Methods and Compositions for Treating Amyloid-Related Diseases

Abstract

Methods, compounds, pharmaceutical compositions and kits are described for treating or preventing amyloid-+related disease.

1 . A compound of Formula I, or Formula VI: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is a substituted or unsubstituted cycloalkyl, heterocyclic, aryl, arylcycloalkyl, bicyclic or tricyclic ring, a bicyclic or tricyclic fused ring group, or a substituted or unsubstituted C 2 -C 10  alkyl group; 
 R 2  is selected from a group consisting of hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl; 
 Y is SO 3   − X + ; 
 X + is hydrogen or a cationic group; and 
 L 1  is independently a substituted or unsubstituted C 1 -C 5  alkyl group or absent; 
 L 2  is a unsubstituted C 1 -C 5  alkyl group or absent, or a pharmaceutically acceptable salt, ester or prodrug thereof, provided that when R 1  is alkyl, L 1  is absent; provided that when R 2  is benzyl, L 1  is methylene, R 1  is phenyl, L 2  is —(CH 2 ) 3 —, Y is not SO 3   − X + , provided that when R 2  is hydrogen, L 2  is —(CH 2 ) 3 —, L 1  is methylene, R 1  is 1,3-benzodioxol-5-yl or 3,4-methoxybenzyl, Y is not SO 3   − X + , and provided that when R 2  is hydrogen, L 2  is —(CH 2 ) 3 —, L 1  is absent, R 1  is t-butyl, isobutyl, pentyl, n-heptyl, n-octyl, n-nonyl, cyclohexyl, isopropyl, isoamyl, 1-hydroxy-2-propyl, 3,5-dimethyl-1-adamantyl, 1-hydroxy-2-pentyl, 3-methyl butyric acid, -4-methyl-pentanoic acid methyl ester, or 2,2-diphenyl-ethyl, Y is not SO 3   − X + ; 
 A is nitrogen or oxygen; 
 R 11  is hydrogen, salt-forming cation, ester forming group, —(CH 2 ) x -Q, or when A is nitrogen, A and R 11  taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof; 
 Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; 
 x is 0, 1, 2, 3, or 4; 
 n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; 
 R 19  is hydrogen, alkyl or aryl; 
 Y 1  is oxygen, sulfur, or nitrogen; 
 Y 2  is carbon, nitrogen, or oxygen; 
 R 20  and R 21  are linked to form an aromatic ring; 
 R 22  K is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl; or R 22  is hydrogen, hydroxyl, alkoxy or aryloxy if Y 1  is nitrogen; or R 22  is absent if Y 1  is oxygen or sulfur; or R 22  and R 21  may be linked to form a cyclic moiety if Y 1  is nitrogen; 
 R 23  is absent; 
 provided that when n is 3, Y 1  is oxygen, Y 2  is oxygen, R 21  is benzyl, A is oxygen, R 19  is not hydrogen; and provided that when n is 3, Y 1  is oxygen, Y 2  is carbon, each of R 20 , R 21 , and R 23  is methyl, R 19  is not hydrogen; 
 and pharmaceutically acceptable salts, esters and prodrugs thereof. 
 
   
   
       2 . A compound of Formula II or Formula IV: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is a substituted or unsubstituted cyclic, bicyclic, tricyclic, or benzoheterocyclic group or a substituted or unsubstituted C 2 -C 10  alkyl group; 
 R 2  is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl, or linked to R 1  to form a heterocycle; 
 Y is SO 3   − X + , OSO 3   − X + , or SSO 3   − X + ; 
 X +  is hydrogen, a cationic group, or an ester forming moiety; 
 m is 0; 
 n is 1, 2, 3, or 4; 
 L is substituted or unsubstituted C 1 -C 3  alkyl group or absent, 
 provided that when R 1  is alkyl, L is absent; 
 
     
       
         
         
             
             
         
       
     
     wherein:
 A is nitrogen and taken together with R 11  are a residue of a natural or unnatural amino acid or a salt or ester thereof; 
 n is 0, 1, 2 ,3, 4, 5, 6, 7, 8, 9, or 10; 
 R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 , and R 7a  are each independently hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, R 4  and R 5  taken together, with the ring atoms they are attached to, form a double bond, or R 6  and R 7  taken together, with the ring atoms they are attached to, form a double bond; 
 m is 0, 1, 2, 3, or 4; 
 R 8 , R 9 , R 10 , R 11  and R 12  are independently selected from a group of hydrogen, halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothiazolyl, and benzoimidazolyl; 
 and pharmaceutically acceptable salts, prodrugs, or esters thereof. 
 
   
   
       3 .- 15 . (canceled) 
   
   
       16 . The compound selected from the group consisting of 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts, prodrugs, or esters thereof. 
   
   
       17 .- 58 . (canceled) 
   
   
       59 . A method of
 a) treating or preventing an amyloid-related disease in a subject comprising administering to a subject in need thereof a compound of any one of Formulae I, II, III, IV or VI or a compound depicted in the Tables and Figures, or a pharmaceutically acceptable salt thereof, in an amount effective to treat or prevent an amyloid related disease;   b) inhibiting amyloid deposition in a subject comprising administering to a subject in need thereof a therapeutic compound of any one of Formulae I, II, III, IV or VI or a compound depicted in the Tables and Figures, or a pharmaceutically acceptable salt thereof in an amount effective to inhibit amyloid deposition; or   c) treating or preventing Alzheimer's disease in a subject, comprising administering to a subject in need thereof a compound of any one of Formulae I, II, III, IV or VI or a compound depicted in the Tables and Figures, or a pharmaceutically acceptable salt thereof, in an amount effective to treat or prevent Alzheimer's disease.   
   
   
       60 . The method according to  claim 59 , wherein said amyloid-related disease is Alzheimer's disease, cerebral amyloid angiopathy, inclusion body myositis, macular degeneration, MCI, Down's syndrome, diabetes, AA amyloidosis, AL amyloidosis, or hemodialysis related amyloidosis (β 2 M). 
   
   
       61 . The method according to  claim 59 , wherein amyloid fibril formation or deposition, neurodegeneration, or cellular toxicity is reduced or inhibited upon administration of said compound. 
   
   
       62 . (canceled) 
   
   
       63 . The method according to  claim 59 , wherein said subject is a human. 
   
   
       64 . The method of  claim 63 , wherein said subject has Alzheimer's disease, Mild Cognitive Impairment, or cerebral amyloid angiopathy, and stabilization of cognitive function, prevention of a further decrease in cognitive function, or prevention, slowing, or stopping of disease progression occurs in said patient upon administration. 
   
   
       65 .- 70 . (canceled) 
   
   
       71 . The method of  claim 59 , wherein the therapeutic compound is administered orally. 
   
   
       72 . The method of  claim 59 , wherein said therapeutic compound is administered in a pharmaceutically acceptable vehicle. 
   
   
       73 .- 80 . (canceled) 
   
   
       81 . A pharmaceutical composition comprising a compound of Formulae I, II, III, IV, VI or a compound depicted in the Tables and Figures. 
   
   
       82 .- 138 . (canceled) 
   
   
       139 . The method of  claim 59 , wherein said subject's brain has amyloid-β amyloid deposits. 
   
   
       140 .- 168 . (canceled) 
   
   
       169 . The pharmaceutical composition of  claim 81 , wherein said pharmaceutical composition further comprises a pharmaceutically acceptable acid, base, buffering agent, inorganic salt, solvent, or preservative or a compound that increases the cerebral bioavailability of said compound. 
   
   
       170 . (canceled) 
   
   
       171 . The pharmaceutical composition of  claim 81 , wherein said compound is dissolved in a liquid pharmaceutically acceptable vehicle. 
   
   
       172 . The pharmaceutical composition of  claim 81 , wherein said compound is present as a homogenous mixture in a capsule or pill. 
   
   
       173 .- 203 . (canceled) 
   
   
       204 . The pharmaceutical composition of  claim 81 , wherein said composition treats or prevents an amyloid-related disease.