Compounds and compositions for use as modulators of tau aggregation and alleviation of tauopathies

Abstract

This invention relates to the use of bis- and tris-dihydroxyaryl compounds as well as sulfonamides, heteroaryls, tricycloalkyl and their analogs and pharmaceutically acceptable salts, for modulating tau aggregation and alleviating tauopathies, such as Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and familial frontotemporal dementia/Parkinsonism linked to chromosome 17 (FTDP-17), amyotrophic lateral sclerosis/Parkinsonism-dementia complex, argyrophilic grain dementia, dementia pugilistic, diffuse neurofibrillary tangles with calcification, progressive subcortical gliosis and tangle only dementia.

We claim: 
     
         1 . A compound and pharmaceutically acceptable salts thereof selected from the group consisting of compounds of the formula: 
       
         
           
           
               
               
           
         
         where R is a C 2 -C 6  alkylene group, in which there is: 
         optionally 1 double bond; 
         1 or 2 methylene groups are replaced by NR′ where R′ is H or a methyl group; and 
         1 or 2 methylene groups are replaced by CO or SO 2 . 
       
     
     
         2 . A compound selected from 
       
         
           
           
               
               
           
         
       
     
     
         3 . A method of disrupting or causing the dissolution of tau aggregates in a mammal suffering from a tauopathy, comprising administering to the mammal suffering from a tauopathy a therapeutically effective amount of the compounds of  claim 1 . 
     
     
         4 . The method of  claim 3 , wherein the mammal is a human. 
     
     
         5 . The method of  claim 3 , wherein the amount of the compound administered is between 0.1 mg/Kg/day and 1000 mg/Kg/day. 
     
     
         6 . The method of  claim 3 , wherein the amount of compound administered is between 1 mg/Kg/day and 100 mg/Kg/day. 
     
     
         7 . The method of  claim 3 , wherein the amount of compound administered is between 10 mg/Kg/day and 100 mg/Kg/day. 
     
     
         8 . The method of  claim 3 , wherein the tauopathy is selected from the group consisting of Alzheimer's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, familial frontotemporal dementia/Parkinsonism linked to chromosome 17, amyotrophic lateral sclerosis I/Parkinsonism-dementia complex, argyrophilic grain dementia, dementia pugilistic, diffuse neurofibrillary tangles with calcification, progressive subcortical gliosis and tangle only dementia. 
     
     
         9 . The method of  claim 3 , wherein the compound administered is administered by one of routes selected from, oral, topical, systemic or parenteral. 
     
     
         10 . A method of disrupting or causing the dissolution of tau aggregates in a mammal suffering from a tauopathy, comprising administering to the mammal suffering from a tauopathy an effective amount of a compound selected from the group consisting of: 3,4 dihydroxybenzoic acid 3,4 dihydroxy N-methyl anilide (DC-51-CH3), 3,4 dihydroxybenzenesulfonic acid 3,4 dihydroxyphenylsulfonamide (DC-51-W1), maleic acid bis(3,4-dihydroxyanilide) (compound DC-0069), 1,3-bis(3,4-dihydroxyphenyl)urea (compound DC-0076), and 1-(3,4-dihydroxyphenyl)-3-(3,4-dihydroxyphenethyl)urea (compound DC-0078); and pharmaceutically acceptable salts thereof.