BACKGROUND Nitric oxide (NO) plays a varied and vital role in the body of a human or other mammals. For example, NO plays a vital role in the control of blood pressure: it acts as a neurotransmitter; it plays a role in inhibition of platelet aggregation (important in thrombosis or blockages of the blood vessels) and in cytostasis (important in fighting of tumours). Overproduction of NO however, has been implicated in a number of disease states, including vascular/pressor diseases such as septic shock, post- ischaemic cerebral damage, migraine and dialysis induced renal hypotension: immunopathologic diseases such as hepatic damage in inflammation and sepsis allograft rejection, graft versus host diseases, diabetes and wound healing: neurodegenerative diseases such as cerebral ischaemia, trauma, chronic epilepsy, Alzheimer's disease, Huntington's disease, and AIDS dementia complex; and side effects of treatment such as restenosis following angioplastic treatment and secondary hypotension following cytokine therapy.

Pharmacological modulation of nitric oxide or other reactive oxygen species in any of these disease states should prove extremely beneficial.

One above-mentioned disease relating to overproduction of NO is septic shock. This is precipitated by local septicaemnia or endotoxaemia, (high local levels of bacterial endotoxins). The result is activation of macrophages, lymphocytes, endothelial cells and other cell types capable of producing NO further mediated by cytokine production by these cells. The activated macrophages produce excess NO which causes vasodilation of the blood vessels, and results in local vascular damage and vascular collapse. This destruction of vascular integrity may be so great that it leads to the collapse of haemodynanic homeostasis, the end result being death.

Current ideas for pharmacological modulation of nitric oxide in such diseases are based on dealing with the mediators of septic shock such as cytokines, endotoxins and platelet activating factor (PAF). The approaches include use of antibodies to cytokines such as tumour necrosis factor (TNF) receptor antagonists such as interleukin I (IL-1) antibodies to lipopolysaccharide (the endotoxins produced by Gram negative bacteria) and PAF antagonists. All such approaches while challenging a factor mediating septic shock do not attempt to deal with the aetiology or cause of the disease. Recent advances in understanding of NO have lead to the proposal that inhibitors of the NO synthase enzyme such as NG-monomethy-L-arginine (L-NMMA) may be useful in the treatment of septic shock and other NO overproduction related to diseases since they inhibit NO production. While these inhibitors have shown some utility in animal models and preliminary clinical studies they have the disadvantage of undesirably inhibiting total NO synthesis in the body.

An aim of the present invention is to provide new compositions which are able to modulate levels of NO and other reactive oxygen species in the body. Examples of other reactive species include superoxide, hydroxyl radical, peroxide, peroxynitrite, and other oxides of nitrogen including protein adducts. The compositions of metal complexes described herein are able to carry out the important role of reducing levels of these harmful species by scavenging.

SUMMARY OF THE INVENTION Some metal complexes are known in pharmaceutical compositions for the treatment of diseases of the body of a human or other mammal. For example certain complexes of platinum and ruthenium have been used or indicated in the treatment of cancer. Metal complexes have not however been previously indicated in the treatment of disease relating to the overproduction of reactive oxygen species (including the overproduction of NO).

This invention provides for the use of a neutral anionic or cationic metal complex having at least one site for coordination with NO of Formula I [Ma (XbL) eYdZe]" Formula I in the manufacture of a medicament for the attenuation of NO levels and other reactive oxygen species when implicated in disease. where:

M is a metal ion or a mixture of metal ions: X is a cation or a mixture of cations: L is a ligand, or mixture of ligands each containing at least two different donor atoms selected from the elements of Group IV, Group V or Group VI of the Periodic Table; Y is a ligand or a mixture of the same or different ligands each containing at least one donor atom or more than one donor atom which donor atom is selected from the elements of Group IV, Group V or Group VI of the Periodic Table: And Z is a halide or pseudohalide ion or a mixture of halide ions and pseudohalide ions: a=1-3; b=0-12; c=0-18; d=0-18; e=0-18; and n=0-10; provided that at least one of c, d and e is 1 or more.

And where c is 0: b is also 0; And where a is 1: c, d and e are not greater than 9; And where a is 2: c, d and e are not greater than 12.

By"complex"in this specification is meant a neutral complex or anionic or cationic species.

The term"Group"which is used herein is to be understood as a vertical column of the periodic table in which elements of each Group have similar physical and chemical properties. The definition of the Periodic Table is that credited to Mendeleev; Chamber Dictionary of Science and Technology, 1974 Published by W & R Chambers Ltd. The nomenclature of the compounds as disclosed herein are based upon common usage. The names of the compounds according to nomenclature of the American Chemical Abstracts Service (American Chemical Society) are also provided in Table 5.

This invention may also be stated as providing a method of attenuation of reactive oxygen species when implicated in diseases of the human body or the bodies of other mammals. Thus the invention comprises administering a pharmaceutical composition containing a neutral, anionic or cationic metal complex of Formula I.

This invention may also provide for the use of a neutral anionic or cationic metal complex of formula I in the manufacture of a medicament for the treatment of

diseases in which reactive oxygen species are overproduced.

This invention may also be stated as providing a method of attenuation of nitric oxide when implicated in diseases of the human body or bodies of other mammals. Thus the invention comprises administering a pharmaceutical composition containing a neutral, anionic or cationic metal complex of Formula I.

This invention may also be stated as providing a method of treatment of diseases of a body of a human or other mammals resultant of overproduction of NO in the body comprising administering a pharmaceutical composition containing a neutral anionic or cationic metal complex of formula I.

Where the formula I represents an anionic species a cation will also be present.

Where formula I represent a cationic species an anion will also be present. The metal complexes may be hydrated.

Preferably M is a first, second or third row transition metal ion. For example M may be an Rh, Ru, Os, Mn, Co, Cr or Re ion, and is preferably an Rh, Ru or Os ion.

Suitably M is in an oxidation state III. We have found surprisingly that when the metal ion for example ruthenium is in oxidation state III, the rate at which it binds with NO is significantly faster than when it is in oxidation state II.

X may be any cation, such as mono-, di-or tri-valent cation. Suitable cations may be H+, K+, Na+, NH4+ or Ca2+. Conveniently X may be H+, K+, or Na+.

Preferably L is a polyaminocarboxylate ligand described herein by the general formulae A and B: Formula A Formula B Where: V', W', X', Y'and Z'are independently selected selected from H, phenyl,

heteroaryl, C 6alkyl, C 6alkylhydroxy, Cs 6alkylthiol, C 6alkylaryl, C 6alkylheteroaryl, Cl 6alkylheterocyclyl and derivatives thereof. Preferred alkylheterocyclic groups are pyridinylmethylene, pyrazinylmethylene, pyrimidinylmethylene. The aromatic and heteroaromatic groups may be suitably substituted in single or multiple positions with halide, C1-6alkyl, C1-6alkoxy, C1- 6alkoxyaryl or benzyloxy, hydroxy, Cl 6hydroxyalkyl, thiol, carboxylic acid, carboxyalkylCI-6, carboxamide, carboxamidoalkylCl-6, anilide.

P'= CH2, (CH2) 2, CHOHCH2, CH (OCz 6alkyl) CH2 V', W', X', Y'and Z'may also be methylenecarboxylic acid, methylenecarboxyCz 6alkyl, methylenecarboxamideCI 6alkyl or heterocyclyl, methylenecarboxanilide, methylenecarboxamido derivatives of an aminoacid or peptide, methylenehydroxamic acid, methylene phosphonic acid, Cl 6alkylthiol.

In the above formulae, the ligands may be optionally fused with a heterocyclic ring R (n= 0 or 1). Prefered heterocyclic groups are pyridine, pyrimidine, pyrazine, imidazole, thiazole, oxazole.

More preferably L is a ligand such as ethylenediamine-N, N'-diacetic acid (edda), ethylenediaminetetraacetic acid (edta), nitrilotriacetic acid (nta), dipicolinic acid (dipic), picolinic acid (pic), diethylenetri-aminepentaacetic acid (dtpa), thiobis (ethylenenitrilo) tetraacetic acid (tedta), dithioethanebis (ethylenenitrilo) tetraacetic acid (dtedta), and N- (2-hydroxethyl) ethylenediamine-triacetic acid (hedtra).

Preferably Y is a ligand containing nitrogen, oxygen, sulphur, carbon or phosphorus donor groups. Suitable nitrogen donor groups may be for example ammine, amine, nitrile and nitride or derivations thereof. Suitable oxygen donor groups may be for example carboxylic acid, ester or derivations thereof, water, oxide, sulphoxide, hydroxide, acetate, lactate, propionate, oxalate and maltolate. Suitable sulphur donor groups may be for example sulphoxide, dialkysulphide, dithiocarbamate or dithiophosphate. Suitable carbon donor groups may be for example carbon monoxide or isocyanide. Suitable phosphorus donor groups may be for example trialkylphosphine.

Z may be any halide and is preferably chloride, bromide or iodide. Most conveniently, Z is chloride.

Examples of metal complexes for use according to the present invention include optionally hydrated ruthenium complexes of Formula II [Ru(HO 6 Li 3Yo-2Clo-4] (0-4 » Formula II where L"is a polyaminocarboxylate ligand as already described herein by the general formulae A and B, more preferably a polydentate aminocarboxylate ligand such as, for example edta, nta, dipic, pic, edda, tropolone, dtpa, hedtra, tedta or dtedta or diamide of edta or dtpa (or an amide or ester derivative thereof) or a mixture of any of these and Y is as defined above and may for example be selected from: acetylacetone (acac) a-diketonate; water; dimethylsulphoxide (dmso); carboxylate; bidentate carboxylate; catechol; kojiic acid; maltol; hydroxide; tropolone; malonic acid; oxalic acid; 2.3-dihydroxynaphthalene; squaric acid; acetate; a sulphate and a glycolate.

The skilled artisan will be able to substitute other known ligands at Y and which will fall within the scope of the inventions.

Preparative methods of tedta, dtedta and diamide of edta and dtpa are described in the following references respectively: P Tse & JE Powell, Inorg Chem, (1985), 24,2727 G Schwartzenbach, H Senner, G Anderegg, Helv Chim Acta 1957,40,1886 MS Konings, WC Dow, DB Love, KN Raymond, SC Quay and SM Rocklage, Inorg Chem (1990), 29,1488-1491 PN Turowski, SJ Rodgers, RC Scarrow and KN Raymond, Inorg Chem (1988), 27,474-481.

Where the complex of Formula II is an anion, a cation will be required. For example the complexes of Formula II are present in K [Ru (Hedta) Cl] 2H20 [Ru (H2edta) (acac)] K [Ru (hedtra) Cl] H20 K [Ru (dipic) 2] H20 (H2Pic) [RuCl2 (pic) 2] (Hpic) H20 K [Ru (H2edta) Cl2] H20 K [Ru (Hnta) 2] I/2H2O K [Ru (H2dtpa) Cl] H20

[Ru (Hhedtra) acac] H20 [Ru (Hhedtra) trop] [Ru (H3dtpa) Cl] Complexes of formula II have not to the best of our knowledge been previously indicated in any pharmaceutical composition. Therefore the present invention also provides a pharmaceutical composition containing an optionally hydrated ruthenium complex of Formula II.

Further examples of metal complexes for use according to the present invention include optionally hydrated complexes of Formula III [M1-3Y1-18Cl0-18](0-6)~Formula III where Y is a sulphur donor ligand. For example, such complex is present in [Ru (mtc) 3] (mtc = 4-morpolinecarbodithoic acid) Ru (S2CNCH2CH2NMeCH2CH2) 3 l/2H20 Complexes of Formula III in which Y is a sulphur donor ligand have not to the best of our knowledge been previously indicated in any pharmaceutical composition.

Therefore, the present invention also provides a pharmaceutical composition containing an optionally hydrated complex of Formula III when Y is a sulphur donor ligand.

Yet further examples of metal complexes for use according to the present invention include optionally hydrated complexes of ruthenium of Formula III III[MIII1-3YIII1-18Cl0-18](0-6)~Formula where MIII is ruthenium and Y'll is an oxygen-donor ligand such as acetate, lactate, water, oxide, propionate (COEt), oxalate (ox), or maltolate (maltol) or a combination of these. For example complexes of Formula III are present in [Ru30 (OAc) 6] (OAc) [Ru30 (lac) 6] (lac) [Ru2 (OAc) 4] NO3 [Ru2 (OCOEt) 4] N03 K3 [RU (OX) 3] [RU2 (OAc) 4] Cl [Ru (maltol) 3]

Some complexes of Formula III have not to the best of our knowledge been previously indicated in any pharmaceutical composition. Therefore the present invention also provides a pharmaceutical composition containing an optionally hydrated complex of ruthenium of Formula III wherein Ml, l is ruthenium and YIII is an oxygen-donor ligand selected from the group acetate, lactate, oxide, propionate and maltolate.

Further examples of metal complexes for use according to the present invention include optionally hydrated complexes of ruthenium of Formula IV IV[RuYIV1-9Cl1-9](0-4)~Formula where Yin is a nitrogen-donor ligand such as: ammine; ethylenediamine (en); pyridine (py); 1,10-phenanthroline (phen): 2,2-bipyridine (bipy) or 1,4,8,11- tetraazacyclotetradecane (cyclam); 1,4,7-triazacyclononane; 1,4,7-triazacyclononane tris acetic acid; 2,3,7,8,12,13,17,18-octaethylporphyrin (oep); or a combination of these. For example complexes of Formula IV are present in [Ru (H3N) 5CI] C12 [Ru (en) 3] I3 trans-[RuCl2 (pY) 4] K [Ru (phen) Cl4] [Ru (cyclam) Cl2] Cl K [Ru (bipy) Cl4] [Ru(NH3)6]Cl3 [Ru (NH3) 4Cl2] Cl Ru (oep) Ph Some complexes of Formula IV have not to the best of our knowledge been previously indicated in any pharmaceutical composition. Therefore the present invention also provides a pharmaceutical composition containing an optionally <BR> <BR> <BR> hydrated complex of ruthenium of Formula IV wherein ylV is a nitrogen-donor ligand selected from the group en, py, phen, bipy, cyclam and oep. Derivations of these ligands can be prepared by a skilled artisan and which will fall within the scope of the inventions.

Still further examples of metal complexes for use according to the present invention invlude optionally hydrated complexes of ruthenium or osmium of general Formula V [MI-3yVl-l8CIO-181 (0-6) Formula where yV is a combination of donor ligands such as are described hereinabove, for example ammine, dmso, oxalate, bipy, acac and methyl cyanide. Complexes of Formula V are present in for example [Ru (NH3) (dmso) 2Cl3] cis- [Ru (dmso) 4Cl2] cis- [Ru (NH3) (dmso) 3Cl2] [Ru (dmso) 3Cl3] [Os (ox) (bipy) 2] H20 [Ru (acac) 2 (MeCN) 2] CF3SO3 The complex ions of the latter two compounds above have not to the best of our knowledge been previously indicated in any pharmaceutical composition.

Therefore the present invention also provides a pharmaceutical composition containing an optionally hydrated complex of formula [Os (ox) (bipy) 2]; and further a pharmaceutical composition containing an optionally hydrated complex of formula [Ru (acac) 2 (MeCN) 21+- In use the complexes of the present invention may be included as an active component in a pharmaceutical composition containing an optionally hydrated complex of any of Formulae I-V, in admixture with a pharmaceutically acceptable carrier or diluent. Said pharmaceutical composition may be formulated according to well known principles, and may be in the form of a solution or suspension for parenteral administration in single or repeat doses or be in capsule, tablet, dragee, or other solid composition or as a solution or suspension for oral administration, or formulated into pessaries or suppositories, or sustained release forms of any of the above. The solution or suspension may be administered by a single or repeat bolus injection or continuous infusion, or any other desired schedule. Suitable diluents, carriers, excipients and other components are known. Said pharmaceutical composition may contain dosages determined in accordance with conventional pharmacological methods, suitable to provide active complexes in the dosage range in

humans of lmg to lOg per day and dosages in other mammals as determined by routine clinical veterinary practice. Actual required dosage is largely dependent on where in the body there is the excess concentration of NO or other reactive oxygen species and for how long overproduction continues or attenuation of the levels of NO or reactive oxygen species, where such reactive oxygen species is implicated in disease, is required.

BRIEF DESCRIPTION OF THE DRAWINGS The foregoing aspects and many of the attendant advantages of this invention will become more readily appreciated as the same becomes better understood by reference to the following detailed description, when taken in conjunction with the accompanying drawings, wherein: FIGURE 1 illustrates pressure changes induced by the compounds of the present invention, which reflect a reduction in available nitric oxide compared with control levels.

FIGURE 2 shows the available nitric oxide concentration (micromoles/liter) following reaction of nitric oxide with compounds of the present invention as compared with control levels.

FIGURE 3 demonstrates the inhibition of tumour growth by AMD6245 and AMD6221.

FIGURE 4A-4G provides chemical structural formulas for the AMD-numbered compounds disclosed.

FIGURE 5A-5C provides chemical structural formulas for the AMD-numbered compounds disclosed.

DETAILED DESCRIPTION OF THE INVENTION Introduction and General Description of the Invention This invention is directed to metal complexes which are useful in binding nitric oxide with sufficiently high affinity as to make such complexes useful as pharmaceutical compositions for the treatment of diseases in mammals, preferably in the human body.

Some metal complexes are known in pharmaceutical compositions for the treatment of diseases in mammals, preferably in diseases of the human body. For example certain complexes of platinum and ruthenium have been used or indicated in

the treatment of cancer. Metal complexes have not however been previously indicated in the treatment of disease relating to the overproduction of reactive oxygen species (including the overproduction of NO). This invention provides for the use of a neutral anionic or cationic metal complex having at least one site for coordination with NO of Formula I [Ma (XbL) cYdZe]" Formula I in the manufacture of a medicament for the attenuation of NO levels and other reactive oxygen species when implicated in disease. where: M is a metal ion or a mixture of metal ions: X is a cation or a mixture of cations: L is a ligand, or mixture of ligands each containing at least two different donor atoms selected from the elements of Group IV, Group V or Group VI of the Periodic Table; Y is a ligand or a mixture of the same or different ligands each containing at least one donor atom or more than one donor atom which donor atom is selected from the elements of Group IV, Group V or Group VI of the Periodic Table: And Z is a halide or pseudohalide ion or a mixture of halide ions and pseudohalide ions: a=1-3; b=0-12; c=0-18; d=0-18; e=0-18; and n=0-10; provided that at least one of c, d and e is 1 or more.

And where c is 0: b is also 0; And where a is 1: c, d and e are not greater than 9; And where a is 2: c, d and e are not greater than 12.

By"complex"in this specification is meant a neutral complex or anionic or cationic species.

The term"Group"which is used herein is to be understood as a vertical column of the periodic table in which elements of each Group have similar physical and chemical properties. The definition of the Periodic Table is that credited to Mendeleev; Chamber Dictionary of Science and Technology, 1974 Published by W & R Chambers Ltd. The nomenclature of the compounds as disclosed herein are based

upon common usage. The names of the compounds according to nomenclature of the American Chemical Abstracts Service (American Chemical Society) are also provided in Table 5.

This invention may also be stated as providing a method of attenuation of reactive oxygen species when implicated in diseases in mammals, preferably in diseases of the human body. Thus the invention comprises administering a pharmaceutical composition containing a neutral, anionic or cationic metal complex of Formula I.

This invention may also provide for the use of a neutral anionic or cationic metal complex of formula I in the manufacture of a medicament for the treatment of diseases in mammals, preferably in diseases of the human body in which reactive oxygen species are overproduced.

This invention may also be stated as providing a method of attenuation of nitric oxide when implicated in diseases in mammals, preferably in diseases of the human body. Thus the invention comprises administering a pharmaceutical composition containing a neutral, anionic or cationic metal complex of Formula I.

This invention may also be stated as providing a method of treatment of diseases of the human body resultant of overproduction of NO in the human body comprising administering a pharmaceutical composition containing a neutral anionic or cationic metal complex of formula I.

Where the formula I represents an anionic species a cation will also be present.

Where formula I represent a cationic species an anion will also be present. The metal complexes may be hydrated.

Preferably M is a first, second or third row transition metal ion. For example M may be an Rh, Ru, Os, Mn, Co, Cr or Re ion, and is preferably an Rh, Ru or Os ion.

Suitably M is in an oxidation state III. We have found surprisingly that when the metal ion for example ruthenium is in oxidation state III, the rate at which it binds with NO is significantly faster than when it is in oxidation state II.

X may be any cation, such as mono-, di-or tri-valent cation. Suitable cations may be H+, K+, Na+, NH4+ or Ca2+. Conveniently X may be H+, K+, or Na+.

Preferably L is a polyaminocarboxylate ligand described herein by the general formulae A and B:

Formula A Formula B Where: V', W', X', Y'and Z'are independently selected from H, phenyl, heteroaryl, C 6alkyl,C1-6alkylaryl,C1-6alkylheteroaryl,C1-C1-6alkylthiol, 6alkylheterocyclyl and derivatives thereof. Preferred alkylheterocyclic groups are pyridinylmethylene, pyrazinylmethylene, pyrimidinylmethylene. The aromatic and heteroaromatic groups may be suitably substituted in single or multiple positions with halide, C1_balkyl, CI-6alkoxy, CI_6alkoxyaryl or benzyloxy, hydroxy, Cl 6hydroxyalkyl, thiol, carboxylic acid, carboxyalkylC, 6, carboxamide, carboxamidoalkylC,-6, anilide.

P'= CH2, (CH2) 2, CHOHCH2, CH (OCl 6alkyl) CH2 V', W', X', Y'and Z'may also be methylenecarboxylic acid, orheterocyclyl,methylenecarboxyC1-6alkyl,methylenecarboxamid eC1-6alkyl methylenecarboxanilide, methylenecarboxamido derivatives of an aminoacid or peptide, methylenehydroxamic acid, methylene phosphonic acid, Cl 6alkylthiol.

In the above formulae, the ligands may be optionally fused with a heterocyclic ring R (n= 0 or 1). Prefered heterocyclic groups are pyridine, pyrimidine, pyrazine, imidazole, thiazole, oxazole.

More preferably L is a ligand such as ethylenediamine-N, N'-diacetic acid (edda), ethylenediaminetetraacetic acid (edta), nitrilotriacetic acid (nta), dipicolinic acid (dipic), picolinic acid (pic), diethylenetri-aminepentaacetic acid (dtpa), thiobis (ethylenenitrilo) tetraacetic acid (tedta), dithioethanebis (ethylenenitrilo) tetraacetic acid (dtedta), and N- (2-hydroxethyl) ethylenediamine-triacetic acid (hedtra).

Preferably Y is a ligand containing nitrogen, oxygen, sulphur, carbon or phosphorus donor groups. Suitable nitrogen donor groups may be for example ammine, amine, nitrile and nitride or derivations thereof. Suitable oxygen donor groups may be for example carboxylic acid, ester or derivations thereof, water, oxide, sulphoxide, hydroxide, acetate, lactate, propionate, oxalate and maltolate. Suitable sulphur donor groups may be for example sulphoxide, dialkysulphide, dithiocarbamate or dithiophosphate. Suitable carbon donor groups may be for example carbon monoxide or isocyanide. Suitable phosphorus donor groups may be for example trialkylphosphine.

Z may be any halide and is preferably chloride, bromide or iodide. Most conveniently, Z is chloride.

Examples of metal complexes for use according to the present invention include optionally hydrated ruthenium complexes of Formula II [Ru (Ho-6 L") i-3Yo-2Clo-4 f" Formula II where LI, is a Preferably L is a polyaminocarboxylate ligand as already described herein by the general formulae A and B. More preferably, L is a polydentate aminocarboxylate ligand, for example edta, nta, dipic, pic, edda, tropolone, dtpa, hedtra, tedta or dtedta or diamide of edta or dtpa (or an amide or ester derivative thereof) or a mixture of any of these and Y is as defined above and may for example be selected from: acetylacetone (acac) a P-diketonate; water; dimethylsulphoxide (dmso); carboxylate; bidentate carboxylate; catechol; kojiic acid; maltol; hydroxide; tropolone; malonic acid; oxalic acid; 2.3-dihydroxynaphthalene; squaric acid; acetate; a sulphate and a glycolate. The skilled artisan will be able to substitute other known ligands at Y and which will fall within the scope of the inventions.

Preparative methods of tedta, dtedta and diamide of edta and dtpa are described in the following references respectively: P Tse & JE Powell, Inorg Chem, (1985), 24,2727 G Schwartzenbach, H Senner, G Anderegg, Helv Chim Acta 1957,40,1886 MS Konings, WC Dow, DB Love, KN Raymond, SC Quay and SM Rocklage, Inorg Chem (1990), 29,1488-1491

PN Turowski, SJ Rodgers, RC Scarrow and KN Raymond, Inorg Chem (1988), 27,474-481.

Where the complex of Formula II is an anion, a cation will be required. For example the complexes of Formula II are present in K [Ru (Hedta) Cl] 2H20 [Ru (H2edta) (acac)] K [Ru (hedtra) Cl] H20 K [Ru (dipic) 2] H20 (H2piC) [RuCl2 (pic) 2] (Hpic) H20 K [Ru (H2edta) Cl2] H20 K [Ru (Hnta) 2] I/2H2O K [Ru (H2dtpa) Cl] H20 [Ru (Hhedtra) acac] H20 [Ru (Hhedtra) trop] [Ru (H3dtpa) Cl] Complexes of formula II have not to the best of our knowledge been previously indicated in any pharmaceutical composition. Therefore the present invention also provides a pharmaceutical composition containing an optionally hydrated ruthenium complex of Formula II.

Further examples of metal complexes for use according to the present invention include optionally hydrated complexes of Formula III [M1-3Y1-18Cl0-18](0-6)~ Formula III where Y is a sulphur donor ligand. For example, such complex is present in [Ru (mtc) 3] (mtc = 4-morpolinecarbodithoic acid) Ru (S2CNCH2CH2NMeCH2CH2) 3 l/2H20 Complexes of Formula III in which Y is a sulphur donor ligand have not to the best of our knowledge been previously indicated in any pharmaceutical composition.

Therefore, the present invention also provides a pharmaceutical composition containing an optionally hydrated complex of Formula III when Y is a sulphur donor ligand.

Yet further examples of metal complexes for use according to the present invention include optionally hydrated complexes of ruthenium of Formula III

III[MIII1-3YIII1-18Cl0-18](0-6)~Formula where MIIIis ruthenium and YIIIis an oxygen-donor ligand such as acetate, lactate, water, oxide, propionate (COEt), oxalate (ox), or maltolate (maltol) or a combination of these. For example complexes of Formula III are present in [Ru30 (OAc) 6] (OAc) [Ru30 (lac) 6] (lac) [Ru2 (OAc) 4] NO3 [Ru2 (OCOEt) 4] NO3 K3 [RU (ox) 3] [RU2 (OAc) 4] Cl [Ru (maltol) 3] Some complexes of Formula III have not to the best of our knowledge been previously indicated in any pharmaceutical composition. Therefore the present invention also provides a pharmaceutical composition containing an optionally hydrated complex of ruthenium of Formula III wherein Ml"is ruthenium and YII'is an oxygen-donor ligand selected from the group acetate, lactate, oxide, propionate and maltolate.

Further examples of metal complexes for use according to the present invention include optionally hydrated complexes of ruthenium of Formula IV IV[RuYIV1-9Cl1-9](0-4)~Formula where Yin is a nitrogen-donor ligand such as: ammine; ethylenediamine (en); pyridine (py); 1,10-phenanthroline (phen): 2,2-bipyridine (bipy) or 1,4,8,11- tetraazacyclotetradecane (cyclam); 2,3,7,8,12,13,17,18-octaethylporphyrin (oep); or a combination of these. For example complexes of Formula IV are present in [Ru (HN3) 5Cl] Cl2 [Ru (en) »] I3 trans-[RuCl2 (pY) 4] K [Ru (phen) Cl4] [Ru (cyclam) Cl2] Cl K [Ru (bipy) Cl4] [Ru(NH3)6]Cl3 [Ru (NH3) 4Cl2] Cl

Ru (oep) Ph Some complexes of Formula IV have not to the best of our knowledge been previously indicated in any pharmaceutical composition. Therefore the present invention also provides a pharmaceutical composition containing an optionally <BR> <BR> <BR> hydrated complex of ruthenium of Formula IV wherein Yin is a nitrogen-donor ligand selected from the group en, py, phen, bipy, cyclam and oep. Derivations of these ligands can be prepared by a skilled artisan and which will fall within the scope of the inventions.

Still further examples of metal complexes for use according to the present invention include optionally hydrated complexes of ruthenium or osmium of general Formula V V[M1-3YV1-18Cl0-18](0-6)~Formula where yV is a combination of donor ligands such as are described hereinabove, for example ammine, dmso, oxalate, bipy, acac and methyl cyanide. Complexes of Formula V are present in for example [Ru (NH3) (dmso) 2Cl3] <BR> <BR> <BR> <BR> cis- [Ru (dmso) 4Cl2]<BR> <BR> <BR> <BR> <BR> <BR> cis- [Ru (NH3) (dmso) 3Cl2] [Ru (dmso) 3Cl3] [Os (ox) (bipy) 2] H20 [Ru (acac) 2 (MeCN) 2] CF3SO3 The complex ions of the latter two compounds above have not to the best of our knowledge been previously indicated in any pharmaceutical composition.

Therefore the present invention also provides a pharmaceutical composition containing an optionally hydrated complex of formula [Os (ox) (bipy) 2]; and further a pharmaceutical composition containing an optionally hydrated complex of formula [Ru (acac) 2 (MeCN) Z) +, In use the complexes of the present invention may be included as an active component in a pharmaceutical composition containing an optionally hydrated complex of any of Formulae I-V, in admixture with a pharmaceutically acceptable carrier or diluent. Said pharmaceutical composition may be formulated according to well known principles, and may be in the form of a solution or suspension for

parenteral administration in single or repeat doses or be in capsule, tablet, dragee, or other solid composition or as a solution or suspension for oral administration, or formulated into pessaries or suppositories, or sustained release forms of any of the above. The solution or suspension may be administered by a single or repeat bolus injection or continuous infusion, or any other desired schedule. Suitable diluents, carriers, excipients and other components are known. Said pharmaceutical composition may contain dosages determined in accordance with conventional pharmacological methods, suitable to provide active complexes in the dosage range in humans of lmg to lOg per day. Actual required dosage is largely dependent on where in the body there is the excess concentration of NO or other reactive oxygen species and for how long overproduction continues or attenuation of the levels of NO or reactive oxygen species, where such reactive oxygen species is implicated in disease, is required. It will be understood that the present invention may be used in combination with any other pharmaceutical composition useful for this purpose.

Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents. Further, all documents referred to throughout this application are incorporated in their entirety by reference herein. Terms as used herein are based upon their art recognized meaning unless otherwise indicated and should be clearly understood by the ordinary skilled artisan.

EXAMPLES Having now generally described the invention, the same will be more readily understood through reference to the following examples which are provided by way of illustration, and are not intended to be limiting of the present invention, unless specified.

A number of commercially available compounds, and compounds prepared by routes known in the literature, containing the complexes of the present invention were tested in vitro, in vitro cell culture, and ex vivo in order to determine ability to coordinate with NO. The complexes tested were as follows: Table 1 Example Compound Literature Reference for Preparation 1 K [Ru (hedta) Cl] 2H2O AA Diamantis & JV Dubrawski, Inorg. Chem. (1981) 20: 1142-50 2 [Ru (H2edta) (acac)] AA Diamantis & JV Dubrawski, Inorg. Chem. (1983) 22: 1934-36 3 K [Ru (hedtra) Cl] H20 HC Bajaj & R van Eldik, Inorg. Chem. (1982) 28: 1980-3 4 K [Ru (dipic) 2] H20 NH Williams & JK Yandell, Aust. J. Chem. (1983) 36 (12): 2377-2386 5 (H2pic) [RuC12 (pic) 2] (Hpic) H20 JD Gilbert, D Rose & G Wilkinson, J. Chem. Soc. (A) (1970): 2765-9 6 K [Ru (H, edta) Cl2] H20 AA Diamantis & JV Dubrawski, Inorg. Chem. (1981) 20: 1142-50 7 K [Ru (hnta) 2] i/2H20 MM Taqui Khan, A Kumar & Z Shirin, J. Chem. Research (M), (1986): 1001-1009 8 K [Ru (H2dtpa) Cl] H20 MM Taqui Khan, A Kumar & Z Shirin, J. Chem. Research (M), (1986): 1001-1009 9 [Ru30 (lac) 6] (lac) A Spencer & G Wilkinson, J. Chem. Soc. Dalton Trans (1972): 1570-77 10 [Ru30 (OAc) 6] (OAc) A Spencer & G Wilkinson, J. Chem. Soc. Dalton Trans (1972): 1570-77 11 [Ru2 (OAc) 4] NO3 M Mukaida, T Nomura & T Ishimori, Bull. Chem. Soc. Japan (1972) 45: 2143-7 12 [Ru2 (OCOEt) 4] NO3 A Bino, FA Cotton & TR Felthouse, Inorg. Chem. (1979) 18: 2599-2604 13 K3 [Ru (ox) 3] CM Che, SS Kwong, CK Poon, TF Lai & TCW Mak, Inorg. Chem. (1985) 24: 1359-63 14 [Ru2 (OAc) 4] CI RW Mitchell, A Spencer & G Wilkinson, J. Chem. Soc. Dalton Trans. (1973) 846-54 15 [Ru (NH3) 5Cl] Clz AD Allen, F Bottomley, RO Harris, VP Reinsalu & CV Senoff, J. Amer. Chem. Soc. (1967) 89: 5595- 5599 16 [Ru (en) 3] I3 TJ Meyer & H Taube, Inorg. Chem. (1968) 7: 2369- 2379 17 K [RuCl4 (phen)] H2O BR James & RS McMillan, Inorg. Nucl. Chem. Lett. (1975) 11 (12): 837-9 18 [Ru (cyclam) Cl2] CI PK Chan, DA Isabirye & CK Poon, Inorg. Chem. (1975) 14: 2579-80 19 K [RuCl4 (bipy)] BR James & RS McMillan, Inorg. Nucl. Chem. Lett. (1975) 11 (12): 837-9 20 [RuCI3 (dmso) 2 (NH3)] Patent: International Publication No. WO 91/13553 21 [Ru (NH3) 6] Cl3 Matthey Catalogue Sales: Cat No [190245] 22 Cis- [RuCl2 (dmso) 4] EA Alessio, G Mestroni, G Nardin, WM Attia, M Calligaris, G Sava & S Zorget, Inorg. Chem. (1988) 27: 4099-4106 Example Compound Literature Reference for Preparation 23 Cis- [RuCl2 (dmso) 3 (NH3)] M Henn, E Alessio, G Mestrni, M Calligaris & WM Attia, Inorg. Chim. Acta (1991) 187: 39-50 24 [RuCl3 (dmso) 3] E Alessio, G Balducci, M Calligaris, G Costa, WM Attia & G Mestroni, Inorg. Chem. (1991) 30: 609- 618 25 [Ru (mtc) 3] AR Hendrickson, JM Hope & RL Martin, J. Chem. Soc. Dalton Trans. (1976) 20: 2032-9 26 [Ru (maltol) 3] WP Griffith & SJ Greaves, Polyhedron (1988) 7 (10): 1973-9 27 [Ru (acac) 2 (MeCN) 2] CF3SO3 Y Kasahara, T Hoshino, K Shimizu & GP Sato, Chem. Lett. (1990) 3: 381-4 28 K2 [RuCls (H20)] Matthey Catalogue Sales: Cat No [190094] 29 [Os (ox) (bipy) 2] H2O DA Buckingham, FP Dwyer, HA Goodwin & AM Sargeson, Aust. J. Chem. (1964) 325-336 GM Bryant, JE Fergusson & HKJ Powell, Aust. J. Chem. (1971) 24 (2): 257-73 30 [Ru (NH3) 4Clz] Cl SD Pell, MM Sherban, V Tramintano & MJ Clarke, Inorg Synth (1989) 26: 65 31 [Ru (Hedtra) (dppm)] MM Taqui Khan, K Venkatasubramanian, Z Shirin, MM Bhadbhade, J Chem Soc Dalt Trans (1992) 885-890 32 Ru (oep) Ph M Ke, SJ Rettig, BR James & D Dolphin, J Chem Soc Chem Commun (1987) 1110

A number of new compounds were prepared according to the following protocols. The first four compounds are examples of rutheniuim complexes of formula [Ru (Ho t-3Yo-2Clo-4] (Formula II), the subsequent two are examples of III).[M1-3Y1-8Cl0-18](0-6)~(formula Preparation of [Ru (Hhedtra) acac]-H20 Excess acetylacetone (lcm3) was added to an aqueous solution (5cm3) of K [Ru (hedtra) Cl] (0.5g). The solution color changed to violet. The mixture was warmed for 20 minutes then left to stand at room temperature for 20 minutes. The violet solution was extracted with chloroform (20cm3). The extraction was repeated twice more. A violet product precipitated from the aqueous fraction. The product was filtered, washed in acetone and dried in vacuo, yield O. lg (18%).

Anal. Calc. For Cl5H250, 0N2Ru: C, 36.43; H, 5.11; N, 5.70. Found: C, 36.16; H, 5.42; N, 5.61%.

Preparation of [Ru (Hhedtra) trop] 2H20 A three-fold excess of tropolone (0.78g) dissolved in 50: 50 water/absolute ehtnaol (5cm3) was added to a warm aqueous solution of K [Ru (hedtra) Cl] (lOcm3).

The mixture was heated for 1 hour. On cooling, the dark green mixture was extracted with 3 x 20cm3 portion sof dichloromethane. On standing, a dark green product precipitated from the aqueous fraction. The product was filtered, washed with water (lcm3), ether and dried in vacuo, yield 0.4g (36%).

Anal. Cal. For C17H22N2O9Ru-2H20: C, 38.13; H, 4.86; N, 5.23. found: C, 38.55; H, 4.67; N, 5.28%.

Preparation of [Ru (H3dtpa) Cl] K2 [RuC15H20]xH20 (lg) was suspended in HC104 (15cm3,1mM) and diethylenetriaminepentaacetic acid (1.05g) added. The reaction mixture was heated under reflux for 1.5 hours forming a yellow/brown solution. On cooling a yellow product crystallised which was collected by filtration, washed with 90% absolute ethanol/water, diethyl ether and dried in vacuo, yield 0.75g, 53%.

Anal. calcd. for C14H2lN3010CIRu: C, 31.85; H, 3.98; N, 7.96; Cl, 6.73.

Found: C, 29.77; H, N, 7.36; Cl, 6.64.

Preparation of K [RuHHBEDC1] 3H20 0.41g of K2 [RuCl5] xH20 was dissolved in water (20ml). To this solution was added 1 equivalent (0.39g) of N, N'di (2-hydroxy-benzyl) ethylene-diamine N, N- diacetic acid (hbed) dissolved in water (50ml) with KOH (0.12g) and MeOH (lml).

This mixture was heated at reflux for 90 minutes. Upon cooling a dark, insoluble precipitate formed. This material was removed by filtration and the resulting red- violet solution was taken to dryness by rotary evapouration. Trituration with water and washing with acetone yilede 90mg of a dark solid.

Anal. Calcd. for Cl8H22N209RuClK: C, 36.89; H, 3.96; N, 4.78; Cl, 6.04.

Found: C, 37.09; H, 4.23; N, 4.92; Cl, 6.28.

Preparation of Ru (S2CNCH2CH2NMeCH2CH2) 3l/2H2O Me4N [S2CNCH2CH2NMeCH2CH2] was made by the standard method and crystallised from methanol-ether in 71% yield.

RuCl3xH20,0.50g, 2.15mmol was refluxed in 30ml of methanol for 10 minutes and cooled. 1.87g, 7.50mmol of Me4N [S2CNCH2CH2NMeCH2CH2] was added and the mixture refluxed for 16 hours. After cooling 0.72g of crude product was filtered off, dissolved in dichloromethane and filtered. The filtrate was loaded into 15cc of basic alumina and eluted with dichloromethane. Removal of solvent and crystallisation from dichloromethane with ether by vapour-phase diffusion gave 0.51g, 0. 80mmol, 37% of brown-black crystals, Ru (S2CNCH2CH2NMeCH2CH2) 3 I/2H20.

Analysis for C, sH34N6O sRuS6: Calc: C, 34.00; H, 5.39; N, 13.22; S, 30.25.

Found: C, 34.21; H, 5.47; N, 13.12; S, 30.36.

Preparation of Ru [S2P (OC2H2OC2H40Me) 2] 3 K [S2P (OC2H4OC2H4OMe) 2] 3 was made by standard method and crystallised from methanol in 76% yield.

RuCl3xH20, l. OOg, 4.30mmol was refluxed in 50ml of 0.1 N HCl with lml of ethanol for 20 minutes and cooled. To this solution was added 5.28g (excess) K [S2P (OC2H4OC2HROMe) 2] and the mixture stirred at 30°C for 1 hour. The reaction mixture was extracted with dichloromethane and the solvent removed. The residue was extracted with ether-hexane and solvents removed. This residue was crystallised from 25ml of hot ether by cooling to-20°C giving 2.98 of red crystals. 2.41g of the crude product was purified by chromatography on 60cc of silica gel with 5% ethanol in ether. The first band was collected, reduced to dryness and crystallised from ether by cooling to-20°C. The yield of red crystals, Ru (S2P [OC2H4OC2H4OMe] 2) 3, was 2.16g, 56%.

Analysis for C3oH66018P3RuS6: Calc: C, 32.72; H, 6.04; S, 17.47. Found: C, 32.68; H, 6.08; S, 17.16.

In the in vitro tests, which were carried out in an atmosphere of argon, each compound (1 x 104 moles) was dissolved in double-distilled deionized and deoxygenated water. The resulting solution was placed in a three-necked pear-shaped

flask and stirred by a magnetic stirrer at constant speed of 1000rpm, at a constant temperature in the range 20°C-24°C. A manometer was attached to the flask, and purified, dried nitric oxide gas (known volume in the range 3-5cm3) was introduced via a septum, using a gas syringe, at atmospheric pressure into the headspace above the reaction solution. The pressure within the flask was recorded periodically over a period of one hour.

A control experiment was carried out according to the above but without any complex present.

The recorded pressures in association with the results of the control experiment were analysed in order to determine the rate of NO uptake as a function of time for each compound tested.

On completion of each in vitro test, the reaction solution was freeze-dried. An infrared spectrum of the freeze-dried product provided information on metal-NO bond formation.

In the in vitro cell culture tests, murine (RAW264) macrophage cell lines, which can be induced to produce nitric oxide, were seeded, 106 cells/well, onto 24 well culture plates of 2ml volume per well, in Eagles modified minimal essential medium (MEM) plus 10% fetal bovine serum without phenol red.

The cells were activated to produce nitric oxide, with 1011gel lipopolysaccharide and 100 units/ml interferon y for 18 hours. Concurrently, test compounds made up in MEM were added at non-cytotoxic concentrations. Control cells as above, which were activated to produce nitric oxide as above, but to which no test compound was added, were used as a measure of the amouint of nitric oxide produced by the cells during the tests. (See S. P. Fricker, E. Slade, N. A. Powell, O. J.

Vaughan, G. R. Henderson, B. A. Murrer, I. L. Megson, S. K. Bisland, F. W. Flitney, Ruthenium complexes as nitric oxide scavengers: a potential therapeutic approach to nitric oxide-mediated diseases, Br. J. Pharmacol., 1997,122,1441-1449.) Background nitric oxide was assessed by measurement of nitrate and nitrite in cells which were not activated.

Cell viability was confirmed by Trypan blue dye exclusion at the end of the incubation period.

Nitric oxide was determined by measurement of nitrate and nitrite in the cell supernatant. These anions are the stable end-products of reactions of NO in solution.

Such reactions may or may not be catalysed in biological systems. The sum of nitrite and nitrate concentrations gives the total NO production. Nitrite was determined using the Griess reaction in which nitrite reacts with 1% sulphanilamide in 5% H3PO4/0. 1 % naphthylethylenediamine dihydrochloride to form a chromophore absorbing at 540nm. Nitrate was determined by reducing nitrate to nitrite with a bacterial nitrate reductase from Pseudomonas oleovorans and then measuring nitrite with the Griess reaction. In the absence of test compounds nitrite concentration plus nitrate concentration is equal to total nitric oxide production. The effect of test compounds on available nitric oxide (measured as nitrite + nitrate) was determined.

The reduction in available nitric oxide compared with the control level may be taken as an indication of the degree of binding of NO by the test compounds.

In the ex vivo tests, segments of rat tail artery were dissected free from normotensive adult Wistar rats. The arteries were internally perfused with Krebs solution (mM: NaCl 118, Ksi 4.7, NaHC03 25, NaH2PO4 1.15, CaCl2 2.5, MgCl2 1.1, glucose 5.6 and gassed with 95% 02/5% C02 to maintain a pH of 7.4) in a constant flow perfusion apparatus. A differential pressure transducer located upstream of the vessel detected changes in back pressure. The rat tail artery preparation was pre-contracted with 6.51lM phenylephrine to give a physiologically normal pressure of 100-120mm Hg. The pre-contracted vessels were then perfused with the test compound. The arteries were perfused with Krebs solution between applications of test compound to wash out the test compound.

Pressure changes in the system served to indicate artery vasoconstriction. The vasoconstriction is a direct result of the removal of endogenous nitric oxide (edrf) from the endothelial cells of the rat tail artery.

RESULTS The results of the in vitro, in vitro cell culture and ex vivo tests were as follows:

IN VITRO TESTS EXAMPLE 1: K [Ru (hedta) Cl] 2H20 A pressure decrease indicated binding of NO to the metal compound. This is illustrated in Figure 1.

The IR spectrum showed a peak at 1897cm'', indicating the presence of a Ru- NO bond.

EXAMPLE 2: [Ru (H2edta) (acac)] The IR spectrum showed a peak at 1896cm-1, indicating the presence of a Ru- NO bond.

EXAMPLE 3: K [Ru (hedtra) Cl] H20 A pressure decrease indicated binding of NO to the metal compound. This is illustrated in Figure 1.

The IR spectrum showed a peak at 1889cl'', indicating the presence of a Ru- NO bond.

EXAMPLE 4: K [Ru (dipic) 2H20 A pressure decrease indicated binding of NO to the metal compound. This is illustrated in Figure 1.

The IR spectrum showed a peak at 1915cl'', indicating the presence of a Ru- NO bond.

EXAMPLE 5: (H2pic) [RuCl2 (pic) 2] (Hpic) H20 The IR spectrum showed a peak at 1888cm-1, indicating the presence of a Ru- NO bond.

EXAMPLE 6: K [Ru (H2edta) Cl2] H20 A pressure decrease indicated binding of NO to the metal compound. This is illustrated in Figure 1.

The IR spectrum showed a peak at 1896cm'', indicating the presence of a Ru- NO bond.

EXAMPLE 7: K [Ru (Hnta) 2] ½H2O A pressure decrease indicated binding of NO to the metal compound. This is illustrated in Figure 1.

The IR spectrum showed a peak at 1889cm-1, indicating the presence of a Ru- NO bond.

EXAMPLE 8: K [Ru (H2dtpa) Cl] H20 A pressure decrease indicated binding of NO to the metal compound. This is illustrated in Figure 1.

The IR spectrum showed a peak at 1905cm-1, indicating the presence of a Ru- NO bond.

EXAMPLE 9: [Ru30 (lac) 6] (lac) The IR spectrum showed a peak at 1884cm-1, indicating the presence of a Ru- NO bond.

EXAMPLE 10: [Ru30 (OAc) 6] (OAc) The IR spectrum showed a peak at 1877cm-1, indicating the presence of a Ru- NO bond.

EXAMPLE 11: [Ru2 (OAc) 4] NO3 The IR spectrum showed a peak at 1891cari', indicating the presence of a Ru- NO bond.

EXAMPLE 12: [Ru (OCOEt) 4] N03 The IR spectrum showed a peak at 1891cl'', indicating the presence of a Ru- NO bond.

EXAMPLE 13: K3 [Ru (ox) 3] The IR spectrum showed a peak at 1889cm~l, indicating the presence of a Ru- NO bond.

EXAMPLE 14: [Ru2 (OAc) 4] Cl The IR spectrum showed a peak at 1895cm-1, indicating the presence of a Ru- NO bond.

EXAMPLE 15: [Ru (NH3) 5Cl] C12 The IR spectrum showed two peaks at l909cm~ and 1928cm~l, indicating the presence of a Ru-NO bond.

EXAMPLE 16: [Ru (en) 3] I3 The IR spectrum showed a peak at 1906cm-1, indicating the presence of a Ru- NO bond.

EXAMPLE 17: K [RuCl4 (phen)] H20 The IR spectrum showed a peak at 1904cm-1, indicating the presence of a Ru- NO bond.

EXAMPLE 18: [Ru (cyclam) Cl2] Cl The IR spectrum showed a peak at 1895cm-1, indicating the presence of a Ru- NO bond.

EXAMPLE 19: K [RuCl4 (bipy)] The IR spectrum showed a peak at 1885cm'', indicating the presence of a Ru- NO bond.

EXAMPLE 20: [RuCl3 (dmso) 2 (NH3)] The IR spectrum showed a peak at 1889cm-1, indicating the presence of a Ru- NO bond.

EXAMPLE 21: [Ru (NH3) 6] Cl3 The IR spectrum showed a peak at 1910cm'', indicating the presence of a Ru- NO bond.

EXAMPLE 22: cis-[RuCl2 (dmso) 4] The IR spectrum showed a peak at 1881cl'', indicating the presence of a Ru- NO bond.

EXAMPLE 23: cis-[RuCl2(dmso) 3 (NH3)] The IR spectrum showed a peak at 1893cm-1, indicating the presence of a Ru- NO bond.

EXAMPLE 24: [RuCl3 (dmso) 3] The IR spectrum showed a peak at 1880cmi', indicating the presence of a Ru- NO bond.

EXAMPLE 25: [Ru (mtc) 3] The IR spectrum showed a peak at 1862cm'', indicating the presence of a Ru- NO bond.

EXAMPLE 26: [Ru (maltol) 3] The IR spectrum showed a peak at 1866cl-1, indicating the presence of a Ru- NO bond.

EXAMPLE 27: [Ru (acac) 2 (MeCN) 2] (CF3SO3) The IR spectrum showed a peak at 1899cl'', indicating the presence of a Ru- NO bond.

EXAMPLE 28: K2[RuCl5(H2O)] The IR spectrum showed a peak at 1903cl'', indicating the presence of a Ru- NO bond.

EXAMPLE 29: [Os (ox) (bipy) 2]H2O The IR spectrum showed a peak at 1894cm-1, indicating the presence of a Ru- NO bond.

IN VITRO CELL CULTURE TESTS Results are shown in Table 2 and Figure 2 for the in vitro cell culture tests using the compounds of Examples: 1-3,6 14,15 and 26, as follows.

EXAMPLE 1: K [Ru (Hedta) Cl] 2H20 Available nitric oxide was reduced in a dose-dependent fashion with a maximum reduction of 75% at a concentration of I OOGM.

EXAMPLE 2: [Ru (H2edta) (acac)] Available nitric oxide was reduced by 82% at 100pM test compound.

EXAMPLE 3: K [Ru (Hedtra) Cl] H20 Available nitric oxide was reduced by 42% at 100ZM.

EXAMPLE 6: K [Ru (H2edta) Cl2] H20 Available nitric oxide was reduced by 77% at 100pM test compound.

EXAMPLE 14: [Ru2 (OAc) 4] Cl Available nitric oxide was reduced by 47% at 100µM.

EXAMPLE 15: [Ru (NH3) 5Cl] C12 Available nitric oxide was reduced by 86% at 100µM test compound.

EXAMPLE 26: [Ru (maltol) 3] Available nitric oxide was reduced by 71 % at 1 OOM.

Table 2 % Decrease of Available Nitric Oxide Example 1 25) iM 12 50µM23 1 OORM 75 Example 2 100µM 82 Example 3 100µM 42 Example 6 1 00pM 77 Example 14 100µM 47 Example 15 86 Example 26 100µM 71 EX VIVO TESTS Results are shown in Table 3 for the ex vivo tests using the compounds of Examples: 2,3,14,15 and 26, as follows.

EXAMPLE 2 Application of test compound resulted in a dose-dependent vasoconstriction at 10, uM and 100juM. This effect was reversible by washout with Krebs solution.

EXAMPLE 14 Application of test compound resulted in a dose-dependent vasoconstriction at lOuM and ICOuM. This effect was reversible by washout with Krebs solution.

EXAMPLE 15 Application of test compound resulted in a dose-dependent vasoconstriction at 1 ORM and 100µM. This effect was reversible by washout with Krebs solution.

EXAMPLE 26 Application of test compound resulted in a dose-dependent vasoconstriction at 10uM and 100µM and 1000µM. This effect was reversible by washout with Krebs solution.

Table 3 % Vasoconstriction 10µM20Example2 1 OORM 69 Exampte3 10M 17 1 OOPM 59 Example 14 101lM 11 1 00pM 40 10µM77Example15 1 oogm 86 10µM10Example26 100µM18 1000µM25 Experimental EXAMPLE 33 AMD7040: Synthesis of the Ru (III) complex of N,N'-[2, 6-pyridylbis (methylene)] bis- iminodiacetic acid (pbbida) N, N'-[2,6-pyridylbis (methylene) lbis-iminodiacetic acid (Na3Hpbbida) An aqueous solution of sodium hydroxide (30 mL, 0. 01M), 2,6- dibromomethylpyridineHBr (1.0 g, 2.9 mmol), iminodiacetic acid dimethyl ester (0.934 g, 5.8 mmol), and cetyltrimethylammonium bromide (0.21 g, 0.58 mmol) was stirred at room temperature for 3 days. A white precipitate formed which was removed by filtration and the filtrate was evaporated to give a white solid. This solid was purified by re-crystallisation from water and ethanol to give the desired <BR> <BR> <BR> compound as the tri-sodium salt (0.9 g, 71%).'H NMR (D2O) S 3.27 (s, 8H), 3.93 (s, 4H), 7.30 (d, 2H, J=7. 5 Hz), 7.80 (t, 1H, J=7.8 Hz).

Preparation of (Ru (H2pbbida) Cl'j-2. 5H20.

[Dihydrogen chloro [[2, 6-(pyridinyl-KN) methyl] bis [N-(carboxymethyl) glycinato- KN, KO]] ruthenium (III)] Na3Hpbbida (0.78 g, 1.8 mmol) was dissolved in HCl (20 mL, 1 mM) and the pH was adjusted to pH 4 with IN HCI. K2 [RuCls (OH2)] (0.67 g, 1.8 mmol) dissolved in a minimum amount of aqueous HCl (1 mM) was added to the ligand solution and the resulting mixture was heated to reflux for 1.5 hours. A yellow precipitate formed throughout the course of the reaction. The reaction mixture was cooled in an ice bath and the yellow solid was collected via filtration, washed with ice cold water, ethanol and diethyl ether and then dried in vacuo at 70 °C for 2 hours (0.55 g, 56%). IR (CSI) v (cm-1) 1734(CO2-) 1649 (CO2) coordinated). Anal. Calcd. for ClSHl7ClN308Ru-2. 5H20: C, 32.82; H, 4.04; N, 7.66; Cl, 6.47. Found: C, 32.82; H, 3.95; N 7.66; Cl, 6.47.

EXAMPLE 34 AMD7043: Synthesis of the Ru (III) complex of N, N'-bis [2- pyridyl (methylene)] ethylenediamine-N, N'-diacetic acid (H2bped) The ligand, H2bped, was prepared according to literature procedures: See P.

Caravan, S. J. Rettig, C. Orvig. Inorg. Chem. 1997,36,1306.

Preparation of rRu (H2bped) CI21CI- [Dihydrogen dichloro [[N, N'-1,2-ethanediyl] bis [ methylglycinato-KN ruthenium (III) chloride] H2bped-2HCl (1.0 g, 2.5 mmol) was dissolved in HCl (25 mL, 1 mM) and the pH was adjusted to pH 4 with IN NaOH. A solution of K2 [RuCl5 (OH2)] in HCl (minimum volume, 1 mM) was added to the ligand solution and the reaction mixture was heated to reflux for 1.5 hours. The dark green solution was reduced to approximately one half the original volume and on slow evaporation a yellow-orange solid precipitated from the reaction mixture. This was collected by filtration and re-

crystallised from H20/EtOH to yield an orange micro-crystalline solid (0.37 g, 26%).

IR (CSI) v (cm'') 1726 (CO2-). Anal. Calcd. for CI8H22Cl3N404Ru: C, 38.21; H, 3.92; N, 9.90; Cl, 18.80. Found: C, 38.21; H, 3.96; N 9.90; Cl, 18.79.

EXAMPLE 35 AMD7056: Synthesis of the Ru (III) complex of N- [2- (2- pyridylcarboxamido) ethyl] iminodiacetic (pceida).

To a stirred solution of N-BOCethylenediamine (0.462 g) in dioxane (10 mL) was added picolinic acid hydroxysuccinimdyl ester (0.635 g) and the mixture was allowed to stir overnight. The reaction mixture was filtered and the filtrate was diluted with dichloromethane and washed with saturated aqueous sodium carbonate and then brine. The organic layer was dried (Na2SO4) and then evaporated to give a white solid (0.691 g, 90%). This was used without further purification.

The solid from above (0.691 g) was dissolved in pre-cooled (0 °C) trifluoroacetic acid (5 mL). The mixture was stirred for 2 hours at 0 °C and then room temperature for 15 minutes. The mixture was evaporated to dryness to give the pyridyl amine intermediate (-quantitative). The residue was dissolved in DMF (20 mL) with stirring and K2C03 (1. 8 g, 5.0 equiv.) followed by t-butyl bromoacetate (0.84 mL, 2.1 equiv.) were added and the reaction mixture was allowed to stir at room temperature for six days. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were then washed with brine and water, dried (MgS04) and evaporated to give the desired bis-t-butyl ester (1.02 g, 100%) as a light yellow oil.'H NMR (CDC13) 5 1.42 (s, 9H), 1.45 (s, 9H), 3.00 (t, 2H, J=6.1 Hz), 3.48 (s, 2H), 3.50-3.60 (m, 2H), 7.40 (m, 2H), 7.82 (dt, 1H,. J=7.8,1.6 Hz), 8.19 (d, 1H, J=7.8 Hz), 8.59 (d, 1H, J=4.6 Hz), 8.70 (br. m, 1H).

N- [2- (2-pyridylcarboxamido) ethylliminodiacetic-TFA salt (H2pceida-TFA).

The di-t-butyl ester (1.02 g) from above was dissolved in dichloromethane (1 mL) and cooled to 0 °C. Pre-cooled trifluoroacetic acid was added (7 mL) and the solution was allowed to stir overnight at room temperature. The reaction mixture was then evaporated and the residue was dissolved in water (10 mL) and lyophilised to give the desired ligand (pceida) as a light yellow solid (0.71 g, 69%).'H NMR (D20)

8 3.53 (t, 2H, J=5.7 Hz), 3.85 (t, 2H, J=5.7 Hz), 3.90 (s, 2H), 7.65 (m, 1H), 7.95-8.10 (m, 2H), 8.65 (s, 1H, J=4.8 Hz). Anal Calcd. for C12H15N305_TFA H20 : C, 40.69; H, 4.39; N, 10.17. Found: C, 40.84; H, 4.32; N, 9.99.

Preparation of rRu (pceida) (OH2) Cl-1. 5H20.

[Aquachloro[[N-2-[(2-pyridinyl-KN) oxo-methyl) aminoethyl] [((2-carboxy- KO) methyl) glycinato-KN, KO]] ruthenium (III)] H2pceida-TFA (0.4 g, 1 mmol) and K2 [RuCls (OHz)] (0.38 g, 1 mmol) were dissolved in de-ionised water (10 mL) and the pH adjusted to pH5 with 1N NaOH.

KCl (0.075 g, 1 mmol) was added to the reaction mixture and the solution was heated to reflux for 3 hours. The solution was cooled to room temperature and subsequently in an ice bath. Upon cooling a dark red-orange precipitate formed which was collected by filtration, washed with ice cold water and dried in vacuo at 40 °C overnight. Yield: 0.13 g, 29%. IR (CSI) v (cri 1) 1649 (CO2). Anal. Calcd. for C12Hl5CIN306Ru-1. 5H20: C, 31.28; H, 3.94; N, 9.12; Cl, 7.69. Found: C, 31.43; H, 3.92; N, 9.05; Cl, 7.80.

EXAMPLE 36 <BR> <BR> <BR> <BR> AMD7046: Synthesis of the Ru (III) complex of N- [2- pyridyl (methylene)] ethylenediamine-N, N', N'-triacetic acid (pedta).

To a solution of 2-pyridinecarboxaldehyde (3.2 g, 0.03 mol) in benzene (50 mL) was added N-BOC ethylenediamine (5.26 g, 1.1 equiv.) and the mixture was heated to reflux with stirring in a Dean-Stark apparatus for 1.5 hours. The reaction mixture was evaporated to dryness, dissolved in methanol (50 mL) and 5% palladium on carbon was added (0.5 g). The mixture was hydrogenated at 50 psi on a Parr apparatus overnight. The mixture was filtered through celite, and the filtrate was <BR> <BR> <BR> evaporated to give the pyridine intermediate (-quantitative).'H NMR (CDCl3) 8 1.40 (s, 9H), 2.75-2.85 (m, 2H), 3.20-3.35 (m, 2H), 3.90 (s, 2H), 5.30 (br. S, 1H), 7.10-7.20 (m, 1H), 7.30-7.36 (m, 1H), 7.60-7.70 (m, 1H), 8.50-8.60 (m, 1H).

To a stirred solution of the pyridine intermediate from above (5.08 g) in dichloromethane (30 mL) was added trifluoroaceti# acid (30 mL) and the mixture was allowed to continue stirring overnight at room temperature. The mixture was evaporated to give a dark oil.'H NMR (d6-DMSO/D20) 8 3.10-3.20 (m, 2H), 3.20- 3.30 (m, 2H), 4.48 (s, 2H), 7.40-7.45 (m, 2H), 7.80-7.90 (m, 1H), 8.60 (m, 1H). This intermediate was used without further purification in the next step.

N- [2-pvridvl (methvlene) 1ethvlenediamine-N. N\N'-triacetic acid tri-t-butvl ester.

To a solution of the oil from above in DMF (-80 mL) was added K2CO3 (27.9 g, 10.0 equiv.) followed by t-butylbromoacetate (8.95 mL, 3.0 equiv.) and the mixture was allowed to stir at room temperature for 48 hours. The reaction mixture was filtered through celite and the filtrate was evaporated to give a dark oil. Purification by column chromatography on silica gel (5% MeOH/CH2Cl2) gave the tri-t-butyl ester (4.14 g, 42% for two steps) as a light yellow oil.'H NMR (CDC13) 6 1.35-1.50 (m, 27H), 2.83-2.86 (m, 4H), 3.37 (s, 2H), 3.43 (s, 4H), 3.95 (s, 2H), 7.10-7.20 (m, 1H), 7.52 (d, 1H, J=7.5 Hz), 7.64 (dt, 1H, J=7.5,1.7 Hz), 8.51 (d, 1H, J=4.7 Hz).

N-r2-pyridvl (methylene) lethylenediamine-N, N', N'-triacetic acid-TFA salt (pedta) The tri-t-butyl ester from above (4.14 g) was dissolved in CH2C12 (20 mL) with stirring and trifluoroacetic acid (30 mL) was added in one portion. The mixture was allowed to stir at room temperature overnight and was then evaporated. The residue was dissolved in water (-40 mL) and charcoal (550 mg) was added. The mixture was heated to 70 °C and filtered through celite and the combined filtrates were then evaporated to small volume and lyophilised to give the desired ligand (pedta) as a yellow solid (3.24 g, 73%). 1H NMR (D20) 6 3.00-3.15 (m, 2H), 3.20- 3.30 (m, 2H), 3.59 (s, 4H), 4.04 (s, 2H), 4.51 (s, 2H), 7.50 (m, 1H), 7.61 (d, 1H, J=7. 7 Hz), 7.98 (dt, 1H,. J=7.7,1.6 Hz), 8.63 (d, 1H, J=5. 0 Hz). Anal. Calcd. for Ci4H) 9N306 ; 1. 8TFA: C, 39.83; H, 3.95; N, 7.92. Found: C, 38.85; H, 4.19; N, 8.06.

Preparation of #Ru (Hpedta) Cll 0. 5H2O [Hydrogen chloro [N-[bis ((2-(carboxy-KO) methyl) imino-KN) ethyl]-(2-pyridinyl- (III)].#N)methylglycinato-#N]ruthenium

H3pedta-TFA (0.75 g, 1.3 mmol) was dissolved in HCl (1.5 mL, 1 mM). A solution of K2 [RuCls (OH2)] (0.5 g, 1.3 mmol) in HCl (2 mL, 1 mM) was added to the ligand solution. The reaction mixture was heated to reflux for 2 hours and subsequently cooled to room temperature. An orange solid precipitated from the solution, which was collected by filtration, washed with ethanol and diethyl ether, and dried in vacuo at 40 °C overnight (0.26 g, 43%). IR (CSI) v (cm~l) 1730 (CO2H); 1688, 1618 (C02-) coordinated). Anal. Calcd. for Cl4Hl7ClN306Ru0.5H20 : C 35.87; H 3.87; N 8.96; Cl 7.56. Found: C, 35.86; H, 3.79; N, 8.98; Cl, 7.58.

EXAMPLE 37 AMD7087: Synthesis of the Ru (III) complex of phenylenediamine-N, N, N', N'- tetraacetic acid (H4pdta).

Phenylenediamine-N, N, N', N'-tetraacetic acid tetramethyl ester 1,2-phenylenediamine (1.4 g, 1.3 mmol), methyl bromoacetate (12.3 mL, 13 mmol) and K2CO3 (17.9 g, 13 mmol) were heated at 85 °C in DMF (130 mL) under an inert atmosphere for 3 days. The DMF was removed under reduced pressure and the residue was dissolved in CH2Cl2. The solution was washed with an aqueous solution of saturated NH4C1 and then H20. The organic layer was dried (MgS04) and evaporated to give a brown oil. This brown oil was triturated with MeOH to yield a white solid, which was removed by filtration and washed with methanol (0.3 g, <BR> <BR> <BR> 5.8%).'H NMR (CDC13) 6 3.65 (s, 12H), 4.30 (s, 8H), 6.92-7.04 (m, 4H). FAB (+ve) m/z 397 [M+H] +. Anal. Calcd. for CI8H24N20g: C, 54.54; H, 6.10; N, 7.07.

Found: C, 54.57; H, 6.21; N, 7.19.

Phenylenediamine-N, N, N', N'-tetraacetic acid (H4pdta) The tetramethyl ester (0.1 g, 0.25mmol) was suspended in MeOH/H20 (25 mL, 3/1) and cooled to 0 °C. Lithium hydroxide monohydrate (0.106 g, 2.5 mmol) was added to the suspension and the reaction mixture was stirred in the dark overnight (during which time it was allowed to warm to room temperature). The clear solution was acidified with HCl (2N) and the solvent was removed under reduced pressure to <BR> <BR> <BR> leave a white solid. IH NMR (D2O/K2C03) 6 4.27 (s, 8H), 7.25-7.4 (m, 4H). The white solid was used without further purification to prepare the ruthenium complex.

Preparation of [Ru (Hpdta) (OH2) 1-3H20 [Hydrogen aqua [N-bis ((2-carboxy-KO) methyl) imino-#N]-1, 2-phendiyl (2- (carboxy- KO) methyl) glycinato-oN] ruthenium (III)] H4pdta-xLiCl (0.25 mmol) was heated in HCl (3 mL, 1 mM) until completely dissolved. K2 [RuCl5 (OH2)] (0.095 g, 0.25 mmol) was added to the ligand solution and the reaction mixture was heated to reflux for 1.5 hours. The solution was allowed to cool to room temperature and the yellow-green precipitate which formed was collected by filtration and washed with HO, ETOH and Et20 (15 mg, 12%). Anal.

Calcd. for Cl4HISN209Rw3H20: C, 32.95; H, 4.15; N, 5.49. Found: C, 32.65; H, 3.91; N, 5.58.

EXAMPLE 38.

AMD7459: Ruthenium (III) complex of N'-benzyldiethylenetriamine-N, N, N", N"- tetraacetic acid (bdtta).

N-(hvdroxvethvl) iminodiacetic acid di-t-butvl ester Ethanolamine (1.84 g, 0.03 mol) was dissolved in dry THF (300 mL) and triethylamine (12.3 g, 0.12 mol) was added. To this stirring solution t- butylbromoacetate (23.5 g, 0.12 mol) was added and the reaction mixture was stirred for 16 hours. The solvent was removed in vacuo and the residue partitioned between Et20 (100 mL) and H20 (100 mL). The aqueous layer was extracted with Et20 (3 x 100 mL), and the combined organic portions were dried over MgS04. The suspension was filtered and the solvent was removed in vacuo to afford the product (7.75 g, 89%) as a white solid.'H NMR (CDCl3) 8 1.46 (6,18H), 2.89 (t, 2H, J = 6.0 Hz), 3.45 (s, 4H), 3.53 (t, 2H, J = 6.0 Hz), 3.75 (bs, 1H). 13C NMR (CDC13) 8 28.15,56.68,57.11, 59.37,81.48,171.48. ES-MS m/z 290 [M+H] +.

N-(fMethanesulfonvl) ethiminodiacetic acid di-t-butvl ester N- (hydroxyethyl) iminodiacetic acid di-t-butyl ester (7.50 g, 0.03 mol) was dissolved in dry CH2C12 (250 mL) and triethylamine (14.8 g, 0.15 mol) was added.

The solution was cooled in an ice bath and methanesulfonylchloride (3.55 g, 0.03 mol) was added dropwise with stirring. The reaction mixture was slowly warmed to

room temperature and stirred for a further 16 hours. The reaction was then quenched with saturated NaHC03 (150 mL) and the aqueous layer was extracted with CH2C12 (2 x 150 mL). The combined organic extracts were dried (MgS04), filtered, and the solvent was removed in vacuo to afford the product (9.5 g, 99%) as an oil.'H NMR (CDC13) 8 1.46 (s, 18H), 3.08 (m, 5H), 3.48 (s, 4H), 4.34 (t, 2H, J = 6.0 Hz).

N'-benzyldiethvlenetriamine-N, N, N", N"-tetraAcetic acid tetra-t-butyl ester General Procedure A: N-[(Methanesulfonyl)[(Methanesulfonyl) ethyl] iminodiacetic acid di-t-butyl ester (4.86 g, 13 mmol) was dissolved in dry acetonitrile (50 mL) and benzylamine (0.47 g, 4.4 mmol) was added with stirring. K2CO3 (2.4 g, 0.45 mol) was added and the suspension was stirred for 16 hours at 45°C. The solvent was removed in vacuo and the residue partitioned between CHC13 (100 mL) and saturated NaHC03 (100 mL). The aqueous portion was extracted with CHC13 (3 x 75 mL), and the combined organic extracts were dried (MgS04), filtered and the solvent was removed in vacuo to afford the crude product as a brown oil. The product was purified by column chromatography on silica gel (2% MeOH, 1% NEt3, CH2C12) to afford the product (1.35 g, 37%) as a <BR> <BR> <BR> colorless oil.'H NMR (CDC13) 8 1.43 (s, 36H), 2.59 (t, 4H, J=6.0 Hz), 2.82 (t, 4H,<BR> <BR> <BR> <BR> <BR> J=6.0 Hz), 3.40 (s, 8H), 7.24 (m, 5H). 13C NMR (CDC13) 5 28.19,52.08,52.86, 56.16,59.17,80.75,126.78,128.14,128.85,139.62,170.74. ES-MS m/z 650 <BR> <BR> <BR> [M+H] +.<BR> <BR> <BR> <BR> <BR> <P>N'-benzvldietAvlenetriamine-N N. N"N"-tetraacetic acid xTFA Rbdtta) General Procedure B: N'-Benzyldiethylenetriamine-N, N, N", N"-tetracetic acid tetra-t-butyl ester (1.0 g, 1.5 mmol) was dissolved in trifluoroacetic acid (14.8 g, 130 mmol) and the solution was left stirring for 16 hours. The solvent was removed in vacuo and the residue was <BR> <BR> <BR> lyophilized to afford the product (1.19 g, 100%) as a white solid : 1H NMR (D20) 8 3.38 (t, 4H, J = 6.0 Hz), 3.48 (t, 4H, I = 6.0 Hz), 3.73 (s, 8H), 4.43 (s, 4H), 7.51 (bs, <BR> <BR> <BR> 5H). 13C NMR (D20) 5 50.22,50.85,55.43,59.04,129.50,130.05,130.90,131.39,<BR&g t; <BR> <BR> <BR> <BR> <BR> 172.64.

Prel2aration of LRu bdtta) Cll-4. 5H, O<BR> <BR> <BR> <BR> [Dihydrogenchloro[[N,N'-[[(phenylmethyl)imino-#N]-2,1-ethane diyl]bis[N- (carboxymethyl) glycinato-rcN, KOJJ ruthenium (III)] General Procedure C: N'-Benzyldiethylenetriamine-N, N, N", N"-tetraacetic acid (bdtta) (0.256 g, 0.33 mmol) was dissolved in lmM HCl (5 mL). K2 [RuCl5 (H20)] (0.124 g, 0.33 mmol) was added and the reaction mixture was heated to 100 °C for 1.5 hours. The solution was then cooled and a yellow/green powder was collected. The powder was washed with the mother liquor, H20 (2 x 10 mL), and Et20 (3 x 5 mL) to afford the product (0.078 g, 24%) as a light yellow powder. Anal. Calcd. for C19H25N3O8RuCl#4. 5 H20: C, 35.60; H, 5.35; N, 6.56; Cl, 5.53. Found: C, 35.62; H, 5.22; N, 6.47; Cl, 5.33. IR (CsI) v (cm'') 1736 (C02H); 1657 (C02-).

EXAMPLE 39 AMD7460: Ruthenium (III) complex of N'- [2- pyridyl (methylene)] diethylenetriamine-N, N, N", N"-tetraacetic acid (pdtta).

Using General Procedure A: N-[(Methanesulfonyl)[(Methanesulfonyl) ethyl] iminodiacetic acid di-t-butyl ester (3.14 g, 8.5 mmol) was reacted with aminomethylpyridine (0.23 g, 2.0 mmol) and the crude reaction mixture was purified by silica gel chromatography (5% MeOH/ CH2Cl2). The product fractions were combined and partitioned between Et20 (30 mL) and NaOH (15 mL 0.1M). The aqueous layer was extracted with Et20 (3 x 20 mL), and the combined organic extracts were dried (MgS04), filtered and the solvent removed in <BR> <BR> <BR> <BR> vacuo to afford the product (0.38 g, 30%) as an oil.'H NMR (CDC13) 6 1.40 (s, 36H), 2.64 (t, 4H, J = 6.0 Hz), 2.81 (t, 4H, J = 6.0 Hz), 3.38 (s, 8H), 3.76 (s, 2H), 7.08 (t, 1H, J= 6.0 Hz), 7.45 (d, 1H, J = 6.0 Hz), 7.57 (t, 1H, J = 6. 0 Hz), 8.46 (d, 1H, 6.0 <BR> <BR> <BR> <BR> Hz). 13C NMR (CDC13) 6 28.28,52.17,53.31,56.14,60.94,121.74,122.90,136.32, 148.86,160.25,170.69. ES-MS m/z 651 [M+H] +.

(pdtta)N'-[2-pyridyl(methylene)]diethylenetriamine-N,N,N" ,N"-tetraaceticacid#xHCl Using General Procedure B: The oil from above (0.381 g, 0.59 mmol) was treated with TFA (7.4 g, 65 mmol). The crude material was purified on Dowex cation exchange resin (H+ form,

50W-200 mesh) to afford the product (0.225 g, 44%) as a white solid.'H NMR<BR> <BR> <BR> <BR> <BR> <BR> (D20) 6 3.09 (t, 4H, J = 6.6 Hz), 3.61 (t, 4H, J = 6.6 Hz), 3.86 (s, 2H), 4.20 (s, 8H), 7.97 (t, 1H, J = 6.9 Hz), 8.03 (d, 1H, J = 8.1 Hz), 8.53, (t, 1H, J = 8.1 Hz), 8.70 (d, 1H, J = 6. 9 Hz).

Preparation of [Ru(H2pdtta)Cl]#2H2O [[N,N'-[[(2-pyridinylmethyl)imino-#N]di-2,1-ethanediyl]bis[N -[Dihydrogenchloro (carboxymethyl) glycinato-ruthenium (III) J.

Using General Procedure C: Pdtta (0.225 g, 0.27 mmol) was reacted with K2[RuCl5(H2O)] (0.095 g, 0.25 mmol).

Anal. Calcd. for C1gH2408N4RuCl-2H20-1.0 KC1-0. 75HC1: C, 30.94; H, 4.15; N, 8.02; Cl, 13.95. Found: C, 30.85; H, 4.30; N, 8.01; Cl, 13.54. IR (CsI) v (cl'') 1740 (C02H); 1657 (C02-); 311 (Ru-Cl).

EXAMPLE 40.

AMD8676: Ruthenium (III) complex of N'-butyldiethylenetriamine-N, N, N", N"- tetraacetic acid (budtta).

N'-butvldiethvlenetriamine-N. N. N". N"-tetraacetic acid tetra-t-butvl ester Using General Procedure A: N-[(Methanesulfonyl)[(Methanesulfonyl) ethyl] iminodiacetic acid di-t-butyl ester (2.97 g, 8.1 mmol) was reacted with butylamine (0.20 g, 3.0 mmol) and the crude reaction mixture was purified by silica gel chromatography (5% MeOH/CH2Cl2) to afford the product <BR> <BR> <BR> (0.439 g, 27%) as a colorless oil.'H NMR (CDC13) 8 0.81 (t, 3H, J = 6.0 Hz), 1.20 (m, 4H), 1.38 (s, 36H), 2.38 (t, 2H, J = 7.5 Hz), 2.54 (t, 4H, J = 6.0 Hz), 2.71 (t, 4H, J = 6.0 Hz), 3.37 (s, 8H). 13C NMR (CDC13) 5 14.36,20.91,28.49,52.43,53.61, 53.76,54.92,56.83,81.31,171.02. ES-MS m/z 616 [M+H] +.

N'-butvldiethvlenetriamine-N. N, N", N"-tetraacetic acid-xTFAbudtta).

Using General Procedure B: The oil from above (0.425 g, 0.69 mmol) was treated with TFA (14.8 g, 100 mmol) to afford the product (0.442 g, 87%) as an off-white solid.'H NMR (D2O) 8 0.672 (bs, 3H), 0.81 (bs, 2H), 1.15 (bs, 2H), 2.71 (bs, 2H), 3.12 (bs, 8H), 3.56 (s, 8H).

ES-MS m/z 448 [M+H] +.

[Ru(H2budtta)Cl]#4H2OPreparationof [Dihydrogen [[N,N'-[(butylimino-#N)di-2,1-ethanediyl] bis [N (carboxymethyl) glycinato-KN, KO]]] chloro ruthenium (III)].

Using General Procedure C: Budtta (0.243 g, 0.33mmol) was reacted with K2 [RuCl5 (H20)] (0.123 g, 0.33 mmol) to afford the product (0.083 g, 42%): Anal. Calcd. for C16H27N30gRuCl-4H20: C, 32.14; H, 5.90; N, 7.03; Cl, 5.93. Found: C, 32.23; H, 5.60; N, 6.94; Cl, 6.02. IR (CsI) v (cm-1) 1736 (CO2H); 1657 (C02-); 411 (Ru-Cl).

EXAMPLE 41 AMD8679: Ruthenium (III) complex of N'-ethyldiethylenetriamine-N, N, N", N"- tetraacetic acid (edtta).

N'-ethyldiethylenetriamine-N,N,N",N"-tetraacetic acid tetra-t-butvl ester Using General Procedure A: N-[(Methanesulfonyl) ethyl] iminodiacetic acid di-t-butyl ester (3.169 g, 8.6 mmol) was reacted with ethylamine (0.13 g, 2.9 mmol) to afford, after purification by column chromatography on silica gel (2% MeOH, 1% NEt3, CH2Cl2), the product (0.7 g, 55%) as a colorless oil.'H NMR (CDC13) 8 1.00 (t, 3H, J = 6.0 Hz), 1.46 (s, 36H), 2.56 (m, 6H), 2.80 (t, 4H, J = 7.5 Hz), 3.45 (s, 8H). 13C NMR (CDC13) 5 28.17, 48.16,52.10,52.61,53.44,56.30,80.77,170.70. ES-MS m/z 588 [M+H] +.

N'-ethyldiethylenetriamine-N, N, N", N"-tetraacetic acid-xTFA (edtta) Using General Procedure B: The oil from above (0.591 g, 1.01 mmol) was treated with TFA (14.8 g, 100 mmol) to afford the product (0.699 g, 98%) as an off-white solid.'H NMR (D20) 5 0.92 (t, 3H, J = 6.9 Hz), 2.96 (d, 2H, J = 6.9 Hz), 3.24 (s, 8H), 3.69 (s, 8H). 13C NMR (D20) å 29.59,49.19,49.35,49.95,55.39,170.68. ES-MS m/z 420 [M+H] +. <BR> <BR> <BR> <BR> <BR> <P>[Ru(H2edtta)Cl]#H2OPreparationof <BR> <BR> <BR> [Dihydrogen chloro [[N, N'-[(ethylimino-KN) di-2, 1-ethanediyl] bis [N (carboxymethyl) glycinato-KN, KO]]] ruthenium (III)].

Using General Procedure C: Reaction of edtta (0.241 g, 0.34 mmol) with K2[RuCl5(H2O)] (0.128 g, 0.34 mmol) afforded the product (0.0373 g, 21 %). Anal. Calcd. for C,4H23N308RuCl-lH200. 1KCl : C, 32.13; H, 4.81; N, 8.03; Cl, 7.45. Found: C, 32.43; H, 4.80; N, 8.02; Cl, 7.81. IR (CsI) 1719 (C02H); 1678,1601 (C02-); 415 (Ru- Cl).

EXAMPLE 42.

AMD8684: Ruthenium (III) complex of N'-phenyldiethylenetriamine-N, N, N", N"- tetraacetic acid (phdtta) N'-phenvldiethvlenetriamine-N, N, N"N"-tetraacetic acid tetra-t-butvl ester Using General Procedure A: Reaction of N- [(methanesulfonyl) ethyl] iminodiacetic acid di-t-butyl ester (3.358 g, 9.1 mmol) with aniline (0.28 g, 3.0 mmol) afforded, after purification by column chromatography on silica gel (4: 1 Hexane: ethylacetate), the product (0.402 g, 21%) as a colorless oil.'H NMR (CDC13) 5 1.46 (s, 36H), 2.86 (t, 4H, J = 7.5 Hz), 3.47 (bs, 12H), 6.62 (t, 1H, J = 7.5 Hz), 6.70 (d, 1H, J = 9.0), 7.17 (t, 1H, J = 9.0 Hz).

N'-phenvldiethvlenetriamine-N. N. N", N"-tetraacetic acidxTFA (phdtta) Using General Procedure B: The oil from above (0.281 g, 0.44 mmol) was reacted with TFA (7.4 g, 50 mmol) affording the product (0.272 g, 81%) as an off-white solid.'H NMR (D2O) 5 3.21 (m, 4H), 3.67 (t, 4H, J = 6.6 Hz), 3.93 (s, 8H), 7.07 (t, 1H, J = 7.8 Hz), 7.08 (t, =7.8Hz),7.29(t,1H,J=7.5Hz).1H,J Preparation of [Ru(H2phdtta)Cl]#1.25H2O <BR> <BR> [Dihydrogenchloro[[N,N'-[(phenylimino-#N)di-2,1-ethanediyl]b is[N-(carboxymethyl)glycinato-<BR> <BR> <BR> <BR> <BR> ruthenium(III)].#N,#O]]] Using General Procedure C: Reaction of phdtta (0.146 g, 0.18 mmol) with K2[RuCl5(H2O)] (0.085 g, 0.23 mmol) afforded the product (0.0194 g, 16%). Anal. Calcd. for C18H23N3O8RuCl#1.25H2O#0.8KCl#0. 8EtOH: C, 35.40; H, 4.59; N, 6.32; Cl, 9.60.

Found: C, 35.73; H, 4.47; N, 5.93; Cl, 9.79. IR (CsI) v (cl'') 1730 (CO2H); 1611 (C02-); 403 (Ru-Cl)

EXAMPLE 43.

AMD7436: Ruthenium (III) complex of N, N"-bis- [2-pyridyl (methylene)] diethylenetriamine-N, N', N"-triacetic acid (bpdtta).

N, N'. N"-Tritosvldiethvlenetriamine To a solution of tosyl chloride (21.18 g, 0.11 mol) in Et20 (120 mL) was added diethylenetriamine (3.82 g, 0.04 mol). To this solution, an aqueous solution of NaOH (4.44 g, 0.11 mol) in de-ionized water (40 mL) was added dropwise. The resulting suspension was stirred for two hours and the white solid was collected by filtration and washed with H20 and then Et20. The crude product was recrystallized from hot MeOH to afford the product (12.63 g, 60.4%) as a white crystalline solid. 1H <BR> <BR> <BR> <BR> NMR (CDCl3) 6 2.43 (bs, 9H), 3.06 (dt, 4H, J= 5.5,6.9 Hz), 3.17 (t, 4H, J= 6.9 Hz), 6.55 (t, 2H, J = 5.5 Hz), 7.40 (m, 6H), 7.63 (d, 2H, J= 8.1 Hz), 7.74 (d, 4H, J= 8.1 <BR> <BR> <BR> Hz).'3C NMR (acetone-d6) 5 21.79,43.51,50.60,128.26,128.50,130.92,131.07, 137.27,139.25,144.38,144.95. ES-MS m/z 588 [M+H] +.

2-lMethanesulfonvl (methvl) j,pvridine 2-Pyridinemethanol (3.39 g, 31.1 mmol) and triethylamine (9.44 g, 93 mmol) were dissolved in dry CH2C12 (250 mL) and the resulting solution was cooled to 0°C in an ice bath. Methanesulfonylchloride (4.27 g, 37.3 mmol) was added dropwise and the reaction mixture was stirred for 50 minutes. The reaction was then quenched with saturated NaHC03 (115 mL). The aqueous layer was washed with CH2C12 (2 x 50 mL), and the organic portions were combined and dried over MgS04. After filtering, the solvent was removed in vacuo to afford the product (6.5 g, 100%) as a red oil.'H <BR> <BR> <BR> <BR> NMR (CDC13) 6 3.11 (s, 3H), 5.33 (s, 2H), 7.30 (m, 1H), 7.48 (d, 1H, J = 7. 8 Hz), 7.77 (dd, 1H, J= 1.7,7.7 Hz), 8.59 (m, 1H).

N, N''-bis-g2-pvridvl (metAvlene) 7-N. N', N"-tritosvldiethvlenetriamine To a solution of N, N', N"-tritosyldiethylenetriamine (8.8 g, 15.6 mmol) in DMF (75 mL) under a nitrogen atmosphere was added NaH (60% in oil, 1.24 g, 31.1 mmol) and the mixture was stirred for 45 minutes. 2- [Methanesulfonyl (methyl)] pyridine (6.5 g, 34.7 mmol) dissolved in 10 mL CH2C12 was then added and the reaction was heated to 80°C for 20 hours. Ethanol was then added and the DMF was removed in vacuo. The residue was dissolved in CH2Cl2 and washed with brine (3 x 100 mL), saturated NH4Cl solution (3 x 100 mL), and finally a

saturated aqueous solution of K2CO3 (3 x 100 mL). The organic layer was dried over Na2S04, filtered and the solvent was removed in vacuo to afford the crude product <BR> <BR> <BR> <BR> (9.0 g) as an off-white solid.'H NMR 6 2.42 (bs, 12H), 3.04 (m, 4H), 3.30 (m, 4H), 4.41 (s, 4H), 7.39 (m, 10H), 7.71 (m, 8H), 8.48 (m, 2H). ES-MS m/z 748 [M+H] +.

This product was used without further purification.

N,N"-bis-[2-pyridyl (methylene) ldiethylenetriamine The solid from above (3.79 g, 5.1 mmol) was added to 13 mL concentrated H2SO4 maintained at a temperature of 120°C. After 5 minutes the reaction mixture was cooled and EtOH (90 mL) was added resulting in the precipitation of a brown solid. The solid was collected by filtration, dissolved in H20 (100 mL) and heated in the presence of activated charcoal. The mixture was filtered through celite and the volume of the filtrate was reduced to approximately 20 mL and then concentrated HCl (20 mL) was added. Most of the solvent was removed in vacuo and cold EtOH was added to precipitate a white solid. The white solid was then dissolved in H20 and the pH was adjusted to 12 with 3M NaOH. The aqueous solution was extracted with CHC13 (3 x 50 mL), and the combined organic extracts were dried (MgS04).

Evaporation of the solvent afforded the product (0.785 g, 54%) as a colorless oil. IH <BR> <BR> <BR> <BR> NMR 6 2.43 (s, 3H), 2.80 (s, 8H), 3.92 (s, 4H), 7.14 (t, 2H, J= 6.0 Hz), 7.30 (d, 2H, J = 6.0 Hz), 7.62 (dd, 2H, J = 3.0,6.0 Hz), 8.53 (d, 2H, J= 3.0 Hz).

N, N"-bis-j2-pvridl (methvlene)] diethylenetriamine-N, N', N"-triacetic acid tri-t-butyl ester The oil from above (0.737 g, 2.59 mmol) was dissolved in dry toluene (20 mL), containing t-butylbromoacetate (3.02 g, 15.50 mmol) and triethylamine (5.20 g, 51.0 mmol) and the reaction mixture was stirred overnight. After 16 hours the solvent <BR> <BR> <BR> <BR> was removed in vacuo and the residue was partitioned between Et20 (40 mL) and H20 (40 mL). The aqueous portion was extracted with Et20 (2 x 40 mL) and the organic portions were combined, and dried over MgS04. Removal of the solvent in <BR> <BR> <BR> <BR> vacuo afforded the desired product (1.00 g, 62%) as an oil.'H NMR (CDCl3) 8 1.40 (s, 9H), 1.45 (s, 18H), 2.75 (s, 8H), 3.27 (s, 2H), 3.32 (s, 4H), 3.91 (s, 4H), 7.12 (t, 2H, 6.0 Hz), 7.50 (d, 2H, 6.0 Hz), 7.62 (dd, 2H, J = 3.0,6.0 Hz), 8.50 (d, 2H, J = 3 Hz). ES-MS m/z 628 [M+H] +.

N, N"-bisU2-pyridyl (methylene) ldiethylenetriamine-N, N', N"-triaceticacid-STFA (bpdtta) The oil from above (1.45 g, 2.30 mmol) was dissolved in trifluoroacetic acid (8.8 g, 78 mmol) and left stirring for 16 hours. The solvent was removed in vacuo and the resulting oil was lyophilized. An off-white powder was obtained (2.05 g, 86%). 1H <BR> <BR> <BR> <BR> NMR (acetone-d6) 6 3.50 (t, 4H, J = 5.7 Hz), 3.69 (s, 4H), 3.79 (t, 4H, J = 5.7 Hz), 4.41 (s, 2H), 4.53 (s, 4H), 8.04 (t, 2H, J = 6.4 Hz), 8.13 (d, 2H, J = 6.4 Hz), 8.59 (t, 2H, J = 7.9 Hz), 8.92 (d, 2H, J=7.9 Hz). ES-MS m/z 461 [M+H] +. Anal. Calcd. for C22H29NsO65TFA2.5H20: C, 35.77; H, 3.66; N, 6.34. Found: C, 35.54; H, 3.30; N, 6.18.

Preparation of [Ru (H2bpdtta) H'CF3C02't2-3H20 [N-[2-[[(carboxy-#O)methyl][(2-pyridinyl-#N)methyl]amino-#N] ethyl-N-[2- [(carboxymethyl) [(2-pyridinyl-KNlmethyl] amino-KNlethyl] glycinato-KNl ruthenium (III) bis (trifluoroacetate).

Bpdtta (0.37g, 0.35 mmol) was dissolved in 1mM HCl (3 mL) and the pH was adjusted to 4 with 1M NaOH. K2 [RuCls (H20)] (0.13 g, 0.35 mmol), dissolved in a minimum amount of 1mM HCl was added to the reaction mixture. The solution was refluxed for 1.5 hours and then cooled in an ice bath. The residue was passed through Sephadex gel (G-10) and a yellow band was collected and lyophilized (0.11 g, 37%).

Anal. Calcd. for C22H28N506Ru-2TFA-3H20: C, 37.19; H, 4.08; N, 8.34. Found: C, 37.16; H, 4.00; N, 8.62. IR (CsI) v (cm-1) 1688 (Co2H); 1630 (CO2-).

EXAMPLE 44.

AMD8701: Ruthenium (III) complex of 1,3-Propanediamine-N, N, N', N'-tetraacetic acid (pdta).

1,3-Propanediamine-N. N, N', N'-tetraacetic acid tetra-t-butvl ester 1,3-propanediamine (0.528 g, 7.1 mmol) was dissolved in a mixture of dry THF (50 mL), triethylamine (5.76 g, 57 mmol) and t-butylbromoacetate (8.34 g, 43 mmol) and the reaction mixture was stirred under a nitrogen atmosphere for 24 hours.

The solvent was then removed in vacuo and the residue partitioned between CHC13 <BR> <BR> <BR> <BR> (40 mL) and saturated NaHC03 (30 mL). The aqueous portion was extracted with CHC13 (3 x 30 mL), and the combined organic portions were dried over MgS04, filtered, and the solvent removed in vacuo. The crude material was purified by silica gel chromatography (4: 1 Hexanes: EtOAc) afforded the product (3.00 g, 80%) as a <BR> <BR> <BR> colorless oil.'H NMR (CDC3) 8 1.45 (s, 36H), 1.63-1.68 (m, 2H), 2.73 (dd, 4H, J =<BR> <BR> <BR> <BR> <BR> 6.0,9.0 Hz), 3.42 (s, 8H). 13C NMR 8 55.76,80.80,170.74. ES-MS m/z 531 [M+H] +.

1,3-Propanediamine-N, N, N', N'-tetraacetic acid-xTFA (pdta) Using General Procedure B: Reaction of the oil from above (0.866 g, 1.63 mmol) with TFA (8.88 g, 78 <BR> <BR> <BR> mmol) afforded the product (0.8405 g, 96%). 1H NMR (CD30D) 5 2.15-2.19 (m, 2H), 3.43 (t, 4H, J = 6.0 Hz), 4.16 (s, 8H). ES-MS m/z 307 [M+H] +.

K[Ru(H@pdta)Cl2]#3H2OPreparationof [Potassium dihydrogen dichloro [[N, N'-1,3-propanediylbis [N (carboxymethyl) glycinato-KN, KO]]] ruthenium (III)] Using General Procedure C: Reaction of pdta (0.291 g, 0.54 mmol) with K2[RuCl5(H2O)] (0.203 g, 0.54 mmol) afforded the product (0.075 g, 24%) as a yellow solid. Anal. Calcd. for CwHl6N208 Cl2RuK 3. 0H20: C, 23.20; H, 3.89; N, 4.92; Cl, 12.45. Found: C, 22.97; H, 3.67; N, 4.80; Cl, 12.15. IR (CsI) v (ci') 1738 (C02H); 1642 (C02-); 316 (Ru-Cl).

EXAMPLE 45. <BR> <BR> <BR> <BR> <P>AMD7494: Ruthenium (III) complex of N- [2- (carboxy)-6- pyridyl (methylene)] iminodiacetic acid (cpida).

Methyl 2- (hydroxymethyl) pyridinecarboxylate Dimethyl-2,6-pyridinedicarboxylate (1.057 g, 5.4 mmol) was dissolved in dry CH2C12 (45 mL) and the solution was cooled to-78°C. DIBAL-H (11 mL, 10.8 mmol) was added dropwise with stirring and the solution was stirred at-78°C for 0.5

hours and then slowly warmed to room temperature over a period of 1 hour. The reaction was quenched with H20 (15 mL)/sodium potassium tartrate (15 mL) and extracted with CH2Cl2 (3 x 80 mL). The combined organic extracts were dried (MgS04) and evaporated in vacuo to afford the crude product. Purification by column chromatography on silica gel (4: 1 Hexanes: Ethyl acetate to 10% MeOH/CH2C12) <BR> <BR> <BR> afforded the desired product (0.220 g, 26%) as a colorless oil.'H NMR (CDCl3) 6 3.33 (t, 1H, J = 4.5 Hz), 4.00 (s, 3H), 4.87 (d, 2H, J = 4.5 Hz), 7.54 (d, 1H, J = 6.0), 7.83 (dd, 1H, J = 6.0,9.0), 8.00 (d, 1H, J = 9.0 Hz).

Methvl2- (methanesulfonvlmethvl) pvridinecarboxvlate To a stirred solution of methyl 2- (hydroxymethyl) pyridinecarboxylate (0.220 g, 1.3 mmol) dissolved in dry CH2C12 (13 mL) and triethylamine (0.40 g, 4.0 mmol) cooled in an ice bath was added dropwise, methanesulfonylchloride (0.18 g, 1.6 mmol). After 30 minutes the reaction was quenched with saturated NaHCO3 (15 mL) and the aqueous phase was separated and extracted with CH2C12 (3 x 15 mL). The combined organic extracts were dried (MgS04) and the solvent was evaporated in vacuo to afford the product (0.347g, 100%) as a yellow orange oil.'H NMR (CDCl3) <BR> <BR> <BR> <BR> 8 3.15 (s, 3H), 4.01 (s, 3H), 5.44 (s, 2H), 7.70 (d, 1H, J = 6.0 Hz), 7.92 (dd, 1H, J = 6.0,9.0 Hz), 8.12 (d, 1H, J = 9.0 Hz).

N-r2-(carboxymethyl)-6-pyridyl (methylene) liminodiacetic(carboxymethyl)-6-pyridyl (methylene) liminodiacetic acid dimethyl ester General ProcedureD: The oil from above (0.323 g, 1.3 mmol) was dissolved in dry DMF (13 mL) and iminodiacetic acid dimethyl ester (0.191 g, 1.2 mmol) was added. Once the reagents had dissolved, K2CO3 (0.36 g, 2.6 mmol) was added and the reaction mixture <BR> <BR> <BR> <BR> was stirred at 35 °C for 16 hours. The solvent was removed in vacuo and partitioned between H20 (10 mL) and CH2C12 (15 mL). The aqueous portion was extracted with CH2CI2 (3 x 15 mL), and the combined organic extracts were dried (MgS04) and evaporated in vacuo. The crude material was purified by silica gel chromatography (75% EtOAc/hexanes) to afford the product (0.200 g, 49%) as a colorless oil.'H <BR> <BR> <BR> <BR> NMR (CDCl3) 8 3.70 (s, 6H), 3.97 (s, 3H), 4.16 (s, 4H), 5.36 (s, 2H), 7.51 (d, 1H, J =<BR> <BR> <BR> <BR> <BR> <BR> 9.0), 7.84 (dd, 1H, J = 6.0,9.0), 8.02 (d, 1H, J = 6.0 Hz). 13C NMR 6 49.48,52.63, 53.32,68.46,124.46,124.79,138.25,155.93,157.31,165.88,170.09 .

N-f2- (carboxy)-6-pyridyl (methylene)] iminodiacetic acid-xHCl (cpida)

The oil from above (0.200 g, 0.65 mmol) was dissolved in MeOH (19 mL) and H20 (6 mL) and the solution was cooled to 0 °C using an ice bath. Lithium hydroxide monohydrate (0.270 g, 6.4 mmol) was added and the mixture was stirred for 17 hours at room temperature in the absence of light. The solution was acidified with 2N HCl and the solvent was removed in vacuo. The crude material was purified on Dowex cation exchange resin (H+form, 50W-200 mesh) to afford the product (0.172 g, 78%). <BR> <BR> <BR> <P>'H NMR (D20) 6 4.02 (s, 2H), 4.15 (s, 2H), 5.39 (s, 2H), 7.95 (d, 1H, J = 7.5 Hz),<BR> <BR> <BR> <BR> <BR> <BR> 8.25 (d, 1H, J = 7.2 Hz), 8.46 (dd, 1H, J = 7.2,7.5 Hz).'3C NMR (D20) 6 50.27, 50.56,127.02,128.74,147.29,152.83,156.73,173.22,173.46. ES-MS m/z 313 [M+H]+.

[Ru(Hcpida)(OH2)(Cl)]#1.5H2OPreparationof [Hydrogen aqua [6-[[[(carboxy-#O) methyl] (carboxymethyl) amino-KNJmethyl]-2- pyridinecarboxylato-KN', KO2] chloro ruthenium (III)].

Using General Procedure C: Reaction of cpida (0.157 g, 0.48 mmol) with K2 [RuCls (H20)] (0.172 g, 0.46 mmol) afforded the product. Anal. Calcd. for CnHi2N207RuCl-1. 5H20-0. 9KCl: C, 25.66; H, 2.94; N, 5.44; Cl, 13.08. Found: C, 25.56; H, 2.64; N, 5.06; Cl, 12.97. IR (CsI) : v (cm~l) 1709 (CO2H); 1632,607 (CO2-) ; 341 (Ru-Cl).

EXAMPLE 46.

AMD7493: Ruthenium (III) complex of N- [2- (Hydroxymethyl)-6- pyridyl (methylene)] iminodiacetic acid (hpida). <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>2- (Methanesulfonmethvlene) 7-6-pvridinecarboxaldehvde<BR> <BR> <BR> <BR> 2- (Hydroxymethyl)-6-pyridinecarboxaldehyde (2.30 g, 0.017 mol) was dissolved in dry CH2C12 (160 mL) containing triethylamine (5.08 g, 0.05 mol). The solution was cooled to 0 °C in an ice bath and methanesulfonylchloride (2.12 g, 0.018 mol) was added dropwise. Stirring was continued for 0.5 hours and the reaction was <BR> <BR> <BR> <BR> quenched with saturated NaHC03 (160 mL). The aqueous portion was extracted with CH2Cl2 (3 x 150 mL), and the combined organic extracts were dried (Na2S04) and the solvent was removed in vacuo to afford the product (3.61 g, 100%) as a brown oil.'H

NMR (CDC13) 8 3.15 (s, 3H), 5.43 (s, 2H), 7.70 (m, 1H), 7.97 (m, 2H), 10.05 (s, 1H).

This was used without further purification.

Using General Procedure D.

Reaction of the oil from above (3.61 g, 0.017 mol) with iminodiaceticacid di-t- butyl ester (3.706 g, 0.015mmol) afforded, after column chromatography on silica (4: 1 hexanes: EtOAc), the product (2.136 g, 40%) as a colorless oil.'H NMR (CDC13) 8 1.46 (s, 18H), 3.50 (s, 4H), 4.14 (s, 2H), 7.85 (m, 1H), 7.94 (m, 1H), 10.05 (s, 1H).

N-r2-(Hvdroxymethyl)-6-pyridyl (methylene !] iminodiacetic(Hvdroxymethyl)-6-pyridyl (methylene !] iminodiacetic acid di-t-butyl ester.

The oil from above (2.25 g, 6.2 mmol) was dissolved in dry MeOH (60 mL) under a nitrogen atmosphere. Sodium borohydride (0.235 g, 6.2 mmol) was added in one portion and the reaction was heated to 60 °C with stirring. After 1 hour the solvent was removed in vacuo and the residue was partitioned between H20 (30 mL) and CH2CI2 (30 mL). The aqueous phase was separated and extracted with CH2C12 (3 x 40 mL) and the combined organic extracts were dried (MgS04) and evaporated in <BR> <BR> <BR> vacuo to afford the product (2.16 g, 95%) as a colorless oil.'H NMR (CDC13) 8 1.46 (s, 18H), 3.48 (s, 4H), 3.98 (t, 1H, J = 4.5 Hz), 4.05 (s, 2H), 4.72 (d, 2H, J = 4.5 Hz), 7.08 (d, 1H, J = 6.0 Hz), 7.53 (d, 1H, J = 9.0 Hz), 7.66 (dd, 1H, J = 6.0,9.0 Hz). 13C <BR> <BR> <BR> <BR> NMR (CDC13) 8 28.57,56.22,59.88,64.13,81.47,119.04,122.02,137.64,158.25, 158.65,170.90. ES-MS m/z 367 [M+H] +.

N- [2- (Hydroxymethyl)-6-pyridyl (methylene) liminodiacetic acid. xTFA (hpida) Using General Procedure B: Reaction of N- [2- (Hydroxymethyl)-6-pyridyl (methylene)] iminodiacetic acid di-t-butyl ester with TFA (4.44 g, 40 mmol) afforded the product (0.492 g, 100%) as <BR> <BR> <BR> a white solid.'H NMR (D20) 8 3.64 (s, 4H), 4.28 (s, 2H), 4.85 (s, 2H), 7.69 (bs, 2H),<BR> <BR> <BR> <BR> <BR> <BR> 8.27 (t, 1H, J = 8.0 Hz). 13C NMR (D20) 8 55.98,60.07,123.75,125.19,147.02, 152.72,155.65,174.85. ES-MS m/z 255 [M+H] +.

[Ru(Hhpida)(OH2)Cl2]#H2OPreparationof [Hydrogen aqua [N-(carboxymethyl)-N-[[6-(hydroxymethyl)-2-pyridinyl- KNlmethyl] glycinato-KN, KO] dichloro ruthenium (III)].

Following General Procedure C: Reaction of hpida (0.152 g, 0.32 mmol) with K2 [RUcls (H2o)] (0.118 g, 0.32 mmol) afforded the product (0.0352 g, 24%). Anal. Calcd. for CoHlsN206Cl2RuH2O: C, 28.64; H, 3.71; N, 6.07; Cl, 15.37. Found: C, 28.44; H, 3.67; N, 6.02; Cl, 15.36. IR (CsI) v (cl'') 1657,1630 (CO2); 316 (Ru-Cl).

EXAMPLE 47.

AMD8699: Ruthenium (III) complex of N- [2- (benzyloxymethyl)-6- pyridyl (methylene)] iminodiacetic acid (bpida).

2- (Benzyloxymethyl)-6- (hydroxymethyl) pyridine 2,6-Pyridinedimethanol (1.523 g, 0.011 mol) was dissolved in DMSO (5 mL) and powdered KOH (0.63 g, 0.011 mol) was added. After 10 minutes benzylbromide (1.87 g, 0.011 mol) was added and the reaction was heated to 80 °C for 17 hours. The reaction mixture was quenched with H20 (9 mL) and extracted with Et20 (3 x 25 mL). The combined organic extracts were dried (MgS04) and the solvent was evaporated in vacuo. The crude product was purified by column chromatography on silica (1: 1 hexanes: EtOAc and then EtOAc) to afford the product (0.971g, 39%) as a <BR> <BR> <BR> <BR> colorless oil.'H NMR (CDC13) 6 3.79 (bs, 1H), 4.66 (s, 2H), 4.70 (s, 2H), 7.48 (d, 2H, J = 3.6 Hz), 7.13 (d, 1H, J = 7.5 Hz), 7.32-7.43 (m, 6H), 7.70 (dd, 1H, J = 7.2, 7.8 Hz).C NMR (CDC13) 8 60.40,63.89,72.96,119.01,119.91,127.80,128.48, <BR> <BR> <BR> <BR> 137. 31, 137.94,157. 57, 158.16.<BR> <BR> <BR> <BR> <BR> <BR> <P>2- (Benzyloxymethyl)-6- (methanesulfonylmethyl) pyridin The oil from above (0.971 g, 4.24 mmol) was dissolved in dry CH2C12 (40 mL) containing triethylamine (1.29 g, 12.7 mmol) under a nitrogen atmosphere and the solution was cooled to 0°C with stirring in an ice bath. Methanesulfonylchloride (0.577 g, 5.0 mmol) was then added dropwise and the mixture was stirred for 45 minutes and then quenched with saturated NaHC03 (30 mL). The separated aqueous phase was extracted with CH2CI2 (2 x 20 mL) and the combined organic extracts were dried (MgS04) and evaporated in vacuo to afford the product (1.18g, 91%) as a brown

oil.'H NMR (CDC13) 8 3.07 (s, 3H), 4.65 (s, 2H), 4.67 (s, 2H), 5.29 (s, 2H), 7.27- 7.38 (m, 6H), 7.50 (d, 1H, J = 9.0 Hz), 7.77 (dd, 1H, J = 6.0,9.0 Hz).

N-[2-(benZvloXvmethvl)-6-pyridvl (methvlene)] iminodiaceticacid di-t-butvl ester Using General Procedure D: Reaction of the oil from above (1.18 g, 3.84mmol) with iminodiacetic acid di- t-butyl ester (0.85 g, 3.47 mmol) afforded, after silica gel chromatography (4: 1 <BR> <BR> <BR> Hexanes: EtOAc), the product (0.772 g, 45%) as a colorless oil.'H NMR (CDC13) 8 1.45 (s, 18H), 3.48 (s, 4H), 4.03 (s, 2H), 4.65 (s, 2H), 4.67 (s, 2H), 7.27-7.38 (m, 6H), <BR> <BR> <BR> 7.54 (d, 1H, J = 7.5 Hz), 7.68 (dd, 1H, J = 7.5,7.8 Hz). 13C NMR (CDCl3) 6 28.19, 55.78,59.83,72.92,73.26,80.98,119.58,121.46,127.71,127.83,12 8.42,137.16, 138.09,157.82,158.86,170.53. ES-MS m/z 457 [M+H] +.

N-r2- (benzyloxymethyl)-6-pyridyl (methylene) liminodiacetic acid-xTFA (bpida).

Using General Procedure B: Reaction of the product from above (0.7 g, 1.53 mmol) with TFA (10.36 g, 90 mmol) afforded the product (0.876 g, 100%) as a yellow viscous oil.'H NMR (D2O) 8 3.77 (s, 4H), 4.44 (s, 2H), 4.75 (s, 2H), 4.92 (s, 2H), 7.33-7.41 (m, 5H), 7.76 (d, 1H, J= 9. 0 Hz), 7.83 (d, 1H, J = 6. 0 Hz), 8.33 (dd, 1H, J= 6.0,9.0 Hz). 13C NMR (D20) <BR> <BR> <BR> 8 55.73,56.51,67.68,68.27,73.62,123.45,124.33,128.18,128.58,13 7.52,144.88, 154.30,172.94. ES-MS m/z 345 [M+H] +.

[Ru(bpida)Cl(OH2)]Preparationof [Aqua [N-[(carboxy-KO) methyl]-N-[[6-[(phenylmethoxy) methyl]-2-pyridinyl- KN] methyl] glycinato-KN, KO] chloro ruthenium (III)] Using General Procedure C: Reaction of bpida (0.376 g, 0.66 mmol) with K2 [RuCl5 (H20)] (0.247 g, 0.66 mmol) afforded the product (0.0910 g, 26%) as a yellow solid. Anal. Calcd. for Cl8H20N206RuCl 0. 4KC1: C, 41.05; H, 3.83; N, 5.32; Cl, 9.42. Found: C, 41.30; H, 3.95; N, Cl, 9.83. IR (CsI) v (cm-1) 1657 (CO2-) ; 391 (Ru-Cl).

EXAMPLE 48.

AMD8677: Ruthenium (III) complex of N- [ (3- carboxymethyl) benzyl] ethylenediamine-N, N', N'-triacetic acid (cmbedta).

EtAvlenediamine-N, N', N'-triacetic acid tri-t-butvl ester To a stirred solution of ethylenediamine (0.50 g, 8.3 mmol) in dry THF (70 mL) and triethylamine (3.34 g, 33 mmol) was added t-butylbromoacetate (4.9 g, 25 mmol) and the reaction mixture was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between CH2Cl2 (80 mL) and H20 (50 mL). The separated aqueous phase was extracted with CH2C12 (2 x 80 mL) and the combined organic extracts were dried (MgS04) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (5% <BR> <BR> <BR> MeOH/CH2CI2) to afford the product (0.887g, 27%) as an oil.'H NMR (CDCl3) 8 1.43 (s, 27H), 2.63 (t, 2H, J = 6.0 Hz), 2.84 (t, 2H, J = 6.0 Hz), 3.28 (s, 2H), 3.42 (s, <BR> <BR> <BR> 4H). i3C NMR (CDC13) 6 28.46,28.51,47.42,51.84,54.15,56.41,81.31,81.36, 171.22,171.68.

N-r (3-carboxymethyl benzyl] ethylenediamine-N. N\N'-triacetic acid tri-t-bu 1 ester General Procedure E: To a stirred solution of the oil from above (0.165 g, 0.41 mmol) in dry THF (5 mL) and triethylamine (0.087 g, 0.86 mmol) was added 3-bromomethylbenzoate (0.094 g, 0.41 mmol) and the reaction was stirred at 35 °C for 22 hours. The solvent was removed in vacuo and the residue was partitioned between CH2C12 (10 mL) and saturated NaHC03 (10 mL). The separated aqueous phase was extracted with CH2C12 (2 x 10 mL), and the combined organic extracts were dried (MgS04) and evaporated <BR> <BR> <BR> <BR> in vacuo. The crude material was purified by radial chromatography on silica gel (7: 1 Hexanes: EtOAc) to afford the product (0.115 g, 51%) as a colorless oil.'H NMR <BR> <BR> <BR> <BR> (CDC13) 8 1.40 (s, 18H), 1.43 (s, 9H), 2.79-2.86 (m, 4H), 3.25 (s, 2H), 3.40 (s, 4H), 3.83 (s, 2H), 3.87 (s, 3H), 7.35 (dd, 1H, J = 6.0,9.0 Hz), 7.55 (d, 1H, J = 9.0 Hz), 7.89 (d, 1H, J = 6.0 Hz), 7.95 (s, 1H).

N- [ (3-carboxymethyl) benzyllethylenediamine-N, N', N'-triacetic acid-xTFA (cmbedta) UsingGeneral Procedure B : Reaction of the oil from above (0.115 g, 0.21 mmol) with TFA (7.4 g, 65 <BR> <BR> <BR> mmol) afforded the product (0.094 g, 74%) as a light brown solid.'H NMR (D20) b

3.16 (bs, 2H), 3.43-3.48 (m, 6H), 3.90 (s, 3H), 4.09 (s, 2H), 4.63 (s, 2H), 7.58 (t, 1H, J = 7.8 Hz), 7.83 (d, 1H, J = 7.8 Hz), 8.10 (d, 1H, J = 7.8 Hz), 8.23 (s, 1H). 13C NMR <BR> <BR> <BR> (D2O) 6 50.93,53.38,54.09,54.53,56.27,60.46,131.15,132.48,132.59,132 .78, 133.58,137.21,168.28,169.47,175.47.

K[Ru(cmbedta)Cl]#H2OPreparationof [Potassium chloro [methyl 3-[[[2-[bis[(carboxy-#O)methyl]amino-#N]ethyl][(carboxy- KO) methyl] amino-KNlmethyl] benzoato ruthenium (III)].

Using General Procedure C: Reaction of cmbedta (0.094 g, 0.16 mmol) with K2 [RuCls (H20)] (0.058 g, 0.16 mmol) afforded the product (0.0334 g, 36%) as a yellow solid. Anal. Calcd. for Cl7Hl9N208RuClK0. 15KClH2O: C, 34.95; H, 3.62; N, 4.80; Cl, 6.98. Found: C, 35.19; H, 3.92; N, 4.80; Cl, 7.28. IR (CsI) v (cl'') 1728 (CO2Me) ; 1686 (C02-); 386 (Ru-Cl).

EXAMPLE 49.

AMD8893: Ruthenium (III) Complex of N- [2- (N-acetylpyrrolidine)] ethylenediamine- N, N', N'-triacetic acid (apedta).

Chloroacetvlpvrrolidine A solution of chloroacetyl chloride (3.6 mL, 45.0 mmol) in anhydrous THF (10 mL) was added dropwise to a stirred mixture of pyrrolidine (2.56 g, 36.0 mmol) and potassium carbonate (7.46 g, 54.0 mmol) in anhydrous THF (50 mL) cooled to 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes and the reaction mixture was then evaporated to give a white solid. The solid was partitioned between CH2C12 and H20 and the aqueous layer was extracted twice with CH2Cl2. The combined organic phases were washed twice with H20, twice with NH4C1 (1 N) then dried <BR> <BR> (MgS04) and evaporated to give a yellow oil (2.97 g, 55. 9%). 1H NMR (CDCl3) 8 1.84 (m, 2H), 2.02 (m, 2H), 3.52 (q, 4H, J=6.0 Hz), 4.02 (s, 2H).

N-[2-(N-acetylpyrrolidine)]ethylenediamine-N,N',N'-triace tic acid tri-t-but ester Potassium carbonate (0. 69 g, 4.98 mmol) was added to a solution of ethylenediamine- N, N', N'-triacetic acid tri-t-butyl ester (0. 80 g, 1.99 mmol) and chloroacetylpyrrolidine (0.59 g, 3.98 mmol) in anhydrous acetonitrile (20 mL). The mixture was heated to reflux for 60 hours under N, and then evaporated. The orange residue was dissolved in a mixture of CH2Cl2 and K2CO3 (saturated).

Theaqueous layer was then separated and extracted twice with CH=CI=. The combined organic phases werewashed twice with saturated aqueous K2CO3, dried (MgSOJ) and evaporated. The resulting orangepurifiedtwiceonsilicagelusingcentrifugalchromatography (usingCH2Cl3asthewas affordthedesiredcompoundasayellowoil(0.48g,47%).1HNMR(CDCl3) #1.44(s,eluent)to (m,2H),1.94(m,2H),2.87(s,4H),3.45(s,br,6H),3.50(s,4H),3.55(s ,2H).ES-MSm/z27H),1.86 514 [M+H7+<BR> <BR> <BR> <BR> N-r2- (N-acetylpyrrolidine) lethylenediamine-N, N', N'-triacetic acid-xTFA (apedta) Trifluoroacetic acid (1.0 mL, 0.49 mmol) was added to a solution of the product from above (0.25 g, 12.98 mmol) in anhydrous CH2CI2 (5 mL) and the mixture was stirred overnight at room temperature under nitrogen. The reaction mixture was evaporated and then lyophilized to afford the desired compound as a pale <BR> <BR> <BR> <BR> yellow solid (0.21 g, 74. 7%). 1H NMR (D20) 8 1.88 (m, 4H), 3.38 (m, 6H), 3.53 (t,<BR> <BR> <BR> <BR> <BR> <BR> <BR> 2H, J=4. 8 Hz), 3.82 (s, 4H), 4.15 (s, 2H), 4.27 (s, 2H). 13C NMR (D20) b 24.03, 25.66,46.41,46.94,50.28,53.32,55.32,56.00,56.46,164.36,169.5 1,172.94. ES- MS m/z 346 [M+H] +, 368 [M+Na] +, 384 [M+K] +. paration of [RuL_qedta) L _ [Aqua [N-[2-[bis [(carboxy-KO) methyl] amino-#N]ethyl]-N-[2-oxo-2-(1- pyrrolidinyl) ethyl] glycinato-KN, #O] ruthenium (III)].

Apedta (0.37 g, 0.65 mmol) was heated in HCl (1 mM, 6 mL) until completely dissolved. The pH of the solution was then adjusted to pH3.0 with KOH (1 N). K2- [RuCl5 (OH2)] (0.24 g, 0.65 mmol) was added to the solution and the reaction mixture was heated to 100 °C for 2 hours. The solution was evaporated and purified by size exclusion column chromatography on Sephadex G-10 resin (H20) and the resulting solid was dried overnight in vacuo at 40 °C to afford a brown crystalline solid (0.062 g, 18.1%). ES-MS m/z 467 [M-OH2+Na] +. IR (CsI) v (cm-1) 1646 (C=O). Anal.

Calcd. for C14H22N308Ru-1. 2 H20-0.6 KCI: C, 31.86; H, 4.66; N, 7.96; Cl, 4.03.

Found: C, 31.75; H, 4.54; N, 7.68; Cl, 4.05.

EXAMPLE 50.

AMD8894: Ruthenium (III) complex of N- [2- (N-acetyl- (L)- isoleucyl)] ethylenediamine-N, N', N'-triacetic acid (aiedta).

N-chloroacetvl-(L)-isoleucine t-butvl ester At 0 °C under nitrogen, a solution of chloroacetyl chloride (0.64 mL, 8.01 mmol) in anhydrous THF (10 mL) was added dropwise to a suspension of (L)- isoleucine t-butyl ester (1.2 g, 6.41 mmol) and potassium carbonate (1.33 g, 9.62 mmol) in anhydrous THF (10 mL). The reaction mixture was stirred at 0 °C for 30 minutes and then the mixture was evaporated to give a white residue, which was dissolved in a mixture of CH2C12 and H2O. The aqueous layer was washed twice with CH2C12 and then the organic layer was washed twice with H20 and twice with NH4Cl (1 N). The combined organic layers were dried (MgS04) and evaporated to afford a yellow oil. The crude product was purified by column chromatography on silica gel (5% MeOH/CH2Cl2) to afford the desired compound as a yellow oil (0.66 g, 40.9%). <BR> <BR> <BR> <BR> <P>'H NMR (CDC13) 8 0.94 (m, 6H), 1.24 (m, 1H), 1.48 (m, 10H), 1.93 (m, 1H), 4.07 (s, 2H), 4.48 (dd, 1H, J=6.0 Hz, 3.0 Hz), 7.09 (br d, 1H, J=6.0 Hz).

A stirred suspension of N-chloroacetyl- (L)-isoleucine t-butyl ester (0.66 g, 2.62 mmol), potassium carbonate (0.46 g, 3.30 mmol) and ethylenediamine-N, N', N'- triacetic acid tri-t-butyl ester (0.53 g, 1.31 mmol) in anhydrous acetonitrile (15 mL) was heated to reflux for 60 hours under nitrogen and then evaporated. The light brown residue was partitioned between CH2C12 and saturated aqueous K2CO3. The separated aqueous layer was extracted twice with CH2C12 and then the combined organic phases were washed twice with K2CO3 (saturated) then dried (MgS04) and evaporated to give an orange oil. The crude product was purified by centrifugal chromatography on silica gel (CH2C12 treated with 1% NH40H) to afford the desired compound as a yellow oil (0.51 g, 63. 4%). 1H NMR (CDC13) 8 0.89 (m, 6H), 1.20 (m, 1H), 1.45 (m, 10H), 1.86 (m, 1H), 2.81 (m, 4H), 3.29 (s, 2H), 3.34 (s, 2H), 3.39 <BR> <BR> <BR> <BR> (s, 4H), 4.40 (dd, 1H, J=4.8 Hz), 7.88 (d, 1H, J=9.0 Hz). 13C NMR (CDC13) 8 12.15, 15.94,25.63,28.45,28.53,38.18,53.00,53.45,56.48,56.95,57.22, 58.89,81.35, 81.70,81.80,170.78,170.90,171.04,171.55.

N-r2- (N-acetyl- (L)-isoleucyl) lethylenediamine-N, N', N'-triacetic acid. xTFA (aiedta).

Trifluoroacetic acid (4.0 mL, 51.9 mmol) was added to a solution of the intermediate from above (0.51 g, 0.83 mmol) in anhydrous CH2Cl2 (8 mL) and the mixture was stirred overnight at room temperature under nitrogen. The solvent was

evaporated and the residue lyophilized to afford a pale yellow solid (0.45 mg, 86%).

IH NMR (D2O) 8 0.89 (m, 6H), 1.20 (m, 1H), 1.45 (m, 1H), 1.93 (m, 1H), 3.32 (t, 2H, J=6.0 Hz), 3.40 (t, 2H, J=6.0 Hz), 3.82 (s, 2H), 3.88 (s, 2H), 3.96 (s, 4H), 4.33 (d, 1H, <BR> <BR> <BR> J=6.0 Hz). I3C NMR (D20) 8 52.03,55.54,55.84, 56.64,58.04,169.77,171.49,172.30,175.52. ES-MS m/z 406 [M+H] +, 428 [M+Na] +, 444 [M+K] +.

[Ru(aiedtaK)(OH2)]1.6H2OPreparationof [Potassium aqua [N-[2-[bis [(carboxy-KO) methyl] amino-aNlethyl]-N-[(carboxy- KO) methyl] glycyl-KN-L-isoleucinato ruthenium (III)].

Aiedta (0.35 g, 0.55 mmol) was heated in aqueous HCl (1 mM, 5.5 mL) until completely dissolved and the pH of the solution was then adjusted to pH=3.0 with KOH (1N). K2 [RuCl5 (OH2)] (0.21 g, 0.55 mmol) was added to the solution and the reaction mixture was heated at 100 °C for 2 hours. The solution was evaporated and the residue was purified by size exclusion column chromatography on Sephadex G-10 resin (H20). The resulting solid was dried overnight in vacuo at 40 °C to afford the desired complex as a brown crystalline solid (0.030 g, 8.6%). ES-MS m/z 527 [M- OH2-K+Na+H] +, 549 [M-OH2-K+2Na] +. IR (CsI) v (cl'') 1626 (C=O). Anal. Calcd. for C16H25N3O10RuK#1.6 H2O#0. 6 KCI: C, 30.35; H, 4.49; N, 6.64; Cl, 3.36. Found: C, 30.48; H, 4.64; N, 6.67; Cl, 3.26.

EXAMPLE 51.

AMD8711: Ruthenium (III) complex of N-benzylethylenediamine-N, N', N'-triacetic acid (bedta).

N-Benzvlethvlenediamine-N. N', N'-triacetic acid tri-t-bu l ester Following General Procedure E: Reaction of ethylenediamine-N, N', N'-triacetic acid tri-t-butyl ester (0.734 g, 1.8 mmol) with benzylbromide (0.316 g, 1.8 mmol) afforded, after column chromatography on silica gel (7: 1 hexanes: EtOAc), the product (0.496 g, 55%) as a <BR> <BR> <BR> colorless oil.'H NMR (CDC13) 8 1.40 (s, 18H), 1.42 (s, 9H), 2.80-2.88 (m, 4H), 3.24 (s, 2H), 3.44, (s, 4H), 3.80 (s, 2H), 7.21-7.34 (m, 5H).

N-benzylethylenediamine-N, N', N'-triacetic acid-xTFA (bedta)

Following General Procedure B: Reaction of the intermediate from above (0.496 g, 1.0 mmol) with TFA (12.6 g, 100 mmol) afforded the product (0.454 g, 82%) as a white solid.'H NMR (MeOD) 8 3.10 (t, 2H, J = 6.0 Hz), 3.39-3.45 (bs, 6H), 4.09 (s, 2H), 4.59 (s, 2H), 7.47-7.50 (m, <BR> <BR> <BR> <BR> 3H), 7.57-7.60 (m, 2H). 13C NMR (MeOD) 6 50.59,53.04,56.26,60.90,130.66, 131.42,132.01,132.78,169.39,175.74. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>K[Ru(Hbedta)Cl2]#1.6H2OPreparationof <BR> <BR> <BR> aqua[N-[2-[[(carboxy-#O)methyl](carboxymethyl)amino-#N]ethyl ]-N-[PotassiumHydrogen <BR> <BR> <BR> <BR> (III)].(phenylmethyl)glycinato-#N,#O]dichlororuthenium Following General Procedure C: Reaction of bedta (0.210 g, 0.38 mmol) with KRuClsO)] (0.142 g, 0.38 mmol) afforded the product (0.0460 g, 21%) as a yellow solid. Anal. Calcd. for Cj5Ht8N206Cl2RuK-1. 6H20-0. 1KCl: C, 31.63; H, 3.75; N, 4.92; Cl, 13.07. Found: C, 31.63; H, 3.96; N, 4.77; Cl, 13.03. IR (CsI) v (cl'') 1726 (CO2H); 1641 (CO2-) ; 391 (Ru-Cl).

EXAMPLE 52.

AMD8702: Ruthenium (III) complex of N- [ (3-carboxy) benzyl] ethylenediamine- N, N', N'-triacetic acid (cbedta).

N, N', N'-triacetic acid (cbedta).

To a stirred solution of N- [ (3-carboxymethyl) benzyl] ethylenediamine- N, N', N'-triacetic acid tri-t-butyl ester (0.771 g, 1.4 mmol) in MeOH (19 mL) and H2O (6 mL) was added lithium hydroxide (0.236 g, 5.6 mmol) and the reaction was stirred for 16 hours at room temperature (in the absence of light) and then the solvent was evaporated in vacuo. This intermediate was used directly in the next step without further purification.

The residue was dissolved in TFA (8.3 g, 73 mmol) and stirred for 16 hours then evaporated in vacuo. EtOH was added to the residue, the resulting suspension was filtered, and the product lyophilized to afford a white solid (1.04 g, 100%).'H NMR (MeOD) 8 3.15 (t, 2H, J = 6 Hz), 3.43-3.48 (bs, 6H), 4.09 (s, 2H), 4.64 (s, 2H), 7.59 (dd, 1H, J = 6.0,9.0 Hz), 7.85 (d, 1H, J = 6.0 Hz), 8.12 (d, 1H, J = 9.0 Hz), 8.26 (s, 1H). i3C NMR (MeOD) 6 60.01,65.74,130.65,132.05, 132.30,133.13,133.48,136.67,168.93,169.07,175.12. ES-MS m/z 369 [M+H] +. <BR> <BR> <BR> <BR> <BR> <BR> <P>K[Ru(H2cbedta)Cl2]#4.5H2OPreparationof <BR> <BR> <BR> [3-[[[(carboxy-#O)methyl][2-[[(carboxy-#O)methyl](carboxymet hyl)amino-[PotassiumDihydrogen <BR> <BR> <BR> ethyl] amino-w methylybenzoato] dichloro ruthenium (III) ç.

Following General Reaction C: Reaction of cbedta (0.377 g, 0.60 mmol) with K2 [RuC15 (H2O)] (0.236 g, 0.60 mmol) afforded the product (51.0 mg, 12%) as a yellow solid. Anal. Calcd. for C16H18N2O8Cl2RuK#4.5H2O#0.1KCl : C, 28.86; H, 4.09; N, 4.21; Cl, 11.18. Found: C, 28.63; H, 3.69; N, 4.29; Cl, 11.08. IR (CsI) v (cl'') 1709 (C02H); 389 (Ru-Cl).

EXAMPLE 53. <BR> <BR> <BR> <BR> <P>AMD8849: Ruthenium (III) complex N, N'-bis [2- (N-acetylpyrrolidine)] ethylenediamine-N, N'-diacetic acid (bpedda).

N, N'-bisE2- (N-acetylpyrrolidine) lethylenediamine-N, N'-diacetic acid (bpedda) A solution of pyrrolidine (0.56 g, 3.90 mmol) in anhydrous THF (20 mL) was added dropwise to a stirred solution of ethylenediamine-N, N, N', N'-tetraacetic acid dianhydride (1.0 g, 7.81 mmol) in anhydrous THF (20 mL) under nitrogen and the mixture was stirred for 15.5 hours. The precipitate which formed was collected by filtration and dried in vacuo overnight to give the product as a white solid (1.59 g, ~ 100%). 1H NMR (D20) 8 1.90 (m, 8H), 3.40 (q, 8H, J=7.2 Hz), 3.52 (s, 4H), 3.83 (s, 4H), 4.13 (s, 4H). ES-MS m/z 399 [M+H] +, 421 [M+Na] +. Anal. Calcd. for Cl8H3oN4 06-0.2 H20: C, 53.77; H, 7.62; N, 13.93. Found: C, 53.68; H, 7.54; N, 13.71.

[Ru(bpedda)Cl(OH2)]#3H2OPreparationof [Aquachloro [[N, N'-1,2-ethanediylbis [N [2-oxo-2- (l-pyrrolidinyl) ethyl] glycinato- KN, KO]]] ruthenium (III)].

Bpedda (0.50 g, 1.26 mmol) was heated in aqueous HCl (1 mM, 10 mL) until completely dissolved. K2 [RuCl5 (OH2)] (0.47,1.26 mmol) was added to the solution and the reaction mixture was heated at 100 °C for 2 hours. The solution was filtered and the filtrate was evaporated. The residue was purified by size exclusion column

chromatography on Sephadex G-10 resin (H20) to afford the desired complex as a red solid (0.039 g, 5.2%). ES-MS m/z 498 [M-Cl-H2O] +. IR (KBr) v (cm-I) 1626 (C=O).

Anal. Calcd. for C18H3oN407ClRu3H20: C, 35.73; H, 6.00; N, 9.26; Cl, 5.86.

Found: C, 35.48; H, 5.50; N, 9.19; Cl, 6.01.

EXAMPLE 54.

AMD7461: Ruthenium (III) complex of 2-Hydroxy-1,3-propanediamine-N, N, N', N'- tetraacetic acid (hpdta).

Preparation of [Ru (H2hpdta) (OH2) (03SCF3)]-EtOH [Dihydrogen aqua [[N,N'-(2-hydroxy-1, 3-propanediyl) bis [N- (carboxymethyl) glycinato-KN, O]]] (trifluoromethanesulfonato-KO) ruthenium (III)].

2-Hydroxy-1,3-propanediamine-N, N, N', N',-tetraaceticacid (0.082 g, 0.25 mmol) was dissolved in EtOH (20 mL) and [Ru (DMF) 6] (OTf) 3 (0.26 g, 0.25 mmol) was added. The reaction was heated to 69 °C for 3 days with stirring, cooled to room temperature and the resulting precipitate was collected by filtration. The solid was washed with EtOH (10 mL) and Et20 (2 x 10 mL) to afford the desired product (0.0420 mg, 26%). Anal. Calcd. for C12H18N2O13RuF3S#1.0EtOH : C, 26.50; H, 3.81; N, 4.42. Found: C, 26.60; H, 3.89; N, 4.76. IR (CsI) v (cl'') 1744 (CO2H); 1647 (CO2-).

EXAMPLE 55.

AMD7462: Ruthenium (III) complex of 1,2-Ethylenediamine-N, N'-diaceticacid (edda).

Preparation of K [Ru (edda) Cl2l 2. 5H2O [Potassium dichloro [[N, N'-1,2-ethanediylbis [glycinato-KN, KO]] ruthenium (III)].

1,2-Ethylenediamine-N, N'-diaceticacid (0.130 g, 0.74 mmol) was dissolved in EtOH (20 mL) and RuCl3#H2O (0.155 g, 0.74 mmol) added. The mixture was heated

to 60 °C during which time a precipitate formed. The solid was collected by filtration and washed with Et20 to afford the desired product (0.0620 g, 22%) as a brown solid.

Anal. Calcd. for C6HIoN204Cl2RuK-2. 1H20: C, 17.03; H, 3.38; N, 6.62; Cl, 16.76.

Found: C, 17.40; H, 3.76; N, 6.80; Cl, 17.20. IR (CsI) v (cm'') 1640 (C02-); 318 (Ru- Cl).

EXAMPLE 56.

Svnthesis of dithiocarbamate ligands General Procedure F: Carbon disulfide (1.5-2 equivalents) was dissolved in anhydrous diethyl ether and cooled to 0 °C in an ice bath. The appropriate amine (1 equivalent) and KOH (1- 2 equivalents) were dissolved in anhydrous methanol and added dropwise to the carbon disulfide solution. The reaction mixture was stirred for 3 hours at 0 °C. The solvent was removed and the resulting residue was triturated with diethyl ether. The white solid was filtered and washed with diethyl ether and dried in vacuo.

The following ligands were prepared using general procedure F: Pyrrolidinedithiocarbamic acid potassium salt [KS2CNC4H81 Carbon disulfide (2.16 mL, 36 mmol) was reacted with pyrrolidine (2 mL, 24 <BR> <BR> <BR> <BR> mmol) and KOH (1.34 g, 24 mmol) to yield 3.8 g (85%) product.'H NMR (D20) 8 1.94-1.99 (m, 4H), 3.71-3.76 (m, 4H).

L-Prolinedithiocarbamic acid dipotassium salt [KS2CNProKl Carbon disulfide (1.04 mL, 17.4 mmol) was reacted with L-proline (1.0 g, 8.7 mmol) and KOH (0.97 g, 17.4 mmol) to yield 1.37 g (59%) product. IH NMR (D20) <BR> <BR> <BR> <BR> 6 1.950-2.05 (m, 3H), 2.25-2.35 (m, 1H), 3.78-3.96 (m, 2H), 4.84 (m, 1H). 13C NMR<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> (D20) 8 24.78,31.62,55.77,69.58,180.32,205.71.

L-Prolinemethyl ester dithiocarbamic acid potassium salt [KS CNProOMel Carbon disulfide (0.53 mL, 8.8 mmol) was reacted with L-proline methyl ester (0.57 g, 4.4 mmol) and KOH (0.49 g, 8.8 mmol) to yield 0.66 g (62%) product. This

product contained some residual starting material and was used without further purification in the preparation of the ruthenium complexes.'H NMR (D20) b 2.03- 2.17 (m, 3H), 2.41-2.44 (m, 1H), 3.78 (m, 1H), 3.91-3.99 (m, 1H), 4.03 (s, 3H), 4.81- 4.85 (m, 0.5H), 5.01 (m, 0.5H). 13C NMR (D20) 6 24.71,31.02,53.30,60.83,66.79, 175.43,208.26.

N-Methyl-L-isoleucinedithiocarbamic acid dipotassium salt [KS2CNMeIleKl Carbon disulfide (0.83 mL, 13.8 mmol) was reacted with N-methyl-L- isoleucine (1.0 g, 6.89 mmol) and KOH (0.77 g, 13.8 mmol) to yield 0.73 g (37%) product. This product contained some starting material and was used without further purification in the preparation of the ruthenium complexes.'H NMR (D20) 8 0. 91 (t, 3H, J=7. 5 Hz), 1.00 (d, 3H, J=6.6 Hz), 1.14-1.23 (m, 1H), 1.30-1.35 (m, 1H), 1.98 (br m, 1H), 3.38 (br s, 3H), 6.01 (d, 1H, J=10.2 Hz).

EXAMPLE 57.

AMD8672: Preparation of Chloro (1,4,7-triazacyclononane) bis- (dimethylsufoxide) ruthenium (II) chloride, [Ru (tacn) (DMSO) 2Cl] Cl.

[Chloro [octahydro-1H-1,4,7-triazonine-KIV', #N4, #N7] bis [(sulfinyl-lcS) bis [methane] ruthenium (II) chloride].

Prepared according to literature procedures: A. Geilenkirchen, P. Neubold, R.

Schneider, K. Wieghardt, U. Florke, H-J. Haupt, B. Nuber J. Chem. Soc., Dalton Trans. 1994,457.

EXAMPLE 58.

AMD8641: Preparation of Trichloro (1,4,7-triazacyclononane) Ruthenium (III): [Ru (tacn) Cl3].

[Trichloro [octahydro-1H-1,4,7-triazonine-KNl, #N4, ruthenium (III)].

Prepared according to literature procedures: A. Geilenkirchen, P. Neubold, R.

Schneider, K. Wieghardt, U. Florke, H-J. Haupt, B. Nuber J. Chem. Soc., Dalton Trans. 1994,457.

EXAMPLE 59. ofTrichloro(1,4,7-trimethyl-1,4,7-triazacyclononane)Rutheniu m(III):AMD8671:Preparation [RU (Me3taCn) CI31- [Trichloro [hexahydro-1,4,7-trimethyl-1,4, 7-triazonine-#N1, #N4, lcN7] ruthenium (III)].

Prepared according to literature procedures: P. Neubold, K. Wieghardt, B.

Nuber, J. Weiss Inorg. Chem. 1989,28,459.

EXAMPLE 60. of[Ru(tacn)(S2CNMe2)2][PF6]AMD8670:Preparation <BR> <BR> [ (Dimethylcarbamodithioato-KS) (dimethylcarbamodithioato-xS, KS') [octahydro-1H- 1,4,7-triazonine-KNl, #N4, #N7] ruthenium (III) hexafluorophosphate].

General Procedure G RuLCl3, where L represents either 1,4,7-triazacyclononane (tacn) or 1,4,7- trimethyl-1,4,7-triazacyclononane (Me3tacn), was suspended in deionized water and heated to 40 °C. Two equivalents of the dithiocarbamic acid salt was added and the reaction continued for 1-1.5 hours during which time the reaction mixture turned a dark blue or purple colour. The reaction mixture was removed from heat and filtered while hot. Saturated NH4PF6 was added to the filtrate, which produced a dark precipitate. The solid was filtered and washed with deionized water and diethyl ether and dried in vacuo.

Using General Procedure G: Ru (tacn) Cl3 (0.30 g, 0.89 mmol) was reacted with N, N- dimethyldithiocarbamic acid sodium salt (NaS2CNMe2-2H20) (Aldrich, 0.32 g, 1.78 mmol) to yield 0.448 g product (80%). Anal. Calcd. for C12H26N5S4RuPF6: C, 23.45; H, 4.26; N, 11.39; S, 20.86. Found: C, 23.23; H, 4.34; N, 11.18; S, 20.61. ES-MS [M-PF6]+.m/z471

EXAMPLE 61. of[Ru(tacn)(S2CNEt2)2][PF6].AMD8803:Preparation <BR> <BR> [ (Diethylcarbamodithioato-K (diethylcarbamodithioato-KS, KS') [octahydro-1H-1,4,7- triazonine-, KN4, KN7] ruthenium (III) hexafluorophosphate].

Using General Procedure G: Ru (tacn) Cl3 (0.10 g, 0.29 mmol) was reacted with N, N-diethyldithiocarbamic acid sodium salt (NaS2CNEt2-3H20) (Aldrich, 0.134 g, 0.6 mmol) to yield 0.163 g product (81%). Anal. Calcd. for C16H35N5S4RuPF6: C, 28.61; H, 5.25; N, 10.43; S, 10.09. Found: C, 28.44; H, 5.12; N, 10.31; S, 19.30. ES-MS m/z 527 [M-PF6].

EXAMPLE 62. of[Ru(tacn)(S2CNC4H8)2][PF6].AMD8842:Preparation [ (1, 4-butanediylcarbamodithioato-xS (1, 4-butanediylcarbamodithioato-KS, KS') [octahydro-lH-1,4,7-triazonine-KNI, KN4, lcN7] ruthenium (III) hexafluorophosphate].

Using General Procedure G: Ru (tacn) Cl3 (0.10 g, 0.29 mmol) was reacted with pyrrolidinedithiocarbamic acid potassium salt (0.109 g, 0.59 mmol) to yield 0.11 g of crude product. This crude product was purified by column chromatography on silica gel (MeCN/sat. KN03/H20 7/1/0.5). The solvent was removed from the combined fractions containing the desired product and the residue was triturated with acetonitrile. The excess KN03 was removed by filtration and saturated solution of NH4PF6 in methanol was added to the filtrate. The resulting precipitate was collected by filtration and washed with deionized water then diethyl ether and dried in vacuo to give the title compound (0.069 g, 36%). Anal. Calcd. for C16H3lN5S4RuPF6-0. 2H20-0.2NH4PF6: C, 27.30; H, 4.61; N, 10.35; S, 18.22. Found: C, 27.06; H, 4.50; N, 10.23; S, 18.24. ES-MS m/z 523 [M-PF6] +.

EXAMPLE 63.

of[Ru(tacn)(S2CNPro)2][PF6]AMD8731:Preparation [Dihydrogen ((1-carboxy)-1, 4-butanediylcarbamodithioato-aS) ((1-carboxy)-1,4- <BR> <BR> <BR> <BR> butanediylcarbamodithioato-KS', KS') [octahydro-1H-1,4,7-triazonine-KA, KN 4 KN] ruthenium (III) hexafluorophosphate].

Using General Procedure G: Ru (tacn) Cl3 (0.30 g, 0.90 mmol) was reacted with with L- prolinedithiocarbamic acid dipotassium salt (0.48 g, 1.8 mmol) to yield 0.273 g (38%) product. Anal. Calcd. for Ci8H3iN504S4RuPF6-1. 8H20: C, 27.43; H, 4.42; N, 8.89; S, 16.27. Found: C, 27.36; H, 4.38; N, 9.07; S, 16.33. ES-MS m/z 611 [M-PF6] +. IR (CsI) v (ci') 1723 (CO2H).

EXAMPLE 64. of[Ru(tacn)(S2CNProOMe)2][PF6].AMD8802:Preparation <BR> <BR> ((1-carboxymethyl)-1,4-butanediylcarbamodithioato-#S)((1-car boxymethyl)-1,4-<BR> <BR> <BR> <BR> <BR> <BR> <BR> butanediylcarbamodithioato-oS',K. S') [octahydro-1H-1, 4, 7-triazonine-xlVl, KN4, KN] ruthenium (III) hexafluorophosphate.

Using General Procedure G: Ru (tacn) Cl3 (0.136 g, 0.40 mmol) was reacted with L-proline methyl ester dithiocarbamic acid potassium salt (0.20 g, 0.80 mmol) to yield 0.078 g (25%) product. Anal. Calcd. for C2oH35N504S4RuPF6: C, 30.65; H, 4.50; N, 8.94; S, 16.35.

Found: C, 30.54; H, 4.47; N, 8.81; S, 16.52. ES-MS m/z 639 [M-PF6] +. IR (CsI) v (CO2Me).(cm-1)1742 EXAMPLE 65. of[Ru(tacn)(S2CNMeIle)2][PF6].AMD8801:Preparation [Dihydrogen (N-methyl-N-sec-butylcarboxycarbamodithioato-KS) (N-methyl-N-sec- <BR> <BR> <BR> <BR> butylcarboxycarbamodithioato-#S,#S')[octayhydro-1H-1,4,7-tri azonine-#N1,#N4,#N7] ruthenium (III) hexafluorophosphate].

Using General Procedure G: Ru (tacn) Cl3 (0.10 g, 0.30 mmol) was reacted with N-methyl-L- isoleucinedithiocarbamic acid dipotassium salt (0.178 g, 0.60 mmol) to yield 0.068 g

(28%) product. Anal. Calcd. for C22H43N504S4RuPF6: C, 32.39; H, 5.31; N, 8.58; S, 15.72. Found: C, 32.41; H, 5.46; N, 8.85; S, 15.58. ES-MS m/z 671 [M-PF6] +. IR (CsI) v (cm-1) 1726 (CO2H).

EXAMPLE 66.

AMD8682: Preparation of [Ru(Me3tacn)(S2CNMe2)2] [PF6]. <BR> <BR> <P>[ (Dimethylcarbamodithioato-KS) (dimethylcarbamodithioato-xS, KS') [hexahydro- 1,4,7-trimethyl-1,4,7-triazonine-KNl, xN4, KW] ruthenium (III) hexafluorophosphate].

Using General Procedure G: Ru (Me3tacn) Cl3 (0.10 g, 0.264 mmol) was reacted with N, N- dimethyldithiocarbamic acid sodium salt (Aldrich, 0.094 g, 0.528 mmol) to yield 0.10 g crude product. This crude product (0.05 g) was purified by column chromatography on silica gel (MeCN/sat. KN03/H20 7/1/0.5). The solvent was removed from the combined fractions containing the desired product and the residue was triturated with acetonitrile. The KN03 was removed by filtration and a saturated solution of NH4PF6 in methanol was added to the filtrate. The resulting precipitate was collected, washed with deionized water and diethyl ether and then dried in vacuo to give the title compound (0.030 g, 35%). Anal. Calcd. for C15H33N5S4RuPF6: C, 27.39; H, 5.06; N, 10.65; S, 19.50; Cl, 0.00. Found: C, 27.51; H, 5.01; N, 10.58, S, 19.28; Cl, 0.00. ES- MS [M-PF6]+.513 EXAMPLE67. <BR> <BR> <P>AMD8800: Preparation of [Ru (tacn) (mida) ff [PF6J.<BR> <BR> <BR> <BR> <P>[(N-(carboxy-KO)-methyl)-N-methylglycinato-KN, KO] [octahydro-1H-1,4,7-triazonine- KNi, 1cN4, KN7] ruthenium (III) hexafluorophosphate].

Ru (tacn) Cl3 (0.10 g, 0.30 mmol) and N-methyliminodiacetic acid (mida) (0.044 g, 0.30 mmol) were refluxed in deionized water (30 mL) for 3 hours. The reaction mixture was filtered hot to remove any unreacted starting material. Saturated aqueous NH4PF6 was added to the filtrate and crystallization was induced by the addition of ethanol. The pale yellow precipitate was collected by filtration, washed with diethyl ether and dried in vacuo to yield 0.041 g (26%) product. Anal. Calcd. for

CnH22N404RuPF6: C, 25.39; H, 4.26; N, 10.77. Found: C, 25.37; H, 4.24; N, 10.59.

ES-MS m/z 376 [M-PF6] +. IR (CsI) v (cm-1) 1642 (CO2-).

EXAMPLE 68.

AMD8811 : Preparation of [Ru (Hnota) CI7.

[Hydrogen chloro [hexahydro-1,4, 7-(tricarboxy-#O,#O'-methyl)-1, 4,7-triazonine- (III)].#N1,#N4,#N7]ruthenium 1,4,7-Triazacyclononane-1,4,7-triacetic acid (nota) (0.50 g, 1 mmol) was dissolved in deionized water (5 mL) and the pH adjusted to pH 3-4 with KOH (1 M).

An aqueous solution of K2[RuCl5(OH2)] (0.40 g, 1 mmol) was added to the solution and the reaction mixture was heated to reflux for 2 hours. The solution was cooled and an insoluble material was removed by filtration. Addition of ethanol to the filtrate resulted in the precipitation of [Ru (H2nota) Cl2] (0. 1 g) which was removed by filtration. Upon allowing the filtrate to stand, a second precipitate was obtained which was collected and washed with diethyl ether to give the title compound (0.040 g, 8.5%). Anal. Calcd. for Ct2Ht9N306RuCl-H20-0. 2KCl: C, 30.62; H, 4.50; N, 8.93; Cl, <BR> <BR> <BR> 9.04. Found: C, 30.48; H, 4.64; N, 8.84; Cl, 9.12. ES-MS m/z 403 [M-C1] +. IR (CsI) v (cari') 1728, (C02H); 1678 (CO2-).

EXAMPLE 69.

AMD7044: Preparation of [Ru (terpy) (bpy) Cl] [PF6].

[Chloro (2,2'-bipyridine-KNi, KNI') (2,2': 6'. 2"-terpyridine-KV', KN2', olV'") ruthenium (II) hexafluorophosphate].

General Procedure H: Terpyridylruthenium trichloride (Ru (terpy) Cl3) (E. C. Constable et al. New J.

Chem. (0.50 g, 1.13 mmol), bidentate ligand, L (one equivalent) and 4- ethylmorpholine (4 drops) were heated to reflux in methanol (100 mL) for 2 hours.

The hot solution was filtered through celite and a saturated solution of NH4PF6 in methanol was added to the filtrate. The volume was reduced to approximately one third the original volume at which time a precipitate formed. The crude product was

collected by filtration and purified either by re-crystallization from an MeCN/MeOH solution or by column chromatography on silica gel (7/1/0.5: MeCN/sat. KN03/H2O).

Using General Procedure H: Reaction of Ru (terpy) Cl3 (0.50 g, 1.13 mmol) and 2,2'-dipyridyl (0.18 g, 1.13 mmol) gave the desired product 0.27 g (35%) following purification by column <BR> <BR> <BR> chromatography on silica gel.'H NMR (CD3CN) 8 6.94 (m, 1H), 7.26 (m, 3H), 7.66 (m, 3H), 7.86 (m, 2H), 7.94 (m, 1H), 8.06 (t, 1H, J=7. 8 Hz), 8.26 (m, 2H), 8.36 (d, 2H, J=8. 1 Hz), 8.47 (d, 2H, J=7.8 Hz), 8.59 (d, 1H, J=8. 2 Hz), 10.20 (d, 1H,. J=5.8 <BR> <BR> <BR> Hz). I3C NMR (CD3CN) 8 123.4,124.23,124.49,124.57,127.09,127.90,128.25, 134.73,136.55,137.54,138.05,153.13,153.25,153.49,157.25,159. 01,159.70, 159.75. Anal. Calcd. for C2sHIgN5ClRuPF6 0. 2NH4PF6: C, 42.68; H, 2.84; N, 10.35; Cl, 5.04. Found: C, 42.83; H, 2.61; N, 10.54; Cl, 4.91.

EXAMPLE 70.

AMD7054: Preparation of [Ru (terpy) (2-pyridinethione) 2Cl] [PF6].

[Chlorobis (2 (lH)-pyridinethione-xS2) (2,2': 6'. 2"-terpyridine-KNl, lcN2), KNI") ruthenium (II) hexafluorophosphate].

Using General Procedure H: Reaction of Ru (terpy) Cl3 (0.50 g, 1.13 mmol) and 2-mercaptopyridine (0.25 g, 2.27 mmol) gave the desired product (0.263g, 32%) after re-crystallization from <BR> <BR> <BR> MeCN/MeOH.'H NMR (CD3CN) 8 6.94 (m, 2H), 7.11 (d, 1H, J=7. 8 Hz), 7.26 (d, 1H, 5.5 Hz), 7.41 (m, 1H), 7. 56 (m, 2H), 7.74 (m, 1H), 7.83 (m, 1H), 8.04-8.21 (m, 5H), 8.28-8.37 (m, 2H), 8.44-8.48 (m, 2H), 9.88 (d, 1H, J=5. 5 Hz). 13C NMR <BR> <BR> <BR> <BR> (CD3CN) 8 122.04,123.55,123.79,124.03,124.13,124.36,124.60,125.05,128. 12, 128.41,137.08,137.79,138.29,139.32,139.40,151.45,152.90,154. 77,155.61, 156.84,158.80,159.12,159.16,159.90,163.65. Anal. Calcd. for C25H2lN5S2ClRuPF6: C, 40.74; H, 2.87; N, 9.50; S, 8.70; Cl, 4.81. Found: C, 40.82; H, 2.80; N, 9.39; S, 8.66; Cl, 4.88.

EXAMPLE 71.

AMD7055: Preparation of [Ru (terpy) (2-pyrimidinethione) 2Cl] [PF6].

[Chlorobis (2 (lhl)-pyrimidinethione-Ks2) (2,: 6. 2s-terpyridine-KNlKN2KN ruthenium (II) hexafluorophosphate].

Using General Procedure H: Reaction of Ru (terpy) Cl3 (0.50 g, 1.13 mmol) and 2-mercaptopyrimidine (0.25 g, 2.28 mmol) gave the desired product (0.073g, 8.6%) following purification by <BR> <BR> <BR> column chromatography on silica gel.'H NMR (CD3CN) 6 6.99-7.05 (m, 2H), 7.43 (m, 1H), 7.55-7.60 (M, 2H), 7.81 (m, 1H), 8.10-8.23 (m, 5H), 8.35-8.39 (m, 2H), 8.47-8.50 (m, 2H), 8.87 (dd, 1H, J=4. 7,4.7 Hz), 9.95 (dd, 1H, J=5.9,2.3 Hz). Anal.

Calcd. for C23HI9N7S2CIRuPF6: C, 37.38; H, 2.59; N, 13.27; S, 8.68. Found: C, 38.27; H, 2.39; N, 13.75; S, 8.45.

EXAMPLE 72.

AMD7086: Preparation of [Ru (terpy) (S2CNMe2) Cl] [PF6].

[Chloro (dimethylcarbamodithioato-#S, K") (2,2': 6'. 2"-terpyridine-xNI, KN2', olNl") ruthenium (III) hexafluorophosphate].

Ru (terpy) Cl3 (0.50 g, 1.14 mmol) and N, N-dimethyldithiocarbamic acid sodium salt (Aldrich, 0.204 g, 1.14 mmol) were heated to reflux in methanol (100 mL) for 2 hours. The hot solution was filtered through celite and the volume of the filtrate was reduced to approximately one half the original volume. Addition of a saturated solution of NH4PF6 in methanol to the filtrate resulted in the formation of a precipitate, which was collected by filtration and purified by column chromatography on silica gel (MeCN/sat. KN03/H20: 7/1/0.5) to give the title compound (0.20g, 28%). Anal. Calcd. for Cl8Hl7N4S2ClRuPF6: C, 34.05; H, 2.70; N, 8.82; S, 10.10.

Found: C, 33.76; H, 2.80; N, 9.62; S, 9.95.

EXAMPLE 73.

AMD7036: Preparation of [Ru (bpy) 2Cl2]-2H20 [Dichlorobis (2,2'-bipyridine-KN', KN'') ruthenium (II) dihydrate].

Prepared according to literature procedures: B. Bosnich, F. P. Dwyer Aust. J.

Chem. 1966,19,2229.

EXAMPLE 74.

AMD7037: Preparation of [Ru (phen) 2CI2] 2H20 [Dichlorobis (1, 10-phenanthroline-N1°) ruthenium (II) dihydrate].

Prepared according to literature procedures: B. Bosnich, F. P. Dwyer Aust. J.

Chem. 1966,19,2229.

EXAMPLE 75.

AMD7039: Preparation of [Ru (bpy) 2 (2-mercaptopyridine)] [CI04].

[Bis (2,2'-bipyridine-KNI, KIV1') (2 (1H)-pyridinethionato-#N1,#S2) ruthenium (II)].

Perchlorate.

Prepared according to literature procedures: B. Kumar Santra, M. Menon, C.

Kumar Pal, G. Kumar Lahiri J. Chem. Soc., Dalton Trans. 1997,1387.

EXAMPLE 76.

AMD7045: Preparation of [Ru (bpy) 2 (2-mercaptopyridine)] [PF6].

[Bis (2,2'-bipyridine-, #N1')(2(1H)-pyridinethionato-#N1,#S2) ruthenium (II) hexafluorophosphate].

[Ru (bpy) 2Cl2]#2H2O (1.0 g, 1.9 mmol) was dissolved in a 1: 1 mixture of methanol water (100 mL). 2-Mercaptopyridine was added to the solution and the reaction mixture was heated to reflux for 1.5 hours. The solution was cooled to room temperature and a saturated solution of NH4PF6 in methanol was added. Upon standing a dark purple precipitate formed which was removed by filtration and washed with water. This crude product was purified by column chromatography on silica gel (2: 1 wCHCl3MeCN) to give the title compound (0.92 g, 72%). 1H NMR <BR> <BR> <BR> <BR> (CD3CN) 8 6.58-6.27 (m, 1H), 6.76 (d, 1H, J=8.16Hz), 7.00-7.02 (m, 1H), 7.13-7.17 (m, 1H), 7.19-7.23 (m, 1H), 7.29-7.34 (m, 1H), 7.55-7.60 (m, 1H), 7.67-7.89 (m, 5H), 8.04 (t, 2H, J=7. 9 Hz), 8.25 (d, 1H, J=5.2 Hz), 8.36 (t, 2H, J=8. 2 Hz), 8.46 (t, 2H,

J=7.3 Hz), 9.84-9.86 (m, 1H). Anal. Calcd. for C25H2oN5SRuPF6: C, 44.91; H, 3.02; N, 10.48; S, 4.80. Found: C, 44.88; H, 3.02; N, 10.58; S, 4.71.

EXAMPLE 77.

AMD8657: Synthesis of [Ru (acac) 2 (MeCN) 2] [CF3S03].

[Bis (acetonitrile) bis (2,4-pentanedionato-KO, KO') ruthenium (III) trifluoromethanesulfonate].

General Procedure I : This synthesis was adapted from a literature procedure: Oomura, K.; Ooyama, D.; Satoh, Y.; Nagao, N.; Nagao, H.; Howell, M.; Mukaida, M. Inorg. Chim. Acta In a schlenk tube, Ru (-diketonato) 3 was dissolved in acetonitrile (~ 1 g/50 mL) and the mixture was stirred for 5 min at 65 °C to yield a orange/red/purple solution; Trifluoromethanesulfonic acid (1.1-4 equivalents) was then added dropwise.

Instantly, the solution became brown/green; a reflux condenser was then attached and the mixture was heated to reflux for 0.5-4 h. The final navy blue (Ru (III)) and/or orange/red/brown (Ru (II)) mixture was concentrated and purified by crystalization or column chromatography. tris- (2,4-pentanedionato) ruthenium (III) [Ru (acac) 3] was Prepared according to procedure adapted from the literature: Johnson, A.; Everett, Jr., G. W. J. Am. Chem. Soc. 1972,94,1419.

Preparation of rRu (acac) 2 (MeCN) 2 [CF3S0 Using General Procedure I: Ru (acac) 3 (1.07 g, 2.68 mmol) was dissolved in acetonitrile (50 mL). Addition of Trifluoromethanesulfonic acid (300 µL, 3.39 mmol) yielded the title complex after stirring for 1 h at reflux; crystallization from a 40: 1 mixture of Et20: CH2Cl2 at 5 °C overnight yielded a dark blue, crystalline solid (1.42 g, 96 %). Anal. Calcd. for C15H20N2O7SF3Ru#H2O : C, 31.85; H, 3.91; N, 3.98. Found: C, 32.13; H, 3.87; N, 3.96. ES-MS m/z 382 [M-CF3SO3] +. IR (KBr) v (cl'') 2326,2296 (C-N); 1524 (C=O).

EXAMPLE 78.

AMD8660: Synthesis of Ru (acac) 2 (MeCN) 2.

[Bis (acetonitrile) bis (2,4-pentanedionato-KO, KO') ruthenium (II)].

Preparation of Ru (acac) 2 (MeCN) 2 [Ru (acac) 2 (MeCN) 2] [CF3S03] (0.201 g, 0.378 mmol) was dissolved in EtOH (10 mL) to give a blue solution. Addition of Me2NCS2Na-2H20 (0.076 g, 0.426 mmol) afforded an orange/brown solution immediately. The mixture was stirred at room temperature for 5 min and then the solvent was removed under reduced pressure. The orange/brown residue was purified by column chromatography on silica gel; 20: 1 CH2Cl2: MeOH). The major orange band was collected in several fractions and the solvent removed under reduced pressure to yield a yellow/orange solid (0.094 g, 65 %). Anal. Calcd. for Ci4H2oN204Ru-0.5C2H60: C, 37.89; H, 5.18; N, 3.19.

Found: C, 38.01; H, 4.99; N, 3.26. ES-MS m/z 382 [M+H] +. IR (KBr) v (cl'') 2333, 2251 (C=N); 1566 (C=O).

EXAMPLE 79. of[Ru(3Meacac)2(MeCN)2][CF3SO3].AMD8892:Synthesis [Bis (acetonitrile) bis (3-methyl-2,4-pentanedionato-KO, KO') ruthenium (III) trifluoromethanesulfonate]. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> tris- (3-methyl-2,4-pentanedionato) ruthenium (III) [Ru (3Meacac) 3] was prepared according to literature procedures: Endo, A.; Shimizu, K.; Sato, G. P. Chem. Lett. 1985,581.

[Ru(3Meacac)2(MeCN)2][CF3SO3]Preparationof Using General Procedure I: Ru (3Meacac) 3 (0.522 g, 1.19 mmol) was dissolved in acetonitrile. Addition of Trifluoromethanesulfonicacid (115 pL, 1.31 mmol) yielded the title complex after 1 h at reflux; crystallization from a 40: 1 mixture of Et20: CH2C12 at 5 °C overnight yielded a dark blue, crystalline solid (0.608 g, 92 %). Anal. Calcd. for C17H24N207SF3Ru: C, 36.56; H, 4.33; N, 5.02; S, 5.74. Found: C, 36.29; H, 4.34; N, 5.04; S, 5.86. ES-MS m/z 410 [M-CF3SO3] +. IR (KBr) v (cm~l) 2316,2296 (C-N); 1535 (C=O).

EXAMPLE 80. ofRu(3Mecac)2(MeCN)2AMD8901:Synthesis [Bis (acetonitrile) bis (3-methyl-2,4-pentanedionato-KO, KO') ruthenium (II)].

Preparation Ru(3Meacac)2(MeCN)2 (0.105g,0.188mmol)wasdissolvedinacetonitrile(25[Ru(3Meacac)2 (MeCN)2][CF3SO3] mL) to give a blue solution. Addition of zinc shavings (12 g) followed by rapid stirring for 4 h at room temperature led to the formation of a bright orange solution. The zinc was removed by filtration, the solvent concentrated in vacuo and then the mixture was purified by column chromatography on silica gel ; 20. 1 CH=CI : MeOH). The major orange band was collected in severalfractions and the solvent removed under reduced pressure to yield a bright orange solid (0. 025 g, 32 % Anal. Calcd. for Cl16H24N2O4Ru#0.1CH2Cl2: C, 46. 27; H, 5.84, N, 6.70. Found: C, 46.00; H, 5. 81; N, 6.43. ES-MS m/z 410 [M+H7+. IR (KBr) v (cm-') 2336,2248 (C--N) ; 1555 (C=O).

EXAMPLE 81.

AMD8883 SynthesisofRu(3Clacac)2(MeCN)2and[Ru(3Clacac)2(MeCN)2][CF3SO 3].AMD8884: [Bis (acetonitrile) bis (3-chloro-2,4-pentanedionato-KO, KO') ruthenium (II)] and [Bis (acetonitrile) bis (3-chloro-2,4-pentanedionato-KO, KO') ruthenium (III) trifluoromethanesulfonate]. <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> tris- (3-chloro-2,4-pentanedionato) ruthenium (III) [Ru (3Clacac) 3] was prepared according to literature procedure: Endo, A.; Shimizu, K.; Sato, G. P. Chem. Lett. 1985,581.

Ru(3Clacac)2(MeCN)2and[Ru(3Clacac)2(MeCN)2][CF3SO3]Prepar ationof Using General Procedure I: Ru (3Clacac) 3 (0.375 g, 0.745 mmol) was dissolved in acetonitrile (25 mL).

Trifluoromethanesulfonic acid (220 µL, 2.48 mmol) was added and the mixture was heated to reflux for 1 h; purification by column chromatography on silica gel (20: 1 CH2Cl2: MeOH) resulted in the isolation of two major bands (orange and blue). The fractions containing the orange band were concentrated to-5 mL and hexanes were added to give a bright orange precipitate of Ru (II) (3Clacac) 2 (MeCN) 2 which was isolated via suction filtration (0.085 g, 25 %). Anal. Calcd. for C14Hl8N204Cl2Ru-0. 4CH2CI2: C, 35.64; H, 3.91; N, 5.76; Cl, 20.72. Found: C, 35.91; H, 4.07; N, 5.61; Cl, 21.00. ES-MS m/z 452 [M+H] +. IR (KBr) v (cm'') 2335,2261 (C_N); 1543 (C=O).

The fractions containing the blue band were concentrated and the dark blue product was crystallized from a 40: 1 mixture of Et20: CH2C12 at 5 °C overnight to

give [Ru (III) (3Clacac) 2 (MeCN) 2] [CF3S03] (0.155 g, 35%). Anal. Calcd. for C15Hl8N207Cl2SF3Rw0. 1C4H1o0: C, 30.48; H, 3.16; N, 4.62; S, 5.28; Cl, 11.69.

Found: C, 30.56; H, 3.28; N, 4.77; S, 5.29; Cl, 11.70. ES-MS m/z 451 [M-CFsSC.

IR (KBr) # 2298(C#N);1532(C=O).2326, EXAMPLE 82.

AMD8881: Synthesis of [Ru(3Bracac)2(MeCN)2][CF3SO3].

[Bis (acetonitrile) bis (3-bromo-2,4-pentanedionato-KO, KO') ruthenium (III) trifluoromethanesulfonate]. tris- (3-bromo-2,4-pentanedionato) ruthenium (III) [Ru (3Bracac) 3] was prepared according to literature procedures: Endo, A.; Shimizu, K.; Sato, G. P. Chem. Lett. 1985,581.

[Ru(3Bracac)2(MeCN)2][CF3SO3]Preparationof Using General Procedure I: Ru (3Bracac) 3 (0.638 g, 1.00 mmol) was dissolved in acetonitrile (25 mL).

Addition of Trifluoromethanesulfonic acid (265 pL, 2.99 mmol) yielded the title complex after 1 h at reflux; the mixture was purified by column chromatography on silica gel (20: 1 CH2Cl2: MeOH) followed by crystallization from a 40: 1 mixture of Et20: CH2C12 at 5 °C overnight, to give a dark blue crystalline solid (0.315 g, 46 %).

Anal. Calcd. for C15H18N207Br2SF3Ru-0.3 C4H, 00: C, 27.39; H, 2.98; N, 3.94; S, 4.51. Found: C, 27.62; H, 2.69; N, 4.25; S, 4.70. ES-MS m/z 539 [M-CF3S03] +. IR (KBr) v (cl'') 2326,2299 (C---Nsym.); 1522 (C=O).

EXAMPLE 83.

AMD8900: Synthesis of Ru (3Bracac). (MeCN)..

[Bis (acetonitrile) bis (3-bromo-2,4-pentanedionato-KO, KO') ruthenium (II)].

Ru(3Bracac)2(MeCN)2Preparationof [Ru (3Bracac) 2 (MeCN) 2] [CF3S03] (0.350 g, 0.508 mmol) was dissolved in acetonitrile (50 mL) to give a blue solution. Addition of basic alumina (-15 g) followed by rapid stirring for 2 h at room temperature resulted in the formation of an orange/brown solution. The alumina was removed by filtration, the solvent concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (20: 1 CH2Cl2: MeOH). The major orange band was collected in several fractions and the solvent was removed under reduced pressure.

The orange residue was recrystallized from acetone: hexanes to yield a bright orange solid (0.115 g, 42 %). Anal. Calcd. for C, 4HlgN204Br2Ru-0. 3C3H60: C, 32.76; H, 3.72; N, 4.93; Br, 28.12. Found: C, 32.74; H, 3.74; N, 4.96; Br, 28.23. ES-MS m/z 540 [M+H] +. IR (KBr) v (cm~l) 2340,2263 (C=N); 1530 (C=O).

EXAMPLE 84.

AMD8896:Synthesisof[Ru(3Iacac)(acac)(MeCN)2][CF3SO3]andAM D8910and [Ru(3Iacac)(MeCN)4][CF3SO3].

[Bis (acetonitrile) (2,4-pentanedionato-KO, KO') (3-iodo-2,4-pentanedionato-KO, KO') ruthenium (III) trifluoromethanesulfonate] and [Tetrakis (acetonitrile) (3-iodo-2,4-pentanedionato-KO, KO') ruthenium (II) trifluoromethanesulfonate]. <BR> <BR> <BR> <BR> <BR> <BR> tris- (3-iodo-2,4-pentanedionato) ruthenium (III) [Ru (31acac) 3] was prepared according to literature procedures: Endo, A.; Shimizu, K.; Sato, G. P. Chem. Lett. 1985,581.

[Ru(3Iacac)2(MeCN)2][CF3SO3]and[Ru(3Iacac)(MeCN)4][CF3SO3 ].Preparationof Using General Procedure I: Ru (31acac) 3 (0.460 g, 0.593 mmol) was dissolved in acetonitrile (25 mL).

Trifluoromethanesulfonic acid (60 J. L, 0.678 mmol) was added and the reaction was heated to reflux for 1 hour; the reaction mixture was purified by column chromatography on silica gel (15: 1 CH2Cl2: MeCN) to give [Ru (3Iacac) (acac) (MeCN) 2] [CF3SO3] as a dark blue crystalline solid (0.089 g, 30 %).

Anal. Calcd. for C15Hl9N207ISF3Ru: C, 27.45; H, 2.92; N, 4.27; S, 4.88; I, 19.33.

Found: C, 27.35; H, 3.00; N, 4.21; S, 4.91; I, 19.46. ES-MS m/z 508 [M-CF3S03J+. IR (KBr) v (cl'') 2326,2297,2249 (C#N), 1523 (C=O).

Repeating the above procedure with 4 equivalents of Trifluoromethanesulfonic acid followed by silica gel column purification and recrystallization of the product from acetone: hexanes gave [Ru (3Iacac) (MeCN) 4] [CF3SO3] as a grey/purple crystalline solid (0.125 g, 33 %). Anal. Calcd. for C14Hl8N405ISF3Ru-0.7 C3H60: C, 28.44; H, 3.29; N, 8.24; S, 4.71. Found: C, 28.12; H, 3.20; N, 8.02; S, 4.39. ES-MS m/z 491 [M-CF3SO3] +. IR (KBr) v (cari 1) 2339,2284 (C#N), 1537 (C=O).

EXAMPLE 85.

AMD8691: Synthesis of [Ru(dpac)2(MeCN)2] [CF3SO3].

[Bis (acetonitrile) bis (1,3-diphenyl-1,3-propanedionato-KO, KO') ruthenium (III) trifluoromethanesulfonate]. tris- (1, 3-diphenyl-1,3-propanedionato) ruthenium (III) [Ru (dpac) 3] was prepared according to procedures adapted from the literature: Endo, A.; Shimizu, K.; Sato, G.

P.; Mukaida, M. Chem. Lett. 1984,437.

[Ru(dpac)2(MeCN)2][CF3SO3]Preparationof Using General Procedure I: Ru (dpac) 3 (8.103 g, 10.5 mmol) was dissolved in acetonitrile (250 mL).

Trifluoromethanesulfonic acid (2.5 mL, 28.2 mmol) was added and the reaction mixture was heated to reflux for 20 mins. The mixture was evaporated to dryness and the residue was purified by column chromatography on silica gel (CH2Cl2 # 20: 1 CH2Cl2: MeOH). The fractions containing the dark green band were combined and evaporated to give a dark green crystalline solid (5.75 g, 70 %). Anal. Calcd. for C35H28N207SF3Ru-0. 4H20: C, 53.49; H, 3.69; N, 3.56; S, 4.08. Found: C, 53.45; H, 3.74; N, 3.43; S, 3.97. ES-MS m/z 630 [M-CF3SO3]+. IR (KBr) v (cm~l) 2363,2337 (C-N); 1523 (C=O).

EXAMPLE 86.

AMD8692 : Synthesis of Ru (dpac), (MeCN).

[Bis (acetonitrile) bis (1,3-diphenyl-1,3-propanedionato-KO, KO') ruthenium (II)].

Ru(dpac)2(MeCN)2Preparationof [Ru (dpac) 2 (MeCN) 2] [CF3S03] (0.225 g, 0.289 mmol) was dissolved in CH2C12 (25 mL) to give a green solution. Addition of basic alumina (-10 g) resulted in an instant colour change to orange. The mixture was stirred for 30 min at room temperature, the alumina was removed by filtration and the filtrate was evaporated to dryness to yield a bright orange solid (0.045 g, 25 %). Anal. Calcd. for C30H28N204Ru 0. 5H2O: C, 64.01; H, 4.57; N, 4.39. Found: C, 64.02; H, 4.58; N, 4.19.

ES-MS m/z 630 [M+H] +. IR (KBr) v (cm-1) 2339,2258 (C-N), 1516 (C=O).

EXAMPLE87. of[Ru(hmac)2(MeCN)2][CF3SO3].AMD8707:Synthesis [Bis (acetonitrile) bis (2,2,6,6-tetramethyl-3,5-heptanedionato-KO, KO') ruthenium (III) trifluoromethanesulfonate]. tris- (2,2,6,6-tetramethyl-3,5-heptanedionato) ruthenium (III) [Ru (hmac) 3] was prepared according to literature procedures: Endo, A.; Katjitani, M.; Mukaida, M.; Shimizu, K.; Sato, G. P. Inorg. Chim. Acta 1988, 150, 25.

Preparation of (Ru (hmac) 2 (MeCN) 21 [CF3S0 Using General Procedure I: Ru (hmac) 3 (0.145 g, 0.207 mmol) was dissolved in acetonitrile (10 mL).

Trifluoromethanesulfonic acid (40 pL, 0.452 mmol) was added and the mixture was heated to reflux for 30 mins. The mixture was evaporated to dryness and the residue was purified by column chromatography on silica gel (CH2C12: hexanes 1: 1 followed by 20: 1 CH2Cl2: MeOH). The fractions containing the blue band were combined and evaporated to give a dark blue crystalline solid (0.104 g, 67 %). Anal. Calcd. for C27H44N207SF3Ru-1. 6CH40: C, 45.79; H, 6.78; N, 3.73. Found: C, 45.86; H, 6.62; N, 3.34. ES-MS m/z 550 [M-CF3SO3] +. IR (KBr) v (cm-1) 2326,2297 (C-N); 1529 (C=O).

EXAMPLE 88.

AMD8658: Synthesis of Ru (hfac), (MeCN), [Bis (acetonitrile) bis (1,1,1,5,5,5-hexafluoro-2,4-pentanedionato-KO, KO') ruthenium (II)]. tris- (1, 1, 1,5,5,5-hexafluoro-2,4-pentanedionato) ruthenium (III) [Ru (hfac) 3]. The ruthenate complex, K [Ru (hfac) 3], was isolated and then oxidized to Ru (hfac) 3 according to a literature procedure: Endo, A.; Katjitani, M.; Mukaida, M.; Shimizu, K.; Sato, G. P. Inorg. Chim. Acta 1988,150,25.

Preparation of Ru (hfac) 2 (MeCN) 2 Using General Procedure I:

Ru (hfac) 3 (4.00 g, 5.54 mmol) was dissolved in acetonitrile (200 mL).

Trifluoromethanesulfonic acid (865 jj. L, 6.06 mmol) was added and the mixture was heated to reflux for 1 hour. The solvent was evaporated and the residue was purified by column chromatography on silica gel (CH2C12) to give a brown/black crystalline solid (2.71 g, 95 %). Anal. Calcd. for Cl4H8N204Fl2Ru : C, 28.15; H, 1.35; N, 4.69.

Found: C, 28.35; H, 1.33; N, 4.62. ES-MS m/z 598 [M+H] +. IR (KBr) v (cm-') 2357, 2285 (C_N), 1546 (C=O).

EXAMPLE 89.

AMD8693and AMD869 . Synthesis of sym and asym-Ru (tfac), (MeCN) = [sym-Bis (acetonitrile) bis (1,1,1-trifluoro-2,4-pentanedionato-KO, KO') ruthenium (II)] and [asym-Bis (acetonitrile) bis (1,1,1-trifluoro-2,4-pentanedionato-KO, KO') ruthenium (II)]. tris- (1, 1, 1-trifluoro-2,4-pentanedionato) ruthenium (III) [Ru (tfac) 3] was prepared <BR> <BR> <BR> <BR> according to literature procedures (a mixture of A and A-isomers isolated): Endo, A.; Katjitani, M.; Mukaida, M.; Shimizu, K.; Sato, G. P. Inorg. Chim. Acta 1988,150,25.

Synthesis of svm and asvm-Ru (tfac) 2 (MeCN) 2 Following General Procedure I: A mixture of A and A-Ru (tfac) 3 (1.57 g, 2.80 mmol) in acetonitrile (100 mL).

Trifluoromethanesulfonic acid (500 pLL, 3.50 mmol) was added and the mixture was heated to reflux for 4 hours during which time the solution turned purple/blue.

Addition of basic alumina (-50 g) afforded an orange solution containing a mixture of the title complexes. The alumina was removed via filtration and the filtrate was purified by column chromatography on silica gel (20: 1 CH2Cl2: MeOH) to give three bands which eluted in the following order: sym-Ru (tfac) 2 (MeCN) 2, symlasym- Ru (tfac) 2 (MeCN) 2 mixture and asym-Ru (tfac) 2 (MeCN) 2. Each fraction was evaporated to dryness to give orange solids; the yields of each compound after recrystallization from acetone/hexanes were: 0.121 g, 0.319 g and 0.244 g, respectively, affording an overall yield of 48%. Both pure isomers have essentially identical analytical data. Anal. Calcd. for Cl4Hl4N204F6Ru 1. 3C3H6O: C, 38.11; H,

3.90; N, 4.95. Found: C, 38.29; H, 3.24; N, 4.97. ES-MS m/z 490 [M+H] +. IR (KBr) v (cm-1) 2345,2270 (C-N); 1591 (C=O).

EXAMPLE 90.

AMD8730Synthesisofsymandasym-Ru(tftmac)2(MeCN).AMD8710: [sym-Bis (acetonitrile) bis ( 1,1,1-trifluoro-5,5-dimethyl-2,4-hexanedionato-KO, KO') ruthenium (II)] and [asym-Bis (acetonitrile) bis (1, 1, 1-trifluoro-5,5-dimethyl-2,4-hexanedionato-KO, KO') ruthenium (II)]. tris- (1,1,1-trifluoro-5,5-dimethyl-2,4-hexanedionato) ruthenium (III) [Ru (tftmac) 3] <BR> <BR> <BR> <BR> was prepared according to literature procedure (a mixture of A and A-isomers isolated): Endo, A.; Katjitani, M.; Mukaida, M.; Shimizu, K.; Sato, G. P. Inorg. Chim.

Acta 1988,150,25.

Preparation of sym and asym-Ru (tftmac) z MeCN 2 Using General Procedure I: A mixture of A and A-Ru (tftmac) 3 (1.30 g, 1.89 mmol) was dissolved in acetonitrile (100 mL). Trifluoromethanesulfonic acid (425 pL, 2.97 mmol) was added and the reaction mixture was heated to reflux for 3 hours during which time the solution turned purple. Addition of basic alumina (-35 g) afforded an orange solution containing a mixture of the title complexes after stirring for 1.5 h at room temperature.

The alumina was removed by filtration and the filtrate was purified by column chromatography on silica gel (CH2C12). Two compounds were isolated which eluted in the order: sym-Ru (tftmac) 2 (MeCN) 2 followed by asym-Ru (tftmac) 2 (MeCN) 2. The fractions collected were evaporated to yield orange solids, which were recrystallized from acetone/hexanes to give 0.098 g and 0.461 g, respectively, affording an overall yield of 64%. Both pure isomers have essentially identical analytical data. Anal.

Calcd. for C2oH26N204F6Rll-0. 5C3H60: C, 42.86; H, 4.85; N, 4.65. Found: C, 42.93; H, 4.60; N, 4.77. ES-MS m/z 574 [M+H] +. IR (KBr) v (cl'') 2330,2268 (C-N); 1591 (C=O).

EXAMPLE 91. of[Ru(maltol)2(MeCN)2][CF3SO3].AMD8757:Synthesis [Bis (acetonitrile) bis [ (3-hydroxy-KO)-2-methyl-4-pyronato-KO'] ruthenium (III) trifluoromethanesulfonate].

[Ru(maltol)2(MeCN)2][CF3SO3]Preparationof Following General Procedure I: Ru (maltol) 3 (0.210 g, 0.441 mmol) was dissolved in acetonitrile (20 mL).

Trifluoromethanesulfonic acid (50 L, 0.565 mmol) was added and the reaction mixture was heated to reflux for 3 hours. The mixture was evaporated and the residue was purified by column chromatography on silica gel (10: 1 CH2CI2: MeOH). The fractions containing the dark green band were combined and evaporated and the residue was then recrystallized from acetone/hexanes to give a dark green crystalline solid (0.085 g, 35 %). Anal. Calcd. for C17Hl6N209SF3Ru-0. 4C3H60: C, 36.09; H, 3.06; N, 4.63. Found: C, 36.06; H, 3.09; N, 4.44. ES-MS m/z 434 [M-CF3S03] +. IR (KBr) v (cl'') 2322,2289 (C-N), 1602,1548 (C=O).

EXAMPLE92.

AMD8695Synthesisof[Ru(acac)2(MeCN)2(tmpd)][CF3SO3]andAMD8 696: [Ru(acac)2(MeCN)2(tmpd)2][CF3SO3].

[Bis (acetonitrile) bis [4- (hydroXy-KO)-3-penten-2-onato] (N, NX, N'-tetrainethyl-1,3- propanediamine-KN, xN') ruthenium (III) trifluoromethanesulfonate] and [Bis (acetonitrile) bis [4- (hydroxy-K0)-3-penten-2-onato] bis (N,N,N',N'-tetramethyl- 1,3-propanediamine-KN) ruthenium (III) trifluoromethanesulfonate].

General Procedure J In a schlenk tube, [Ru (acac) 2 (MeCN) 2] [CF3S03] was dissolved in CH2CI2 to give a blue solution Dropwise addition of an amine ligand, resulted in an immediate colour change to red/orange. The mixture was stirred at 40 °C for 0.5-3 h before the solvent was removed under reduced pressure and the red/brown residue was purified by column chromatography on silica gel. The amine ligands used included: N, N, N', N'-tetramethyl-1, 3-propanediamine (tmpd), diethylenetriamine (dien), 2- (2- aminoethylamino) ethanol (aeae), N- (2-aminoethyl)-1,3-propanediamine (aepd), N- (3- aminopropyl)-1,3-propanediamine (appd), and L1.

Preparation of rRu (acac) 2 (MeCN) 2 (tmpd) irCF3S03l and (Ru (acac) 2 (MeCN) 2 (tmpd)2] rCF3SO31 Using General Procedure J: Addition of tmpd (135 1L, 0.807 mmol) to a CH2C12 solution of [Ru (acac) 2 (MeCN) 2] [CF3S03] (0.353 g, 0.665 mmol) afforded a red/orange solution after 1.5 hours. The mixture was purified by column chromatography on silica gel (20: 1 CH2Cl2: MeOH) to give a red product and an orange product. The fractions from the red and orange bands were evaporated to give dark red (0.039 g, 9 %) and bright orange (0.069 g, 13 %) solids, respectively. The red solid was characterized as [Ru (acac) 2 (MeCN) 2 (tmpd)] [CF3SO3]. Anal. Calcd. for C22H38N407SF3Ru-1. 3CH2Cl2: C, 36.25; H, 5.30; N, 7.25. Found: C, 36.18; H, 5.29; N, 7.46. ES-MS m/z 512 [M- CF3SO3] +. IR (KBr) v (cm-1) 2361,2340 (C-N); 1620,1524 (C=O). The orange solid was characterized as [Ru (acac) 2 (MeCN) 2 (tmpd) 2] [CF3S03]. Anal. Calcd. for C29Hs6N607SF3Ru1. 8CH2Cl2: C, 39.27; H, 6.38; N, 8.93. Found: C, 39.18; H, 6.39; N, 9.17. ES-MS m/z 642 [M-CF3SO3]+. IR (KBr) v (cl'') 2300 (C-N); 1624,1608, 1548,1521 (C=O).

EXAMPLE 93. <BR> <BR> <BR> <BR> <P>AMD8704 and AMD8705: Synthesis of sym and asym-[Ru(acac)2(MeCN)2(dien)] [CF3SO3].

[Bis (acetonitrile) [N, N'-bis [2-(amino-KN) ethyl] amine] bis [4-(hydroxy-KO)-3-penten-2- onato] ruthenium (III) trifluoromethanesulfonate] and [Bis (acetonitrile) [N-(2-aminoethyl)-1, 2-ethanediamine-KN, KN] bis [4-(hydroxy-#O)-3- penten-2-onato] ruthenium (III) trifluoromethanesulfonate].

Preparation andasym-[Ru(acac)2(MeCN)2(dien)][CF3SO3]sym Following General Procedure J: Addition of dien (70 pL, 0.613 mmol) to a CH2Cl2 solution of [Ru (acac) 2 (MeCN) 2] [CF3S03] (0.325 g, 0.613 mmol) afforded a red/orange solution after 1 hour. The volume was reduced to 5 mL and Et20 (-50 mL) was added to give an orange/brown precipitate which was removed via filtration. The brilliant orange filtrate was concentrated under reduced pressure and the residue was purified by

column chromatography on silica gel (20: 1 # 12: 1 CH2CI2: MeOH). The first orange band afforded a bright orange solid (0.048 g, 12 %) whose characterisation data was consistent with the structure asym- [Ru (acac) 2 (MeCN) 2 (dien)] [CF3SO3]. Anal. Calcd. for Cl9H33N507SF3Ru: C, 36.02; H, 5.25; N, 11.05. Found: C, 35.75; H, 5.18; N, 10.78. ES-MS m/z 485 [M-CF3SO31+. IR (KBr) v (cm-1) 1628,1514 (C=O).

The second orange band afforded an orange solid (0.035 g, 9%) whose characterisation data was consistent with the structure sym- [Ru (acac) 2 (MeCN) 2 (dien)] [CF3SO3]. Anal. Calcd. for C19H33N5O7SF3Ru#3.6CHCl3 : C, 25.50; H, 3.46; N, 6.58.

Found: C, 25.44; H, 3.75; N, 6.61. ES-MS m/z 485 [M-CF3S03] +. IR (KBr) v (cm-1) 1624, 1521 (C=O).

EXAMPLE 94. of[Ru(acac)2(MeCN)2(aeae)][CF3SO3].AMD8874:Synthesis [Bis (acetonitrile) [2-(2-amino-KN-ethylamino-KNs) ethanol] bis [4-(hydroxy-#O)-3- penten-2-onato] ruthenium (III) trifluoromethanesulfonate].

Synthesis of [Ru (acac) 2(MeCN)2(aeae)][CF3SO3 Using General Procedure J: Addition of aeae (85 µL, 0.841 mmol) to a CH2CI2 solution of [Ru (acac) 2 (MeCN) 2] [CF3S03] (0.391 g, 0.737 mmol) afforded a red/orange solution after 5 hours. The mixture was purified by column chromatography on silica gel (15: 1 to 10: 1 CH2CI2: MeOH) to give a red/brown solid (0.127 g, 27%). Anal. Calcd. for C19H32N4O8SF3Ru#1.2CF3SO3H#0.8H2O : C, 29.26; H, 4.23; N, 6.76; S, 8.51. Found: C, 29.25; H, 4.01; N, 6.41; S, 8.40. ES-MS m/z 486 [M-CF3S03] +. IR (KBr) v (cm-1) 2263 (C-N), (C=O).

EXAMPLE 95.

AMD8878: Synthesis of [Ru (acac) 2 (MeCN) 2 (appd)] [CF3S03].

[Bis (acetonitrile) [N-(3-aminopropyl)-1,3-propanediamine-#N,#N'] bis [4- (hydroxy- KO)-3-penten-2-onato] ruthenium (III) trifluoromethanesulfonate].

Preparation of [Ru (acac) 2 (MeCN) 2tappd) 1 [CF3SO3l

Using General Procedure J: Addition of appd (110 µL, 0.774 mmol) to a CH2C12 solution of [Ru (acac) 2 (MeCN) 2] [CF3S03] (0.373 g, 0.704 mmol) afforded a red/orange solution after 5 hours. The mixture was purified by column chromatography on silica gel (20: 1 to 8: 1 CH2CI2: MeOH) to give an orange solid (0.041 g, 9%). Anal. Calcd. for C2lH37N507SF3Ru 0. 4CF3SO3H 0. 7CH2C12: C, 33.98; H, 5.01; N, 8.97; S, 5.75.

Found: C, 34.28; H, 4.97; N, 8.33; S, 5.89. ES-MS m/z 513 [M-CF3S03] +. IR (KBr) v (cm-1) 2335, 2289 (C#N); 1626, 1551 (C=O).

EXAMPLE 96. <BR> <BR> <BR> <BR> <P>AMD8879:Synthesis of [Ru (acac) 2 (MeCN). (aepd)] [CF3503].<BR> <BR> <BR> <P>[Bis(acetonitrile)[N-(2-aminoethyl)-1,3-propanediam ine-#N.#N']bis[4-(hydroxy-#O)-3-penten-2- onatoJ ruthenium (III) trifluoromethanesulfonateJ.

Preparation of (Ru (acac) 2 (MeCN) 2 (aepd) 1 [CF3SO Following General Procedure J: Addition of aepd (100 µL, 0.782 mmol) to a CH2C12 solution of [Ru (acac) 2 (MeCN)2][CF3SO3] (0.377 g, 0.711 mmol) afforded a red/orange solution after 2 hours. The mixture was purified by column chromatography on silica gel (20: 1 to 8: 1 CH2CI2: MeOH) to give an orange solid (0.055 g, 12%). Anal. Calcd. for C2oH3sN507SF3Ru-0. 4H20: C, 36.68; H, 5.51; N, 10.69; S, 4.90. Found: C, 36.96; H, 5.38; N, 10.33; S, 4.85. ES-MS m/z 499 [M-CF3S03] +. IR (KBr) v (cm'') 2367,2334 (C#N), 1624,1550 (C=O).

EXAMPLE 97.

AMD8813: Synthesis of [Ru (acac) 2 (MeCN) 2 (Ll)] [CF3S03].

[Bis (acetonitrile) [N, N-bis [2-(amino-KN) ethyl]-L-isoleucyl-L-prolinato] bis [4- (hydroxy-KO)-3-penten-2-onato] ruthenium (III) trifluoromethanesulfonate].

Synthesis (L1)N,N-bis(2-aminoethyl)-Ile-Pro To a solution of nosyl aziridine (0.744 g, 3.26 mmol) in dry THF (20 mL) was added the dipeptide Ile-Pro (0.372 g, 1.63 mmol). The white slurry was stirred for 16 h at 65 °C under N2 resulting in a clear, yellow solution. The solvent was removed in

vacuo to give a yellow oil which was purified by column chromatography on silica gel (3: 2 EtOAc: hexanes and then 25: 1 CH2Cl2: MeOH) to give the desired intermediate as <BR> <BR> <BR> a pale yellow oil (0.377 g, 34 %). 1H NMR (CDC13) 8 0.79 (t, 3H), 0.91 (d, 4H), 1.04 (m, 1H), 1.55 (m, 2H), 1.94 (m, 2H), 2.29 (dm, 1H), 2.79 (m, 2H), 3.35-3.56 (m, 8H), 4.27 (m, 1H), 4.34 (m, 1H), 6.13 (s, 1H), 6.34 (s, 1H), 7.71 (m, 6H), 8.04 (m, 2H); 13C NMR (CDC13) 8 11.63,16.13,24.79,25.69,29.26,38.21,42.75,44.20,47.29,53.93, 59.69,64.13,65.07,124.74,125.62,131.01,133.47,133.20,133.62, 134.03,134.34, 148.29,172.31. ES-MS m/z 707 [M+Na] +, 685 [M+H] +.

To a solution of the oil from above (0.377 g, 0.550 mmol) in dry acetonitrile (15 mL) was added K2CO3 (0.761 g, 5.50 mmol) and thiophenol (454 L, 4.41 mmol). The mixture was stirred for 3.5 h at room temperature under nitrogen, during which time, a bright yellow slurry formed. The mixture was filtered and the solid was washed with acetonitrile. The combined filtrates were evaporated and the residue was purified by column chromatography on neutral alumina using 5: 1 CH2C12: MeOH followed by 7: 2: 1 CH2C12: MeOH: NH40H to give LI as a pale yellow oil (0.085 g, 49 %). ES-MS m/z 337 [M+Na] +, 315 [M+H] +.

Preparation of [Ru (acac) 2 (MeCN) 2 (LI) l [CF3SO Using General Procedure J: Addition of LI (0.085 g, 0.271 mmol) to a CH2CI2 solution of [Ru (acac) 2 (MeCN) 2] [CF3S03] (0.126 g, 0.238 mmol) afforded a red/orange solution after the mixture was heated to reflux for 5 hours. The mixture was purified by column chromatography on silica gel (14: 1 to 10: 1 CH2Cl2: MeOH) to give a deep red solid (0.041 g, 25 %). Anal. Calcd. for C3oH5oN60) oSF3Ru-3. 6CH2d2: C, 35.07; H, 5.01; N, 7.30. Found: C, 35.11; H, 4.90; N, 7.05. ES-MS m/z 696 [M-CF3SO3] +.

EXAMPLE 98. of[Ru(acac)2(S2CNM2)].AMD8656:Synthesis <BR> <BR> [ (Dimethylcarbamodithioato-KS, KS") bis (2,4-pentanedionato-KO, KO') ruthenium (III)].

General Procedure K: In a schlenk tube, [Ru (-diketonato) 2 (MeCN) 2] [CF3S03] (where-diketonato = acac or dpac) was dissolved in EtOH: H20 (20: 1) to give a blue or green solution.

Addition of a dithiocarbamate salt resulted in an immediate colour change to red/brown. The mixture was stirred at 70 °C for 4-16 h before the solvent was removed under vacuum and the red/brown residue was purified using column chromatography. The dithiocarbamate salts were either purchased from Aldrich (NaS2CNMe2 2H2O) or synthesized according to general procedure F (KS2CNProK, KS2CNProOMe, KS2CNMeIleK).

Preparation of Ru (acac) 2 (S2CNMe2) Using General Procedure K: Addition of NaS2CNMe22H20 (0. 101 g, 0.563 mmol) to a solution of [Ru (acac) 2 (MeCN) 2] [CF3S03] (0.263 g, 0.496 mmol) in a mixture of ethanol and water gave an immediate colour change from blue to orange. The mixture was stirred at 70 °C for 5 h yielding a red/brown mixture which was purified by column chromatography on silica gel (20: 1 CH2C12: MeOH) to give a dark red solid upon drying in vacuo (0.092 g, 44 %). Anal. Calcd. for CI3H2oN04S2Ru-0.5EtOH: C, 37.89; H, 5.18; N, 3.19. Found: C, 38.01; H, 4.99; N, 3.26. ES-MS m/z 443 [M+Na] +.

EXAMPLE 99. <BR> <BR> <BR> <BR> <P>AMD8792: Synthesis of [Ru (dpac) 2 (5rCNMe2) j.<BR> <BR> <BR> <BR> <P>[(Dimethylcarbamodithioato-KS, KS') bisf 1, 3-diphenyl-1, 3-propanedionato-KO, KO') ruthenium (III)].

Preparation of [Ru (dpac) 2 (S2CNMe2) 1 Using General Procedure K: Addition of NaS2CNMe2-2H20 (0.073 g, 0.409 mmol) to a solution of [Ru (dpac) 2 (MeCN) 2] [CF3S03] (0.290 g, 0.372 mmol) in a mixture of ethanol and water gave an immediate colour change from green to red/orange. The mixture was stirred at 70 °C for 16 h to give a red/brown mixture which was evaporated and purified by column chromatography on silica gel (5: 1 CH2C12: hexanes) to give a deep red solid (0.025 g, 11 %). Anal. Calcd. for C33H28NO4S2Ru#0.3MeCN#0. 4hexanes: C,

60.51; H, 4.87; N, 2.55; S, 8.97. Found: C, 60.25; H, 4.90; N, 2.38; S, 8.50. ES-MS m/z 650 [M+Na] +. IR (KBr) v (cl'') 1514 (C=O).

EXAMPLE 100.

AMD8822: Synthesis of [Ru (acac) 2 (S2CNProOMe)].

[ (l-carboxymethyl)-1, 4-butanediylcarbamodithioato-KS, KS'] bis (2,4-pentanedionato- KO, KO') ruthenium (III).

Preparation of fRu (acac) 2 (S2CNProOMe) 1 Using General Procedure K: Addition of KS2CNProOMe (0.548 g, 2.24 mmol) to solution of [Ru (acac) 2 (MeCN) 2] [CF3S03] (1.06 g, 2.00 mmol) in a mixture of ethanol and water gave an immediate colour change from blue to orange. The mixture was stirred at 70 °C for 4 h to give a red/orange mixture which was evaporated and the residue purified by column chromatography on silica gel (50: 1 CH2CI2: MeOH) to give a deep red solid (0.147 g, 13 %). Anal. Calcd. for C17H24NO6S2Ru: C, 40.55; H, 4.80; N, 2.78; S, 12.73. Found: C, 40.68; H, 4.82; N, 2.76; S, 12.60. ES-MS m/z 527 [M+Na] +, 505 [M+H] +. IR (KBr) v (cm-1) 1746 (CO2Me), 1549 (C=O).

EXAMPLE 101.

AMD8823 and AMD8826: Synthesis of Ru (dpac) 2 (S2CNProOMe) and Ru (dpac) 2 (Pro).

[ (1-carboxymethyl)-1, 4-butanediylcarbamodithioato-KS, KS'] bis (1, 3-diphenyl-1,3- propanedionato-KO, KO') ruthenium (III) and [L-prolinato (1-)-KN, KO] bis (1,3-diphenyl-1,3-propanedionato-KO, KO') ruthenium (III) Synthesis of Ru (dpac) 2 (S2CNProOMe) and Ru (dpac) 2 (Pro) Using General Procedure K: Reaction of KS2CNProOMe (0.382 g, 2.24 mmol) with [Ru (dpac) 2 (MeCN) 2] [CF3S03] (0.947 g, 1.22 mmol) in ethanol/water solution followed by purification of the reaction mixture by column chromatography on silica gel (50: 1 CH2Cl2: MeOH) gave two products. A red solid whose characterisation data

was consistent with [Ru (dpac) 2 (S2CNProOMe)] (0.065 g, 5%). Anal. Calcd. for C37H32NO6S2Ru0.3dpac-1. 0EtOH: C, 60.41; H, 4.81; N, 1.62; S, 7.41. Found: C, 60.48; H, 4.91; N, 1.80; S, 7.64. ES-MS m/z 752 [M+H] +. IR (KBr) v (cl'') 1746 (CO2Me) ; 1587 (C=O). An orange/brown solid whose characterisation data were consistent with [Ru (dpac) 2 (Pro)] (0.095 g, 18 %). Anal. Calcd. for C35H29N06Ru: C, 63.63; H, 4.42; N, 2.12. Found: C, 63.45; H, 4.43; N, 2.24. ES-MS m/z 661 [M+H] +.

IR (KBr) v (cl'') 1667 (CO2-), 1586 (C=O).

EXAMPLE 102.

AMD8736: Synthesis of [Ru (acac) 2 (S2CNProK)].

[Potassium [(1-carboxy)-1,4-butanediylcarbamodithioata-#S,#S'] bis (2,4- pentanedionato-KO, KO') ruthenium (III)].

Preparation of [Ru (acac) 2 (S2CNProK) Using General Procedure K: Reaction of KS2CNProK (0.422 g, 1.58 mmol) with [Ru (acac) 2 (MeCN) 2] [CF3S03] (0.756 g, 1.42 mmol) gave a dark blue slurry. The mixture was stirred at reflux for 1 h giving a red/black mixture, which was evaporated to dryness. Sonication of the residue with CH2Cl2 gave a black solid, which was removed via filtration. The filtrate was purified by column chromatography on silica gel (20: 1 to 12: 1 CH2C12: MeOH) to give a deep red solid (0.105 g, 15 %). Anal.

Calcd. for Cl6H2lNO6S2RuK2. 1H2O#0.2KCF3SO3: C, 32.26; H, 4.21; N, 2.32; S, 11.69. Found: C, 32.43; H, 4.25; N, 2.25; S, 11.66. ES-MS m/z 490 [M+H] +. IR (KBr) v (C=O).1558 EXAMPLE 103.

AMD8791: Synthesis of [Ru (acac) 2 (NMeIle)].

[N-methyl-L-isoleucinato (1-)-KN, KO] bis (2,4-pentanedionato-KO, KO') ruthenium (III).

Preparation of (Ru (acac) 2 (NMeIle) l Using General Procedure K:

Reaction of KS2CNMeIleK (0.269 g, 0.903 mmol) with [Ru (acac) 2 (MeCN) 2] [CF3S03] (0.445 g, 0.839 mmol) in a mixture of ethanol and water gave an immediate colour change from blue to orange/brown. The mixture was stirred at 70 °C for 7 h giving a red/brown solution. The volume of the reaction mixture was reduced to-3 mL and Et20 was added to give a brown precipitate, which was separated by filtration. The filtrate was purified by column chromatography on silica gel (20: 1 CH2Cl2: MeOH) to give an orange/brown solid (0.050 g, 12%). Anal.

Calcd. for Cl7H27NO6Ru 0. 2C4HloO: C, 46.75; H, 6.39; N, 3.06. Found: C, 47.03; H, 6.16; N, 3.28. ES-MS m/z 465 [M+Na] +, 443 [M+H] +. IR (KBr) v (cm-1) 1670, 1560 (C=O).

EXAMPLE 104.

AMD8795: Synthesis of [Ru (acac) 2 (NMeIle)] 2 Bis [µ-[N-methyl-L-isoleucinato(o1-)-#N:#O]] tetrakis (2,4-pentanedionato-KO, KO') diruthenium (III).

Preparation of [Ru(acac)2(NMeIle)]2 [Ru (acac) 2 (MeCN) 2] [CF3S03] (0.270 g, 0.508 mmol) was dissolved in EtOH (6 mL) to give a dark blue solution. NMeIle (0.084 g, 0.581 mmol) was added and the mixture was stirred at 75 °C for 16 h to give an orange solution. The solvent was removed under reduced pressure and the orange residue was purified by column chromatography on silica gel (20: 1 CH2Cl2: MeOH) to give an orange solid (0.150 g, 67%). Anal. Calcd. for C34H56N2012Ru2-0. 3C6H14: C, 47.11; H, 6.65; N, 3.07. Found: C, 47.21; H, 6.62; N, 3.08. ES-MS m/z 911 [M+Na] +. IR (KBr) v (cm~l) 1649,1552 (C=O).

EXAMPLE 105.

AMD8845: Synthesis of [Ru (dpac) 2 (Pro)] 2 [Bis [µ-[L-prolinato(1-)-#N : KO]] tetrakis (1, 3-diphenyl-1, 3-propanedionato-KO, KO') diruthenium (III)].

Preparation of [Ru (dpac) 2 (Pro)] 2

[Ru (dpac) 2 (MeCN) 2] [CF3S03] (0.493 g, 0.633 mmol) was dissolved in EtOH (8 mL) to give a dark green solution. (L)-Proline (0.078 g, 0.677 mmol) was added and the mixture was stirred at 75 °C for 16 h to give a brown/orange solution. The solvent was removed under reduced pressure and the brown residue was purified by column chromatography on silica gel (50: 1 CH2Cl2: MeOH) to give an orange/brown solid (0.035 g, 8%). Anal. Calcd. for C7oH6oN2012Ru2-0. 4CH2Cl2: C, 62.43; H, 4.50; N, 2.06. Found: C, 62.44; H, 4.53; N, 1.98. ES-MS m/z 1345 [M+Na] +. IR (KBr) v (cl'') 1666,1522 (C=O).

EXAMPLE 106.

AMD8856: Synthesis of Ru (acac) 2 (2-pyridine thiolato) (2-pyridinethione).

[bis (2,4-pentanedionato-KO, KO') [2 (lH)-pyridinethionato-KS2] [2 (lH)-pyridinethione- K, S] ruthenium (III)].

Ru(acac)2(2MP)2Preparationof [Ru (acac) 2 (MeCN) 2] [CF3S03] (0.399 g, 0.751 mmol) was dissolved in EtOH (10 mL) to give a dark blue solution. 2-Mercaptopyridine (0.340 g, 3.06 mmol) was added and the mixture was stirred and heated at 75 °C for 5 h to give a red/purple solution. The solvent was removed under reduced pressure and the purple residue was purified via preparative TLC on silica gel (20: 1 CH2Cl2: MeOH) to give a purple solid (0.057 g, 14 %). Anal. Calcd. for C2oH23N204S2Ru: C, 46.14; H, 4.45; N, 5.38; S, 12.32. Found: C, 46.15; H, 4.48; N, 5.42; S, 12.23. ES-MS m/z 522 [M+H] +. IR (KBr) v (cm-') 1545 (C=O), 1120 (C=S).

EXAMPLE 107.

AMD8857: Synthesis of Ru (acac) 2 (#2-2-pyridinethiolato).

[bis (2,4-pentanedionato-KO, KO') [2 (1H)-pyridinethionato-KN, KS2] ruthenium (III)].

Preparation of [Ru (acac) 2 (2MP)].

[Ru (acac) 2 (MeCN) 2] [CF3S03] (0.292 g, 0.550 mmol) was dissolved in EtOH (10 mL) to give a dark blue solution. 2-Mercaptopyridine (0.065 g, 0.588 mmol) and KOH (0.036 g, 0.645 mmol) were added to give an instantaneous orange solution. The mixture was stirred at 80 °C for 4 h to give a turquoise solution. The solvent was

removed under reduced pressure and the blue residue was purified by column chromatography on silica gel (25: 1 CH2C12: MeOH). A turquoise blue band was isolated which was further purified via preparative TLC to afford a blue solid (0.089 g, 40 %). Anal. Calcd. for C15H18NO4SRu#0.3C3H6O : C, 44.74; H, 4.68; N, 3.28; S, 7.51. Found: C, 44.70; H, 4.55; N, 3.37; S, 7.51. ES-MS m/z 433 [M+Na] +, 411 [M+H] +. IR (KBr) v (cl'') 1545 (C=O).

EXAMPLE 108.

AMD8865: Synthesis of [Ru (acac) 2 (4ImP) 2] [CF3S03].

[bis (2,4-pentanedionato-KO, KO') bis [4- (lH-imidazol-1-yl-KN3) phenol] ruthenium (III) trifluoromethanesulfonate].

Preparation of [Ru (acac) 2 (4ImP) 2][CF3SO3] [Ru (acac) 2 (MeCN) 2] [CF3S03] (0.405 g, 0.550 mmol) was dissolved in EtOH (10 mL) to give a dark blue solution. 4- (Imidazol-1-yl) phenol (4ImP) (0.538 g, 3.36 mmol) was added and the mixture was stirred at 80 °C for 21 h to give a deep red solution. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (20: 1 CH2C12: MeOH) to give a red crystalline solid (0.203 g, 34 %). Anal. Calcd. for C29H3oN409SF3Ru: C, 45.31; H, 3.93; N, 7.29; S, 4.17. Found: C, 45.44; H, 4.11; N, 7.00; S, 3.88. ES-MS m/z 620 [M- CF3SO3] +. IR (KBr) v (cl'') 1524 (C=O).

EXAMPLE 109.

AMD8873 and AMD8877: Synthesis of [Ru (dpac) 2 (4ImP) (MeCN)] [CF3SO3] EtOH and [Ru (dpac) 2 (4ImP) 2] [CF3S03].

[ (Acetonitrile) bis (1,3-diphenyl-1,3-propanedionato-KO, KO') [4-(1H-imidazol-1-yl- #N3) phenol] ruthenium (III) trifluoromethanesulfonate] and [bis (1,3-diphenyl-1,3-propanedionato-KO, #O') bis [4-(1H-imidazol-1-yl-#N3) phenol] ruthenium (III) trifluoromethanesulfonate].

[Ru (dpac) 2 (MeCN) 2] [CF3S03] (0.305 g, 0.341 mmol) was dissolved in EtOH (10 mL) to give a dark green solution. 4- (Imidazol-1-yl) phenol (0.327 g, 2.04 mmol)

was added and the mixture was stirred at 80 °C for 24 h to give a brown solution. The solvent was removed under reduced pressure and the brown residue was purified by column chromatography on silica gel (20: 1 CH2Cl2: MeOH) to give two products: [Ru (dpac) 2 (4ImP) 2] [CF3SO3] as a brown solid (0.080 g, 25 %). Anal. Calcd. for C44H39N309SF3Ru: C, 55.99; H, 4.16; N, 4.45; S, 3.40. Found: C, 56.18; H, 4.25; N, 4.46; S, 3.16. ES-MS m/z 795 [M-CF3SO3] +. IR (KBr) v (cm-1) 2361 (C#N), 1522 (C=O); and [Ru (dpac) 2 (4ImP) (MeCN)] [CF3SO3]-EtOH as a brown solid (0.085 g, 24 %). Anal. Calcd. for C49H38N4O9SF3Ru#3.4C9H8N2O : C, 61.22; H, 4.21; N, 9.69; S, 2.05. Found: C, 61.51; H, 4.44; N, 9.42; S, 1.87. ES-MS m/z 868 [M-CF3SO3] +. IR (KBr) v (cl'') 1522 (C=O).

EXAMPLE 110.

AMD8866: Synthesis of [Ru (acac) 2 (ImProOMe) 2] [CF3S03].

[Bis [methyl-1-[(1H-imidazol-1-yl-#N3) acetyl]-L-prolinate] bis (2,4-pentanedionato- KO, KO') ruthenium (III) trifluoromethanesulfonate].

Synthesis of the ligand: ImProOMe N- (2-chloro) acetamido- (L)-proline methvl ester Chloroacetic acid (0.674 g, 7.13 mmol) was dissolved in THF (40 mL) at 0 °C under nitrogen. N-Methylmorpholine (784 L, 7.18 mmol) was then added and the colourless mixture was stirred for 10 minutes iso-butylchloroformate (1.01 mL, 7.84 mmol) was added and the mixture was stirred for 30 min during which a white slurry was formed. The ice-bath was removed, and (L)-proline methyl ester (0.600 g, 4.65 mmol) and N-methylmorpholine (550 uL, 5.04 mmol) were added. The reaction slurry was stirred at room temperature for 5.5 h and the resulting white precipitate was filtered off and washed with THF (3 x 5 mL). The combined filtrates were evaporated to dryness and the residue was purified by column chromatography on silica gel (22: 1 CH2C12: MeOH) to give the title compound as a pale yellow oil (0.422 g, 44 %). ES- <BR> <BR> <BR> MS m/z 206 [M+H] +. IH NMR (CDC13) 8 1.96 (m, 2H), 2.14 (m, 2H), 3.56 (m, 2H),<BR> <BR> <BR> <BR> <BR> <BR> 3.63 (s, 3H), 3.96 (d, 2H,-J=3.3 Hz), 4.42 (dd, 1H, J=8.5 Hz); 13C NMR (CDC13) 8 25.2,29.5,42.3,47.4,52.7,59.7,165.2,172.5.

Preparation of ImProOMe N- (2-chloro) acetamido- (L)-proline methyl ester (0.422 g, 2.05 mmol) was added to a suspension of sodium imidazolate (0.281 g, 3.12 mmol) in DMF (5 mL) at room temperature and the mixture was heated to 75 °C for a further 16 hours. The reaction mixture was evaporated and the residue was purified by column chromatography on silica gel (20: 1 CH2Cl2: MeOH) to give white crystalline solid <BR> <BR> <BR> <BR> (0.244 g, 50 %). ES-MS m/z 238 [M+H] +.'H NMR (CDCl3) 8 1.83-2.11 (m, 4H), 3.34-3.46 (m, 2H), 3.54 (s, 3H), 4.33 (dd, 1H, J=8.4 Hz), 3.61 (s, 2H), 6.82 (s, 1H), <BR> <BR> <BR> <BR> 6.87 (s, 1H), 7.34 (s, 1H); 13C NMR (CDC13) 6 25.1,29.2,46.6,48.8,53.3,59.5, 165.5,172.5.

Preparation of [Ru (acac) 2 (ImProOMe) 2lfCF3S03l [Ru (acac) 2 (MeCN) 2] [CF3S03] (0.275 g, 0.518 mmol) was dissolved in EtOH (10 mL) to give a dark blue solution. ImProOMe (0.244 g, 1.08 mmol) was added and the mixture was stirred and heated at 80 °C for 20 h to give a red/purple solution. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (20: 1 CH2Cl2: MeOH) to give a red solid (0.127 g, 32 %). Anal. Calcd. for C33H44N6013SF3Ru: C, 42.95; H, N, 9.11; S, 3.47. Found: C, 43.06; H, 4.94; N, 8.83; S, 3.27. ES-MS m/z 774 [M-CF3S03] +. IR (KBr) v (cm-1) 1670,1522 (C=O).

EXAMPLE 111.

AMD8891: Synthesis of [Ru (acac) 2 (histamine) (MeCN)] [CF3S03].

[(Acetonitrile) (4-ethylamino-lH-imidazol-cN3) bis (2,4-pentanedionato-KO, KO') ruthenium (III)].

Preparation of [Ru (acac) 2 (histamine) (MeCN) lLCF3SO3] [Ru (acac) 2 (MeCN) 2] [CF3S03] (0.338 g, 0.638 mmol) was dissolved in EtOH (10 mL) to give a dark blue solution. Histamine (0.083 g, 0.744 mmol) was added and the mixture was stirred at 80 °C for 1 h and then at room temperature for 18 h to give a red/brown solution. The solvent was removed under reduced pressure and the brown residue was purified by column chromatography on silica gel (20: 1 CH2Cl2: MeOH)

to give an orange solid (0.066 g, 17 %). Anal. Calcd. for C8H26N407SF3Ru 0. 9C3H6O: C, 38.09; H, 4.85; N, 8.58; S, 4.91. Found: C, 38.15; H, 4.61; N, 8.41; S, 4.70. ES-MS m/z 452 [M-CF3SO3] +. IR (KBr) v (cl'') 2291 (C-N), 1670,1547 (C=O).

EXAMPLE 112.

AMD8903: Preparation of [Ru (edtmp)]. 3H20.

A mixture of K2 [RuCI5 (H20)] (0.35 g) and ethylenediaminetetraphosphonic acid, edtmp (0.40 g) in water (15 mL) was heated to reflux for one hour. The dark solution was allowed to stand for 2 days then evaporated to approximately 3 mL.

Methanol (-15 mL) was added resulting in the formation of green precipitate. The solid was collected by filtration and methanol was added to the filtrate to precipitate a yellow solid. The yellow solid was also collected by filtration, washed with ether and dried in vacuo to give the title compound (60 mg, 11%). Anal. Calcd. for C6H23N2P4OIsRu: C, 12.24; H, 3.95; N, 4.76. Found: C, 11.82; H, 3.43; N, 4.43.

EXAMPLE 113.

AMD6245: Preparation of [Ru (Hedta)] H20.

K [Ru (Hedta) Cl]-2H20 (16.0 g, 0.032 mmol) was heated to reflux in de-ionized water (750 mL) for 2 hours. The volume of the solution was reduced to one half the original volume and the solution was seeded with approximately 2-3 mg Ru (Hedta) (OH2). Upon cooling a precipitate formed which was removed by filtration and washed with ice-cold water, ethanol and diethyl ether. The product was dried in vacuo at 40 °C overnight (10.0 g, 77%). Anal. Calcd. for CloHIsN2OgRu: C, 29.42; H, 3.70; N, 6.86; Cl, 0.0. Found: C, 29.34; H, 3.66; N, 6.92; Cl, 0.0. IR (CsI) v (cl'') 3148 (OH); 1741 (C02H); 1651 (CO2). (Mukaida et al, Nippon Kagaku Zasshi, 86, 589 (1965)) EXAMPLE 114. Results on the inhibition of tumour growth by AMD6245 and AMD6221 NO is important in controlling tumour growth and vascularisation (Thomsen et al., Cancer and Metastasis Rev. 17 107-118, (1998); Jenkins et al., Proc. Natl. Acad.

Sci. USA, 92,4392-4396, (1995); Edwards et al., J. Surg. Res., 63,49-52, (1996)).

Nitric oxide synthases have been shown to be expressed in numerous human and rodent cancers including human gynecological cancers (Thomsen et al., Cancer Res.,

54,1352-1354, (1994), Thomsen et al., Biochem. Pharmacol., 56,1365-1370, (1998)) and the stroma of human breast cancers (Thomsen et al., Br. J. Cancer, 72, 41-44, (1995)), human lung cancer (Ambs et al., Br. J. Cancer, 78,233-239, (1998)), human colon cancer (Ambs et al., Cancer Res., 58,334-341, (1998)), and rat colon tumours (Takahashi et al., CancerRes., 57,1233-1237, (1997)). Nitric oxide is an active mediator of angiogenesis (growth of new blood vessels) (Fukumura et al., Cancer and Metastasis Rev., 17,77-89, (1998); Ziche et al., J. Clin. Invest., 99,2625- 2634, (1997); Gallo et al.,, J. Natl. Cancer Inst., 90,587-596 (1998)). The establishment of an adequate blood supply is essential to the growth of solid tumours.

In addition nitric oxide has been shown to be important for the maintaining the vasodilatory tone of tumours (Tozer et al., Cancer Res, 57,948-955, (1997)), regulating tumour blood flow (Tozer et al., Cancer Res, 57,948-955, (1997), Doi et al., Cancer, 77,1598-1604, (1996)) and tumour oxygenation and energy status (Wood et al., Biochem. Biphys. Res. Commun., 192, 505-510, (1993)). The angiogenic process is intimately linked with metastasis of solid tumours. Nitric oxide increased vascular permeability in tumour bearing mice, (Doi et al., Cancer, 77,1598-1604, (1996); Maeda et al., Jpn. J. Cancer Res., 85,331-334, (1994); Wu et al., Cancer Res., 58,159-165, (1998)) a prerequisite for metastasis. The inhibition of NO synthesis by a NOS inhibitor has been shown to inhibit an increase in metastases and tumour size associated with increased NO production in the EMT-6 murine breast tumour (Edwards et al., J. Surg. Res., 63, 49-52, (1996)). Administration of a NOS inhibitors has been shown to inhibit the growth of experimental tumours in vivo (Kennovin et al., in Biology of Nitric Oxide, Vol. 4, (S. Moncada, M. Feelisch, R.

Busse, and A. E. Higgs, eds.), Portland Press, London, 1994, pp. 473-479), Thomsen et al., Cancer Res., 57,3300-3304, (1997)).

The effect of AMD6245 (Example 113) and AMD6221 (Example 8) on tumour growth was assessed using the rat P22 carcinosarcoma grown in BD-IX rats (Kennovin et al., in Biology of Nitric Oxide, Vol. 4, (S. Moncada, M. Feelisch, R.

Busse, and A. E. Higgs, eds.), Portland Press, London, 1994, pp. 473-479). The tumour was implanted subcutaneously on the dorsal surface of male BD-IX rats on Day 0. Tumour growth was measured daily using calipers and tumour volume

calculated from the equation Volume = (X2. Y2) 7r/6 where X = the short tumour axis and Y = the long tumour axis. Tumours were measurable by Day 10. AMD6245 and AMD6221 were administered daily by intraperitoneal injection at a dose of 50 mg/kg from Day 10-Day 28. Tumour vascularisation (Microvascular Density or MVD) was measured by Chalkley point counting after immunostaining with anti-CD31 antibody (Vermeulen et al., Eur. J. Cancer, 32A, 2474-2484, (1996)). Nitrite/nitrate was measured by the Griess assay (see Table 4). These anions are the stable end products of NO in solution. Nitrate was first reduced to nitrite by nitrite reductase. The sum of nitrite and nitrate gives the total NO production.

AMD6245 and AMD6221 inhibited the growth of the P22 carcinosarcoma (Figure 3). Tumour vascularisation (MVD) was lower in tumours from AMD6245 treated animals (Mean Chalkey score = 3.0) and AMD6221 treated animals (Mean Chalkey score = 5. 3) compared with untreated, control tumours (Mean Chalkey score = 13.0). Nitrite/nitrate levels at Day 28 were lower in AMD6245 treated animals (3.88 µmoles/litre plasma) and AMD6221 treated animals (5.09 moles/litre plasma), compared with untreated, control animals (7.75 moles/litre plasma). Therefore, AMD6245 and AMD6221 inhibited tumour growth. This was associated with a decrease in tumour blood supply and a decrease in plasma NO levels.

Table 4 Results are presented as net decrease in nitrite in the stimulated in vitro RAW264 cell culture supernatant as measured by the Griess assay. #NitriteConcn(µM)AMD##NitriteAMD# Concn (µM) (, uM) (, uM) 7459 19. 3 100 8884 7460 21. 4 100 8881 8676 24. 9 100 8900 8679 38. 5 100 8910 8684 8896 34.5 50 7436 4. 9 100 8691 25.3 50 8701 5. 1 50 8692 7494 12. 2 100 8707 7493 13 100 8658 5.1 25 8699 14. 9 50 8693 8677 3.6 50 8694 18.8 25 8893 6.6 25 8730 8894 8710 8711 4.4 50 8757 38.1 100 8702 5.2 100 8695 8849 8.8 50 8696 26.4 100 7461 12.7 100 8704 7462 7.8 100 8705 37.4 100 8672 15.2 100 8874 26.3 25 8641 8878 8671 3.5 100 8879 8670 43.4 50 8813 8803 8656 8842 8792 8731 24 50 8822 8802 28.9 25 8823 8801 19 25 8826 8682 23.9 50 8736 36.5 100 8800 18.6 50 8791 8811 9.3 50 8795 39.1 25 7044 4.9 100 8845 7054 15.9 100 8856 7055 37.7 50 8857 7086 14.8 25 8865 47.2 50 7036 7.3 100 8873 7037 4.8 100 8877 15.3 25 7039 18.7 50 8866 15.3 25 7045 24 50 8891 8657 39.4 50 6245 12.2 100 8660 40.4 100 8892 8901 8883

Typical result for AMD6221 is 37.6 M at 100 M, 250 µM L-NMMA gives similar results to 100 u. M AMD6221. All compounds were tested at 100µM unless otherwise stated. The lower concentrations were used because of toxicity at 100pM.

Table 5 COMPOUND NAMES SUMMARY AMD Dihydrogen chloro [[2, 6-(pyridinyl-KN) methyl] bis [N- 7040 (carboxymethyl) glycinato-KN, KO ruthenium (III) AMD Dihydrogen dichloro [[N, N'-1,2-ethanediyl] bis [ (2-pyridinyl- 7043 (III)chlorideruthenium AMDAquachloro[[N-2-[(2-pyridinyl-#N)oxo-methyl)aminoethyl][( (2-carboxy- 7056 KO) methyl) glycinato-KN, KO ruthenium (III) AMD Hydrogen chloro [N-[bis ((2-(carboxy-KO) methyl) imino-#N)ethyl]-(2- ruthenium(III)7046pyridinyl-#N)methylglycinato-#N] AMD Hydrogen aqua [N-bis((2-carboxy-#O)methyl)imino-#N]-1, 2-phendiyl (2- 7087 (carbox-KO) methyl) glycinato-KM ruthenium (III) AMD Dihydrogen chloro [[N, N'-[[(phenylmethyl) imino-KNl-2, 1-ethanediyl] bis [N- 7459 (carboxymethyl)glycinato-#N,#O ruthenium (III) AMDDihydrogen chloro[[N,N'-[[(2-pyridinylmethyl)imino-#N]di-2,1- 7460 ethanediyl] bis N-(carboxymethyl)glycinato-#N,#O ruthenium (III) [[N,N'-[(butylimino-#N)di-2,1-ethanediyl]bis[N-AMDDihydrogen 8676 (carboxymethyl) glycinato-KN, KO chloro ruthenium (III) AMD Dihydrogen chloro [[N, N'-[(ethylimino-KN) di-2, 1-ethanediyl] bis [N 8679 (carboxymethyl) glycinato-KN, KO ruthenium (III) AMD Dihydrogen chloro [[N, N'-[(phenylimino-KN) di-2, 1-ethanediyl] bis [N 8684 (carboxymethyl) glycinato-KN, KO]]] ruthenium (III) AMD [N-[2-[[(carboxy-#O)methyl][(2-pyridinyl-#N)methyl]amino-#N] ethyl-N-[2- 7436 [(carboxymethyl)[(2-pyridinyl-#N]methyl]amino-#N]ethyl]glyci nato-#N] ruthenium (III) bis (trifluoroacetate) AMD Potassium dihydrogen dichloro [[N, N'-1,3-propanediylbis [N- 8701 (carboxymethyl) glycinato-KN, KO]]] ruthenium (III) AMD Hydrogen aqua [6-[[[(carboxy-#O) methyl] (carboxymethyl) amino-KNlmethyl]- 7494 2-pyridinecarboxylato-#N1,#O2 chloro ruthenium (III) AMD Hydrogen aqua [N-(carboxymethyl)-N-[[6-(hydroxymethyl)-2-pyridinyl- 7493 methyl]glycinato-#N,#O]dichloro ruthenium (III) AMDAqua[N-[(carboxy-#O)methyl]-N-[[6-[(phenylmethoxy)methyl] -2-pyridinyl- 8699 methyl]glycinato-#N,#O]chloro ruthenium (III) chloro[methyl3-[[[2-[bis[(carboxy-#O)methyl]amino-AMDPotassi um etc 1][(carboxy-#O)methyl]amino-#N]methyl]benzoato ruthenium (III) AMDAqua[N-[2-[bis[(carboxy-#O)methyl]amino-#N]ethyl]-N-[2-ox o-2-(1- ruthenium(III)8893pyrrolidinyl)ethyl]glycinato-#N,#O] AMD Potassium aqua [N-[2-[bis[(carboxy-#O) methyl] amino-KN ethyl]-N- 8894 [ (carboxy-KO) methyl] glycyl-KN-L-isoleucinato ruthenium (III) AMD Hydrogen aqua [N-[2-[[(carboxy-KO) methyl] (carboxymethyl) amino- 8711 ethyl]-N-(phenylmethyl)glycinato-#N,#O chloro ruthenium (III) AMDDihydrogen aqua[3-[[[(carboxy-#O)methyl][2-[[(carboxy- 8702 KO) methyl (carbox eth 1) amino- eth 1 amino- xN] methyl] benzoato] chloro ruthenium (III) AMD Aquachloro[[N,N'-1,2-ethanediylbis[N-[2-oxo-2-(1- ruthenium(III)8849pyrrolidinyl)ethyl]glycinato-#N,#O]]] AMD Dihydrogen aqua [[N, N'-(2-hydroxy-1,3-propanediyl) bis [N- 7461 (carboxymethyl) glycinato-KN, O]]] (trifluoromethanesulfonato-KO) ruthenium (III) AMD Potassium dichloro [[N, N'-1,2-ethanediylbis [glycinato-KN, KO]] ruthenium 7462 (III) AMDChloro[octahydro-1H-1,4,7-triazoninato-#N1,#N4,#N7]bis[(s ulfinyl- 8672 #S)bis[methane ruthenium (II) chloride ruthenium(III)AMDTrichloro[octahydro-1H-1,4,7-triazonine-#N1 ,#N4,#N7] 8641 AMD Trichloro [hexahydro-1,4,7-trimethyl-1,4, 7-triazonine-#N1,#N4,#N7] (III8671ruthenium AMD (Dimethylcarbamodithioato-KS) (dimethylcarbamodithioato-KS, KS') 8670 [octahydro-1H-1, 4,7-triazonine-KN', Kan4, #N7] ruthenium (III) hexafluorophosphate AMD (Diethylcarbamodithioato-KS) (diethylcarbamodithioato-KS, #S') [octahydro- ruthenium(III)hexafluorophosphate88031H-1,4,7-triazonine-#N1 ,#N4,#N7] AMD (1,4-butanediylcarbamodithioato-#S)(1,4-butanediylcarbamodit hioato-#S,#S') 8842 [octahydro-lH-1,4, 7-triazonine-#N1, #N4, KN7] ruthenium (III) hexafluorophosphate AMD Dihydrogen ( (1-carboxy)-1, 4-butanediylcarbamodithioato-KS) ( (1-carboxy)- [octahydro-1H-1,4,7-triazonine-87311,4-butanediylacarbamodit hioato-#S,#S') (III)hexafluorophosphate#N1,#N4,#N7]ruthenium AMD ((1-carboxymethyl)-1, 4-butanediylcarbamodithioato-KS) ((1-carboxymethyl)- [octahydro-1H-1,4,7-triazonine-88021,4-butanediylcarbamodith ioato-#S,#S') #N1,#N4,#N7 ruthenium (III) hexafluorophosphate (N-methyl-N-sec-butylcarboxycarbamodithioato-#S)(N-methyl-AM DDihydrogen [octahydro-1H-1,4,7-triazonine-8801N-sec-butylcarboxycarbamo dithioato-#S,#S') (III)hexafluorophosphate#N1,#N4,#N7]ruthenium AMD (Dimethylcarbamodithioato-KS) (dimethylcarbamodithioato-KS, #S') 8682 (III)ruthenium hexafluorophosphate AMD [(N-(carboxy-#O)-methyl)-N-methylglycinato-#N,#O][octahydro- 1H-1, 4,7- 8800 triazonine-#N1,#N4,#N7 ruthenium (III) hexafluorophosphate AMD Hydrogen chloro [hexahydro-1,4, 7-(tricarboxy-#O,#O'-methyl)-1, 4,7- ruthenium(III8811triazonine-#N1,#N4,#N7] AMD Chloro (2,2'-bipyridine-KNl, KN) (2,2': 6'. 2"-terpyridine-KN', KN2', KNi") 7044 ruthenium II hexafluorophosphate AMDChlorobis(2(1H)-pyridinethione-#S2)(2,2':6'.2"-terpyridin e-#N1,#N2,,#N1,,) 7054 ruthenium (II) hexafluorophosphate AMD Chlorobis (2 (1H)-pyrimidinethione-KS2) (2,2': 6'. 2"-terpyridine- 7055 #N1,#N2,,#N1,, ruthenium (II) hexafluorophosphate AMD Chloro (dimethylcarbamodithioato-KS, KS') (2,2': 6'. 2"-terpyridine- ruthenium(III)hexafluorophosphate7086#N1,#N2,,#N1,,) AMDAMDDichlorobis(2,2'-bipyridine-#N1,#N1,) ruthenium (II) dihydrate 7036 AMD Dichlorobis (l, 10-phenanthroline-KN/, KN1°) ruthenium (II) dihydrate 7037 rutheniumAMDBis(2,2'-bipyridine-#N1,#N1,)(2(1H)-pyridinethio nato-#N1,#S2) 7039 perchlorate AMD Bis (2,2'-bipyridine-KNl, #N1,) (2 (lH)-pyridinethionato-KN', K. S'z) ruthenium 7045 hexafluorophosphate AMD Bis (acetonitrile) bis (2,4-pentanedionato-KO, KO') ruthenium (III) 8657 trifluoromethanesulfonate AMD Bis (acetonitrile) bis (2,4-pentanedionato-KO, KO') ruthenium (II) 8660 AMD Bis (acetonitrile) bis (3-methyl-2,4-pentanedionato-KO, KO') ruthenium (III) 8892 trifluoromethanesulfonate AMD Bis (acetonitrile) bis (3-methyl-2,4-pentanedionato-KO, KO') ruthenium (II) 8901 AMD Bis (acetonitrile) bis (3-chloro-2,4-pentanedionato-KO, KO') ruthenium (II) 8883 AMD Bis (acetonitrile) bis (3-chloro-2,4-pentanedionato-KO, KO') ruthenium (III) 8884 trifluoromethanesulfonate AMD Bis (acetonitrile) bis (3-bromo-2,4-pentanedionato-KO, KO') ruthenium (III) 8881 trifluoromethanesulfonate AMD Bis (acetonitrile) bis (3-bromo-2,4-pentanedionato-KO, KO') ruthenium (II) 8900 AMD Bis (acetonitrile) (2,4-pentanedionato-KO, KO') (3-iodo-2,4-pentanedionato- 8910 KO, KO') ruthenium (III) trifluoromethanesulfonate AMD Tetrakis (acetonitrile) (3-iodo-2,4-pentanedionato-KO, KO') ruthenium (II) 8896 trifluoromethanesulfonate AMD Bis (acetonitrile) bis (1,3-diphenyl-1,3-propanedionato-KO, KO') ruthenium (III) 8691 trifluoromethanesulfonate AMD Bis (acetonitrile) bis (1,3-diphenyl-1,3-propanedionato-KO, KO') ruthenium (II) 8692 AMD Bis (acetonitrile) bis (2,2,6,6-tetramethyl-3,5-heptanedionato-KO, KO') 8707 ruthenium (III) trifluoromethanesulfonate AMD Bis (acetonitrile) bis (1,1,1,5,5,5-hexafluoro-2,4-pentanedionato-KO, KO') 8658 ruthenium (II) AMD sym-Bis (acetonitrile) bis (l, 1, 1-trifluoro-2, 4-pentanedionato-KO, KO') 8693 ruthenium (II) AMD asym-Bis (acetonitrile) bis (1, 1, 1-trifluoro-2, 4-pentanedionato-KO, KO') 8694 ruthenium (II) AMD sym-Bis (acetonitrile) bis (1, 1, 1-trifluoro-5,5-dimethyl-2,4-hexanedionato- 8730 KO, K0') ruthenium (II) AMD asym-Bis (acetonitrile) bis (1,1,1-trifluoro-5, 5-dimethyl-2,4-hexanedionato- 8710 KO, KO') ruthenium (II) AMD Bis (acetonitrile) bis [ (3-hydroxy-KO)-2-methyl-4-pyronato-KO'] ruthenium 8757 (III) trifluoromethanesulfonate AMDBis(acetonitrile)bis[4-(hydroxy-#O)-3-penten-2-onato](N,N ,N',N'- ruthenium(III)8695tetramethyl-1,3-propanediamine-#N,#N') trifluoromethanesulfonate AMD Bis (acetonitrile) bis [4-(hydroxy-#O)-3-penten-2-onato] bis (N, N, N', A'- ruthenium(III)8696tetramethyl-1,3-propanediamine-#N) trifluoromethanesulfonate AMD Bis (acetonitrile) [N, N'-bis [2-(amino-KN) ethyl] amine] bis [4-(hydroxy-KO)-3- 8704penten-2-onato] ruthenium (III) trifluoromethanesulfonate AMD Bis (acetonitrile) [N-(2-aminoethyl)-1,2-ethanediamine-#N,#N'] bis [4- 8705 (hydroxy-KO)-3-penten-2-onato] ruthenium (III) trifluoromethanesulfonate AMD Bis (acetonitrile) [2-(2-amino-#N-ethylamino-#N')ethanol] bis [4- (hydroxy- 8874 KO)-3-penten-2-onato] ruthenium (III) trifluoromethanesulfonate AMD Bis (acetonitrile) [N-(3-aminopropyl)-1, 3-propanediamine-KN, KN'] bis [4- 8878 droxy-#O)-3-penten-2-onato ruthenium (III) trifluoromethanesulfonate AMDBis(acetonitrile)[N-(2-aminoethyl)-1,3-propanediamine-#N, #N']bis[4- 8879 droxv-#O)-3-penten-2-onato ruthenium (III) trifluoromethanesulfonate AMD Bis (acetonitrile) [N, N-bis [2- (amino-xl ethyl]-L-isoleucyl-L-prolinato] bis [4- 8813 (hydroxy-KO)-3-penten-2-onato] ruthenium (III) trifluoromethanesulfonate AMD (Dimethylcarbamodithioato-KS, KS') bis (2,4-pentanedionato-KO, KO') (III8656ruthenium AMD (Dimethylcarbamodithioato-KS, KS') bis (1,3-diphenyl-1,3-propanedionato- ruthenium(III)8792#O,#O') AMD [ (1-carboxymethyl)-1, 4-butanediylcarbamodithioato-KS, xS'] bis (2,4- ruthenium(III8822pentanedionato-#O,#O') AMD [ (l-carboxymethyl)-1, 4-butanediylcarbamodithioato-KSKS'] bis (1,3-diphenyl- 8823 1, 3-propanedionato-KO, KO') ruthenium (III) AMD [L-prolinato (1-)-#N,#O] bis (1,3-diphenyl-1,3-propanedionato-KO, KO') (III8826ruthenium AMD Potassium [(1-carboxy)-1, 4-butanediylcarbamodithioato-KS, KS'] bis (2,4- 8736 pentanedionato-KO, KO') ruthenium (III) AMD [N-methyl-L-isoleucinato (1-)-KN, KO] bis (2,4-pentanedionato-KO, KO') 8791 ruthenium (III) AMD Bis [p-[N-methyl-L-isoleucinato (1-)-KN : KO]] tetrakis (2,4-pentanedionato- 8795 KO, KO') diruthenium (III) AMD Bis[µ-[L-prolinato(1-)-#N:#O]] tetrakis (1,3-diphenyl-1,3-propanedionato- 8845 (III)diruthenium AMD bis (2,4-pentanedionato-KO, KO') [2 (lH)-pyridinethionato-xSz] [2 (1H)- 8856 pyridinethione-KS21 ruthenium (III) AMD bis (2,4-pentanedionato-KO, KO') [2 (1H)-pyridinethionato-KN, KS2] ruthenium 8857 (III) AMD bis (2,4-pentanedionato-KO, KO') bis [4-(1H-imidazol-1-yl-#N3)phenol] (III)trifluoromethanesulfonate8865ruthenium AMD (Acetonitrile) bis (1,3-diphenyl-1,3-propanedionato-KO, KO') [4- (lH-imidazol- 8873 1-yl-KN3) phenol] ruthenium (III) trifluoromethanesulfonate AMD bis (1, 3-diphenyl-1,3-propanedionato-KO, KO') bis [4-(1H-imidazol-1-yl- 8877 KN3) phenol] ruthenium (III) trifluoromethanesulfonate AMD Bis[methyl-1-[(1H-imidazol-1-yl-#N3)acetyl]-L-prolinate] bis (2,4- 8866 pentanedionato-KO, KO') ruthenium (III) trifluoromethanesulfonate AMD (Acetonitrile) (4-ethylamino-1H-imidazol-#N3] bis (2,4-pentanedionato- 8891 KO, KO') ruthenium (III)