Cyclic salen-metal compounds: reactive oxygen species scavengers useful as antioxidants in the treatment and prevention of diseases

Abstract

This invention provides antioxidant cyclic salen-metal compounds, compositions of such antioxidant cyclic salen-metal compounds having superoxide activity, catalase activity and/or peroxidase activity and methods of using such antioxidant cyclic salen-metal compositions to treat or prevent a disease associated with cell or tissue damage produced by free radicals, such as superoxide.

1 . A salen-metal compound having the following general structure:  
     
       
         
         
             
             
         
       
     
     wherein: 
 M is a metal;  
 A is an anion;  
 X 1  and X 2  are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryls, substituted aryls, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid esters, alkoxys, aryloxys and acyloxys;  
 Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6  are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryls, substituted aryls, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid esters, alkoxys, aryloxys and acyloxys;  
 R 1 , R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryl, substituted aryl, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid esters, alkoxys, aryloxys and acyloxys; with the proviso that one of R 1  or R 2  may be covalently linked to one of R 3  or R 4  forming a cyclic structure;  
 Z is a bridging group;  
 Q 1  and Q 2  are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryls, substituted aryls, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid esters, alkoxys, aryloxys and acyloxys; and  
 n is 0, 1, or 2.  
 
   
   
       2 .- 43 . (canceled)  
   
   
       44 . A salen-metal compound having the following general structure:  
     
       
         
         
             
             
         
       
     
     wherein: 
 M is a metal;  
 A is an anion;  
 X 1  and X 2  are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryls, substituted aryls, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid esters, alkoxys, aryloxys and acyloxys;  
 Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6  are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryls, substituted aryls, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid esters, alkoxys, aryloxys and acyloxys;  
 R 1 , R 2 , R 3  and R 4  are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryl, substituted aryl, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid esters, alkoxys, aryloxys and acyloxys; with the proviso that one of R 1  or R 2  may be covalently linked to one of R 3  or R 4  forming a cyclic structure;  
 Z is a bridging group;  
 Q 1  and Q 2  are independently selected from the group consisting of hydrogen, halogens, alkyls, substituted alkyls, aryls, substituted aryls, heterocyclics, substituted heterocyclics, heteroaryls, substituted heteroaryls, silyls, aminos, fatty acid esters, alkoxys, aryloxys and acyloxys; and  
 n is 0, 1, or 2.  
 
   
   
       45 .- 98 . (canceled)  
   
   
       99 . A method for arresting or treating a free-radical associated disease state in a mammal, said method comprising administering to said mammal a therapeutically effective amount of an antioxidant salen-metal compound of  claim 1  or  claim 44 .  
   
   
       100 . The method in accordance with  claim 99 , wherein said salen-metal compound is formulated in a pharmaceutically acceptable form with a carrier, excipient or adjuvant.  
   
   
       101 . The method in accordance with  claim 99 , wherein said free-radical associated disease state is a member selected from the group consisting of neurological damage resulting 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; and iatrogenic free-radical toxicity.  
   
   
       102 . The method in accordance with  claim 99 , wherein said mammal is a human.  
   
   
       103 . A method for treating cardiac tissue necrosis resulting from cardiac ischemia, acute lung injury from sepsis and/or endotoxemia, neuronal damage resulting from anoxia or trauma, or iatrogenic free-radical toxicity resulting from MPTP intoxication, said method comprising administering to a mammal a therapeutically-effective amount of an antioxidant salen-metal compound of  claim 1  or  claim 44 .  
   
   
       104 . A method for treating ischemia or reoxygenation injury, said method comprising administering to a mammal a therapeutically-effective amount of an antioxidant salen-metal compound of  claim 1  or  claim 44 .  
   
   
       105 . A method for treating inflammation in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a salen-metal compound of  claim 1  or  claim 44 .  
   
   
       106 . The method in accordance with  claim 105 , wherein said salen-metal compound is formulated in a pharmaceutically acceptable form with a carrier, excipient or adjuvant.  
   
   
       107 . The method in accordance with  claim 105 , wherein said salen-metal compound is formulated in a pharmaceutically acceptable topical carrier.  
   
   
       108 . A method for preventing or retarding the aging of skin, said method comprising applying to said skin an effective amount of a salen-metal complex of  claim 1  or  claim 44 .  
   
   
       109 . A method for preventing the deleterious effects of ultraviolet light exposure to skin, said method comprising topically applying to said skin an effective amount of a salen-metal complex of  claim 1  or  claim 44 .  
   
   
       110 . The method in accordance with  claim 109 , wherein said salen-metal complex is topically applied to said skin prior to ultraviolet light exposure.  
   
   
       111 . The method in accordance with  claim 109 , wherein said salen-metal complex is topically applied to said skin in conjunction with ultraviolet light exposure.  
   
   
       112 . The method in accordance with  claim 109 , wherein said salen-metal complex is topically applied to said skin after ultraviolet light exposure.  
   
   
       113 . A method for enhancing the recovery of skin of a mammal to a wound, said method comprising applying to said skin an effective amount of a salen-metal compound of  claim 1  or  claim 44 .  
   
   
       114 . The method in accordance with  claim 113 , wherein said wound is a member selected from the group consisting of surgical incisions, burns, inflammation, ulcers and irritations due to oxidative damage.  
   
   
       115 . A method for protecting cells from the deleterious effects of ionizing radiation, said method comprising: contacting said cells with an effective amount of a salen-metal compound of  claim 1  or  claim 44 .  
   
   
       116 . The method in accordance with  claim 115 , wherein said ionizing radiation is ultraviolet radiation.  
   
   
       117 . The method in accordance with  claim 115 , wherein said ionizing radiation is gamma (γ)-radiation.  
   
   
       118 . The method in accordance with  claim 115 , wherein said cells are human cells.  
   
   
       119 . The method in accordance with  claim 115 , wherein said contacting is carried out by administering to a human said salen-metal compound.  
   
   
       120 . A method for protecting cells from the deleterious effects of a chemotherapeutic agent, said method comprising: contacting said cells with an effective amount of a salen-metal compound of  claim 1  or  claim 44 .  
   
   
       121 . The method in accordance with  claim 120 , wherein said cells are human cells.  
   
   
       122 . (canceled)