New drug for inhibiting aggregation of proteins involved in diseases linked to protein aggregation and/or neurodegenerative diseases

Abstract

The present invention relates to a compound represented by formula (E). The present invention also relates to a compound represented by the formula (E) for use in the treatment or prevention of diseases linked to protein aggregation and/or neurodegenerative diseases. Moreover, the present invention relates to pharmaceutical and diagnostic compositions comprising the compound of the invention as well as to a kit. Furthermore, the present invention relates to a method of imaging deposits of aggregated protein. A kit for preparing a detectably labelled compound of the present invention is also disclosed. Formula (E) wherein X, Y and L are independently nondirectionally selected from —C(R 1 )(R 2 )—, —C(R 3 )═, —N(R 4 )—, —N═, —N + (R 5 )═, —O— and —S—; M and Z are independently nondirectionally selected from formula (I) and formula (II).

1 . A compound represented by formula (E) 
       
         
           
           
               
               
           
         
         wherein 
         X, Y and L are independently nondirectionally selected from —C(R 1 )(R 2 )—, —C(R 3 )═, —N(R 4 )—, —N═, —N + (R 5 )═, —O— and —S—; 
         M and Z are independently nondirectionally selected from 
       
       
         
           
           
               
               
           
         
         - - - - represents an optional double bond; 
         R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are independently selected from hydrogen; C 1-4  alkyl; —C 1-4  alkylene-halogen; —C 1-4  alkylene-OH; —C 1-4  alkylene-C 1-4  alkoxy; —C(O)—C 1-4  alkyl; and C 6-10  aryl, wherein the aryl ring can be optionally substituted by C 1-4  alkyl or halogen; 
         Hal is selected from F, Cl, Br, and I; 
         R E1  is selected from hydroxy, C 1-6  alkoxy, and —NR E5 R E6 ; or 
         R E2  is selected from hydrogen, halogen, hydroxy, C 1-6  alkoxy, and —NR E5 R E6 ; or 
         if R E1  and R E2  are attached to adjacent carbon atoms, R E1  and R E2  together can alternatively non-directionally form a structure -T-(CR E7 R E8 ) n —V—, wherein T is selected from CR E9 R E10 , NH and O and V is selected from CR E9 R E10 NH and O, as well as corresponding structures in which a double bond is present; 
         R E5  and R E6  are independently selected from hydrogen and C 1-6  alkyl; 
         R E7  and R E8  are independently H or F; 
         R E9  and R E10  are independently H or F; 
         n is 1 to 3; 
         R E3  is a C 1-6  alkyl group or a C 5-10  aryl group; 
         m is 0 to 2; 
         R E4  is a halogen atom, a C 1-6  alkyl group or a C 5-10  aryl group; 
         p is 0 to 2; 
         as well as a prodrug, ester, solvate or salt of the compound represented by formula (E); 
         with the proviso that the following compounds are excluded: 
         3(5)-(2-hydroxy-5-methylphenyl)-5(3)-(4-chlorophenyl)pyrazol; 
         ortho-hydroxyphenyl-5 dichloro-3′-4′ phenyl-3 methyl-2 pyrazole; 
         ortho-hydroxyphenyl-5 dichloro-3′-4′ phenyl-3 phenyl-2 pyrazole; 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . A compound according to  claim 1  wherein the compound represented by formula (E) is a compound represented by formula (A) or (B) 
       
         
           
           
               
               
           
         
         wherein 
         m, n, p, T, V, X, Y, L, M, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R E7 , R E8  and Hal are defined as in  claim 1 ; 
         wherein in formula (A): 
         R A1  and R A2  are each independently selected from hydrogen, halogen, hydroxy, C 1-6  alkoxy, and —NR A5 R A6 ; or 
         with the proviso that at least one of R A1  and R A2  is hydroxy, C 1-6  alkoxy, or —NR A5 R A6 ; 
         alternatively R A1  and R A2  can together non-directionally form a structure -T-(CR E7 R E8 ) n —V—; 
         R A3  is a C 1-6  alkyl group or a C 5-10  aryl group; 
         R A4  is a halogen atom, a C 1-6  alkyl group or a C 5-10  aryl group; and 
         R A5  and R A6  are independently selected from hydrogen and C 1-6  alkyl; 
         wherein in formula (B): 
         R B1  is selected from hydroxy, C 1-6  alkoxy, and —NR B5 R B6 ; and 
         R B2  is selected from hydrogen, halogen, hydroxy, C 1-6  alkoxy; and —NR B5 R B6 ; 
         R B3  is a C 1-6  alkyl group or a C 5-10  aryl group; 
         R B4  is a halogen atom, a C 1-6  alkyl group or a C 5-10  aryl group; and 
         R B5  and R B6  are independently selected from hydrogen and C 1-6  alkyl; 
         as well as a prodrug, ester, solvate or salt of the compound represented by formula (A) or (B). 
       
     
     
         3 . The compound according to  claim 1 , wherein ring D is directionally selected from the following structures: 
       
         
           
           
               
               
           
         
         wherein 
         R 8  and R 9  are selected from hydrogen; C 1-4  alkyl; —C 1-4  alkylene-halogen; and C 6-10  aryl, wherein the aryl ring can be optionally substituted by C 1-4  alkyl or halogen. 
       
     
     
         4 . The compound according to  claim 3 , wherein ring D is directionally selected from the following structures: 
       
         
           
           
               
               
           
         
         wherein: 
         R 8  is as defined in  claim 3 ; and 
         R 9  is H. 
       
     
     
         5 . The compound according to  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein: 
         R is selected from hydrogen; C 1-4  alkyl; and —C 1-4  alkylene-halogen; and 
         Hal is selected from F, Cl, Br, and I; 
         R E7  and R E8  are independently H or F; 
         R A7  is H or C 1-4  alkyl; 
         R A8  is H or C 1-4  alkyl; 
         R A9  is H or C 1-4  alkyl; 
         R A10  is H or C 1-4  alkyl; and 
         R B7  is H or C 1-4  alkyl; 
         as well as a prodrug, ester, solvate or salt of these compounds. 
       
     
     
         6 . The compound according to  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein Hal is Cl or Br; 
         as well as a prodrug, ester, solvate or salt of these compounds. 
       
     
     
         7 . The compound according to,  claim 1 , wherein the compound is detectably labeled. 
     
     
         8 . A pharmaceutical or diagnostic composition comprising a compound as defined in  claim 1  and optionally a pharmaceutically acceptable carrier. 
     
     
         9 - 10 . (canceled) 
     
     
         11 . A method of treating or preventing a disease linked to protein aggregation and/or a neurodegenerative disease comprising administering a therapeutically effective amount of a compound represented by formula (E) to a patient in need thereof, 
       
         
           
           
               
               
           
         
         wherein 
         X, Y and L are independently nondirectionally selected from —C(R 1 )(R 2 )—, —C(R 3 )═, —N(R 4 )—, —N═, —N + (R 5 )═, —O— and —S—; 
         M and Z are independently nondirectionally selected from 
       
       
         
           
           
               
               
           
         
         - - - - represents an optional double bond; 
         R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are independently selected from hydrogen; C 1-4  alkyl; —C 1-4  alkylene-halogen; —C 1-4  alkylene-OH; —C 1-4  alkylene-C 1-4  alkoxy; —C(O)—C 1-4 alkyl; and C 6-10  aryl, wherein the aryl ring can be optionally substituted by C 1-4  alkyl or halogen; 
         Hal is selected from F, Cl, Br, and I; 
         R E1  is selected from hydroxy, C 1-6  alkoxy, and —NR E6 R E6 ; 
         R E2  is selected from hydrogen, halogen, hydroxy, C 1-6  alkoxy, and —NR E5 R E6 ; or 
         if R E1  and R E2  are attached to adjacent carbon atoms, R E1  and R E2  together can alternatively non-directionally form a structure -T-(CR E7 R E8 ) n —V— wherein T is selected from CR E9 R E10 , NH and O and V is selected from CR E9 R E10 , NH and O, as well as corresponding structures in which a double bond is present; 
         R E5  and R E6  are independently selected from hydrogen and C 1-6  alkyl; 
         R E7  and R E8  are independently H or F; 
         R E9  and R E10  are independently H or F; 
         n is 1 to 3; 
         R E3  is a C 1-6  alkyl group or a C 5-10  aryl group; 
         m is 0 to 2; 
         R E4  is a halogen atom, a C 1-6  alkyl group or a C 5-10  aryl group; 
         p is 0 to 2; 
         as well as a prodrug, ester, solvate or salt of the compound represented by formula (E). 
       
     
     
         12 . The the method according to  claim 11 , wherein the disease linked to protein aggregation is characterized by the presence of an aggregated form of at least one protein or a fragment or derivative thereof, wherein the protein is selected from the group consisting of prion protein, amyloid precursor protein (APP), alpha-synuclein, superoxide dismutase, tau, immunoglobulin, amyloid-A, transthyretin, beta 2-microglobulin, cystatin C, apolipoproteine A1, TDP-43, islet amyloid polypeptide, ANF, gelsolin, insulin, lysozyme, fibrinogen, huntingtin and ataxin and other proteins with a Poly-Q stretch. 
     
     
         13 . The method according to  claim 11 , wherein the disease is selected from the group consisting of Parkinson's disease, prion disease, Alzheimer's disease, multiple system atrophy, Diffuse Lewy body disease, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington disease's, spinocerebellar ataxias and other Poly-Q diseases, hereditary cerebral amyloid angiopathy, familial amyloid polyneuropathy, primary systemic amyloidosis (AL amyloidosis), reactive systemic amyloidosis (AA amyloidosis), type II diabetes, injection-localized amyloidosis, beta-2 microglobulin amyloidosis, hereditary non-neuropathic amyloidosis, and Finnish hereditary systemic amyloidosis. 
     
     
         14 . The method according to  claim 11 , wherein the prion disease is selected from Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, genetic human prion disease, Bovine Spongiform Encephalopathy (BSE) and Scrapie. 
     
     
         15 . (canceled) 
     
     
         16 . A kit comprising the compound as defined in  claim 11  and, in addition, an antibody or antibody fragment specifically binding to the compound; and/or a monomeric or aggregated protein; and/or a monomeric or aggregated protein optionally complexed with the compound; and instructions for use, in one or more containers, wherein a fragment or derivative thereof, wherein the protein is selected from the group consisting of prion protein, amyloid precursor protein (APP), alpha-synuclein, superoxide dismutase, tau, immunoglobulin, amyloid-A, transthyretin, beta 2-microglobulin, cystatin C, apolipoproteine A1, TDP-43, islet amyloid polypeptide, ANF, gelsolin, insulin, lysozyme, fibrinogen, huntingtin and ataxin and other proteins with a Poly-Q stretch. 
     
     
         17 . A method of imaging deposits of aggregated protein, the method comprising the steps of:
 (i) introducing a detectable quantity of a composition comprising a detectably labelled compound as defined in  claim 11  into a subject;   (ii) allowing sufficient time for the compound to be associated with the aggregated protein; and   (iii) detecting the compound associated with the aggregated protein.   
     
     
         18 . A kit for preparing a detectably labelled compound as defined in  claim 11 , wherein the kit comprises at least two precursor compounds which upon reaction form the compound as defined in claim  9 , wherein at least one of X, Y and L is —N(R 4 )— and R 4  comprises a detectable label. 
     
     
         19 . The method according to  claim 17 , wherein the detectable label is selected from  18 F,  11 C,  125 I,  123 I,  131 I,  77 Br and  76 Br, in particular  18 F and  11 C.