Composition and method for the treatment of tauopathies

Abstract

The present invention refers to the use of a specific indolocarbazole compound of general formula (1) or a pharmaceutically-acceptable a salt thereof for the preparation of a pharmaceutical composition for the prevention or treatment of a neurode-generative and/or dementing illness driven by the molecular pathology of microtubule-associate tau such as Alzheimer's disease, frontal lobe dementia, Pick's disease, Parkinson disease with dementia, corticobasal degeneration, argyrophilic grains disease, or supranuclear palsy. A method for treating or preventing such illnesses is also disclosed. Furthermore, methods for the identification of efficacious inhibitors of neurofibrillary degeneration, and methods for the determination of an appropriate dosage of an inhibitor of the PHF-type tau hyperphosphorylation for the treatment of a condition characterized by neurofibrillary pathology are described.

1 . Use of a indolocarbazole compound of general formula 1 or a pharmaceutically-acceptable salt thereof 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is either COOR (R═H, methyl, ethyl or cyclopropyl) or CONHR 4  (R 4 ═H, methyl, ethyl or cyclopropyl); 
         R 2  and R 3  are independently H, F, methyl, OH, NH 2  or NR 5 R 6  (R 5  and R 6  independently H or methyl); and 
         Z is either (H, H) or O; 
         for the preparation of a pharmaceutical composition for the prevention or treatment of a neurodegenerative and/or dementing illness driven by the molecular pathology of microtubule-associated tau. 
       
     
     
         2 . Use according to  claim 1 , wherein the illness is selected from the group consisting of Alzheimer's disease, frontal lobe dementia, Picks disease, Parkinson disease with dementia, corticobasal degeneration, argyrophilic grains disease, progressive supranuclear palsy, subacute sclerosing panencephalitis, multiple system tauopathy dementia, familial Gerstmann-Straussler-Scheinker Disease, and prion protein cerebral amyloid angiopathy. 
     
     
         3 . Use according to  claim 1  wherein the indolocarbazole compound is a compound of formula 2 or 3 or a pharmaceutically-acceptable salt thereof 
       
         
           
           
               
               
           
         
       
     
     
         4 . A method for treating or preventing a neurodegenerative and/or dementing illness driven by the molecular pathology of microtubule-associate tau, wherein the method comprises administering an effective amount of a compound of general formula 1 or a pharmaceutically-acceptable salt thereof 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is either COOR (R═H, methyl, ethyl or cyclopropyl) or CONHR 4  (R 4 ═H, methyl, ethyl or cyclopropyl); 
 R 2  and R 3  are independently H, F, methyl, OH, NH 2  or NR 5 R 6  (R 5  and R 6  independently H or methyl); and 
 Z is either (H, H) or O; 
 to a subject in need thereof. 
 
     
     
         5 . A method according to  claim 4 , wherein the illness is selected from the group consisting of Alzheimer's disease, frontal lobe dementia, Picks disease, Parkinson disease with dementia, corticobasal degeneration, argyrophilic grains disease, progressive supranuclear palsy, subacute sclerosing panencephalitis, multiple system tauopathy dementia, familial Gerstmann-Straussler-Scheinker Disease, and prion protein cerebral amyloid angiopathy. 
     
     
         6 . A method according to  claim 4 , wherein the indolocarbazole compound is a compound of formula 2 or 3 or a pharmaceutically-acceptable salt thereof 
       
         
           
           
               
               
           
         
       
     
     
         7 - 16 . (canceled) 
     
     
         17 . A indolocarbazole compound of general formula 1 or a pharmaceutically-acceptable salt thereof 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is either COOR (R═H, methyl, ethyl or cyclopropyl) or CONHR 4  (R 4 ═H, methyl, ethyl or cyclopropyl); 
 R 2  and R 3  are independently H, F, methyl, OH, NH 2  or NR 5 R 6  (R 5  and R 6  independently H or methyl); and 
 Z is either (H, H) or O. 
 
     
     
         18 . The indolocarbazole compound of  claim 17 , having the formula 2 or a pharmaceutically-acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein R═H. 
     
     
         19 . (canceled)