Reversibly protected thiolated electrophilic fatty acids as prodrugs

Abstract

Various embodiments of this invention are directed to pharmaceutical compositions and methods for treating disease. The compositions of such embodiments include thiolated nitro fatty acids. The methods of various embodiments include administering an effective amount of any of these pharmaceutical compositions to a patient in need of treatment.

What is claimed is: 
     
         1 . A composition comprising an effective amount of a thiolated nitro fatty acid of the formula: 
       
         
           
           
               
               
           
         
         wherein R is hydrogen (—H), methyl, or C 2  to C 6  alkyl, alkenyl, or alkynyl, or (S)xR may be a sulfur containing functional group such as, sulfino (—SOOH), sulfo (—SOOOH), or thiocyanate (—SCN), x is an integer from 1 to 5, and q and m are each, independently, an integer from 1 to 10; or 
       
       
         
           
           
               
               
           
         
         wherein R is hydrogen (—H), methyl, or C 2  to C 6  alkyl, alkenyl, or alkynyl, or (S)xR may be a sulfur containing functional group such as, sulfino (—SOOH), sulfo (—SOOOH), or thiocyanate (—SCN), x is an integer from 1 to 5, and q and m are each, independently, an integer from 1 to 10; or 
       
       
         
           
           
               
               
           
         
         wherein each Y is, independently, oxygen (O) or nitrogen (N), each x is, independently, an integer from 1 to 5, and q, m, p, and t are each, independently, an integer from 1 to 10; or 
       
       
         
           
           
               
               
           
         
         wherein R1 and R2 are independently selected from —H and any electron withdrawing groups including, but not limited to —COH, —COR, —COOH, —COOR, —Cl, —F, —Br, —I, —CF 3 , —CN, —SO 3 —, —SO 2 R, —SO 3 H, —NH 3 +, —NH 2 R + , —NHR 2   + , —NR 3   +  and —NO 2 ; wherein at least one of R 1  and R 2  is an electron withdrawing group; wherein Y 1  and Y 2  are independently selected from —H, —COH, —COR, —COOH, and —COOR; wherein at least one of R 1  and R 2  is an electron withdrawing group; and wherein x is an integer from 1 to 5, and q, m, p, and t are, independently, an integer from 1 to 10; or 
       
       
         
           
           
               
               
           
         
         wherein x is an integer from 1 to 5, and q, m, p, and t are, independently, an integer from 1 to 10; and 
         a pharmaceutically acceptable excipient. 
       
     
     
         2 . A compound, or a pharmaceutically acceptable salt thereof, of formula: 
       
         
           
           
               
               
           
         
         wherein R is hydrogen (—H), methyl, or C 2  to C 6  alkyl, alkenyl, or alkynyl, or (S)xR may be a sulfur containing functional group such as, sulfino (—SOOH), sulfo (—SOOOH), or thiocyanate (—SCN), x is an integer from 1 to 5, and q and m are each, independently, an integer from 1 to 10; or 
       
       
         
           
           
               
               
           
         
         wherein R is hydrogen (—H), methyl, or C 2  to C 6  alkyl, alkenyl, or alkynyl, or (S)xR may be a sulfur containing functional group such as, sulfino (—SOOH), sulfo (—SOOOH), or thiocyanate (—SCN), x is an integer from 1 to 5, and q and m are each, independently, an integer from 1 to 10; or 
       
       
         
           
           
               
               
           
         
         wherein each Y is, independently, oxygen (O) or nitrogen (N), each x is, independently, an integer from 1 to 5, and q, m, p, and t are each, independently, an integer from 1 to 10; or 
       
       
         
           
           
               
               
           
         
         wherein R1 and R2 are independently selected from —H and any electron withdrawing groups including, but not limited to —COH, —COR, —COOH, —COOR, —Cl, —F, —Br, —I, —CF 3 , —CN, —SO 3 —, —SO 2 R, —SO 3 H, —NH 3   + , —NH 2 R + , —NHR 2   + , —NR 3   +  and —NO 2 ; wherein at least one of R 1  and R 2  is an electron withdrawing group; wherein Y 1  and Y 2  are independently selected from —H, —COH, —COR, —COOH, and —COOR; wherein at least one of R 1  and R 2  is an electron withdrawing group; and wherein x is an integer from 1 to 5, and q, m, p, and t are, independently, an integer from 1 to 10; or 
       
       
         
           
           
               
               
           
         
         wherein x is an integer from 1 to 5, and q, m, p, and t are, independently, an integer from 1 to 10. 
       
     
     
         3 . A method for treating an inflammatory condition, obesity, metabolic syndrome, acute kidney disease, chronic kidney disease, atherogenesis, adipogenesis, neointimal proliferation, kidney I/R and xenobiotic injury, focal myocardial I/R injury, Ang II-induced systemic hypertension, pulmonary hypertension, cardiac and pulmonary fibrosis, inflammatory bowel disease, nociception, stroke, motor neuron degeneration, diabetes, asthma, or COPD comprising administering to a subject in need thereof the composition of  claim 1 . 
     
     
         4 . The method of  claim 1 , wherein the thiolated nitro fatty acid provides an extended release of a nitro fatty acid. 
     
     
         5 . The method of  claim 4 , wherein the thioloated nitro fatty acid releases the nitro fatty acid and a hydrogen sulfide, further providing additional protective measures. 
     
     
         6 . The method of  claim 3 , wherein the reduction of a nitro fatty acid alkene is prevented. 
     
     
         7 . The method of  claim 3 , wherein the adduction of a nitro fatty acid with glutathione is delayed. 
     
     
         8 . The method of  claim 3 , wherein side effects from nitro fatty acids are reduced. 
     
     
         9 . The method of  claim 8 , wherein the side effects of the gastrointestinal tract is selected from the group consisting of diarrhea, cramping irritation, inflammatory bowel disease, colitis, and ulcers. 
     
     
         10 . The method of  claim 3 , wherein the subject is treated for an inflammatory condition, obesity, metabolic syndrome, acute kidney disease, or chronic kidney disease. 
     
     
         11 . The method of  claim 3 , wherein the administered thiolated nitro fatty acid releases a nitro fatty acid. 
     
     
         12 . The method of  claim 3 , wherein the administered thioloated nitro fatty acid releases a nitro fatty acid and a hydrogen sulfide.