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:  
       
         
           
           
               
               
           
         
       
       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 hydrogen or alkyl;  
 Y is SO 3   − X + ;  
 X +  is hydrogen or a cationic group; and  
 each of L 1  and L 2  is independently a substituted or 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 + .  
 
     
     
         2 . A compound of Formula II:  
       
         
           
           
               
               
           
         
       
       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,  
 or a pharmaceutically acceptable salt, ester or prodrug thereof, provided that when R 1  is alkyl, L is absent.  
 
     
     
         3 .- 15 . (canceled)  
     
     
         16 . The compound of  claim 1  or  2 , wherein said compound is:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
     
     
         17 . A compound of Formula III:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is nitrogen or oxygen;  
 R 11  is hydrogen, salt-forming cation, ester forming group, or —(CH 2 ) x -Q;  
 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 3 , R 3a , 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, or two R groups on adjacent ring atoms taken together with the ring atoms form a double bond, provided that one of R 3 , R 3a , R 5 , R 5a , R 6 , and R 6a  is a moiety of Formula IIIa:  
                     
 wherein:  
 m is 0, 1, 2, 3, or 4;  
 R A , R B , R C , R D , and R E  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, esters, and prodrugs thereof, provided that said compound is not 3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)-1-propanesulfonic acid, and provided that when R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7  and R 7a  are hydrogen, and R 3  is not a moiety of Formula IIIa.  
 
     
     
         18 .- 32 . (canceled)  
     
     
         33 . The compound of  claim 17 , wherein said compound is:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or prodrug thereof.  
     
     
         34 . A compound of Formula IV:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is nitrogen or oxygen;  
 R 11  is hydrogen, salt-forming cation, ester forming group, or —(CH 2 ) x -Q;  
 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 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; or pharmaceutically acceptable salts, esters, and prodrugs thereof.  
 
     
     
         35 .- 40 . (canceled)  
     
     
         41 . The compound of  claim 34 , wherein said compound is:  
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts, esters, or prodrugs thereof.  
     
     
         42 . A compound of Formula V:  
       
         
           
           
               
               
           
         
       
       wherein: 
 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, wherein A and R 11  taken together are not a leucine residue;  
 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;  
 aa is a natural or unnatural amino acid residue;  
 m is 0, 1, 2, or 3;  
 R 14  is hydrogen or protecting group;  
 R 15  is hydrogen, alkyl or aryl;  
 and pharmaceutically acceptable salts, esters, or prodrugs thereof.  
 
     
     
         43 .- 50 . (canceled)  
     
     
         51 . The compound of  claim 42 , wherein said compound is:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts, esters, or prodrugs thereof.  
     
     
         52 . The compound of the Formula VI:  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;  
 A is oxygen or nitrogen;  
 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;  
 R 19  is hydrogen, alkyl or aryl;  
 Y 1  is oxygen, sulfur, or nitrogen;  
 Y 2  is carbon, nitrogen, or oxygen;  
 R 20  is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;  
 R 21  is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl, or absent if Y 2  is oxygen;  
 R 22  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 hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl, or absent if Y 2  is nitrogen or oxygen;  
 or pharmaceutically acceptable salts, esters, or prodrugs thereof, provided that when n is 3, Y 1  is oxygen, Y 2  is oxygen, R 21  is benzyl, A is oxgen, 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 provided that R 21  and R 22  are not linked to form an aryl ring.  
 
     
     
         53 .- 62 . (canceled)  
     
     
         63 . The compound of  claim 52 , wherein said compound is selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, esters, and prodrugs thereof.  
     
     
         64 . A compound of Formula VII, wherein said compound is of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is 2, 3, or 4;  
 A is oxygen or nitrogen;  
 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;  
 G is a direct bond or oxygen, nitrogen, or sulfur;  
 z is 0, 1, 2, 3, 4, or 5;  
 m is 0 or 1;  
 R 24  is selected from a group consisting of hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, aroyl, alkylcarbonyl, aminoalkylcarbonyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl;  
 each R 25  is independently selected from hydrogen, halogen, cyano, hydroxyl, alkoxy, thiol, amino, nitro, alkyl, aryl, carbocyclic, or heterocyclic; and pharmaceutically acceptable salts, esters, and prodrugs thereof.  
 
     
     
         65 .- 73 . (canceled)  
     
     
         74 . The compound of  claim 64 , wherein said compound is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, esters, and prodrugs thereof.  
     
     
         75 . A compound of the formula:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts and esters thereof.  
     
     
         76 . (canceled)  
     
     
         77 . A kit for use in treating amyloid related disease comprising a compound of  claim 1  or Table 2A, and instructions for use in the method of the instant invention.  
     
     
         78 . A method of treating or preventing an amyloid-related disease in a subject comprising administering to a subject in need thereof a compound of  claim 1  or depicted in the Tables and Figures in an amount effective to treat or prevent an amyloid related disease.  
     
     
         79 .- 83 . (canceled)  
     
     
         84 . A method for inhibiting amyloid deposition in a subject comprising administering to a subject an effective amount of a therapeutic compound of  claim 1  or depicted in the Tables and Figures or a pharmaceutically acceptable salt thereof, such that said therapeutic compound inhibits an interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane to inhibit amyloid deposition.  
     
     
         85 . A method for inhibiting amyloid deposition in a subject comprising orally administering to said subject an effective amount of a therapeutic compound of  claim 1  or depicted in the Tables and Figures or a pharmaceutically acceptable salt thereof.  
     
     
         86 . A method for reducing amyloid deposits in a subject having amyloid deposits, the method comprising administering to said subject an effective amount of a therapeutic compound of  claim 1  or depicted in the Tables and Figures, or pharmaceutically acceptable salts thereof.  
     
     
         87 .- 88 . (canceled)  
     
     
         89 . A method for inhibiting amyloid deposition in a subject comprising administering to a subject an effective amount of a therapeutic compound of  claim 1  or depicted in the Tables and Figures, or a pharmaceutically acceptable salt thereof, such that amyloid deposition is inhibited.  
     
     
         90 .- 98 . (canceled)  
     
     
         99 . A pharmaceutical composition for the treatment or prevention of an amyloid-related disease comprising a compound according to  claim 1 .  
     
     
         100 . A pharmaceutical composition comprising a compound according to  claim 1 .  
     
     
         101 . (canceled)  
     
     
         102 . A pharmaceutical composition for treating amyloidosis comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit amyloid deposition in a subject.  
     
     
         103 .- 207 . (canceled)  
     
     
         208 . A method for preventing, slowing, or stopping disease progression comprising administering to a subject an effective amount of a compound of  claim 1 , such that said disease progression is prevented slowed, or stopped.  
     
     
         209 . (canceled)  
     
     
         210 . A method for treating a subject for an amyloid-related disease, comprising: 
 administering a cognitive test to a subject prior to administration of a compound of  claim 1;     administering an effective amount of the compound to the subject, and    administering a cognitive test to the subject subsequent to administration of said compound, such that said subject is treated for said amyloid-related disease, wherein the subject's score on said cognitive test is improved.    
     
     
         211 .- 220 . (canceled)  
     
     
         221 . A method for inhibiting fibril formation, comprising administering to a subject an effective amount of a compound of  claim 1  or depicted in the Tables or Figures, wherein said effective amount is effective to inhibit protein-protein interactions, such that fibril formation is inhibited.  
     
     
         222 . A method for treating CAA or hereditary cerebral hemorrhage, comprising administering an effective amount of a compound of  claim 1  or depicted in the Tables of Figures, wherein said effective amount is effective to decrease or prevent the recurrence of hemorrhagic stroke.  
     
     
         223 .- 229 . (canceled)  
     
     
         230 . A method of treating Alzheimer's Disease in a subject, comprising administering to a subject in need thereof a compound of  claim 1  in an amount effective to treat Alzheimer's Disease.  
     
     
         231 . A method of treating Mild Cognitive Impairment in a subject, comprising administering to a subject in need thereof a compound of  claim 1  in an amount effective to treat Mild Cognitive Impairment.  
     
     
         232 . A method of treating neurotoxicity associated with Aβ amyloid in a subject, comprising administering to a subject in need thereof a compound of  claim 1  in an amount effective to treat neurotoxicity associated with Aβ amyloid.