METHODS AND COMPOSITIONS FOR TREATING AMYLOID-RELATED DISEASES

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.