Compositions and methods of use of gamma-ketoaldehyde scavengers for treating, preventing or improving nonalcoholic fatty liver disease (nafld), nash, ald or conditions related to the liver

Abstract

Methods and compositions for use in treating, preventing or improving diseases related to the liver in an animal, including but not limited to nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD) or nonalcoholic steatohepatitis (NASH), are described. The compounds of the present invention are gamma-ketoaldehyde scavengers.

1 . A method for treating, preventing, or ameliorating liver disease to an animal with or at risk of liver disease, thereby inhibiting or treating the liver disease, comprising the step of administering to the animal and effective amount of the compound having a structure represented by a compound of the following formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R is N or C; 
         R 2  is independently H, hydroxy, halogen, nitro, CF 3 , C 1-6  alkyl, C 1-6  alkoxy, C 3-10  cycloalkyl, C 3-8  membered ring containing C, O, S or N, optionally substituted with one or more R 2 , R 3  and R 4 , and may cyclize with to one or more R 2 , R 3 , or R 5  to form an optionally substituted C 3-8  membered ring containing C, O, S or N; 
         R 3  is H, hydroxy, halogen, nitro, CF 3 , C 1-6  alkyl, C 1-6  alkoxy, C 3-10  cycloalkyl, C 3-8  membered ring containing C, O, S or N, optionally substituted with one or more R 4 , R 2  and R 3  may cyclize with to one or more R 2  or R 5  to form an optionally substituted C 3-8  membered ring containing C, O, S or N; 
         R 4  is H, hydroxy, halogen, nitro, CF 3 , C 1-6  alkyl, C 1-6  alkoxy, C 3-10  cycloalkyl, C 3-8  membered ring containing C, O, S or N, optionally substituted with one or more R 4 , R 2  and R 3  may cyclize with to one or more R 2 , R 3 , or R 5  to form an optionally substituted C 3-8  membered ring containing C, O, S or N; 
         R 5  is a bond, H, hydroxy, halogen, nitro, CF 3 , C 1-6  alkyl, C 1-6  alkoxy, C 3-10  cycloalkyl, C 3-8  membered ring containing C, O, S or N, optionally substituted with one or more R 4 , R 2  and R 3  may cyclize with to one or more R 2 , R 3 , or R 4  to form an optionally substituted C 3-8  membered ring containing C, O, S or N; and stereoisomers and analogs thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the liver disease further comprises nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD) or nonalcoholic steatohepatitis (NASH). 
     
     
         3 . The method of  claim 1 , wherein the compound is selected from the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R is N or C; 
         R 2  is independently H, substituted or unsubstituted alkyl; 
         R 3  is H, halogen, alkoxy, hydroxyl, nitro; 
         R 4  is H, substituted or unsubstituted alkyl, carboxyl; and pharmaceutically acceptable salts thereof. 
       
     
     
         4 . The method of  claim 1 , wherein the compound is salicylamine (2-hydroxybenzylamine or 2-HOBA). 
     
     
         5 . The method of  claim 1 , wherein the compound is selected from the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . The method of  claim 1 , wherein the compound is selected from the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The method of  claim 1 , wherein the compound is selected from the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The method of  claim 1 , wherein the compound is selected from the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . The method of  claim 1 , wherein the compound is selected from the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 . A nutritional composition comprising a pharmaceutically acceptable carrier and a compound of the following formula, and its use as agents in a method for treating, preventing, or ameliorating liver disease to an animal with or at risk of liver disease, thereby inhibiting or treating the liver disease: 
       
         
           
           
               
               
           
         
         wherein: 
         R is N or C; 
         R 2  is independently H, hydroxy, halogen, nitro, CF 3 , C 1-6  alkyl, C 1-6  alkoxy, C 3-10  cycloalkyl, C 3-8  membered ring containing C, O, S or N, optionally substituted with one or more R 2 , R 3  and R 4 , and may cyclize with to one or more R 2 , R 3 , or R 5  to form an optionally substituted C 3 -8 membered ring containing C, O, S or N; 
         R 3  is H, hydroxy, halogen, nitro, CF 3 , C 1-6  alkyl, C 1-6  alkoxy, C 3-10  cycloalkyl, C 3-8  membered ring containing C, O, S or N, optionally substituted with one or more R 4 , R 2  and R 3  may cyclize with to one or more R 2  or R 5  to form an optionally substituted C 3-8  membered ring containing C, O, S or N; 
         R 4  is H, hydroxy, halogen, nitro, CF 3 , C 1-6  alkyl, C 1-6  alkoxy, C 3-10  cycloalkyl, C 3-8  membered ring containing C, O, S or N, optionally substituted with one or more R 4 , R 2  and R 3  may cyclize with to one or more R 2 , R 3 , or R 5  to form an optionally substituted C 3-8  membered ring containing C, O, S or N; 
         R 5  is a bond, H, hydroxy, halogen, nitro, CF 3 , C 1-6  alkyl, C 1-6  alkoxy, C 3-10  cycloalkyl, C 3-8  membered ring containing C, O, S or N, optionally substituted with one or more R 4 , R 2  and R 3  may cyclize with to one or more R 2 , R 3 , or R 4  to form an optionally substituted C 3-8  membered ring containing C, O, S or N; 
         and stereoisomers and analogs thereof.