Thioflavin derivates for use in the antemortem diagnosis of alzheimer's 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 of the following formula or a water soluble, non-toxic salt thereof: 
       
         
           
           
               
               
           
         
         wherein
 Y is NR 1 R 2 ; Z is S; R 1  is H;
 wherein R 2  is selected from the group consisting of a lower alkyl group, (CH 2 ) n OR′ (wherein n=1, 2, or 3 and R′ is H or a lower alkyl group), CF 3 , CH 2 —CH 2 X, CH 2 —CH 2 —CH 2 X (wherein X=F, Cl, Br or I), R ph , and (CH 2 ) n R ph  (wherein n=2, 3, or 4) R ph  represents an optionally substituted phenyl group); or 
 wherein 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; 
           
           R 3  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′, 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′ is H or a lower alkyl group and R ph  represents an optionally substituted phenyl group) and a tri-alkyl tin;
 R 4  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′ is H or a lower alkyl group and R ph  represents an optionally substituted phenyl group), and a tri-alkyl tin; 
 R 5  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′, 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′ is H or a lower alkyl group and R ph  represents an optionally substituted phenyl group), and a tri-alkyl tin; 
 R 6  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′ is H or a lower alkyl group and R ph  represents an optionally substituted phenyl group), and a tri-alkyl tin; 
 R 7  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′ is H or a lower alkyl group and R ph  represents an optionally substituted phenyl group), and a tri-alkyl tin; 
 R 8  is selected from the group consisting of H, F, Cl, Br, I, ethyl, propyl, butyl, (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′ is H or a lower alkyl group and R ph  represents an optionally substituted phenyl group), and a tri-alkyl tin; 
 R 9  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′ is H or a lower alkyl group and R ph  represents an optionally substituted phenyl group), and a tri-alkyl tin; 
 R 10  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′ is H or a lower alkyl group and R ph  represents an optionally substituted phenyl group), and a tri-alkyl tin; 
 or one of R 3 -R 10  is 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. 
       
     
     
         2 . The compound of  claim 1  wherein the optional substituents of R ph  are selected from the group consisting of 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′ (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. 
       
     
     
         3 . The compound of  claim 1 , wherein R 2 =CH 3 , R 3 -R 7 ═H, R 8 =OH and R 9 -R 10  are H. 
     
     
         4 . The compound of  claim 1 , wherein R 2 =CH 3  and R 8  is selected from the group consisting of CN, CH 3 , OH, OCH 3  and NH 2 . 
     
     
         5 . The compound of  claim 4 , wherein R 3 -R 7  and R 9 -R 10  are H. 
     
     
         6 . The compound of claim any one of  claims 1 - 5 , wherein the compound binds to Aβ with a dissociation constant (K D ) between 0.0001 and 10.0 μM when measured by binding to synthetic Aβ peptide or Alzheimer's Disease brain tissue.