Nitroalkene Trolox Derivatives and Methods of Use Thereof In The Treatment And Prevention of Inflammation Related Conditions

Abstract

The present invention is directed to a class of anti-inflammatory, antioxidant nitroalkene compounds used in biological or biochemical applications to reduce oxidative stress or damage. The nitroalkene compounds described herein further avoid disadvantageous metabolism currently present in this field.

What is claimed is: 
     
         1 . A method of treating an inflammation related disorder comprising the steps of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically-acceptable salt thereof, wherein R is a C 1 -C 15  nitroalkenyl; 
         R 1 , R 2 , R 4 , and R 5  are independently a —H or —CH 3 ; and 
         R 3  is selected from the group consisting 
         of —H, —OH, —OBOC, —OCH 3 , —OBn, —SH, —NO 2 , —NH 2 , —CN, a carbonyl, a sulfonate, an amidino. 
       
     
     
         2 . The method of treating an inflammation related disorder of  claim 1 , wherein the inflammation related disorder is selected from the group consisting of atherosclerosis, obesity, metabolic syndrome, arterial hypertension (HTA), acne vulgaris, asthma, autoimmune diseases, autoinflammatory diseases, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel diseases, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sacroidosis, transplant rejection, vasculitis, and interstitial cystitis. 
     
     
         3 . The method of treating an inflammation related disorder of  claim 1  comprising the steps of administering to a subject in need thereof a therapeutically effective amount of the compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein R 3  is selected from the group consisting of —H, a —OH, —OBOC, —OCH 3 , and —OBn. 
       
     
     
         4 . The method of treating an inflammation related disorder of  claim 1 , wherein R 1 , R 2 , R 4 , and R 5  are each —CH 3 . 
     
     
         5 . The method of treating an inflammation related disorder of  claim 1 , wherein R is a nitrovinyl. 
     
     
         6 . The method of treating an inflammation related disorder of  claim 1 , wherein R 3  is —OH. 
     
     
         7 . The method of treating an inflammation related disorder of  claim 1 , wherein the compound of Formula I is selected from the group consisting of:
 2,5,7,8-tetramethyl-2-(2-nitrovinyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(2-nitropentenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(2-nitro-2-pentenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(3-nitro-2-pentenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(3-nitro-3-pentenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(4-nitro-3-pentenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(4-nitro-4-pentenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(5-nitro-4-pentenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(2-nitrooctenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(2-nitro-2-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(3-nitro-2-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(3-nitro-3-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(4-nitro-3-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(4-nitro-4-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(5-nitro-4-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(5-nitro-5-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(6-nitro-5-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(6-nitro-6-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(7-nitro-6-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(7-nitro-7-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(8-nitro-7-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(2-nitrotridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(2-nitro-2-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(3-nitro-2-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(3-nitro-3-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(4-nitro-3-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(4-nitro-4-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(5-nitro-4-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(5-nitro-5-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(6-nitro-5-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(6-nitro-6-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(7-nitro-6-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(7-nitro-7-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(8-nitro-7-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(8-nitro-8-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(9-nitro-8-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(9-nitro-9-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(10-nitro-9-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(10-nitro-10-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(11-nitro-10-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(11-nitro-11-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(12-nitro-11-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(12-nitro-12-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(13-nitro-12-tridecenyl)chroman-6-ol,   or a physiologically acceptable salt thereof.   
     
     
         8 . The method of treating an inflammation related disorder of  claim 1 , wherein the compound of Formula I is 2,5,7,8-tetramethyl-2-(2-nitrovinyl)chroman-6-ol or a physiologically acceptable salt thereof. 
     
     
         9 . The method of treating an inflammation related disorder of  claim 1 , wherein the compound of Formula I is (2S)-2,5,7,8-tetramethyl-2-[(E)-2-nitrovinyl]chroman-6-ol or a physiologically acceptable salt thereof. 
     
     
         10 . The method of treating an inflammation related disorder of  claim 1 , wherein R is a 2-nitrovinyl and the absolute configuration of the chiral carbon adjacent the oxygen atom on the chromanol ring structure is (S). 
     
     
         11 . The method of treating an inflammation related disorder of  claim 1 , wherein R is a 2-nitroalkenyl and the absolute configuration of the chiral carbon adjacent the oxygen atom on the chromanol ring structure is (S). 
     
     
         12 . The method of treating an inflammation related disorder of  claim 1 , wherein R is a 3-nitroallyl and the absolute configuration of the chiral carbon adjacent the oxygen atom on the chromanol ring structure is (S). 
     
     
         13 . The method of treating an inflammation related disorder of  claim 1 , wherein R is a 3-nitroalkenyl and the absolute configuration of the chiral carbon adjacent the oxygen atom on the chromanol ring structure is (S). 
     
     
         14 . The method of treating an inflammation related disorder of  claim 1 , wherein R has a nitroalkenyl disposed at fourth to fifteenth carbon on the C 4 -C 15  hydrocarbon tail and the absolute configuration of the chiral carbon adjacent the oxygen atom on the chromanol ring structure is (R). 
     
     
         15 . A method of treating an inflammation related disorder comprising the steps of administering to a subject in need thereof a pharmaceutical composition comprising a carrier and a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically-acceptable salt thereof, wherein R is a C 1 -C 15  nitroalkenyl; 
         R 1 , R 2 , R 4 , and R 5  are independently a —H or —CH 3 ; and 
         R 3  is selected from the group consisting of —H, —OH, —OBOC, —OCH 3 , —OBn, —SH, —NO 2 , —NH 2 , —CN, a carbonyl, a sulfonate, an amidino. 
       
     
     
         16 . The method of treating an inflammation related disorder of  claim 15 , wherein R is a nitrovinyl. 
     
     
         17 . The method of treating an inflammation related disorder of  claim 15 , wherein R 3  is —OH. 
     
     
         18 . The method of treating an inflammation related disorder of  claim 15 , wherein the compound of Formula I is selected from the group consisting of:
 2,5,7,8-tetramethyl-2-(2-nitrovinyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(2-nitropentenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(2-nitro-2-pentenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(3-nitro-2-pentenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(3-nitro-3-pentenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(4-nitro-3-pentenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(4-nitro-4-pentenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(5-nitro-4-pentenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(2-nitrooctenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(2-nitro-2-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(3-nitro-2-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(3-nitro-3-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(4-nitro-3-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(4-nitro-4-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(5-nitro-4-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(5-nitro-5-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(6-nitro-5-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(6-nitro-6-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(7-nitro-6-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(7-nitro-7-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(8-nitro-7-octenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(2-nitrotridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(2-nitro-2-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(3-nitro-2-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(3-nitro-3-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(4-nitro-3-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(4-nitro-4-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(5-nitro-4-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(5-nitro-5-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(6-nitro-5-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(6-nitro-6-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(7-nitro-6-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(7-nitro-7-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(8-nitro-7-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(8-nitro-8-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(9-nitro-8-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(9-nitro-9-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(10-nitro-9-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(10-nitro-10-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(11-nitro-10-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(11-nitro-11-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(12-nitro-11-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(12-nitro-12-tridecenyl)chroman-6-ol,   2,5,7,8-tetramethyl-2-(13-nitro-12-tridecenyl)chroman-6-ol,   or a physiologically acceptable salt thereof.   
     
     
         19 . The method of treating an inflammation related disorder of  claim 15 , wherein the compound of Formula I is 2,5,7,8-tetramethyl-2-(2-nitrovinyl)chroman-6-ol or a physiologically acceptable salt thereof. 
     
     
         20 . The method of treating an inflammation related disorder of  claim 19 , wherein the compound of Formula I is (2S)-2,5,7,8-tetramethyl-2-[(E)-2-nitrovinyl]chroman-6-ol or a physiologically acceptable salt thereof.