Novel Compounds for the Treatment, Alleviation or Prevention of Disorders Associated with Tau Aggregates

Abstract

The present invention relates to novel compounds that can be employed in the treatment, alleviation or prevention of a group of disorders and abnormalities associated with Tau (Tubulin associated unit) protein aggregates including, but not limited to, Neurofibrillary Tangles (NFTs), such as Alzheimer's disease (AD).

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, thereof; 
         wherein 
         A is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
          wherein 
       
       
         
           
           
               
               
           
         
          can be attached to the N atom at any available position, and wherein 
       
       
         
           
           
               
               
           
         
          is substituted by one or more substituents R j ; 
         B is selected from the group consisting of O and NR a ; 
         E and V are independently selected from the group consisting of N, NR 5 , O and S; 
         G is selected from the group consisting of a benzene ring and a pyridine ring; 
         J is selected from the group consisting of O, N—R 1  and CH 2  or J is selected from the group consisting of CH or C if J is attached to R 2 ; 
         Y, Y 1 , Y 2  and Y 3  are CZ; 
         Z is independently selected from the group consisting of H, halogen, O-alkyl, alkyl and CN; 
         R is independently selected from the group consisting of 
       
       
         
           
           
               
               
           
         
          and —NR 3 R 4 ; 
         R a  is selected from the group consisting of H and alkyl; 
         R d , R e , R f , and R g  are independently selected from the group consisting of H and alkyl, or any two of R d , R e , R f , and R g  may be joined to form a 3 to 8-membered ring;
 wherein when A is 
 
       
       
         
           
           
               
               
           
         
         
            R j  is independently selected from the group consisting of -halogen, —O-alkyl, —NR 3 R 4 , —CN 
         
       
       
         
           
           
               
               
           
         
         
            wherein a C 1-2  carbon atom-containing bridge or a bond can be present between the a carbon atom and the c or d carbon atom or wherein a C 1-2  carbon atom-containing bridge or a bond can be present between the b carbon atom and the c or d carbon atom; 
           and wherein when A is 
         
       
       
         
           
           
               
               
           
         
         
            R j  is independently selected from the group consisting of —F, —O—(C 1 -C 6  alkyl), —NR 3 R 4 , —CN, 
         
       
       
         
           
           
               
               
           
         
         
            (wherein a C 1-2  carbon atom-containing bridge or a bond can be present between the a carbon atom and the c or d carbon atom or wherein a C 1-2  carbon atom-containing bridge or a bond can be present between the b carbon atom and the c or d carbon atom; 
         
         R 1  is selected from the group consisting of H and alkyl; 
         R 2  is independently selected from the group consisting of alkyl, or —O-alkyl and wherein if two R 2  are geminal they can be joined to form a 3 to 6-membered ring; 
         R 3  and R 4  are independently selected from the group consisting of H and alkyl; 
         R 5  is selected from the group consisting of H and alkyl; 
         n is 0, 1, 2, 3 or 4; 
         r and s are independently 0, 1, 2 or 3; and 
         t and u are independently 1, 2 or 3. 
       
     
     
         2 . The compound according to  claim 1 , which is a compound of formula (Ia): 
       
         
           
           
               
               
           
         
         wherein A, R a , R d , R e , R f , R g , Y, Y 1 , Y 2  and Y 3  are as defined in  claim 1 . 
       
     
     
         3 . The compound according to  claim 2 , wherein A is 
       
         
           
           
               
               
           
         
       
       wherein 
       
         
           
           
               
               
           
         
       
       can be attached to the N atom at any available position, wherein 
       
         
           
           
               
               
           
         
       
       is substituted by one or more substituents R j , and wherein R j  is as defined in  claim 1 . 
     
     
         4 . The compound according to  claim 3 , which is a compound of the formula (Ib): 
       
         
           
           
               
               
           
         
         wherein R a , R j  and Z are as defined in  claim 1  and p is 1 or 2. 
       
     
     
         5 . The compound according to  claim 1 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . A pharmaceutical composition comprising a compound as defined in  claim 1  and optionally a pharmaceutically acceptable carrier or excipient. 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . A method of treating, preventing or alleviating a disorder associated with Tau protein aggregates, the method comprising administering an effective amount of a compound of Formula (I). 
       
         
           
           
               
               
           
         
         or stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, thereof; 
         wherein 
         A is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
          wherein 
       
       
         
           
           
               
               
           
         
          can be attached to the N atom at any available position and wherein 
       
       
         
           
           
               
               
           
         
          is substituted by one or more substituents R j ; 
         B is selected from the group consisting of O and NR a ; 
         E and V are independently selected from the group consisting of N, NR 5 , O and S; 
         G is selected from the group consisting of a benzene ring and a pyridine ring; 
         J is selected from the group consisting of O, N—R 1  and CH 2  or J is selected from the group consisting of CH or C if J is attached to R 2 ; 
         Y, Y 1 , Y 2  and Y 3  are CZ; 
         Z is independently selected from the group consisting of H, halogen, O-alkyl, alkyl and CN; 
         R is independently selected from the group consisting of 
       
       
         
           
           
               
               
           
         
          and —NR 3 R 4 ; 
         R a  is selected from the group consisting of H and alkyl; 
         R d , R e , R f , and R g  are independently selected from the group consisting of H and alkyl, or any two of R d , R e , R f , and R g  may be joined to form a 3 to 8-membered ring; 
         R j  is independently selected from the group consisting of -halogen, —O-alkyl, —NR 3 R 4 , —CN, 
       
       
         
           
           
               
               
           
         
          wherein a C 1-2  carbon atom-containing bridge or a bond can be present between the a carbon atom and the c or d carbon atom or wherein a C 1-2  carbon atom-containing bridge or a bond can be present between the b carbon atom and the c or d carbon atom; 
         R 1  is selected from the group consisting of H and alkyl; 
         R 2  is independently selected from the group consisting of alkyl, or —O-alkyl and wherein if two R 2  are geminal they can be joined to form a 3 to 6-membered ring; 
         R 3  and R 4  are independently selected from the group consisting of H and alkyl; 
         R 5  is selected from the group consisting of H and alkyl; 
         n is 0, 1, 2, 3 or 4; 
         r and s are independently 0, 1, 2 or 3; and 
         t and u are independently 1, 2 or 3 
         to a subject in need thereof. 
       
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 9 , wherein the disorder is Alzheimer's Disease. 
     
     
         14 . The method of  claim 9 , wherein the disorder is PSP. 
     
     
         15 . A method of decreasing Tau aggregation, the method comprising administering an effective amount of a compound as defined in  claim 1  to a subject in need thereof. 
     
     
         16 . A method of preventing the formation of Tau aggregates and/or of inhibiting Tau aggregation, the method comprising administering an effective amount of a compound as defined in  claim 1  to a subject in need thereof. 
     
     
         17 . A method of interfering intracellularly with Tau aggregates, the method comprising administering an effective amount of a compound as defined in  claim 1  to a subject in need thereof. 
     
     
         18 . The method of  claim 13 , wherein the subject is animal or human. 
     
     
         19 . A mixture comprising a compound as defined in  claim 1  and at least one further biologically active compound selected from a therapeutic agent different from the compound as defined in any one of  claims 1  to  5 , a pharmaceutically acceptable carrier, a diluent or an excipient. 
     
     
         20 . The mixture according to  claim 19 , wherein the further biologically active compound is a compound used in the treatment of amyloidosis. 
     
     
         21 . The mixture according to  claim 19 , wherein the further biologically active compound is selected from the group consisting of compounds against oxidative stress, anti-apoptotic compounds, metal chelators, inhibitors of DNA repair such as pirenzepine and metabolites, 3-amino-1-propanesulfonic acid (3APS), 1,3-propanedisulfonate (1,3PDS), α-secretase activators, β- and γ-secretase inhibitors, Tau proteins, neurotransmitter, β-sheet breakers, attractants for amyloid beta clearing/depleting cellular components, inhibitors of N-terminal truncated amyloid beta including pyroglutamated amyloid beta 3-42, anti-inflammatory molecules, or cholinesterase inhibitors (ChEIs) such as tacrine, rivastigmine, donepezil, and/or galantamine, M1 agonists, other drugs including any amyloid or Tau modifying drug and nutritive supplements, an antibody, including any functionally equivalent antibody or functional parts thereof or a vaccine. 
     
     
         22 . The mixture according to  claim 19 , wherein the compound and/or the further biologically active compound is/are present in a therapeutically effective amount. 
     
     
         23 . The method according to  claim 9 , wherein the disorder is selected from Alzheimer's disease (AD), familial AD, Primary Age-Related Tauopathy (PART), Creutzfeldt-Jacob disease, dementia pugilistica, Down's Syndrome, Gerstmann-Straussler-Scheinker disease (GSS), inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Parkinsonism-dementia complex of Guam, non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Hallervorden-Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle predominant dementia, postencephalitic Parkinsonism, myotonic dystrophy, subacute sclerosis panencephalopathy, mutations in LRRK2, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, Lewy body dementia (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-related dementia, adult onset diabetes, senile cardiac amyloidosis, glaucoma, ischemic stroke, psychosis in AD and Huntington's disease. 
     
     
         24 . (canceled) 
     
     
         25 . (canceled)