Compounds, compositions and methods for treating or preventing hypoxic or ischemic injury

Abstract

Compositions and methods of treating or preventing disease or injury to a human patient or biological material undergoing ischemic or hypoxic conditions.

What is claimed is: 
     
         1 . A compound represented by the following structure: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently a branched or straight chain C 1-10  alkyl; a branched or straight chain C 1-10  alkyl substituted with —ONO 2 ; or, a branched or straight chain C 1-10  alkyl substituted with —OH; wherein R 3  and R 4  are independently a branched or straight chain C 1-10  alkanediyl; wherein R 5  and R 6  are independently OH, an amino acid moiety, or, a straight or branched chain C 1-10  amine substituted with —ONO 2 ; wherein X and Y are independently C═O or SO 2 ; and, wherein m is 3 or 4; Z is selected from H, CH 3 , and CH 2 CH 3 ; or, a salt, ester, hydrate, solvate, or stereoisomer thereof, with the proviso that when m is 3, Z is H, X and Y are C═O, R 3  and R 4  are CH 2 , and R 5  and R 6  are OH, then R 1  and R 2  are not C 1-10  alkyl. 
       
     
     
         2 . The compound of  claim 1  wherein m is 3, Z is H, and R 5  and R 6  are OH. 
     
     
         3 . The compound of  claim 2  wherein X and Y are SO 2 , R 1  and R 2  are CH 3 , and R 3  and R 4  are CH 2 . 
     
     
         4 . The compound of  claim 2  wherein X and Y are C═O and
 a) R 1  and R 2  are CH 3 , and R 3  and R 4  are C(CH 3 ) 2  or (CH 2 ) 2 ; 
 b) R 1  and R 2  are CH 3 , R 3  is CH 2  and R 4  is C(CH 3 ) 2 ; or 
 c) R 1  is CH 3 , R 2  is CH 2 CH 3 , and R 3  and R 4  are CH 2 . 
 
     
     
         5 . The compound of  claim 1  wherein m is 3, X and Y are C═O, Z is H and R 1  and R 2  are CH 3 , R 3  and R 4  are CH 2 , and,
 a) R 5  and R 6  are NHCH 2 CO 2 H; 
 b) R 5  is OH and R 6  is NHCH 2 CO 2 H; or 
 c) R 5  is OH and R 6  is NH(CH 2 ) 2 ONO 2 . 
 
     
     
         6 . The compound of  claim 2  wherein X is C═O, Y is SO 2 , R 1  and R 2  are CH 3 , and R 3  and R 4  are CH 2 . 
     
     
         7 . The compound of  claim 1  wherein m is 4, Z is H, and R 5  and R 6  are OH. 
     
     
         8 . The compound of  claim 1  wherein m is 3, X and Y are C═O, R 1  and R 2  are CH 3 , R 3  and R 4  are CH 2 , Z is CH 3 , and, R 5  and R 6  are OH. 
     
     
         9 . A compound represented by the structure: 
       
         
           
           
               
               
           
         
         wherein R 10 , R 11  and R 12  are each independently a side chain of a naturally-occurring or a non-naturally occurring amino acid, a branched or straight chain C 1-10  alkyl, a straight or branched chain C 1-10  alkyl substituted with —ONO 2 , or, a straight or branched chain C 1-10  alkyl substituted with —OH; wherein R 13  and R 14  are independently a branched or straight chain C 1-10  alkanediyl; and, wherein X is independently C═O or SO 2 ; 
         or a compound represented by the structure: 
       
       
         
           
           
               
               
           
         
         wherein R 15 , R 16 , R 17  and R 18  are each independently a side chain of a naturally occurring or a non-naturally occurring amino acid, a branched or straight chain C 1-10  alkyl, a straight or branched chain C 1-10  alkyl substituted with —ONO 2 , or, a straight or branched chain C 1-10  alkyl substituted with —OH; wherein R 19  and R 20  are each independently a branched or straight chain C 1-10  alkanediyl; and, wherein each X is independently C═O or SO 2 ; 
         or, a salt, ester, hydrate, solvate or stereoisomer thereof. 
       
     
     
         10 . The compound of  claim 9  wherein each X is C═O; R 12  and R 18  are CH 3 ; and R 10 , R 11 . R 12 , R 15 , R 16 , R 17  and R 18  are each independently a side chain of a naturally-occurring or a non-naturally occurring amino acid; or a salt, ester, free acid, hydrate, or solvate or stereoisomer thereof. 
     
     
         11 . A pharmaceutical composition comprising a compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently a branched or straight chain C 1-10  alkyl; a branched or straight chain C 1-10  alkyl substituted with —ONO 2 ; or, a branched or straight chain C 1-10  alkyl substituted with —OH; wherein R 3  and R 4  are independently a branched or straight chain C 1-10  alkanediyl; wherein R 5  and R 6  are independently OH, an amino acid moiety, or, a straight or branched chain C 1-10  amine substituted with —ONO 2 ; wherein X and Y are independently C═O or SO 2 ; and, wherein m is 3 or 4; Z is selected from H, CH 3 , and CH 2 CH 3 ; 
       
       
         
           
           
               
               
           
         
         wherein R 10 , R 11  and R 12  are each independently a side chain of a naturally-occurring or a non-naturally occurring amino acid, a branched or straight chain C 1-10  alkyl, a straight or branched chain C 1-10  alkyl substituted with —ONO 2 , or, a straight or branched chain C 1-10  alkyl substituted with —OH; wherein R 13  and R 14  are independently a branched or straight chain C 1-10  alkanediyl; and, wherein X is independently C═O or SO 2 ; 
       
       
         
           
           
               
               
           
         
         wherein R 15 , R 16 , R 17  and R 18  are each independently a side chain of a naturally occurring or non-naturally occurring amino acid, a branched or straight chain C 1-10  alkyl, a straight or branched chain C 1-10  alkyl substituted with —ONO 2 , or, a straight or branched chain C 1-10  alkyl substituted with —OH; wherein R 19  and R 20  are independently a branched or straight chain C 1-10  alkanediyl; and, wherein X is independently C═O or SO 2 ; and 
         a salt, ester, hydrate, solvate or stereoisomer thereof; 
         and a pharmaceutically acceptable vehicle, wherein the pharmaceutical composition has a pH of 5.0 to 6.5. 
       
     
     
         12 . The pharmaceutical composition of  claim 11 , which comprises a dosing concentration in the range of 2 to 40 mg/ml. 
     
     
         13 . A method of making a linear symmetrical or asymmetrical trisulfide compound represented by the structure: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently a branched or straight chain C 1-10  alkyl; a branched or straight chain C 1-10  alkyl substituted with —ONO 2 ; or, a branched or straight chain C 1-10  alkyl substituted with —OH; wherein R 3  and R 4  are independently a branched or straight chain C 1-10  alkanediyl; wherein R 5  and R 6  are independently OH, an amino acid moiety, or, a straight or branched chain C 1-10  amine substituted with —ONO 2 ; wherein X and Y are independently C═O or SO 2 ; and, wherein Z is selected from H, CH 3 , and CH 2 CH 3 ; the method comprising: 
         reacting a compound represented by the following structure 
       
       
         
           
           
               
               
           
         
         wherein R 1 , X, R 3  and R 5  are as defined above, with an equal molar amount of 2,2′-thiodiisoindoline-1,3-dione in acetonitrile and water to produce a ((1,3-dioxoisoindolin-2-yl)disulfanyl)-containing intermediate; 
         isolating the intermediate; and 
         reacting the intermediate with a compound represented by the following structure 
       
       
         
           
           
               
               
           
         
         wherein R 2 , X, R 4  and R 6  are as defined above, in an aqueous alcohol solution, thereby forming the trisulfide compound. 
       
     
     
         14 . The method of  claim 13 , wherein the aqueous alcohol solution comprises 50% isopropanol. 
     
     
         15 . The method of  claim 13  wherein the method comprises reacting a compound represented by the structure: 
       
         
           
           
               
               
           
         
         with the 2,2′-thiodiisoindoline-1,3-dione, thereby forming the trisulfide compound represented by the structure 
       
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 13  wherein the compound which is reacted with the 2,2′-thiodiisoindoline-1,3-dione is prepared by a method comprising reacting a compound represented by the structure 
       
         
           
           
               
               
           
         
         with methanesulfonyl chloride to produce a reaction product represented by the structure 
       
       
         
           
           
               
               
           
         
       
       and
 treating the reaction product with triethylsilane and trifluoroacetic acid to produce the compound. 
 
     
     
         17 . A method of making a cyclic trisulfide compound represented by the structure: 
       
         
           
           
               
               
           
         
         wherein the method comprises preparing a dilute solution of a first compound represented by the structure 
       
       
         
           
           
               
               
           
         
         and 2,2′-thiodiisoindoline-1,3-dione in acetonitrile and water, and reacting the first compound and the 2,2′-thiodiisoindoline-1,3-dione to produce the cyclic trisulfide compound. 
       
     
     
         18 . The method of  claim 17  wherein the concentration of the first compound in the dilute solution is about 0.07 mM. 
     
     
         19 . A method of treating or preventing injury to biological matter exposed to ischemic or hypoxic conditions comprising administering to a patient in need thereof a therapeutically effective dose of a compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently a branched or straight chain C 1-10  alkyl; a branched or straight chain C 1-10  alkyl substituted with —ONO 2 ; or, a branched or straight chain C 1-10  alkyl substituted with —OH; wherein R 3  and R 4  are independently a branched or straight chain C 1-10  alkanediyl; wherein R 5  and R 6  are independently OH, an amino acid moiety, or, a straight or branched chain C 1-10  amine substituted with —ONO 2 ; wherein X and Y are independently C═O or SO 2 ; and, wherein m is 3 or 4; Z is selected from H, CH 3 , and CH 2 CH 3 ; 
       
       
         
           
           
               
               
           
         
         wherein R 10 , R 11  and R 12  are each independently a side chain of a naturally-occurring or a non-naturally occurring amino acid, a branched or straight chain C 1-10  alkyl, a straight or branched chain C 1-10  alkyl substituted with —ONO 2 , or, a straight or branched chain C 1-10  alkyl substituted with —OH; wherein R 13  and R 14  are independently a branched or straight chain C 1-10  alkanediyl; and, wherein X is independently C═O or SO 2 ; 
       
       
         
           
           
               
               
           
         
         wherein R 15 , R 16 , R 17  and R 18  are each independently a side chain of a naturally occurring or a non-naturally occurring amino acid, a branched or straight chain C 1-10  alkyl, a straight or branched chain C 1-10  alkyl substituted with —ONO 2 , or, a straight or branched chain C 1-10  alkyl substituted with —OH; wherein R 19  and R 20  are independently a branched or straight chain C 1-10  alkanediyl; and, wherein X is independently C═O or SO 2 ; and 
         a salt, ester, hydrate, solvate or stereoisomer thereof. 
       
     
     
         20 . The method of  claim 19  wherein the hypoxic or ischemic conditions are related to reperfusion injury, tissue or organ transplantation, septic shock, cardiac arrest, exposure to cold or radiation, burns, wounds, amputations, stroke, hemorrhagic shock, surgical procedures, systemic inflammatory response syndrome, acute respiratory distress syndrome, kidney failure, liver failure or multiple organ failure. 
     
     
         21 . The method of  claim 19  wherein the compound is administered parenterally, intravenously, as a bolus or a repeated bolus. 
     
     
         22 . A ((1,3-dioxoisoindolin-2-yl)disulfanyl)-containing compound represented by the following structure: 
       
         
           
           
               
               
           
         
         wherein R 1  is a branched or straight chain C 1-10  alkyl; a branched or straight chain C 1-10  alkyl substituted with —ONO 2 ; or, a branched or straight chain C 1-10  alkyl substituted with —OH; wherein R 3  is a branched or straight chain C 1-10  alkanediyl; wherein R 5  is OH, an amino acid moiety, or, a straight or branched chain C 1-10  amine substituted with —ONO 2 ; wherein X is C═O or SO 2 ; and, wherein Z is selected from H, CH 3 , and CH 2 CH 3 .