Methods for in vivo reduction of free radical levels and compostions useful therefor

Abstract

In accordance with the present invention, there are provided methods for the in vivo reduction of free radical levels in mammalian subjects in need thereof. In contrast to the inhibitory approach described in the prior art (i.e., wherein the function of the species responsible for free radical production is inhibited), the present invention employs a scavenging approach whereby overproduced free radical is bound in vivo to a suitable free radical scavenger. An exemplary free radical scavenger contemplated for use in the practice of the present invention is a dithiocarbamate-ferrous iron complex. This complex binds to free radicals, forming a stable, water-soluble free radical-containing complex. When administered to a subject afflicted with a disorder associated with free radical overproduction (e.g., SARS), the water-soluble free radical-containing complex is produced and then filtered through the kidneys, concentrated in the urine, and eventually excreted by the subject, thereby reducing in vivo free radical levels.

What is claimed is:  
     
         1 . A method for treating free radical overproduction associated with severe acute respiratory syndrome (SARS) in a subject in need thereof, said method comprising administering to said subject an effective amount of at least one physiologically compatible dithiocarbamate-containing free radical scavenger, wherein said dithiocarbamate-containing free radical scavenger has the structure I or II as follows:  
       [R 1 R 2 N—C(S)—S − ] x M +1, +2, +3    (I)  
       wherein: 
 each of R 1  and R 2  is a C 1  up to C 18  alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, or substituted arylalkyl; provided however, that at least one of R 1  and R 2  is heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl, or  
 R 1  and R 2  can cooperate to form a 5-, 6- or 7-membered ring including N, R 1  and R 2 ,  
 x is 1 or 2, and  
 M is a monovalent cation when x is 1, or M is a physiologically compatible divalent or trivalent transition metal cation when x is 2 or 3, or  
 M +1,+2,+3 [S—C(S)—NR 1 ] x —R 3 —[R 1 N—C(S)—S − ] x M +1, +2,+3    (II)  
 wherein:  
 each R 1  is a C 1  up to C 18  alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, or substituted arylalkyl; provided however, that at least one R 1  is heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl,  
 R 3  is a divalent moiety selected from the group consisting of alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, substituted alkenylene, arylene, substituted arylene, alkarylene, substituted alkarylene, aralkylene and substituted aralkylene,  
 x is 1 or 2, and  
 M is a monovalent cation when x is 1, or M is a physiologically compatible divalent or trivalent transition metal cation when x is 2 or 3.  
 
     
     
         2 . The method of  claim 1  wherein said free radical scavenger has the structure (III) as follows:  
       [R 1 R 2 N—C(S)—S − ] 2 M +2,+3    (III)  
       wherein: 
 each of R 1  and R 2  is a C 1  up to C 18  alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, or substituted arylalkyl; provided however, that at least one of R 1  or R 2  is heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl, or  
 R 1  or R 2  is a divalent moiety selected from the group consisting of alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, substituted alkenylene, arylene, substituted arylene, alkarylene, substituted alkarylene, aralkylene and substituted aralkylene; provided however, that at least one of R 1  or R 2  is heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl, wherein said divalent moiety serves as the same substituent for two dithiocarbamate structures, thereby linking said structures together so as to form a bis(dithiocarbamate) species, and  
 M is Fe.  
 
     
     
         3 . The method of  claim 1  wherein said free radical scavenger is substantially hydrophilic.  
     
     
         4 . The method of  claim 1  wherein said free radical scavenger has structure I, 
 each of R 1  and R 2  is a C 1  up to C 12  alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, wherein the substituents are selected from carboxyl, —C(O)H, oxyacyl, phenol, phenoxy, pyridinyl, pyrrolidinyl, amino, amido, hydroxy, nitro or sulfuryl, and  
 M is Fe +2  or Fe +3 , provided that R 1  and R 2  are not both C 2  alkyl.  
 
     
     
         5 . The method of  claim 1  wherein said free radical scavenger has structure I, 
 R 1  is a C 2  up to C 8  alkyl or substituted alkyl, wherein the substituents are selected from carboxyl, acetyl, pyridinyl, pyrrolidinyl, amino, amido, hydroxy or nitro,  
 R 2  is selected from a C 1  up to C 6  alkyl or substituted alkyl, or R 2  can cooperate with R 1  to form a 5-, 6- or 7-membered ring including N, R 2  and R 1 , and  
 M is Fe +2 , provided that R 1  and R 2  are not both C 2  alkyl.  
 
     
     
         6 . The method of  claim 1  wherein said free radical scavenger has structure I, 
 R 1  is a C 2  up to C 8  alkyl or substituted alkyl, wherein the substituents are selected from carboxyl, acetyl, amido or hydroxy,  
 R 2  is a C 1  up to C 4  alkyl or substituted alkyl, and  
 M is Fe +2 , provided that R 1  and R 2  are not both C 2  alkyl.  
 
     
     
         7 . The method of  claim 1  further comprising administering to said subject at least one additional agent useful for the treatment of SARS.  
     
     
         8 . The method of  claim 7  wherein said additional agent is selected from the group consisting of beta-glucans, N-acetyl cysteine, interferons, antiviral drugs, protease inhibitors, steroids and vaccines.  
     
     
         9 . The method of  claim 1  wherein said free radical scavenger is delivered orally, intravenously, subcutaneously, parenterally, topically, rectally or by inhalation.  
     
     
         10 . The method of  claim 1  wherein said free radical scavenger is delivered in the form of a solid, solution, emulsion, dispersion, micelle or liposome.  
     
     
         11 . A method for treating a subject with SARS, said method comprising administering to said subject an effective amount of at least one physiologically compatible dithiocarbamate-containing free radical scavenger, wherein said dithiocarbamate-containing free radical scavenger has the structure I or II as follows:  
       [R 1 R 2 N—C(S)—S − ] x M +1, +2, +3    (I)  
       wherein: 
 each of R 1  and R 2  is a C 1  up to C 18  alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, or substituted arylalkyl; provided however, that at least one of R 1  and R 2  is heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl, or  
 R 1  and R 2  can cooperate to form a 5-, 6- or 7-membered ring including N, R 1  and R 2 ,  
 x is 1 or 2, and  
 M is a monovalent cation when x is 1, or M is a physiologically compatible divalent or trivalent transition metal cation when x is 2 or 3, or  
 M +1,+2,+3 [S—C(S)—NR 1 ] x —R 3 —[R 1 N—C(S)—S − ] x M+ 1 ,+ 2 ,+ 3    (II)  
 wherein: each R 1  is a C 1  up to C 18  alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, or substituted arylalkyl; provided however, that at least one R 1  is heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl,  
 R 3  is a divalent moiety selected from the group consisting of alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, substituted alkenylene, arylene, substituted arylene, alkarylene, substituted alkarylene, aralkylene and substituted aralkylene,  
 x is 1 or 2, and  
 M is a monovalent cation when x is 1, or M is a physiologically compatible divalent or trivalent transition metal cation when x is 2 or 3.  
 
     
     
         12 . The method of  claim 11  wherein said free radical scavenger has the structure (III) as follows:  
       [R 1 R 2 N—C(S)—S − ] 2 M +2,+3    (III)  
       wherein: 
 each of R 1  and R 2  is a C 1  up to C 18  alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, or substituted arylalkyl;  
 provided however, that at least one of R 1  or R 2  is heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl, or  
 R 1  or R 2  is a divalent moiety selected from the group consisting of alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, substituted alkenylene, arylene, substituted arylene, alkarylene, substituted alkarylene, aralkylene and substituted aralkylene; provided however, that at least one of R 1  or R 2  is heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl, wherein said divalent moiety serves as the same substituent for two dithiocarbamate structures, thereby linking said structures together so as to form a bis(dithiocarbamate) species, and  
 M is Fe.  
 
     
     
         13 . The method of  claim 11  wherein said free radical scavenger is substantially hydrophilic.  
     
     
         14 . The method of  claim 11  wherein said free radical scavenger has structure I, 
 each of R 1  and R 2  is a C 1  up to C 12  alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, wherein the substituents are selected from carboxyl, —C(O)H, oxyacyl, phenol, phenoxy, pyridinyl, pyrrolidinyl, amino, amido, hydroxy, nitro or sulfuryl, and  
 M is Fe +2  or Fe +3 , provided that R 1  and R 2  are not both C 2  alkyl.  
 
     
     
         15 . The method of  claim 11  wherein said free radical scavenger has structure I, 
 R 1  is a C 2  up to C 8  alkyl or substituted alkyl, wherein the substituents are selected from carboxyl, acetyl, pyridinyl, pyrrolidinyl, amino, amido, hydroxy or nitro,  
 R 2  is selected from a C 1  up to C 6  alkyl or substituted alkyl, or R 2  can cooperate with R 1  to form a 5-, 6- or 7-membered ring including N, R 2  and R 1 , and  
 M is Fe +2 , provided that R 1  and R 2  are not both C 2  alkyl.  
 
     
     
         16 . The method of  claim 11  wherein said free radical scavenger has structure I, 
 R 1  is a C 2  up to C 8  alkyl or substituted alkyl, wherein the substituents are selected from carboxyl, acetyl, amido or hydroxy,  
 R 2  is a C 1  up to C 4  alkyl or substituted alkyl, and  
 M is Fe +2 , provided that R 1  and R 2  are not both C 2  alkyl.  
 
     
     
         17 . The method of  claim 11  further comprising administering to said subject at least one additional agent useful for the treatment of SARS.  
     
     
         18 . The method of  claim 17  wherein said additional agent is selected from the group consisting of beta-glucans, N-acetyl cysteine, interferons, antiviral drugs, protease inhibitors, steroids and vaccines.  
     
     
         19 . The method of  claim 11  wherein said free radical scavenger is delivered orally, intravenously, subcutaneously, parenterally, topically, rectally or by inhalation.  
     
     
         20 . The method of  claim 11  wherein said free radical scavenger is delivered in the form of a solid, solution, emulsion, dispersion, micelle or liposome.  
     
     
         21 . A composition comprising: 
 at least one agent selected from the group consisting of beta-glucans, N-acetyl cysteine, interferons, antiviral drugs, protease inhibitors, steroids and vaccines, and    an effective amount of at least one physiologically compatible dithiocarbamate, wherein said dithiocarbamate has the structure I or II as follows:    [R 1 R 2 N—C(S)—S − ] x M +1, +2, +3    (I)    wherein:    each of R 1  and R 2  is a C 1  up to C 18  alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, or substituted arylalkyl; provided however, that at least one of R 1  and R 2  is heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl, or    R 1  and R 2  can cooperate to form a 5-, 6- or 7-membered ring including N, R 1  and R 2 ,    x is 1 or 2, and    M is a monovalent cation when x is 1, or M is a physiologically compatible divalent or trivalent transition metal cation when x is 2 or 3, or    M +1,+2,+3 [S—C(S)—NR 1 ] x —R 3 —[R 1 N—C(S)—S − ] x M +1,+2,+3    (II)    wherein:    each R 1  is a C 1  up to C 18  alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, or substituted arylalkyl; provided however, that at least one R 1  is heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl,    R 3  is a divalent moiety selected from the group consisting of alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, substituted alkenylene, arylene, substituted arylene, alkarylene, substituted alkarylene, aralkylene and substituted aralkylene,    x is 1 or 2, and    M is a monovalent cation when x is 1, or M is a physiologically compatible divalent or trivalent transition metal cation when x is 2 or 3.    
     
     
         22 . The composition of  claim 21  wherein said dithiocarbamate has the structure (III) as follows:  
       [R 1 R 2 N—C(S)—S − ] 2 M +2,+3    (III)  
       wherein: 
 each of R 1  and R 2  is a C 1  up to C 18  alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, or substituted arylalkyl; provided however, that at least one of R 1  or R 2  is heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl, or  
 R 1  or R 2  is a divalent moiety selected from the group consisting of alkylene, substituted alkylene, oxyalkylene, substituted oxyalkylene, alkenylene, substituted alkenylene, arylene, substituted arylene, alkarylene, substituted alkarylene, aralkylene and substituted aralkylene; provided however, that at least one of R 1  or R 2  is heterocyclic, substituted heterocyclic, heteroaryl, or substituted heteroaryl, wherein said divalent moiety serves as the same substituent for two dithiocarbamate structures, thereby linking said structures together so as to form a bis(dithiocarbamate) species, and  
 M is Fe.  
 
     
     
         23 . The composition of  claim 21  wherein said dithiocarbamate has the structure I, 
 each of R 1  and R 2  is a C 1  up to C 12  alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl, wherein the substituents are selected from carboxyl, —C(O)H, oxyacyl, phenol, phenoxy, pyridinyl, pyrrolidinyl, amino, amido, hydroxy, nitro or sulfuryl, and  
 M is Fe +2  or Fe +3 , provided that R 1  and R 2  are not both C 2  alkyl.  
 
     
     
         24 . The composition of  claim 21  wherein said dithiocarbamate has the structure I, 
 R 1  is a C 2  up to C 8  alkyl or substituted alkyl, wherein the substituents are selected from carboxyl, acetyl, pyridinyl, pyrrolidinyl, amino, amido, hydroxy or nitro,  
 R 2  is selected from a C 1  up to C 6  alkyl or substituted alkyl, or R 2  can cooperate with R 1  to form a 5-, 6- or 7-membered ring including N, R 2  and R 1 , and  
 M is Fe +2 , provided that R 1  and R 2  are not both C 2  alkyl.  
 
     
     
         25 . The composition of  claim 21  wherein said dithiocarbamate has the structure I, 
 R 1  is a C 2  up to C 8  alkyl or substituted alkyl, wherein the substituents are selected from carboxyl, acetyl, amido or hydroxy,  
 R 2  is a C 1  up to C 4  alkyl or substituted alkyl, and  
 M is Fe +2 , provided that R 1  and R 2  are not both C 2  alkyl.  
 
     
     
         26 . The composition of  claim 21  wherein said additional agent is a beta-glucan .   
     
     
         26 . The composition of  claim 21  wherein said additional agent is an N-acetyl cysteine.  
     
     
         27 . The composition of  claim 21  wherein said additional agent is an interferon.  
     
     
         28 . The composition of  claim 21  wherein said additional agent is an antiviral drug.  
     
     
         29 . The composition of  claim 21  wherein said additional agent is a protease inhibitor.  
     
     
         30 . The composition of  claim 21  wherein said additional agent is a steroid.  
     
     
         31 . The composition of  claim 21  wherein said additional agent is a vaccine.  
     
     
         32 . The composition of  claim 21  wherein said composition is suitable for delivery orally, intravenously, subcutaneously, parenterally, topically, rectally or by inhalation.  
     
     
         33 . The composition of  claim 21  wherein said composition is formulated for delivery in the form of a solid, solution, emulsion, dispersion, micelle or liposome.