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 VIII, XII, XIV or XV: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is hydrogen, 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; 
 R h  is hydrogen, benzyl, aryl-alkyl, aryl, or alkyl; 
 R i  is hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, alkenyl, carbocyclic, heterocyclic, absent or together with R k , R k  or R m  may be linked to form a ring structure; 
 R j , R l , R m , R n , and R o  are each independently hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted benzyl, alkyl, alkenyl, carbocyclic, heterocyclic, absent or together may be linked to form a ring structure; 
 R s  is hydrogen or when n 2  is 3, R s  is (CH 2 ) 3 —SO 3   − X + ; 
 R q  and R r  are each selected independently from hydrogen or alkyl, 
 R t  is hydrogen, alkyl, or aryl; 
 R u  and R v  are each independently for each occurrence selected from hydrogen, aryl, benzyl, alkyl, alkenyl, carbocyclic, heterocyclic, or two R u  or R v  groups on adjacent carbon atoms may form a double bound, or together with the carbon atoms they are attached to forming a carbocyclic or heterocyclic ring; 
 Y is SO 3   − X + , OSO 3   − X + , or SSO 3   − X + ; 
 X +  is hydrogen, a cationic group, or an ester-forming group; 
 L 1  is a substituted or unsubstituted C 1 -C 5  alkyl group or absent, 
 B is C 1 -C 5  alkyl, alkenyl, or alkynyl group, and optionally fused with W when M is absent; 
 M is a covalent bond, amino, C 1 -C 6  alkyl, alkenyl, alkynyl, carboxyl, oxy, amide, ester, thioether, thioester or absent; 
 W is a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, bicyclic or tricyclic ring, a bicyclic or tricyclic fused ring group, heterocyclic, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; 
 v is 1, 2, 3, 4, 5, or 6; 
 n 2  is 0, 1, 2, or 3, selected such that three carbons are between the SO 3   − X +  group and the nitrogen atom in the ring; 
 n 3  is 4, 5, 6, or 7; and 
 t 1  and t 2  are each single or double bonds, provided that both t 1  and t 2  are not both double bonds: 
 or a pharmaceutically acceptable salt, ester or prodrug thereof, provided that when Y is methyl, R 1  and R 2  are hydrogen, Y is SO 3   − X + , and M is a covalent bond, B is not CH 2 —CH(M-W)—CH 2 . 
 
     
     
         2 - 3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein v is 1. 
     
     
         5 . The compound of  claim 1 , wherein M is a covalent bond or a C 1 -C 3  alkyl. 
     
     
         6 - 12 . (canceled) 
     
     
         13 . The compound of  claim 1 , wherein B is —CH(M-W)—CH 2 —CH 2 —. —CH 2 —CH(M-W)—CH 2 —, or —(CH 2 )—CH 2 —CH(M-W)—. 
     
     
         14 - 16 . (canceled) 
     
     
         17 . A compound of Formula IX, X, XI, or XIII: 
       
         
           
           
               
               
           
         
       
       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 the group consisting of hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl; 
 R 3  is hydrogen or a protecting group; 
 R a  is hydrogen, substituted or unsubstituted alkyl, aryl, heteroaryl, carboxyl, alkyloxycarbonyl, or aminocarbonyl; 
 R b  and R c  are each selected independently from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, CONH 2 , or R b , R c  and the carbon atom they are attached to can form a substituted or unsubstituted cyclic structure of 4 to 8-membered ring or a fused ring system; 
 R d  is H or alkyl; 
 R e  and R f  are each independently hydrogen, C 1 -C 6  alkyl, or R e  and R f  taken together with the carbon they are attached to form a 3 to 6-membered ring; 
 R g  is independently selected for each occurrence from the group consisting of: hydrogen, alkyl, alkoxy, halogen, NO 2 , and alkyl-SO 2 ; 
 R p  and aa are each a natural or unnatural amino acid residue; 
 Ar is aryl or heteroaryl; 
 P is a covalent bond, alkyl, alkyloxy, amino, alkylamino, sulfur, or alkylthio; 
 Y is SO 3   − X + , OSO 3   − X + , or SSO 3   − X + ; 
 X +  is hydrogen, a cationic group, or an ester-forming group; and 
 Z is —(CH 2 ) 0-3 —, —(CHOH)—, (CH 2 ) 1-3 O(CH 2 ) 1-3 , or a carbonyl group; 
 each of L 1  and L 2  is independently a substituted or unsubstituted C 1 -C 5  alkyl group or absent; 
 L 3  is a covalent bond, amino, C 1 -C 6  alkyl, alkenyl, alkynyl, carboxyl, amide, aminoalkyl, ether, ester, thioether, thioester or absent; 
 q is 1, 2, 3, 4, or 5; and 
 n 1  is 0, 1, 2, or 3; 
 or a pharmaceutically acceptable salt, ester or prodrug thereof. 
 
     
     
         18 - 61 . (canceled) 
     
     
         62 . A compound of Table 3A or Table 3B, or a pharmaceutically acceptable salt, ester, or prodrug thereof. 
     
     
         63 . (canceled) 
     
     
         64 . 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 a pharmaceutically acceptable salt thereof, in an amount effective to treat or prevent an amyloid related disease. 
     
     
         65 . The method according to  claim 64 , wherein said amyloid-related disease is Alzheimer's disease, cerebral amyloid angiopathy, inclusion body myositis, macular degeneration, MCI, or Down's syndrome. 
     
     
         66 . (canceled) 
     
     
         67 . The method according to  claim 64 , wherein said amyloid-related disease is diabetes, AA amyloidosis, AL amyloidosis, ATTR-related amyloidosis, or hemodialysis related amyloidosis (β 2 M). 
     
     
         68 - 70 . (canceled) 
     
     
         71 . A method for treating or preventing an amyloid-related disease in a subject in need thereof, comprising administering to said subject a therapeutic compound of  claim 17 , or a pharmaceutically acceptable salt thereof, in an amount effective to treat or prevent an amyloid related disease. 
     
     
         72 . A method for treating or preventing an amyloid-related disease in a subject in need thereof, comprising administering to said subject a therapeutic compound of  claim 62 , or pharmaceutically acceptable salts thereof, in an amount effective to treat or prevent an amyloid related disease. 
     
     
         73 - 119 . (canceled) 
     
     
         120 . The method according to  claim 64 , 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-Strä ussler-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. 
     
     
         121 - 202 . (canceled) 
     
     
         203 . The method according to  claim 64 , wherein the amyloid protein is amyloid λ, amyloid κ, amyloid κIV, amyloid γ, or amyloid γ1. 
     
     
         204 - 219 . (canceled) 
     
     
         220 . The method according to  claim 71 , wherein said amyloid-related disease is Alzheimer's disease, cerebral amyloid angiopathy, inclusion body myositis, macular degeneration, MCI, or Down's syndrome. 
     
     
         221 . The method according to  claim 71 , wherein said amyloid-related disease is diabetes, AA amyloidosis, AL amyloidosis, ATTR-related amyloidosis, or hemodialysis related amyloidosis (β 2 M). 
     
     
         222 . The method according to  claim 71 , 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-Strä ussler-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. 
     
     
         223 . The method according to  claim 71 , wherein the amyloid protein is amyloid λ, amyloid κ, amyloid κIV, amyloid γ, or amyloid γ1. 
     
     
         224 . The method according to  claim 72 , wherein said amyloid-related disease is Alzheimer's disease, cerebral amyloid angiopathy, inclusion body myositis, macular degeneration, MCI, or Down's syndrome. 
     
     
         225 . The method according to  claim 72 , wherein said amyloid-related disease is diabetes, AA amyloidosis, AL amyloidosis, ATTR-related amyloidosis, or hemodialysis related amyloidosis (β 2 M). 
     
     
         226 . The method according to  claim 72 , 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-Strä ussler-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. 
     
     
         227 . The method according to  claim 72 , wherein the amyloid protein is amyloid λ, amyloid κ, amyloid κIV, amyloid γ, or amyloid γ1.