Alkylamine-substituted perthiocarbamates as dual precursors to hydropersulfide and carbonyl sulfide

Abstract

Alkylamine-substituted perthiocarbamates capable of controllable release of hydropersulfides (RSSH) and carbonyl sulfide (COS) and their use in treating or preventing ischemia-reperfusion injury are described.

That which is claimed: 
     
         1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; 
 R 1  is selected from the group consisting of branched or unbranched alkyl, heterocycloalkyl, aryl, heteroaryl, a cysteine residue, a N-acetylcysteine residue, a homocysteine residue, a glutathione residue, and: 
 
       
       
         
           
           
               
               
           
         
         
           wherein: 
           R 4  and R 5  are each independently selected from the group consisting of H, C 1 -C 4  alkyl, and aryl; 
           R 6  is C 1 -C 4  alkyl or aryl; 
           R 7  is —OR 8  or —NR 9 R 10 , wherein R 8 , R 9 , and R 10  are each independently selected from the group consisting of H, C 1 -C 4  alkyl, and aryl; 
           R 2  is selected from the group consisting of H, alkyl, aryl, and a functional group that responds to a stimulus selected from the group consisting of light, a redox reaction, and an enzymatic reaction; 
           R 3  is selected from the group consisting of H, alkyl, and aryl; and 
           X −  is an anion. 
         
       
     
     
         2 . The compound of  claim 1 , wherein n is an integer selected from the group consisting of 1, 2, and 3. 
     
     
         3 . The compound of  claim 1 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
         n is an integer selected from the group consisting of 1, 2, and 3; 
         R 4  and R 5  are each independently H or C 1 -C 4  alkyl; 
         R 6  is C 1 -C 4  alkyl or aryl; 
         R 7  is —OR 8  or —NR 9 R 10 , wherein R 8 , R 9 , and R 10  are each independently selected from the group consisting of H, C 1 -C 4  alkyl, and aryl; 
         R 2  is selected from the group consisting of H, C 1 -C 4  alkyl, and a functional group that responds to a stimulus selected from the group consisting of light, a redox reaction, and an enzymatic reaction; 
         R 3  is selected from the group consisting of H, alkyl, and aryl; and 
         X −  is an anion. 
       
     
     
         4 . The compound of  claim 3 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
         wherein:
 n is 1 or 2; and 
 R 2  is H or CH 3 . 
 
       
     
     
         5 . The compound of  claim 4 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein X −  is selected from the group consisting of Cl − , Br − , (PO 4 ) 3− , CF 3 COO − , CH 3 COO − , and C 6 H 5 COO − . 
     
     
         7 . The compound of  claim 1 , wherein the functional group that responds to a stimulus selected from the group consisting of light, a redox reaction, and an enzymatic reaction is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein:
 X 1  and X 2  are each independently selected from the group consisting of O, NR 14 , and CR 15 R 16 ; wherein R 14 , R 15 , and R 16  are each independently H or branched or unbranched C 1 -C 4  alkyl; 
 R 11  and R 12  are each independently selected from the group consisting of H, and branched or unbranched alkyl, or R 11  and R 12  together can form a cyclic alkyl or substituted cyclic alkyl; and 
 R 13  is selected from the group consisting of branched or unbranched alkyl and aryl. 
 
       
     
     
         8 . The compound of  claim 6 , wherein X −  is CF 3 COO −  and the compound of formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         9 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         10 . A kit comprising a compound of  claim 1 . 
     
     
         11 . The kit of  claim 10 , further comprising instructions for use in treating or preventing ischemia/reperfusion injury. 
     
     
         12 . A method for treating a disorder, disease, or condition associated with oxidative stress in a subject in need of treatment thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) of  claim 1 . 
     
     
         13 . The method of  claim 12 , wherein the disorder, disease, or condition associated with oxidative stress comprises ischemia/reperfusion injury. 
     
     
         14 . The method of  claim 13 , wherein the treating comprises preventing, reducing the occurrence of or severity of, or protecting against ischemia/reperfusion injury. 
     
     
         15 . The method of  claim 13 , wherein the subject is at risk of an ischemia/reperfusion injury or an ischemic event. 
     
     
         16 . The method of  claim 15 , wherein the risk of an ischemia/reperfusion injury or an ischemic event includes a therapeutic intervention. 
     
     
         17 . The method of  claim 16 , comprising administering a compound of formula (I) to the subject before the therapeutic intervention. 
     
     
         18 . The method of  claim 13 , wherein the compound of formula (I) is administered to the subject after ischemia. 
     
     
         19 . The method of  claim 18 , wherein the compound of formula (I) is administered to the subject after ischemia, but before reperfusion. 
     
     
         20 . The method of  claim 13 , wherein the ischemia/reperfusion injury comprises myocardial ischemia/reperfusion injury. 
     
     
         21 . A method for preventing or reducing ischemia/reperfusion injury to an organ to be transplanted, the method comprising administering to or contacting the organ with a therapeutically effective amount of a compound of formula (I) of  claim 1 . 
     
     
         22 . The method of  claim 21 , comprising administering a compound of formula (I) to a transplant donor prior to harvesting the organ therefrom.