Thiocarbonates as Anti-Inflammatory and Antioxidant Compounds Useful For Treating Metabolic Disorders

Abstract

The invention is directed to thiocarbonate compounds of Formula (I)-(III) and methods of treating atherosclerosis, neuropathy, nephropathy, retinopathy, inflammatory disorders, COPD, cardiovascular diseases, metabolic disorders, type I diabetes mellitus, type II diabetes mellitus, LADA, Wolfram Syndrome 1, Wolcott-Rallison syndrome, metabolic syndrome, dyslipidemia, hyperglycemia, or insulin resistance. The compounds of the invention are also useful for protecting pancreatic beta-cells and for reducing free fatty acids, triglycerides, advanced glycated end products, ROS, lipid peroxidation, tissue and plasma TNFalpha and IL6 levels, or for delaying or preventing cardiovascular complications associated with atherosclerosis.

1 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 n is 1 or 2; 
 R 1  is OR 6 ; 
 R 2  is H or 2,4-difluorophenyl; 
 R 3  is H or (C 1 -C 6 )alkyl; 
 R 4  is H or acetyl; 
 R 5  is H or trifluoromethyl; 
 R 6  is independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are independently optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens and each Z 1  and Z 2  is independently H or (C 1 -C 6 )alkyl. 
 
       
     
     
         2 . (canceled) 
     
     
         3 . The compound of  claim 1 , wherein R 6  is H or (C 1 -C 6 )alkyl. 
     
     
         4 - 5 . (canceled) 
     
     
         6 . The compound of  claim 1 , wherein R 1  is methoxy, ethoxy or hydroxy. 
     
     
         7 - 12 . (canceled) 
     
     
         13 . The compound of  claim 1 , wherein R 2  is 2,4-difluorophenyl. 
     
     
         14 . The compound of  claim 1 , wherein R 3  is hydrogen or methyl. 
     
     
         15 . The compound of  claim 1 , wherein R 4  is acetyl. 
     
     
         16 - 18 . (canceled) 
     
     
         19 . The compound according to  claim 1 , wherein n is 1. 
     
     
         20 . The compound according to  claim 1 , wherein n is 2. 
     
     
         21 . The compound of  claim 20 , wherein R 6  is H, methyl or ethyl. 
     
     
         22 . A compound of Formula (II) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 R 1  is OR 6  or NR 6 R 7 ; 
 R 2  is H or 2,4-difluorophenyl; 
 R 3  is H or (C 1 -C 6 )alkyl; 
 R 8  is H or (C 1 -C 6 )alkyl 
 R 5  is H or trifluoromethyl; 
 R 6  and R 7  are independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl are independently optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens, and each Z 1  and Z 2  is independently H or (C 1 -C 6 )alkyl; or R 6  and R 7  together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane. 
 
       
     
     
         23 . The compound of  claim 22 , wherein R 6  is H or (C 1 -C 6 )alkyl. 
     
     
         24 . The compound of  claim 22 , wherein R 6  is (C 3 -C 6 )alkyl or optionally-substituted benzyl. 
     
     
         25 . The compound of  claim 22 , wherein R 1  is OR 6 . 
     
     
         26 . The compound of  claim 22 , wherein R 1  is hydroxy, methoxy, ethoxy n-propyloxy, i-propyloxy, t-butyoxy, benzyloxy, or 4-methoxybenzyloxy. 
     
     
         27 . The compound of  claim 22 , wherein
 R 1  is NR 6 R 7 ; and   R 7  is H, (C 1 -C 6 )alkyl, or (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, wherein the alkyl, or cycloalkyl groups are optionally substituted with 1, 2, 3, or 4 substituents that are independently (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, halogen, hydroxy, hydroxycarbonyl, NZ 1 Z 2 , or phenyl, wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5 halogens; or R 6  and R 7  together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, piperazine, N-methylpiperazine, morpholine, or azepane   
     
     
         28 . (canceled) 
     
     
         29 . The compound of  claim 27 , wherein R 6  and R 7  are independently H or (C 1 -C 6 )alkyl. 
     
     
         30 . The compound of  claim 22 , wherein R 1  is amino, methylamino, or dimethylamino. 
     
     
         31 . (canceled) 
     
     
         32 . The compound of  claim 22 , wherein R 2  is 2,4-difluorophenyl. 
     
     
         33 . The compound of  claim 22 , wherein R 3  is hydrogen. 
     
     
         34 . The compound of  claim 22 , wherein R 8  is H or methyl. 
     
     
         35 - 41 . (canceled) 
     
     
         42 . A compound according to  claim 22  that is
 2-(2-((2′,4′-Difluoro-3-(methoxycarbonyl)biphenyl-4-yloxy)carbonylthio) propanamido)acetic acid, or 
 (R)-2-Acetamido-3-(2-(benzyloxycarbonyl)-5-(trifluoromethyl)phenoxy) carbonylthio)propanoic acid, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         43 - 45 . (canceled)