Benzylamino-oxoethyl benzamide analogs and methods of use

Abstract

Benzylamino-oxoethyl benzamide compounds for use in treating diseases and conditions associated with abnormal cell function related to endoplasmic reticulum (ER) stress. For example, the compounds can be used as suppressors of ER stress-induced pancreatic β-cell dysfunction and death, for example in the treatment of Type 1 and Type 2 diabetes. The compounds can also be used in treatments for chronic heart disease, neurodegenerative diseases, retinal degeneration, and other metabolic disorders associated with ER stress.

What is claimed is: 
     
         1 . A compound having a formula as represented by chemical structure I: 
       
         
           
           
               
               
           
         
         wherein:
 R=H, Alkyl, or Phenyl; 
 R 1 =H, Me, Cl, F, OMe, OH, or Phenyl; 
 R 2 =H, Me, Cl, F, OMe, OH, or Phenyl; 
 R 3 =H, NH 2 , Me, Cl, F, OMe, OH, or Phenyl; 
 R 4 =H, Me, Cl, F, OMe, OH, or Phenyl; 
 R 5 =H, Me, Cl, F, OMe, or OH; 
 R 6 =H, Me, Cl, F, OMe, OH, CCl 3 , or CF 3 ; 
 R 7 =H, Me, Cl, F, OMe, OH, or Piperonyl; 
 R 8 =H, Me, Cl, F, OMe, OH, CCl 3 , CF 3 , or Piperonyl; 
 R 9 =H, Me, Cl, F, or OMe; 
 R 10 =H, Me, Cl, F, OMe, OH, CCl 3 , or CF 3 ; and 
 n=0, 1, 2, or 3. 
 
       
     
     
         2 . The compound of  claim 1 , wherein R, R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and R 10 =H, R 2 =OH, R 8 =CF 3 , and n=1. 
     
     
         3 . The compound of  claim 1 , wherein R, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and R 10 =H, R 4 =OH, and R 8 =CF 3 , and n=1. 
     
     
         4 . The compound of  claim 1 , wherein n=1, R=H, R 8 =CF 3 , and R 2  and R 4  are selected from the group consisting of H and OH, with the proviso that one of R 2  and R 4 =H, and one of R 2  and R 4 =OH. 
     
     
         5 . The compound of of  claim 1  disposed in a pharmaceutically-acceptable carrier, diluent or vehicle, forming a composition. 
     
     
         6 . A conjugate, comprising the compound of  claim 1  covalently linked to a targeting molecule, wherein the targeting molecule is able to bind to a target cell or a portion of a target cell. 
     
     
         7 . The conjugate of  claim 6 , wherein the targeting molecule targets a pancreatic β-cell. 
     
     
         8 . A method of treating a condition associated with abnormal cell function related to endoplasmic reticulum (ER) stress, comprising: administering to a subject in need of such therapy an effective amount of a compound having a formula as represented by chemical structure I: 
       
         
           
           
               
               
           
         
         wherein:
 R=H, Alkyl, or Phenyl; 
 R 1 =H, Me, Cl, F, OMe, OH, or Phenyl; 
 R 2 =H, Me, Cl, F, OMe, OH, or Phenyl; 
 R 3 =H, NH 2 , Me, Cl, F, OMe, OH, or Phenyl; 
 R 4 =H, Me, Cl, F, OMe, OH, or Phenyl; 
 R 5 =H, Me, Cl, F, OMe, or OH; 
 R 6 =H, Me, Cl, F, OMe, OH, CCl 3 , or CF 3 ; 
 R 7 =H, Me, Cl, F, OMe, OH, or Piperonyl; 
 R 8 =H, Me, Cl, F, OMe, OH, CCl 3 , CF 3 , or Piperonyl; 
 R 9 =H, Me, Cl, F, or OMe; 
 R 10 =H, Me, Cl, F, OMe, OH, CCl 3 , or CF 3 ; and 
 n=0, 1, 2, or 3. 
 
       
     
     
         9 . The method of  claim 8 , wherein in chemical structure I: R, R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and R 10 =H, R 2 =OH, R 8 =CF 3 , and n=1. 
     
     
         10 . The method of  claim 8 , wherein in chemical structure I: R, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and R 10 =H, R 4 =OH, R 8 =CF 3 , and n=1. 
     
     
         11 . The method of  claim 8 , wherein in chemical structure I: n=1, R=H, R 8 =CF 3 , and R 2  and R 4  are selected from the group consisting of H and OH, with the proviso that one of R 2  and R 4 =H, and one of R 2  and R 4 =OH. 
     
     
         12 . The method of  claim 8 , wherein the compound is covalently linked to a targeting molecule forming a conjugate, wherein the targeting molecule is able to bind to a target cell or a portion of a target cell. 
     
     
         13 . The method of  claim 12 , wherein wherein the targeting molecule of the conjugate targets a pancreatic β-cell. 
     
     
         14 . The method of  claim 8 , wherein the compound is provided in a composition comprising a pharmaceutically-acceptable carrier, diluent or vehicle. 
     
     
         15 . The method of  claim 8 , wherein the condition associated with abnormal cell function is Type 1 diabetes or Type 2 diabetes.