Antidotes to Cyanide Poisoning

Abstract

The present application provides, inter alia, a compound of Formula (I): or a pharmaceutically acceptable salt thereof, and methods of use of the compound of Formula (I) for treatment and prevention of cyanide poisoning.

What is claimed is: 
     
         1 . A method of treating or preventing cyanide poisoning, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is selected from C 1-3  alkyl, C 1-3  haloalkyl, C 2-4  alkenyl, C 2-4  alkynyl, and C 6-10  aryl; 
         R 2  is selected from C 1-3  alkyl, C 1-3  haloalkyl, C 2-4  alkenyl, C 2-4  alkynyl, and C 6-10  aryl; or 
         R 1  and R 2  together form a group selected from C 1-3  alkylene, C 2-4  alkenylene, or C 2-4  alkynylene; 
         n is an integer selected from 1, 2, 3, 4, and 5; 
         each L is a ligand independently selected from halogen, NR c1 R d1 , NR c1 R d1 R e1 , C 2-12  alkene, OR a1 , H 2 O, HOR 3 , NC—R 3 , P(R a1 ) 3 , S(O) 2 R 1 R 2 , SR 1 R 2 , and 5-10 membered heteroaryl; or 
         any two L together form a bidentate ligand selected from C 4-12  alkyldiene, 12-16 membered fused heteroaryl, and bis (5-10 membered heteroaryl); 
         each R a1  is independently selected from H, C 1-6  alkyl, C 1-3  haloalkyl, C 2-4  alkenyl, C 2-4  alkynyl, and C 6-10  aryl; 
         each R c1 , R d1 , and R e1  is independently selected from H, C 1-3  alkyl, C 1-3  haloalkyl, C 2-4  alkenyl, C 2-4  alkynyl, and C 3-10  cycloalkyl; or 
         any two R c1  together form a group selected from C 1-3  alkylene, C 2-4  alkenylene, and C 3-10  cycloalkylene; and 
         R 3  is selected from C 1-3  alkyl, C 1-3  haloalkyl, C 2-4  alkenyl, C 2-4  alkynyl, and C 6-10  aryl. 
       
     
     
         2 . The method of  claim 1 , wherein the compound of Formula (I) has formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The method of  claim 1 , wherein the compound of Formula (I) has formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The method of  claim 1 , wherein the compound of Formula (I) has formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The method of  claim 1 , wherein:
 R 1  and R 2  are each independently C 1-3  alkyl,   n is an integer selected from 1,3, and 5;   each L is independently selected from halogen, NR c1 R d1 R e1 , C 2 -12 alkene, NC—R 3 , P(R a1 ) 3 , S(O) 2 R 1 R 2 , SR 1 R 2 , and 5-10 membered heteroaryl; or   any two L together form a bidentate ligand selected from C 4-12  alkyldiene, 12-16 membered fused heteroaryl, and bis (5-10 membered heteroaryl);   each R a1  is independently selected from C 1-6  alkyl and C 6-10  aryl;   each R c1 , R d1 , and R e1  is independently selected from H, C 1-3  alkyl, and C 3-10  cycloalkyl; or   any two R c1  together form a group selected from C 1-3  alkylene and C 3-10  cycloalkylene; and   R 3  is selected from C 1-3  alkyl and C 6-10  aryl.   
     
     
         6 . The method of  claim 1 , wherein:
 R 1  and R 2  are each independently C 1-3  alkyl,   n is an integer selected from 1,3, and 5;   each L is independently selected from halogen, NR c1 R d1 R e1 , S(O) 2 R 1 R 2 , and SR 1 R 2 ; and   each R c1 , R d1 , and R e1  is independently selected from H and C 1-3  alkyl.   
     
     
         7 . The method of  claim 1 , wherein the compound of Formula (I) is selected from: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The method of  claim 7 , wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . The method of  claim 7 , wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 . The method of  claim 7 , wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . The method of  claim 7 , wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The method of  claim 7 , wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . The method of  claim 7 , wherein the compound of Formula (I) is:
 or a pharmaceutically acceptable salt thereof.   
     
     
         14 . The method of  claim 1 , wherein the compound of Formula (I) is selected from: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         15 . The method of  claim 1 , wherein the pharmaceutical composition is suitable for administration by an intramuscular injection. 
     
     
         16 . The method of  claim 1 , wherein the pharmaceutical composition further comprises at least one additional therapeutic agent useful in treating or preventing cyanide poisoning, or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The method of  claim 16 , wherein the additional therapeutic agent is selected from: hydroxocobalamin, methemoglobin, riboflavin, methotrexate, sulfanegen, 3-mercaptopyruvic acid (3-MP), amyl nitrite, sodium nitrite, sodium thiosulfate, 4-dimethylaminophenol (4-DMAP), dicobalt edetate, glucose, and oxygen therapy. 
     
     
         18 . The method of  claim 1 , further comprising administering to the subject a pharmaceutical composition comprising at least one additional therapeutic agent useful in treating or preventing cyanide poisoning, or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method of  claim 18 , wherein the pharmaceutical composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition comprising the additional therapeutic agent, or a pharmaceutically acceptable salt thereof, are administered to the subject in separate dosage forms. 
     
     
         20 . The method of  claim 18 , wherein the additional therapeutic agent is selected from: hydroxocobalamin, methemoglobin, riboflavin, methotrexate, sulfanegen, 3-mercaptopyruvic acid (3-MP), amyl nitrite, sodium nitrite, sodium thiosulfate, 4-dimethylaminophenol (4-DMAP), dicobalt edetate, glucose, and oxygen therapy.