Methods and Compositions for Treating Amyloid-Related Diseases

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.