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 - 232 . (canceled) 
     
     
         233 . A compound of Formula I or Formula II, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
       
         
           
           
               
               
           
         
         wherein in Formula I:
 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, 
 provided that when R 1  is alkyl, L 1  is absent; 
 provided that when R 2  is benzyl, L 1  is methylene, L 2  is —(CH 2 ) 3 —, Y is SO 3   − X + , then R 1  is not phenyl; 
 provided that when R 2  is hydrogen, L 2  is —(CH 2 ) 3 —, L 1  is methylene, Y is SO 3   − X + , then R 1  is not 1,3-benzodioxol-5-yl or 3,4-methoxybenzyl; and 
 provided that when R 2  is hydrogen, L 2  is —(CH 2 ) 3 —, L 1  is absent, Y is SO 3   − X + , then R 1  is not 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; 
 and wherein in Formula II: 
 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. 
 
       
     
     
         234 . The compound of  claim 233 , wherein R 2  is hydrogen. 
     
     
         235 . The compound of  claim 233 , wherein R 1  is straight chain alkyl. 
     
     
         236 . The compound of  claim 233 , wherein R 1  is t-butyl. 
     
     
         237 . The compound of  claim 233 , wherein R 1  is carbocyclic. 
     
     
         238 . The compound of  claim 233 , wherein R 1  is C 7 -C 10  bicycloalkyl. 
     
     
         239 . The compound of  claim 233 , wherein said bicyclic fused ring group is indolyl. 
     
     
         240 . The compound of  claim 233 , wherein L 1  is CH 2 CH 2  or absent. 
     
     
         241 . The compound of  claim 233 , wherein said compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or prodrug thereof. 
     
     
         242 . The compound of  claim 233 , wherein said compound is 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 1, 2, 3, or 4; 
 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. 
 
         
       
     
     
         243 . The compound of  claim 242 , wherein said compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or prodrug thereof. 
     
     
         244 . The compound of  claim 233 , wherein said compound is 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 1, 2, 3, or 4; 
 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. 
       
     
     
         245 . The compound of  claim 244 , wherein said compound is: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts, esters, or prodrugs thereof. 
     
     
         246 . A 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 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 provided that R 21  and R 22  are not linked to form an aryl ring. 
 
       
     
     
         247 . The compound of  claim 246 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, esters, and prodrugs thereof. 
     
     
         248 . The compound of  claim 233 , wherein said compound is a compound of Formula VII: 
       
         
           
           
               
               
           
         
         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, 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. 
 
       
     
     
         249 . The compound of  claim 248 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, esters, and prodrugs thereof. 
     
     
         250 . A compound of the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts and esters thereof. 
     
     
         251 . 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 233  in an amount effective to treat or prevent an amyloid related disease. 
     
     
         252 . The method according to  claim 251 , wherein said amyloid-related disease is Alzheimer's disease, cerebral amyloid angiopathy, inclusion body myositis, macular degeneration, MCI, or Down's syndrome. 
     
     
         253 . The method according to  claim 251 , wherein amyloid fibril formation or deposition, neurodegeneration, microglial inflammatory response, or cellular toxicity is reduced or inhibited upon administration of said compound. 
     
     
         254 . The method according to  claim 251 , wherein said amyloid-related disease is diabetes, AA amyloidosis, AL amyloidosis, or hemodialysis related amyloidosis (β 2 M). 
     
     
         255 . The method of  claim 251 , 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. 
     
     
         256 . A method for inhibiting amyloid deposition in a subject comprising administering to a subject an effective amount of a therapeutic compound of  claim 233  or a pharmaceutically acceptable salt thereof. 
     
     
         257 . A pharmaceutical composition comprising a compound according to  claim 233  together with a pharmaceutically acceptable carrier. 
     
     
         258 . The method of  claim 251 , wherein said amyloid-related disease is familial amyloid polyneuropathy (FAP), senile systemic amyloidosis, Tenosynovium, familial amyloidosis, Ostertag-type, non-neuropathic amyloidosis, cranial neuropathy, hereditary cerebral hemorrhage, familial dementia, chronic dialysis, familial Creutzfeldt-Jakob disease; Gerstmann-Sträussler-Scheinker syndrome, hereditary spongiform encephalopathies, prion diseases, familial Mediterranean fever, Muckle-Well's syndrome, nephropathy, deafness, urticaria, limb pain, cardiomyopathy, cutaneous deposits, multiple myeloma, benign monoclonal gammopathy, maccoglobulinaemia, myeloma associated amyloidosis, medullary carcinomas of the thyroid, isolated atrial amyloid, or diabetes. 
     
     
         259 . The method of  claim 256 , wherein the amyloid is amyloid-β protein, IAPP protein, AA amyloid protein, AL amyloid protein, amyloid λ, amyloid κ, amyloid κIV, amyloid γ, or amyloid γ1.