally be administered in the form of a pharmaceutical. composition comprising the complex together with a pharmaceutically acceptable carrier.
  • the composition can.
  • a lipophilic carrier eg., a medium chain triglyceride (MCT) formulation
  • MCT medium chain triglyceride
  • a formulation having a colloidal structure as described in International Application No. PCT/AU2005/000442, the 0 contents of which is incorporated herein by eross-referenee in its entirety.
  • a formulation having a colloidal structure or which forms a colloidal structure post administration is particularly desirable for administration of - metal complexes.
  • compositions having a colloidal structure or which form a colloidal structure upon, or following administration are exemplified in PCT/AU2005/00042 and any suitable such formulations for the selected mode of administration can be utilised in methods embodied by the present invention. Formation of the colloidal structure can for instance occur when the composition contacts an aqueous biological fluid in the human or animal body, for example, on contact with an aqueous fluid in the digestive tract.
  • a composition has a colloidal structure if it comprises a colloidal system.
  • a colloidal system is a system in which particles of a colloidal size of any nature ⁇ eg., solid as liquid or gas) are dispersed in a colloidal phase of a different composition or state.
  • the composition comprises micelles in. an aqueous carrier or is an oil-in-water emulsion, or forms micelles or an oil-in-water emulsion when the composition is administered to a human or animal body.
  • the colloidal structure protects the metal complex from interaction with acids or other compounds which would otherwise interact with the complex to cause the complex to dissociate. 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 i$ administered are able to interact with the complex and which cause the complex to dissociate before it is absorbed.
  • the colloidal structure may limit the extent to which compounds present in stomach acid are able to interact with the complex to cause the complex to dissociate before it is absorbed through the gastrointestinal tract.
  • the colloidal structure may limit the extent to which compounds that come into contact with the composition after it is administered, e,g. strong chelators of Cu(II), such as peptides, or reductants of Cu(Jl), such as thiol -containing biom ⁇ lecules, are able to interact with the complex to cause the complex; to dissociate.
  • 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 i$ formed.
  • a colloidal structure i$ formed.
  • the colloidal structure is maintained for a sufficient time after administration of the composition for the majority, for example more than 70%, 80% or 90%, of the metal complex, to be absorbed by the body as a metal complex.
  • Oils for use in the compo$itio ⁇ $ 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-chaio triglycerides, combinations of triglycerides with fish oil; vegetable oils, such as, soya oil, safflower oil and sunflower oils; isopropyl myristate; and paraffins.
  • Such oils are suitable for use in compositions for oral, injectable, or topical administration.
  • the composition comprises micelles in an aqueous carrier, the composition will typically further comprise one or more surfactants for formation of the micelles.
  • 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 pause 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 tnonooleate (Span 80), sorbitan tristearate (Span ⁇ S5), sorbitan monostearate (Span 60), sorbitan mo ⁇ opalmitate (Span 40), and sorbitan motiolaurate (Span 20).
  • Other suitable surfactants include me macrogol (polyoxyethylene) esters and ethers. These surfactants include, but are not limited to, the caster oil polyoxyethylene group of surfactants, such a$ Termul 1284 and caster oil ethoxylatc.
  • 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 polyoxyethyleae (20) sorbitan monooleate (Tween 80).
  • surfactants that may be used include the block copolymers based on ethylene oxide and propylene oxide such Poloxamer 124 (Pluronic IAA NF), P ⁇ l ⁇ xamer 188 (Phironic F68 NF), Poloxamer 331(Pluronic LlOl NF), and Poloxamer 407 (Plirf ⁇ nic Fl 27 NF).
  • Suitable surfactants also include the polyethylene glycol fatty acid esters (PEG esters) group of surfactants.
  • Such surfactants comprise mono-, tri-, or partial esters of fatty acids such as oleic, lauric, palmic, oleic, and stearic acids, including but not limited to PEG 200 monolaurate, PEC 300 dilaurate, ethylene glycol distearate, PEG 300 raonooleate, PEG 400 monooleate, PEG 350 monostearate, PEG 300 monostearate, PEG 400 monostearate, PEG 600 monostearate, PEG 1000 monostearate, PEG 1800 monostearate, PEG 6500 tnonostearate, PEG 400 mono-iso stearate, PEG 600 mono-iso-stearate, PEG 200 dilaurate, PEG 600 distearate, PEG 6000 distearate, PEG 200 distearate, PEG 300 distearate, and PEG 400 distearate.
  • PEG 200 monolaurate PEC 300 dilaurate, ethylene glycol di
  • compositions have more than 80%, preferably more than 90%, and mote preferably more than 95%, of the total amount of the carboxylate, or hydroxamate, hydroximate, ester, or amide derivative having anti-inflammatory activity present in the composition as part of a metal complex.
  • a metal complex Preferably, also less than 10% of the carboxylate, or hydroxamate, hydroximate, ester or amide derivative complexed with the metal dissociates from the metal when the composition i$ stored for 12 months in the absence of light at room temperature (18 0 C to 25 0 C).
  • the amount of the carboxylate, or hydoxamate, hydroximate, ester or amide remaining bound to the metal complex can be readily determined by a person skilled in the art using known methods $uch a$ EPR spectroscopy for complexes that give EPR signals or using more specialized experiments involving X-ray absorption spectroscopy for all complexes (e.g., XAFS Studies of Anti-inflammatory Dinuclear and Mononuclear Zn(II) Complexes of Indomethacin. Zhou, Q.; Hambley, T. W.; Kennedy, B. J.; Lay, P. A.
  • the compositions preferably do not comprise, or are substantially free of, peptides, carb ⁇ xylate donors, reductant$ and thiolate groups, apart from those in the derivatives of the NSAID utilised.
  • the composition is also not strongly acidic or basic a$ strong acids and bases can cause metal carboxylate complexes to dissociate.
  • the metal-NSATD complex can be dissolved in the composition or can be present in the composition as a solid.
  • the solid complex can be in the form of a crystal containing solvents of crystallisation and/or waters of crystallisation. When the complex is charged, the complex will be associated with a counter ion.
  • a "pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering the complex to a human or animal.
  • the carrier can be liquid or solid and is selected with the intended manner of administration in mind, The carriei 1 i$ ''pharmaceutically acceptable” in the sense of being not biologically or otherwise undesirable, i.e., the carrier maybe administered to a buman or animal along with the complex without causing any or a substantial adverse reaction ,
  • the carrier can be a solvent or dispersion medium containing one or more of physiological saline, ethanol, polyol (e.g. glycerol, propylene glycol, liquid polyethylene glycol and the like), vegetable oils and mixtures thereof.
  • composition for use in the method of the invention can 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, i ⁇ trathecally, intranasally. by inhalation, infusion, or via IV group patch and by implant.
  • the metal-NSAID complexes can also be delivered into cavities such as for example the pleural or peritoneal cavity.
  • a pharmaceutical composition as described herein can also conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy.
  • Such methods include the step of bringing into association the complex with the carrier.
  • the carrier comprises two or more ingredients.
  • the composition is prepared by uniformly and intimately bringing into association the complex with the carrier, and then, if necessary, shaping the product.
  • the complex and the one or more components making up the carrier may be mixed in any order. However, it is preferred that the components are mixed in a manner that minimises the amount of the complex that dissociates during the preparation of the composition.
  • a composition for oral administration can be in the form of a viscous paste, an ingestible tablet, a capsule, a chewable composition, or any other form suitable for oral administration.
  • the composition can be encapsulated in a hard or soft capsule (e.g. gelatine) by techniques known in the art.
  • the metal complex can be provided in the form of buccal tablets, troches, elixirs, suspensions or syrups.
  • 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 s ⁇ rbic acid, in order to produce pharmaceutically elegant and palatable preparations.
  • 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 such as s ⁇ rbic acid
  • preserving agents e.g. such as s ⁇ rbic acid
  • a chewable composition can, for example, comprise the complex, one or more flavours, a base formulation, one or more preservatives, one or more pH modifiers, one or more desiccants and one or more fillers.
  • the base may comprise pre-gel starch, gelatine, flour and water.
  • the composition may also comprise other components including phosphoric acid, salt, sugar, sorbitol and/or glycerol, sorbic acid and/or potassium sorbate, benzoic acid, propionic acid and maltodextrin,
  • a chewable composition for an animal such as a dog for example, may comprise the complex, meat emulsion, an acidulate (e.g.
  • a composition for topical application may comprise the complex in a conventional oil-uvwater emulsion, water-in-oil emulsion, or water-immiscible pharmaceutical carrier suitable for topical application.
  • Such carriers include for example, laciilubc, cctomacrogol cream BiP, wool fat ointment BP or emulsifying ointment BP.
  • Such carriers are typically in the form of an emulsion or are immiscible with water. Topical formulations could, for instance be used in patches or other $low release vehicles.
  • composition for topical application to skin is a composition comprising 0.5-2% w/w of the complex in an emulsifying cream with chlorocresol (4- chloro-3-methylphenol) as a preservative, the emulsifying cream comprising:
  • compositions for parenteral administration include compositions in the form of sterile aqueous or non-aqueous suspensions and emulsions.
  • the composition can also include one or more pharmaceutically active components in addition to the complex that have anti-inflammatory or other therapeutic activity.
  • active components include conventionally used anti -inflammatory drugs.
  • a metal complex will constitute about 0.025% to about 20% by weight of the composition, preferably about 0.025% to about 20% by weight of the composition, more preferably about 0.1% to about 20% by weight of the composition and most preferably, the complex constitutes about 0.1 % to about 10% by weight of the composition.
  • a composition embodied by the invention may comprise the metal complex in an amount of about J % by weight of the composition or less.
  • Suitable pharmaceutically acceptable carriers and formulations useful in the present invention may for instance be found in handbooks and texts well known to the skilled addressee, such as "Remington: The Science and Practice of Pharmacy (Mack Publishing Co., 1995)” and subsequent update versions thereof, the contents of which is incorporated herein in it$ entirety by reference.
  • the mammalian subject can be a human or an animal.
  • the animal can, for example, be a companion animal such as a dog or cat, or a domestic animal such as a horse, pony, donkey, mule,- camel, llama, alpaca, pig, cow or sheep, or a zoo animal.
  • Suitable animals include members of the Orders Primates, Rodentia, Lagomorpha,
  • Cetacea, Carnivora, Perissodactyla and Artiodactyla Typically, the subject will be a 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,
  • Metal complexes useful in one or more embodiments of methods of the invention were prepared as follows.
  • Cu(Il) acetate monohydrate (0.028 g, 0.140 mmol) in water (0.75 niL) was added drop wise to indometnacin (0,1 g, 0.28 mmol) dissolved in ethanol (1.75 mL) at room temperature. Warming the eihanol mildly ( ⁇ 40°C) helped solubilise the 5 indomethaoin before adding the Cu(II) acetate solution.
  • On addition of the Cu(II) acetate mo ⁇ ohydrate in water bright green Culndo/aqua complex precipitated out of solution immediately. This precipitate was filtered, washed with water and dried.
  • Ketorolac tris salt (0.452 g, 1.20 mmol) was dissolved ia water (5 mL).
  • VOSO 4 -SH 2 O 50.6 mg, 0.200 mmol
  • IndpHAHj 149 mg, 0.400 mmol
  • methanol MeOH, HPLC grade, 5.0 mL
  • the solution immediately turned dark-red.
  • This solution was added to ice-cold H 2 O (Milli-Q grade, 50 mL), which led to the formation of a fine brown precipitate.
  • the precipitate was isolated by centrifugation (5 min at 4000 g) and dissolved in a minimal volume of MeOH (-20 mL).
  • the resultant solution (which was slightly cloudy) was filtered through a small-pore (No. 4) glass filter under vacuum.
  • An acidic aqueous solution of Ga(IIT) (0.64 M) was prepared by partial dissolution of a piece of metallic Ga (99.99%, Fluka) in aqueous HCl ( ⁇ 5 M, ultra-pure, Merck), and the amount of dissolved Ga was determined by the mass difference. A portion of this solution (5,0 mM) was evaporated to dryness at 100 0 C, and the residue was dried under vacuum overnight and dissolved in anhydrous MeOH (5.0 mL), giving a solution OfGaCl 3 (0.64 M) in MeOH.
  • the Ga content in the complex determined spcctrophotometrically with 4-(2-pyridylazo)resorcine (PAR) after digestion of the complex with concentrated HNOj, was 8.0 and 8.7% (for two parallel samples).
  • the data the formation of a bis-ligated Ga(III) hydroxamato complex, [Ga(LH) 2 (OHa) 2 J +
  • Rat paw oedema studies on this complex using the methodology described in Example 2 gave 30% reduction in inflammation and, remarkably, no gastric ulceration when dosed at 10 ⁇ g/kg Indo molar equivalent and dissolved into an MCT paste.
  • HBTU ⁇ 9-(Benzotriazol-l - yl)-N, ⁇ W'.N-tetramethyluronium hexafluorophosphate
  • ligands can be prepared by the following reaction schemes and can coordinate to metal i ⁇ n$ via the di ⁇ l functions.
  • Complexes such as the Co(III) complex described in Example 1.1.3 offer the potential of systemic delivery of even higher concentrations of NSAIDs through oral, injectable, and topical delivery and incorporation into slow release patches, A$ demonstrated by this example, the complex exhibits significant antiinflammatory.
  • Rats were dosed with indomethaci ⁇ and [Cu 2 (Indo) 4 (DMF)i] for 28 days.
  • Acute gastrointestinal toxicity was measured using gastrointestinal permeability markers, gastrointestinal ulceration and bleeding, and measurement of an acute phase protein haptoglobin.
  • the effects of acute and chronic administration of indomcthacin. and [Cu 2 (Indo) 4 (DMF) 2 ] on urinary electrolyte concentrations were examined.
  • CMQ carboxymethylcellulose
  • HEPES penicillin-streptomycin
  • sodium bicarbonate sucrose McCoy's 5A medium and methylene blue
  • [Cu 2 (LIdO) 4 (DMF) 2 was used as supplied by Biochemical and Veterinary Research Limited (Mittagong, MSW, Australia) and Vetafarm (Wagga Wagga, Australia). Sprague-Dawley rats weighing 200-250 g were used throughout this study.
  • Animals were housed in polypropylene cages and allowed free access to standard laboratory rat chow (Purina Rat Chow, Ralston Purina, St Louis MO, USA) aad tap water. Animals were housed in an animal care facility at ambient temperature and S humidity with a 12-h light-dark cycle. The experimental animal protocols were approved by animal ethics committees at The University .of Sydney, Australia and Washington State University, USA.
  • the rats received either oral indomethacin at doses of 10 mg/kg or [Cu 2 (Indo) 4 (DMF) 2 ] at do$es of ⁇ 3.3 mg/kg via gavage.
  • Plasma was obtained by cardiac puncture using a 23 gauge (G) needle, attached to a 10 mL syringe, under halothane anaesthesia.
  • Haptoglobin concentration (milligrams per millilitre) was measured using a 5 commercially available kit Dade Behring (Mannheim, Germany) by radial immunodiffusion using 5- ⁇ L $am ⁇ les in each well.
  • Normal range values are a diffusion zone of approximately 6 mm of diameter (1.22 g/L).
  • the diameter of the precipitin zone is directly proportional to the concentration of the relevant protein in the sample (Nabumetone, an effective anti-inflammatory agent, lacks gastrointestinal irritancy in 0 the rat when dosed orally for one month; comparison with tiaprofenic acid and etodolac.
  • the rats received either oral indomethacin at doses of 10 mg/kg or [Cuj(Indo)4(DMF)j] at doses of 133 mg/kg via gavage. Since [Cu 2 (InUo) 1 I(DMF) 2 J consists of a copper moiety and an indomethacin moiety, a higher dose of this compound was given so that an equivalent amount of the NSAID moiety was being delivered as in the i ⁇ domethacin-treated rats.
  • the compounds 0 were suspended in 2% carboxymethylcellulose.
  • Rats were deprived of food, but not water, for 18 h and were administered indomethacin, [Cu2(-ndo)4(DMF)2] or vehicle. Animals were anesthetized with halothane 3 h after the dose and the stomach was excised and opened by an incision along the greater curvature for assessment of macroscopic visible damage by an observer unaware of the treatment the rats had received using a method described previously (Aspirin causes rapid up-regulation of cydooxygenase-2 expression in the stomach of rats. Davies, N.M.; Sharkey, K.A.; Asfaha, S.; Macnaughton, W.K.; Wallace, J.L. Aliment. Pharmacol Ther. 1997, 11, 1101-18).
  • the length of lesions was measured (in millimetres) using digital callipers and then the lengths of all lesions observed in each stomach were added together ($ee Figure 2). After scoring, the gastric tissue was fixed in neutral buffered formalin and processed by routine techniques prior to embedding in paraffin, sectioning and $taioing with hematoxylin and eosin.
  • Sucrose permeability changes were measured using a previously reported method (Sucrose urinary excretion in the rat using a simple assay; a model of gastroduodcnal permeability. Davies, N.M.; Corrigan ⁇ B.W.; Ja ⁇ iali, F. Pkarnt. Res. 1995, 12, 1733-6).
  • Rats ( « 4 for each treatment) were deprived of food, but not water, for 18 h and fasted overnight.
  • the rats received either oral ind ⁇ methacin at doses of 10 mg/kg or [Cu 2 (lndo) 4 (DMFh] at doses of 13,3 mg/kg via gavage.
  • an aqueous solution 0.5 niL
  • Urine was collected 0-24 h following the administration of the sucrose solution.
  • Relative permeability was determined by calculating the sucrose present in each urine sample as a percent of the administered dose (sec Figure 3).
  • Rats ( « 4 for each treatment) received either oral ind ⁇ methacin at doses of 10 mg/kg or [Cua(Indo)4(DMF) 2 ] at doses of 13.3 mg/kg via gavage.
  • oral ind ⁇ methacin at doses of 10 mg/kg or [Cua(Indo)4(DMF) 2 ] at doses of 13.3 mg/kg via gavage.
  • the animals were sacrificed 24 h after dosing and the intestines removed. A vertical mid-line abdominal incision was made, and the entire length of the small intestine was isolated, excised, and examined extending 10 cm distal to the ligament of Treitz to the ileocecal junction.
  • a 26 G needle attached to 5-mL syringe was used to flush the intestine in order to avoid distension.
  • Intestinal ulceration was determined by measuring the length of lesions in millimetres using digital callipers and the lengths of all lesions observed in each intestine summed (NO-naproxen vs. naproxen: ulcerogenic, analgesic and antiinflammatory effects. Davies, N.M.; Roseth, A.G.; Appleyard, C.B.; etal Aliment, Pharmacol. Ther. 1997, //, 69-79) (see Figure 5).
  • tissue sections were obtained from damaged areas for histology. Tissue sections were embedded in plastic using a commercially available kit (JB-4 embedding kit, Polysciences. Inc. Wa ⁇ ington, PA). Embedded tissues were cut to thin sections (1-1.5 ⁇ rn) and the sections were stained with Lee's methylene blue- basic fuchsin for 30 seconds. Sections were then examined by light microscopy.
  • Rats ( « 4 for each treatment) received either oral indomethacin at doses of 10 mg/kg or [Cu2(Indo)i)(DMF) 2 ] at doses of 13.3 mg/kg via gavage.
  • the animals were sacrificed 24 h after dosing and the intestines were removed. A vertical mid-line abdominal incision was made, and the entire length of the small intestine was isolated, excised, and examined extending 10 cm distal to the ligament of Treitz to the ileocecal junction.
  • Intestinal tissue samples (-1 g) were obtained from the distal ileum, placed into Petri dishes containing sterile phosphate-buffered saline (pH 7.4), and weighed.
  • the tissues were homogenized and plated onto MacConk ⁇ y agar No. 2 (Oxoid, NSW, Australia) and incubated at 37°C for 24 h under aerobic conditions. Plates containing between 20 and 200 colony-forming units (CFU) were analysed to determine total enteric bacterial numbers per gram of tissue (Nonsteroidal anti-inflammatory drug enteropathy in rats: role of permeability, bacteria, and enterohepatic circulation. Reuter, B.K.; Davies, N.M.; Wallace, LL. Gastroenterology 1997, 112, 109-17) (see Figure 8). 23.6 Mitochondrial DNA
  • Quantitative polymerase chain reaction (QPCR) was used as previously described (Chemotherapy B induced gastrointestinal toxicity in rats: involvement of mitochondrial DNA, gastrointestinal permeability and eyclooxygenase-2. Yanez, J.A.; Teng, X. W.; Roupe, K.A.; Fariss, M, W,; Davies, N.M. J, Pharm, Pharm. Sd 2003, 6, 308-314).
  • DNA was isolated from afflicted intestinal tissue using Qiagen® genomic tip and genomic DNA buffer $et kit for mammalian DNA extractions (Valencia, CA 1 USA).
  • 0 DNA quantitation utilized the PicoGreen® dsDNA Quantitation Kit (Molecular Probes, Eugene, OR, USA), Picogreen® wa$ u$ed to quantify dsDNA fragment.
  • QPCR involved the use of GeneAmp XL PCR kit (Applied Biosystems, Branchburg, NJ, USA) and dNTP$ (Pharmacia, Peapack, NJ, USA). Primers were based on sequences already optimized by Van Houten (Analysis of gene-specific DNA damage and repair using 5 quantitative polymerase chain reaction.
  • Rat$ 10 rag/kg or [Oi 2 (Indo) 4 (DMF) 2 ] at doses of 13.3 mg/kg via gavage.
  • Rat$ were housed in special metabolic cages where urine and faeces were collected separately 0-24 h after administration.
  • the colorinietric assay kit was obtained from Boehringer Mannheim. The instructions and procedures were followed as documented by the manufacturer. 0 S-Cresolsulfonphthalenyl-N-acetyl- ⁇ -D-glucosaminide, sodium salt was hyd ⁇ oly$ed by
  • a composition comprising the [Cu2(Indo) ⁇ (OHz)2] complex in MCT oil was prepared for subcutaneous and intramuscular injections.
  • the competition comprised the following ingredients:
  • Tetraglycol is the solvent; Delios V MCT oil is a medium chain triglyceride oil.
  • the composition was prepared as follows:
  • the composition was a single-phase dark green oil immiscible in water.
  • the 25 composition contained >95% of Indo in the composition as part of the dimer
  • 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 acce$$ to standard laboratory rat chow (ftirina 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.
  • the control cohort was injected with equivalent volumes of neat MCT, Subcutaneous injections were made in the lower dorsal surface and intramuscular injections were made in the right hind thigh muscle. 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
  • composition containing [Cu2(I ⁇ d ⁇ )4 ⁇ OH 2 )2] in MCT oil has a similar efficacy and safety profile in r»t$ a$ those observed following subcutaneous injections, although the efficacy for treatment of inflammation i$ higher in the plateau region of the dose-response curve,
  • compositions containing and IndoH have similar efficacy
  • the composition containing [Cu2(I ⁇ do) 4 ( ⁇ H2)2] in MCT oil resulted in less GI toxicity.
  • composition containing the complex in MCT oil Both subcutaneous and intramuscular administration of the composition containing the complex in MCT oil have considerable efficacy, with the latter mode of administration being more efficacious. If the composition was delivered as a physical mixture of a Cu salt and IndoH or the composition caused the complex to dissociate with the release of free Indo, then toxicity effects similar to those of ⁇ idoH are expected,
  • compositions The composition containing the metal complexes in medium chain triglyceride
  • MCT organogel paste and/or an aqueous 2% w/w CMC solution were freshly prepared for each experiment.
  • the organogel paste is described in PCT International Patent Application No. PCT/AU2005/000442.
  • Sprague-Dawley rats (weighing 200-250 g) used for these studies were supplied by the laboratory animal services at The University of Sydney, Sydney Australia, Animals were housed in polypropylene cages and allowed free access to standard laboratory rat chow (Purina Rat Chow, Ralston Purina, St Louis MO) and tap water. Animals were housed in the animal care facility of the Faculty of Pharmacy at ambient temperature and humidity with a 12-h light-dark cycle. The experimental animal protocols were approved by the Animal Ethics Committee of the University of Sydney.
  • Inflammation was induced (1 h after dosing by gavage with an injection of csrrageenan (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..
  • 24 h-fasted animals were euthanased and the stomach was excised and opened by incision along the greater curvature. The stomach was rinsed and examined to determine the extent of macroscopic gastric toxicity, which is reported as the summation of the area of macroscopic ulcerations (mm 2 ).
  • DP placebo groups
  • drug was administered as a single gavage dose (4 mg/kg of oxametaci ⁇ equivalent, delivered as the vanadium complex in an MCT organogel) between 7 and 9 am in the morning.
  • tail vein blood was obtained immediately before administration and at 2, 4, 6, 8 and 18 hr following administration of the vanadium complex. Blood sugar level was measured by glucometer (Ames).
  • the BSL of diabetic animals treated with either drug (black circles) or placebo (open circles) are shown in Fig. 11.
  • treatment of diabetic animals with the vanadium complex induced a 6-10-mmoH decrease in blood glucose level when compared with the placebo treated group. This decrease was maintained for a farther 6 hr and had returned to baseline levels by 24 hr.
  • Treatment of non-diabetic control animals had no blood sugar lowering effect over a similar time course (data not shown).
  • These data indicate that the drug has insulin-like action in that it can lower blood glucose levels in diabetic animals at much lower concentrations of vanadium than is normally administered to observe such effects.
  • the results also illustrate the potential role for the drug in simultaneously treating diabetes and inflammatory conditions in the one dose (cither alone or in combination therapy with drug(s) conventionally used for the treatment of diabetes) for humans and animals suffering from this condition.
  • V hydroximato complexes previously used for lowering BSL have comparable activity to BMOV ("Synthesis of vanadium(lV,V) hydroxamic acid complexes and in vivo assessment of their insulin-like activity".
  • Cr(IIl) complexes described herein such as Cr(IIIj-IndoHA, as Cr(III) complexes (non-NSAlD complexes) are known anti-diabetic agents and are comsumed as dietary supplements to improve glucose metabolism.
  • Synergistic effects as observed for the vanadium complex would render the dose of the Cr(IIl) ion below the normal dietary intake of Cr such that no essentially no toxic side-effects would be expected (Chromium in Biology: Nutritional. Aspects and Toxicology. Levins, A.; Codd, R.; Dillon, C. T.; Lay, P, A.

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Abstract

L'invention porte sur des méthodes de prophylaxie ou de traitement d'états diabétiques ou prédiabétiques. Les méthodes consistent à administrer une dose thérapeutique d'un complexe de métal et d'un carboxylate, ou un dérivé d'un carboxylate, ayant une activité anti-inflammatoire.
PCT/AU2007/000381 2006-03-28 2007-03-28 Prophylaxie ou traitement du diabète WO2007109845A1 (fr)

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AU2006901583A AU2006901583A0 (en) 2006-03-28 Method for prophylaxis or treatment
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AU2006905170A AU2006905170A0 (en) 2006-09-19 Metal complexes having anti-inflammatory activity
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AU2006905265A AU2006905265A0 (en) 2006-09-22 Metal complexes having anti-inflammatory activity II
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AU2006905378A AU2006905378A0 (en) 2006-09-28 Metal complexes having anti-inflammatory activity II
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010062221A1 (fr) * 2008-11-27 2010-06-03 Алла Xem, Ллс Acides 2-(5-hydroxy-2-méthyl-1n-indole-3-il) acétiques substitués, leurs éthers et leur utilisation pour traiter des maladies virales
CN110066288A (zh) * 2018-01-24 2019-07-30 南京大学 一种具有抑制脲酶活性的萘普生铜配合物及其制备方法

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WO2002036127A2 (fr) * 2000-10-31 2002-05-10 Nutrition 21, Inc. Methodes et compositions avec complexes au chrome pour personnes atteintes de polykystose ovarienne
WO2002036202A2 (fr) * 2000-11-02 2002-05-10 Nutrition 21, Inc. Procedes et compositions permettant d'ameliorer la sensibilite insulinique, de reduire l'hyperglycemie, et de reduire l'hypercholesterolemie a l'aide de complexes de chrome et d'acide alphalipoique
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WO2002024180A2 (fr) * 2000-09-21 2002-03-28 Nutrition 21, Inc. Procedes et compositions pour le traitement du diabete, la reduction des graisses corporelles, l'amelioration de la sensibilite a l'insuline, la reduction de l'hyperglycemie et la reduction de l'hypercholesterolemie, a l'aide de complexes de chrome, d'acides gras conjugues et/ou d'alcools gras conjugues
WO2002036127A2 (fr) * 2000-10-31 2002-05-10 Nutrition 21, Inc. Methodes et compositions avec complexes au chrome pour personnes atteintes de polykystose ovarienne
WO2002036202A2 (fr) * 2000-11-02 2002-05-10 Nutrition 21, Inc. Procedes et compositions permettant d'ameliorer la sensibilite insulinique, de reduire l'hyperglycemie, et de reduire l'hypercholesterolemie a l'aide de complexes de chrome et d'acide alphalipoique
WO2006099677A1 (fr) * 2005-03-24 2006-09-28 Medical Therapies Limited Complexes metalliques
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010062221A1 (fr) * 2008-11-27 2010-06-03 Алла Xem, Ллс Acides 2-(5-hydroxy-2-méthyl-1n-indole-3-il) acétiques substitués, leurs éthers et leur utilisation pour traiter des maladies virales
CN110066288A (zh) * 2018-01-24 2019-07-30 南京大学 一种具有抑制脲酶活性的萘普生铜配合物及其制备方法

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