Synthetic catalytic free radical scavengers useful as antioxidants for prevention and therapy of disease

Abstract

The invention provides antioxidant salen-metal complexes, compositions of such antioxidant salen-metal complexes having superoxide activity, catalase activity, and/or peroxidase activity, compositions of salen-metal complexes in a form suitable for pharmaceutical administration to treat or prevent a disease associated with cell or tissue damage produced by free radicals such as superoxide, and cosmetic and free radical quenching formulations of salen metal compounds.

1 . A method for preventing, arresting, or treating a free radical-associated disease state by administering to a patient a therapeutically-effective dose of an antioxidant salen-metal complex pharmaceutical composition comprising an antioxidant salen metal complex of the formula:  
     
       
         
         
             
             
         
       
       wherein M is selected from the group consisting of Mn, Co, Fe, V, Cr, and Ni; A is an anion;  
       n is either 0, 1, or 2;  
       X 1 , X 2 , X 3  and X 4  are independently selected from the group consisting of hydrogen, silyls, aryls, arylalkyls, primary alkyls, secondary alkyls, tertiary alkyls, alkoxys, aryloxys, aminos, quaternary amines, heteroatoms, and hydrogen;  
       Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6  are independently selected from the group consisting of hydrogen, halides, alkyls, aryls, arylalkyls, silyl groups, aminos, alkyls or aryls bearing heteroatoms, alkoxys, and halide; and  
       R 1 , R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, aryl, fatty acid esters, substituted alkoxyaryls, heteroatom-bearing aromatic groups, arylalkyls, primary alkyls, secondary alkyls, and tertiary alkyls.  
     
   
   
       2 . The method of  claim 1 , wherein the antioxidant salen-metal complex is selected from the group consisting of: Structure IV, Structure V, Structure VI, Structure VII, Structure VIII, and Structure IX.  
   
   
       3 . The method of  claim 1 , wherein the antioxidant salen-metal complex is selected from the group consisting of: C1, C4, C6, C7, C9, C15, C17, C20, C22, C23, C25, C27, C28, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51, and C52.  
   
   
       4 . The method of  claim 3 , wherein the salen-metal complex is C31, C40, C43, C44, C46, C47, or C48.  
   
   
       5 . The method of  claim 1 , wherein the antioxidant salen-metal complex is formulated in a pharmaceutically acceptable form with an excipient or carrier.  
   
   
       6 . The method of  claim 1 , wherein the free radical-associated disease state is: neurological damage from Parkinson's disease, Alzheimer's disease, or transient cerebral anoxia injury, cardiac tissue necrosis resulting from cardiac ischemia, autoimmune neurodegeneration, acute lung injury from sepsis and/or endotoxemia, neuronal damage resulting from anoxia or trauma, or iatrogenic free-radical toxicity.  
   
   
       7 . The method of  claim 1 , wherein the patient is a non-human veterinary animal.  
   
   
       8 . The method of  claim 6 , wherein the salen metal complex is C31, C40, C43, C44, C46, C47, or C48.  
   
   
       9 . A method for treating cardiac tissue necrosis resulting from cardiac ischemia or acute lung injury from sepsis or endotoxemia, neuronal damage resulting from anoxia, or iatrogenic free-radical neurotoxicity toxicity resulting from MPTP intoxication, comprising administering a therapeutically effective dose of an antioxidant salen-metal complex selected from the group consisting of: C1, C4, C6, C7, C9, C15, C17, C20, C22, C23, C25, C27, C28, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51, and C52.  
   
   
       10 . The method of  claim 9 , wherein the antioxidant salen-metal complex is C31, C40, C43, C44, C46, C47, or C48.  
   
   
       11 . A method for treating ischemia/reoxygenation injury, comprising administering to a patient a therapeutically-effective dose of an antioxidant salen-metal complex pharmaceutical composition comprising an antioxidant salen metal complex of the formula:  
     
       
         
         
             
             
         
       
       wherein M is selected from the group consisting of Mn, Co, Fe, V, Cr, and Ni; A is an anion;  
       n is either 0, 1, or 2;  
       X 1 , X 2 , X 3  and X 4  are independently selected from the group consisting of hydrogen, silyls, aryls, arylalkyls, primary alkyls, secondary alkyls, tertiary alkyls, alkoxys, aryloxys, aminos, quaternary amines, heteroatoms, and hydrogen;  
       Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6  are independently selected from the group consisting of hydrogen, halides, alkyls, aryls, arylalkyls, silyl groups, aminos, alkoxys, alkyls or aryls bearing heteroatoms, and halide; and  
       R 1 , R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, aryl, fatty acid esters, substituted alkoxyaryls, heteroatom-bearing aromatic groups, arylalkyls, primary alkyls, secondary alkyls, and tertiary alkyls.  
     
   
   
       12 . The method of  claim 11 , wherein the antioxidant salen-metal complex is selected from the group consisting of: Structure IV, Structure V, Structure VI, Structure VII, Structure VIII, and Structure IX.  
   
   
       13 . The method of  claim 11 , wherein the antioxidant salen-metal complex is selected from the group consisting of: C1, C4, C6, C7, C9, C15, C17, C20, C22, C23, C25, C27, C28, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51, and C52.  
   
   
       14 . The method of  claim 13 , wherein the salen-metal complex is C31, C40, C43, C44, C46, C47, or C48.  
   
   
       15 . A pharmaceutically acceptable composition comprising an antioxidant salen-metal compound having the structural formula selected from the group of compounds consisting of: C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51, and C52.  
   
   
       16 . A pharmaceutically acceptable composition of  claim 15  comprising a solid non-toxic carrier.  
   
   
       17 . A pharmaceutically acceptable composition of  claim 15  having detectable superoxide dismutase activity and/or detectable catalase activity.  
   
   
       18 . A salen-metal complex having the structural formula selected from the group of compounds consisting of: C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51, and C52.  
   
   
       19 . A salen-metal complex of  claim 18 , wherein said salen-metal complex has a predetermined superoxide dismutase activity and/or catalase activity per mmole dissolved in an aqueous solution.  
   
   
       20 . A composition comprising a predetermined amount of a salen-metal complex selected from the group of compounds consisting of: C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, C47, C48, C49, C50, C51, and C52, wherein said preselected amount comprises a predetermined level of superoxide dismutase activity and/or catalase activity per mmole dissolved in an aqueous solution.  
   
   
       21 . A composition according to  claim 15 , wherein the salen-metal complex is formulated in immunoliposomes.  
   
   
       22 . A composition according to  claim 20  comprising a salen-metal complex and mammalian blood.  
   
   
       23 . A non-human animal containing an antioxidant salen-metal complex of  claim 15 .  
   
   
       24 . A mammalian cell containing an antioxidant salen-metal complex of  claim 15 .  
   
   
       25 . A human organ or human blood comprising an antioxidant salen-metal complex of  claim 15.