Novel therapeutic uses of benzylideneguanidine derivatives for the treatment of proteopathies

Abstract

in treating a disorder associated with the PPP1R15A pathway and associated with protein misfolding stress and in particular with accumulation of misfolded proteins selected in the group of tauopathies, synucleinopathies, polyglutamine and polyalanine diseases, leukodystrophies, cystic fibrosis, multiple sclerosis, lysosomal storage disorders, amyloidosis diseases, inflammation, metabolic disorders, cardio-vascular disorders, osteoporosis, nervous system trauma, ischemia.

What is claimed is: 
     
         1 . A method for treating a disorder selected from the group consisting of an inflammatory condition, an infectious disease, dystrophy, oculopharyngeal muscular dystrophy (OPMD), systemic inflammatory response syndrome (SIRS), and sepsis comprising administering to a patient in need thereof, a compound of formula (I), or a tautomer or pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is alkyl, O-alkyl, Cl, F or Br; 
         R 2  is H or F; 
         R 3  is H or alkyl; 
         R 4  is H or C(O)R 6 ; 
         R 5  is H; 
         or R 4  and R 5  are linked to form a 5 to 6 membered saturated or unsaturated heterocyclic group optionally comprising 1 or 2 heteroatoms such as N, in addition to the N atoms to which R 4  and R 5  are bound, and where said heterocyclic group is optionally substituted with one or more R 10  groups; 
         R 6  is selected from the group consisting of R 7 , OR 7  and NR 8 R 9 ; 
         R 7 , R 8  and R 9  are each independently selected from the group consisting of alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclyl, and aryl, each of which is optionally substituted with one or more R 10  groups; 
         each R 10  is independently selected from the group consisting of halogen, OH, ═O, CN, COO-alkyl, aralkyl, 50 2 -alkyl, 50 2 -aryl, COOH, CO-alkyl, CO-aryl, NH 2 , NH-alkyl, N(alkyl) 2 , CF 3 , alkyl, and alkoxy; 
         X and Z are each independently CR 11 , and Y is CR 11  or N; and 
         R 11  is H, alkyl or F. 
       
     
     
         2 . A method for treating a disorder selected from the group consisting of an inflammatory condition and an infectious disease comprising administering to a patient in need thereof, a compound of formula (I), or a tautomer or pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is alkyl, Cl, F or Br; 
         R 2  is H or F; 
         R 3  is H or alkyl; 
         R 4  is H or C(O)R 6 ; 
         R 5  is H; 
         or R 4  and R 5  are linked to form a 5 to 6 membered saturated or unsaturated heterocyclic group optionally comprising 1 or 2 heteroatoms such as N, in addition to the N atoms to which R 4  and R 5  are bound, and where said heterocyclic group is optionally substituted with one or more R 10  groups; 
         R 6  is selected from the group consisting of R 7 , OR 7  and NR 8 R 9 ; 
         R 7 , R 8  and R 9  are each independently selected from the group consisting of alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclyl, and aryl, each of which is optionally substituted with one or more R 10  groups; 
         each R 10  is independently selected from the group consisting of halogen, OH, CN, COO-alkyl, aralkyl, SO 2 -alkyl, SO2-aryl, COOH, CO-alkyl, CO-aryl, NH 2 , NH-alkyl, N(alkyl) 2 , CF 3 , alkyl, and alkoxy; 
         X and Z are each independently CR 11 , and Y is CR 11  or N; and 
         R 11  is H, or F. 
       
     
     
         3 . The method according to  claim 1  wherein R 1  is Cl, Br, Me, or F. 
     
     
         4 . The method according to  claim 1  wherein R 1  is Cl. 
     
     
         5 . The method according to  claim 1  wherein R 2  is H. 
     
     
         6 . The method according to  claim 1  wherein Y is CR 11 . 
     
     
         7 . The method according to  claim 1  wherein R 3  and R 4  are both H. 
     
     
         8 . The method according to  claim 1  wherein R 3  is H and R 4  is C(O)R 6 , with wherein R 6  is Me or OMe. 
     
     
         9 . The method according to  claim 1  wherein in Formula (I):
 R 1  is Cl, R 2  is H, R 3 =R 4 =R 5 =H, X=Z=CH, Y is CR 11 , and R 11  is F. 
 
     
     
         10 . The method according to  claim 1  wherein said compound is selected from the group consisting of the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a tautomer or acceptable salt thereof. 
     
     
         11 . The method according to  claim 1  where the compound is selected from the group consisting of the following compounds: 
       
         
           
           
               
               
           
         
       
       or a tautomer or acceptable salt thereof. 
     
     
         12 . The method according to  claim 1  where the inflammatory condition is selected from the group consisting of lung infections, Respiratory Distress Syndrome, bronchopulmonary dysplasia, colitis, ulcerative colitis, Inflammatory Bowel Disease, diabetic nephropathy, hemorrhagic shock, spondylo-arthropathies, pancreatitis; inflammation-induced cancer, allergy, asthma, hypercytokinemia, graft versus host disease (GVHD), and acute respiratory distress syndrome (ARDS), 
     
     
         13 . The method according to  claim 1  where the infectious disease is selected from the group consisting of influenza virus infection, smallpox virus infection, herpes virus infection, severe acute respiratory syndrome (SARS), chikungunya virus infection, West Nile Virus infection, dengue virus infection, Japanese encephalitis virus infection, yellow fever virus infection, and hepatitis C virus infection. 
     
     
         14 . The method according to  claim 2  wherein R 1  is Cl, Br, Me, or F. 
     
     
         15 . The method according to  claim 2  wherein R 1  is Cl. 
     
     
         16 . The method according to  claim 2  wherein R 2  is H. 
     
     
         17 . The method according to  claim 2  wherein Y is CR 11 . 
     
     
         18 . The method according to  claim 2  wherein R 3  and R 4  are both H. 
     
     
         19 . The method according to  claim 2  wherein R 3  is H and R 4  is C(O)R 6 , and wherein R 6  is Me or OMe. 
     
     
         20 . The method according to  claim 2  wherein in Formula (I):
 R 1  is Cl, R 2  is H, R 3 =R 4 =R 5 =H, X=Z=CH, Y is CR 11 , and R 11  is F. 
 
     
     
         21 . The method according to  claim 2  wherein said compound is selected from the group consisting of the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a tautomer or acceptable salt thereof. 
     
     
         22 . The method according to  claim 2  where the compound is selected from the group consisting of the following compounds: 
       
         
           
           
               
               
           
         
       
       or a tautomer or acceptable salt thereof. 
     
     
         23 . The method according to  claim 2  where the inflammatory condition is selected from the group consisting of lung infections, Respiratory Distress Syndrome, bronchopulmonary dysplasia, colitis, ulcerative colitis, Inflammatory Bowel Disease, diabetic nephropathy, hemorrhagic shock, spondylo-arthropathies, pancreatitis; inflammation-induced cancer, allergy, asthma, hypercytokinemia, graft versus host disease (GVHD), and acute respiratory distress syndrome (ARDS), 
     
     
         24 . The method according to  claim 2  where the infectious disease is selected from the group consisting of influenza virus infection, smallpox virus infection, herpes virus infection, severe acute respiratory syndrome (SARS), chikungunya virus infection, West Nile Virus infection, dengue virus infection, Japanese encephalitis virus infection, yellow fever virus infection, and hepatitis C virus infection.