Polyethylene glycolated superoxide dismutase mimetics

Abstract

Compounds and methods for utilizing compounds comprising a superoxide dismutase mimetic covalently linked to polyethylene glycol. Methods are also provided for preparing a superoxide dismutase mimetic covalently linked to a polyethylene glycol, the methods comprising reacting an activated polyethylene glycol with a superoxide dismutase mimetic, or alternatively, reacting a superoxide dismutase mimetic with an activated polyethylene glycol. A method is also provided for preventing or treating a disease or disorder in which superoxide anions are implicated, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound comprising a superoxide dismutase mimetic covalently linked to a polyethylene glycol. Methods of determining the safety and efficacy of the compounds are also provided. Methods for determining the safety and efficacy can include methods in lab animals and humans.

1 . A method for treating a disease or disorder affected by superoxide dismutase activity, the method comprising administering a therapeutically effective amount of a compound comprising a superoxide dismutase mimetic covalently linked to a polyethylene glycol to a subject in need thereof. 
     
     
         2 . The method according to  claim 1 , wherein the subject is a mammal; or said mammal is a human. 
     
     
         3 . The method according to  claim 1 , wherein the disease or disorder is selected from the group consisting of reperfusion injury to the ischemic myocardium, general inflammation, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, hypertension, psoriasis, organ transplant rejections, organ preservation, radiation—induced injury, platelet aggregation, stroke, autoimmune diseases, refractory hypotension, adult respiratory distress, carcinogenesis, severe chronic pain, reversal of opioid tolerance, hyperalgesia, and sepsis. 
     
     
         4 . The method according to  claim 1 , wherein the disease or disorder is central pain or peripheral pain. 
     
     
         5 . The method according to  claim 1 , wherein superoxide dismutase mimetic comprises: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The method according to  claim 1 , wherein the superoxide dismutase mimetic comprises: 
       
         
           
           
               
               
           
         
         n is between about 7 and about 1,000. 
       
     
     
         7 . The method according to  claim 1 , wherein the superoxide dismutase mimetic is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         n is between about 7 and about 1,000. 
       
     
     
         8 . The method according to  claim 7 , wherein n is about 23. 
     
     
         9 . The method according to  claim 7 , wherein n is about 45. 
     
     
         10 . The method according to  claim 7 , wherein n is about 114. 
     
     
         11 . The method according to  claim 7 , wherein n is about 455. 
     
     
         12 . The method according to  claim 7 , wherein the polyethylene glycol has a molecular weight from about 300 Da to about 44 kDa. 
     
     
         13 . The method according to  claim 8 , wherein:
 the polyethylene glycol has a molecular weight from about 300 Da to about 44 kDa;   the polyethylene glycol has a molecular weight from about 2500 Da to about 40 kDa;   the polyethylene glycol has a molecular weight from about 1 kDa to about 35 kDa;   the polyethylene glycol has a molecular weight from about 5 kDa to about 25 kDa;   the polyethylene glycol has a molecular weight from about 800 Da to about 1200 Da;   the polyethylene glycol has a molecular weight from about 1800 Da to about 2200 Da;   the polyethylene glycol has a molecular weight from about 4800 Da to about 5200 Da;   the polyethylene glycol has a molecular weight from about 9800 Da to about 10,200 Da; or   the polyethylene glycol has a molecular weight from about 1800 to about 2200 kDa.   
     
     
         14 . A method for decreasing a dose which is lethal to 50% (LD 50 ) of a population, the method comprising:
 (i) covalently attaching at least one polyethylene glycol to a superoxide dismutase mimetic;   (ii) administering the superoxide dismutase mimetic comprising the polyethylene to a living cell;   (iii) determining the LD 50  of a superoxide dismutase mimetic comprising the polyethylene glycol;   (iv) administering an identical superoxide dismutase mimetic not comprising the polyethylene to a living cell;   (v) determining the LD 50  of an identical superoxide dismutase mimetic not comprising the polyethylene glycol; and   (vi) comparing the LD 50  of the superoxide dismutase mimetic comprising the polyethylene glycol with an identical superoxide dismutase mimetic not comprising the polyethylene glycol.   
     
     
         15 . A method according to  claim 14 , wherein at least one of the following features is satisfied:
 (a) the LD 50  is determined in a mammal;   (b) increasing the LD 50  of a superoxide dismutase mimetic comprising covalently attaching at least one polyethylene glycol molecule to a superoxide dismutase mimetic compound to create a molecule of the following formula:   
       
         
           
           
               
               
           
         
         
           wherein n is between about 7 and about 1,000; n is between about 35 and about 55; n is 45; n is about 23; n is about 45; n is about 114; or n is about 455; 
           the polyethylene glycol has a molecular weight from about 300 Da to about 44 kDa; from about 2500 Da to about 40 kDa; from about 1 kDa to about 35 kDa; from about 5 kDa to about 25 kDa; from about 800 Da to about 1200 Da; from about 1800 Da to about 2200 Da; from about 4800 Da to about 5200 Da; from about 9800 Da to about 10,200 Da; or from about 1800 to about 2200 kDa; 
         
         (c) the superoxide dismutase mimetic compound is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           wherein n is between about 7 and about 1,000; n is between about 35 and about 55; n is 45; n is about 23; n is about 45; n is about 114; n is about 455; 
         
         (d) the polyethylene glycol has a molecular weight from about 300 Da to about 44 kDa; from about 2500 Da to about 40 kDa; from about 1 kDa to about 35 kDa; from about 5 kDa to about 25 kDa; from about 800 Da to about 1200 Da; from about 1800 Da to about 2200 Da; from about 4800 Da to about 5200 Da; from about 9800 Da to about 10,200 Da; or from about 1800 to about 2200 kDa; or 
         (e) the polyethylene glycol is selected from the group consisting of formula—(OCH 2 CH 2 ) f —R 13 , —(CH 2 CH 2 O) f —R 13 , or —CH 3 O—(CH 2 CH 2 O) f —R 13 , or combinations thereof. 
       
     
     
         16 . A method for determining a dose lethal to 50% of a population, the method comprising:
 (i) administering a compound of  claim 3  to at least a cell, tissue or organism; and   (ii) monitoring the cell, tissue, or organism during and after the course of said administration to assess the viability of the cell, tissue, or organism.