Methods and compositions for treating amyloid-related diseases

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.