Metal delivery agents and therapeutic uses of the same

Abstract

The present invention relates to metal complexes, processes for their preparation and their use as pharmaceutical or veterinary agents, in particular for the treatment of conditions in which metal delivery can prevent, alleviate or ameliorate the condition. There are a number of clinical conditions which are caused by or associated with abnormal levels of metals (typically low metal levels). Conditions in of this type include cancer and conditions characterised by or associated with oxidative damage, more specifically neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease or Huntington's disease. The invention also relates to ligands useful in the preparation of metal complexes of this type.

1 . A method of treatment or prophylaxis of a condition in a subject in which metal delivery can prevent, alleviate or ameliorate the condition, the method including administration of a therapeutically effective amount of a metal complex of Formula (I). 
       
         
           
           
               
               
           
         
         wherein M is a divalent metal; 
         R 1  and R 2  are each independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, —N═R 7 , —NH(R 7 ), —N(R 7 ) 2 , —COOH, —COR 7 , —COOR 7 , —CONHR 7 , —CSNHR 7 , —S(O)R 7 , —S(O) 2 R 7 , —C(O)N(R 7 ) 2 , —SO 2 N(R 7 ) 2 , —(CH 2 ) m R 8  and acyl, each of which may be optionally substituted; or 
         R 1  and R 2  when taken together to the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl or heteroaryl group; 
         R 3  and R 4  are each independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, each of which may be optionally substituted; 
         or R 3  and R 4  when taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl group; 
         R 5  and R 6  are each independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, —N═R 7 , —NH(R 7 ), —N(R 7 ) 2 , —COOH, —COR 7 , —COOR 7 , —CONHR 7 , —CSNHR 7 , —S(O)R 7 , —S(O) 2 R 7 , —C(O)N(R 7 ) 2 , —SO 2 N(R 7 ) 2 , —(CH 2 ) m R 8  and acyl, each of which may be optionally substituted; or 
         R 5  and R 6  when taken together to the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl or heteroaryl group; 
         each R 7  is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, and acyl, each of which may be optionally substituted; 
         each R 8  is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which may be optionally substituted; 
         m is an integer selected from the group consisting of 1, 2, 3, 4, 5 and 6. 
       
     
     
         2 . A method according to  claim 1  wherein the condition is selected from the group consisting of tau related disorders, disorders caused by or associated with oxidative stress, and Abeta related disorders. 
     
     
         3 - 5 . (canceled) 
     
     
         6 . A method according to  claim 1  wherein the condition is selected from the group consisting of cardiovascular disease, central nervous system disorders, cancers and neurological disorders. 
     
     
         7 . A method according to  claim 1  wherein the condition is selected from the group consisting of acute intermittent porphyria; adriamycin-induced cardiomyopathy; AIDS dementia and HIV-1 induced neurotoxicity; Alzheimer's disease; amylotrophic lateral sclerosis; atherosclerosis; cataract; cerebral ischaemia; cerebral palsy; cerebral tumour; chemotherapy-induced organ damage; cisplatin-induced nephrotoxicity; coronary artery bypass surgery; Creutzfeldt-Jacob disease and its new variant associated with “mad cow” disease; diabetic neuropathy; Down's syndrome; drowning; epilepsy and post-traumatic epilepsy; Friedrich's ataxia; frontotemporal dementia; glaucoma; glomerulopathy; haemochromatosis; haemodialysis; haemolysis; haemolytic uraemic syndrome (Weil's disease); Menke's disease; haemorrhagic stroke; Hallerboden-Spatz disease; heart attack and reperfusion injury; Huntington's disease; Lewy body disease; intermittent claudication; ischaemic stroke; inflammatory bowel disease; macular degeneration; malaria; methanol-induced toxicity; meningitis (aseptic and tuberculous); motor neuron disease; multiple sclerosis; multiple system atrophy; myocardial ischaemia; neoplasia; Parkinson's disease; peri-natal asphyxia; Pick's disease; progressive supra-nuclear palsy; radiotherapy-induced organ damage; restenosis after angioplasty; retinopathy; senile dementia; schizophrenia; sepsis; septic shock; spongiform encephalopathies; subharrachnoid haemorrage/cerebral vasospasm; subdural haematoma; surgical trauma, including neurosurgery; thalassemia; transient ischaemic attack (TIA); transplantation; vascular dementia; viral meningitis; and viral encephalitis. 
     
     
         8 - 9 . (canceled) 
     
     
         10 . A method according to  claim 6  wherein the disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis (ALS). 
     
     
         11 - 12 . (canceled) 
     
     
         13 . A method according to  claim 1  wherein the metal is copper. 
     
     
         14 - 15 . (canceled) 
     
     
         16 . A method according to  claim 1  wherein R 3  and R 4  are independently selected from the group consisting of H, methyl, ethyl and phenyl. 
     
     
         17 - 18 . (canceled) 
     
     
         19 . A method according to  claim 1  wherein R 1  is selected from the group consisting of H, alkyl and aryl, each of which may be optionally substituted. 
     
     
         20 . (canceled) 
     
     
         21 . A method according to  claim 1  wherein R 2  is selected from the group consisting of H, alkyl, aryl, and —(CH 2 ) m R 8 , each of which may be optionally substituted. 
     
     
         22 .- 25 . (canceled) 
     
     
         26 . A method according to  claim 1  wherein R 5  is selected from the group consisting of H, alkyl and aryl, each of which may be optionally substituted. 
     
     
         27 . (canceled) 
     
     
         28 . A method according to  claim 1  wherein R 6  is selected from the group consisting of H, alkyl, aryl, and —(CH 2 ) m R 8 , each of which may be optionally substituted. 
     
     
         29 - 32 . (canceled) 
     
     
         33 . A method according to  claim 1  wherein the complex is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         34 - 66 . (canceled) 
     
     
         67 . A method of phosphorylation of a kinase in a cell, the method including exposing the cell to a metal complex of Formula (I). 
       
         
           
           
               
               
           
         
         wherein M is a divalent metal; 
         R 1  and R 2  are each independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, —N═R 7 , —NH(R 7 ), —N(R 7 ) 2 , —COOH, —COR 7 , —COOR 7 , —CONHR 7 , —CSNHR 7 , —S(O)R 7 , —S(O) 2 R 7 , —C(O)N(R 7 ) 2 , —SO 2 N(R 7 ) 2 , —(CH 2 ) m R 8  and acyl, each of which may be optionally substituted; or 
         R 1  and R 2  when taken together to the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl or heteroaryl group; 
         R 3  and R 4  are each independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, each of which may be optionally substituted; 
         or R 3  and R 4  when taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl group; 
         R 5  and R 6  are each independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, —N═R 7 , —NH(R 7 ), —N(R 7 ) 2 , —COOH, —COR 7 , —COOR 7 , —CONHR 7 , —CSNHR 7 , —S(O)R 7 , —S(O) 2 R 7 , —C(O)N(R 7 ) 2 , —SO 2 N(R 7 ) 2 , —(CH 2 ) m R 8  and acyl, each of which may be optionally substituted; or 
         R 5  and R 6  when taken together to the nitrogen atom to which they are attached form an optionally substituted heterocycloalkyl or heteroaryl group; 
         each R 7  is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, and acyl, each of which may be optionally substituted; 
         each R 8  is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which may be optionally substituted; 
         m is an integer selected from the group consisting of 1, 2, 3, 4, 5 and 6. 
       
     
     
         68 - 69 . (canceled) 
     
     
         70 . A method according to  claim 67  wherein the kinase is selected from the group consisting of ERK, PI3K, Akt, GSK3 and INK. 
     
     
         71 . A method according to  claim 67  wherein the metal is copper. 
     
     
         72 .- 73 . (canceled) 
     
     
         74 . A method according to  claim 67  wherein R 3  and R 4  are independently selected from the group consisting of H, methyl, ethyl and phenyl. 
     
     
         75 - 76 . (canceled) 
     
     
         77 . A method according to  claim 67  wherein R 1  is selected from the group consisting of H, alkyl and aryl, each of which may be optionally substituted. 
     
     
         78 . (canceled) 
     
     
         79 . A method according to  claim 67  wherein R 2  is selected from the group consisting of H, alkyl, aryl, and —(CH 2 ) m R 8 , each of which may be optionally substituted. 
     
     
         80 - 83 . (canceled) 
     
     
         84 . A method according to  claim 67  wherein R 5  is selected from the group consisting of H, alkyl and aryl, each of which may be optionally substituted. 
     
     
         85 . (canceled) 
     
     
         86 . A method according to  claim 67  wherein R 6  is selected from the group consisting of H, alkyl, aryl, and —(CH 2 ) m R 8 , each of which may be optionally substituted. 
     
     
         87 - 90 . (canceled) 
     
     
         91 . A method according to  claim 67  wherein the complex is selected from the group consisting of