Thioflavin derivatives for use in the antemortem diagnosis of alzheimers disease and in vivo imaging and prevention of amyloid deposition

Abstract

This invention relates to novel thioflavin derivatives, methods of using the derivatives in, for example, in vivo imaging of patients having neuritic plaques, pharmaceutical compositions comprising the thioflavin derivatives and method of synthesizing the compounds. The compounds find particular use in the diagnosis and treatment of patients having diseases where accumulation of neuritic plaques are prevalent. The disease states or maladies include but are not limited to Alzheimer's Disease, familial Alzheimer's Disease, Down's Syndrome and homozygotes for the apolipoprotein E4 allele.

1 . An amyloid binding compound having one of structures A-E or a water soluble, non-toxic salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein Z is S, NR′, O or CR′ in which case the correct tautomeric form of the heterocyclic ring becomes an indole in which R′ is H or a lower alkyl group: 
       
         
           
           
               
               
           
         
       
       wherein Y is NR 1 R 2 , OR 2 , or SR 2 ; 
       wherein the nitrogen of 
       
         
           
           
               
               
           
         
       
       is not a quaternary amine; 
       or an amyloid binding compound having one of structures F-J or a water soluble, non-toxic salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein each Q is independently selected from one of the following structures: 
       
         
           
           
               
               
           
         
       
       wherein n=0, 1, 2, 3 or 4, 
       
         
           
           
               
               
           
         
       
       wherein Z is S, NR′, O, or C(R′) 2  in which R′ is H or a lower alkyl group; 
       wherein U is CR′ (in which R′ is H or a lower alkyl group) or N (except when U=N, then Q is not 
       
         
           
           
               
               
           
         
       
       wherein Y is NR 1 R 2 , OR 2 , or SR 2 ; 
       wherein the nitrogen of 
       
         
           
           
               
               
           
         
       
       is not a quaternary amine; 
       wherein each R 1  and R 2  independently is selected from the group consisting of H, a lower alkyl group, (CH 2 ) n OR′ (wherein n=1, 2, or 3), CF 3 , CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X (wherein X=F, Cl, Br or I), (C═O)—R′, R ph , and (CH 2 ) n R ph  (wherein n=1, 2, 3, or 4 and R ph  represents an unsubstituted or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined below for R 3 -R 14  and R′ is H or a lower alkyl group); 
       and wherein each R 3 -R 14  independently is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH 2 ) n OR′ (wherein n=1, 2, or 3), CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 —CH 2 X (wherein X=F, Cl, Br or I), CN, (C═O)—R′, N(R′) 2 , NO 2 , (C═O)N(R′) 2 , O(CO)R′, OR′, SR′, COOR′, R ph , CR′═CR′-R ph , CR 2 ′-CR 2 ′-R ph  (wherein R ph  represents an unsubstituted or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined for R 1 -R 14  and wherein R′ is H or a lower alkyl group), a tri-alkyl tin and a chelating group (with or without a chelated metal group) of the form W-L or V—W-L, wherein V is selected from the group consisting of —COO—, —CO—, —CH 2 O— and —CH 2 NH—; W is —(CH 2 ) n  where n=0, 1, 2, 3, 4, or 5; and L is: 
       
         
           
           
               
               
           
         
       
       wherein M is selected from the group consisting of Tc and Re; 
       or wherein each R 1  and R 2  is a chelating group (with or without a chelated metal group) of the form W-L, wherein W is —(CH 2 ) n  where n=2, 3, 4, or 5; and L is: 
       
         
           
           
               
               
           
         
       
       wherein M is selected from the group consisting of Tc and Re; 
       or wherein each R 1 -R 14  independently is selected from the group consisting of a chelating group (with or without a chelated metal ion) of the form W-L and V—W-L, wherein V is selected from the group consisting of —COO—, and —CO—; W is —(CH 2 ) n  where n=0, 1, 2, 3, 4, or 5; L is: 
       
         
           
           
               
               
           
         
       
       and wherein R 15  independently is selected from the following: 
       
         
           
           
               
               
           
         
       
       or an amyloid binding, chelating compound (with or without a chelated metal group) or a water soluble, non-toxic salt thereof of the form: 
       
         
           
           
               
               
           
         
       
       wherein R 15  independently is selected from the following: 
       
         
           
           
               
               
           
         
       
       and R 16  is 
       
         
           
           
               
               
           
         
       
       wherein Q is independently selected from one of the following structures: 
       
         
           
           
               
               
           
         
       
       wherein n=0, 1, 2, 3 or 4, 
       
         
           
           
               
               
           
         
       
       wherein Z is S, NR′, O, or C(R′) 2  in which R′ is H or a lower alkyl group; 
       wherein U is N or CR′; 
       wherein Y is NR 1 R 2 , OR 2 , or SR 2 ; 
       wherein each R 17 -R 24  independently is selected from the group consisting of H, F, Cl, Br, I, a lower alkyl group, (CH 2 ) n OR′ (wherein n=1, 2, or 3), CF 3 , CH 2 —CH 2 X, O—CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X, O—CH 2 —CH 2 —CH 2 X (wherein X=F, Cl, Br or I), CN, (C═O)—R′, N(R′) 2 , NO 2 , (C═O)N(R′) 2 , O(CO)R′, OR′, SR′, COOR′, R ph , CR′═CR′—R ph  and CR 2 ′-CR 2 ′-R ph  (wherein R ph  represents an unsubstituted or substituted phenyl group with the phenyl substituents being chosen from any of the non-phenyl substituents defined for R 17 -R 20  and wherein R′ is H or a lower alkyl group).