NZ550116A

NZ550116A - Phosphono-carboxylate compounds for treating amyloidosis

Info

Publication number: NZ550116A
Application number: NZ550116A
Authority: NZ
Inventors: Walter Szarek; Xianqi Kong
Original assignee: Neurochem Int Ltd
Priority date: 1997-08-18
Filing date: 1998-04-10
Publication date: 2008-03-28
Also published as: CA2300910C; JP2001515039A; WO1999008685A1; CA2300910A1; EP1014994A1; IL134619A0

Abstract

Disclosed is a pharmaceutical composition for modulating amyloid deposition in a subject, comprising a pharmaceutically acceptable vehicle and an effective amount of a therapeutic compound, wherein the therapeutic compound is of formula (I) in which: Z is R4 or XR2; R1 and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; R3 is hydrogen, lower alkyl, aryl, or a salt-forming cation; R4 is hydrogen, lower alkyl, aryl or -NRaRb; X is, independently for each occurrence, O or S; Y1 and Y2 are each independently hydrogen, halogen, alkyl, -NRaRb, hydroxyl, alkoxy, or aryloxy; n is an integer from 0 to 12 and the substituents are as described in the specification, wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phosphonopentanoic acid.

Description

New Zealand Paient Spedficaiion for Paient Number 5501 16 *10052674196* 550116 NEW ZEALAND PATENTS ACT, 1953 No: Divided out of No. 539160 Date: Dated 10 April 1998 COMPLETE SPECIFICATION PHOSPHONO-CARBOXYLATE COMPOUNDS FOR TREATING AMYLOIDOSIS We, QUEEN'S UNIVERSITY AT KINGSTON, of Kingston, Ontario K7L 3N6, Canada, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by la) INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 6 SEP 2006 RECEIVED - la - PHOSPHONO-CARBOXYLATE COMPOUNDS FOR TREATING AMYLOIDOSIS Background of Invention Amyloidosis refers to a pathological condition characterized by the presence of amyloid. Amyloid is a generic term referring to a group of diverse but specific extracellular protein deposits which are seen in a number of different diseases. Though diverse in their occurrence, all amyloid deposits have common morphologic properties, stain with specific dyes (e.g., Congo red), and have a characteristic red-green 10 birefringent appearance in polarized light after staining. They also share common ultrastructural features and common x-ray diffraction and infrared spectra.

Amyloidosis can be classified clinically as primary, secondary, familial and/or isolated. Primary amyloidosis appears de/jovo without any preceding disorder.

Secondary amyloidosis is that form which appears as a complication of a previously 15 existing disorder. Familial amyloidosis is a genetically inherited form found in particular geographic populations. Isolated forms of amyloidosis are those that tend to involve a single organ system. Different amyloids are also characterized by the type of protein present in the deposit. For example, neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, Creutzfeldt-Jakob disease and the like are characterized 20 by the appearance and accumulation of a protease-resistant form of a prion protein (referred to as AScr or PrP-27) in the central nervous system. Similarly, Alzheimer's disease, another neurodegenerative disorder, is characterized by congophilic angiopathy, neuritic plaques and neurofibrillary tangles, all of which have die characteristics of amyloids. In this case, the plaque and blood vessel amyloid is formed by the beta 25 protein. Other systemic or localized diseases such as adult-onset diabetes, complications of long-term hemodialysis and sequelae of long-standing inflammation or plasma cell dyscrasias are characterized by the accumulation of amyloids systemically. In each of these cases, a different amyloidogenic protein is involved in amyloid deposition.

Summary of the Invention This invention provides methods and compositions which are useful in the treatment of amyloidosis. Also described herein are methods which are useful in the treatment of amyloidosis. The methods described herein involve administering to a subject a therapeutic compound which inhibits amyloid deposition. Accordingly, the compositions of the invention and methods described herein are useful for inhibiting amyloidosis in disorders in which deposition occurs. The methods can be used therapeutically to treat amyloidosis or can be used prophylactically in a subject susceptible to amyloidosis. Without wishing to be bound by theory, it is believed that INTELLECTUAL PROPERTY OFFICE OF N.Z. 21 DEC 2007 RECEIVED the methods described herein are based, at least in part, on inhibiting an interaction between an amyloidogenic protein and a constituent of basement membrane to inhibit & amyloid deposition. The constituent of basement membrane can be a glycoprotein or proteoglycan, preferably heparan sulfate proteoglycan. In certain embodiments, a 5 therapeutic compound used in the methods described herein preferably can interfere with binding of a basement membrane constituent to a target binding site on an amyloidogenic protein, thereby inhibiting amyloid deposition.

The invention relates to phosphonocarboxylate compounds, i.e., compounds which include a phosphonate group and a carboxylate group, or a pharmaceutically 10 acceptable salt or ester thereof. In one embodiment, the methods described herein involve administering to a subject an effective amount of a therapeutic compound of the invention having the formula (Formula I): X .P—(CYlY2)nC(X)XR3 R1X I Z IS in which Z is XR2 or R4, R1 and R2 are each independently hydrogen, a substituted or unsubstituted aliphatic group (preferably a branched or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain; or an unsubstituted or substituted cyclic aliphatic moiety having from 4 to 7 carbon atoms in the aliphatic ring; preferred 20 aliphatic and cyclic aliphatic groups are alkyl groups, more preferably lower alkyl), an aryl group, a heterocyclic group, or a salt-forming cation; R3 is hydrogen, lower alkyl, aryl, or a salt-forming cation; R4 is hydrogen, lower alkyl, aryl or amino (including i ^ alkylamino, dialkylamino (including cyclic amino moieties), arylamino, diarylamino, and alkylaiylamino); X is, independently for each occurrence, O or S; Y1 and Y2 are 25 each independently hydrogen, halogen (e.g., F, CI, Br, or I), alkyl (preferably lower alkyl), amino, hydroxy, alkoxy, or aryloxy; and n is an integer from 0 to 12 (more preferably 0 to 6, more preferably 0 or 1): wherein in each occurrence, RaandRb are each independently hydrogen, alkyl, aryl, or heteroaryl, or RaandRb taken together with the nitrogen atom to which they are attached form a cyclic moiety having from 3 to 8 atoms 30 in the cycle; and wherein when any of R1, R2, R3, R4, Y1, and Y2 is an aliphatic, an alkyl or an aryl group, then the aliphatic, alkyl or aryl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxy 1, phosphate, phosphonato, phosphinato, cyano, intellectual property office of n.z. 21 DEC 2007 -2a- (Followed by page 3) -NH2, alkyl amino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, and an aromatic or heteroaromatic moiety; such that amyloid deposition is modulated.

In preferred embodiments, therapeutic compounds of the invention prevent or inhibit amyloid deposition in a subject to which the therapeutic compound is administered. Preferred therapeutic compounds for use in the invention include compounds in which both R1 and R2 are pharmaceutical^ acceptable salt-forming cations. It will be appreciated that the stoichiometry of an anionic compound to a salt-forming counterion (if any) will vary depending on the charge of the anionic portion of the compound (if any) and the charge of the counterion. In a particularly preferred 1248378 l.DOC INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 1 DEC 2007 RPr.PIVFD embodiment, R', R2 and R3 are each independently a sodium, potassium or calcium cation. In certain embodiments in which at least one of R1 and R2 is an aliphatic group, the aliphatic group has between 1 and 10 carbons atoms in the straight or branched chain, and is more preferably a lower alkyl group. In other embodiments in which at least one of Rl and R2 is an aliphatic group, the aliphatic group has between 10 and 24 carbons atoms in the straight or branched chain. In certain preferred embodiments, n is 0 or 1; more preferably, nisO. In certain preferred embodiments of the therapeutic compounds, Yl and Y2 are each hydrogen.

In a particularly preferred embodiment the invention provides a pharmaceutical composition for modulating amyloid deposition in a subject, comprising a pharmaceutically acceptable vehicle and an effective amount of a therapeutic compound, wherein the therapeutic compound has the formula: v 1 R1 -C-Y2 -C(X)XR in which Z is R4 or XR2; R1 and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; R3 is hydrogen, lower alkyl, aryl, or a salt-forming cation; R4 is hydrogen, lower alkyl, aryl or -NRaRb; X is, independently for each occurrence, O or S; Y1 and Y2 are each independently hydrogen, halogen, alkyl, -NRaRb, hydroxy, alkoxy, or aryloxy; n is an integer from 0 to 12; wherein in each occurrence, Raand Rb are each independently hydrogen, alkyl, aryl, or heteroaryl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a cyclic moiety having from 3 to 8 atoms in the cycle; and wherein when any of R1, R2, R3, R4, Y1, and Y2 is an aliphatic, an alkyl or an aryl group, then the aliphatic, alkyl or aryl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, INTELLECTUAL PROPERTY OFFICE 6F N.Z. 21 DEC 2007 received -3a- (Followed by page 3b) -NH2, alkyl amino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, and an aromatic or heteroaromatic moiety; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

In another particularly preferred embodiment, the invention provides a pharmaceutical composition for modulating amyloid deposition in a subject, comprising a pharmaceutically acceptable vehicle and an effective amount of a therapeutic compound, wherein the therapeutic compound has the formula: R1 OR2 Y1 Yz -CH(NRaRb)C(0)0R3 in which R1 and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; R3 is hydrogen, lower alkyl, aryl, or a salt-forming cation; X is, independently for each occurrence, O or S; Y1 and Y2 are each independently hydrogen, halogen, alkyl, NRaRb, hydroxy, alkoxy, or aryloxy; n is an integer from 0 to 12; and wherein in each occurrence Ra and R5 are each independently hydrogen, alkyl, aryl, or heterocyclyl, or Ra and R^, taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the cycle; wherein when any of R1, R2, R3, Y', and Y2 is an aliphatic, an alkyl or an aryl group, then the aliphatic, alkyl or aryl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, -NH2, alkyl amino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, and an aromatic or heteroaromatic moiety; 1248378_1.DOC INTELLECTUAL PROPERTY OFFI0E OF N.Z. 21 DEC 2007 received -3b- (Followed by page 3c) wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

In yet another particularly preferred embodiment, the invention provides a pharmaceutical composition for modulating amyloid deposition in a subject in which said amyloid deposition is characterized by interaction between an amyloidogenic protein and a constituent of a basement membrane, comprising a pharmaceutically acceptable vehicle and an effective amount of a therapeutic compound, wherein the therapeutic compound has the formula: r Y1 R1 OR' Y2 -C(0)0R in which R1 and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclyl group, or a salt-forming cation; R3 is hydrogen, lower alkyl, aryl or a salt-forming cation; Y1 and Y2 are each independently hydrogen, halogen, lower alkyl, —NRaRb, hydroxy, alkoxy, or aryloxy, wherein Ra and Rb are each independently hydrogen, alkyl, aryl, or heteroaryl, or RaandRb taken together with the nitrogen atom to which they are attached form a cyclic moiety having from 3 to 8 atoms in the cycle; and n is an integer from 0 to 12; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

In certain preferred embodiments, the therapeutic compound of the invention can be represented by the formula (Formula II): X XR2 in which R1, R2, R3, Y1, Y2, X and n are as defined above. In more preferred embodiments, the therapeutic compound of the invention can be represented by the formula (Formula III): RIO 1 O P—(CYlY2)nCH(NRaRb)C(0)0R3 R2 1248378_1.DOC INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 1 DEC 2007 Rcrci\/cn -3c- (Followed by page 4) in which R1, R2, R3, Y1, Y2, and X are as defined above, Ra and Rb are each independently hydrogen, alkyl, aryl, or heterocyclyl, or Ra and Rfc, taken together with the nitrogen atom to winch they are attached, form a cyclic moiety having from 3 to 8 atoms in the ring, and n is an integer from 0 to 6. In certain preferred embodiments, Ra and Rb are each hydrogen. In certain preferred embodiments, a compound of the invention comprises an a-amino acid (or a-amino acid ester), more preferably a L-a-amino acid or ester.

In another embodiment, the compounds of the invention can be represented by the formula (Formula IV): in which G represents hydrogen or one or tnore substituents on the aryl ring (e.g., alkyl, aryl, halogen, amino, and the like) and L is a substituted alkyl group (in certain INTELLECTUAL PROPERTY OFFICE OF N.Z. 21 DEC 2007 received embodiments, preferably a lower alkyl), more preferably a hydroxy-substituted alkyl or an alkyl substituted with a nucleoside base.

The therapeutic compounds of the invention are administered to a subject by a route which is effective for modulation of amyloid deposition. Suitable routes of administration include oral, transdermal, subcutaneous, intravenous, intramuscular and intraperitoneal injection. A preferred route of administration is oral administration. The therapeutic compounds can be administered with a pharmaceutically acceptable vehicle:.

Also described herein are methods for treating a disease state associated with amyloidosis by administering to a subject an effective amount of a therapeutic compound having the formula described supra, such that a disease state associated with amyloidosis is treated.

Further described herein are methods for modulating amyloid deposition characterized by interaction between an amyloidogenic protein and a constituent of a basement membrane by administering to the subject an effective amount of a therapeutic compound having the formula described supra, such that modulation of amyloid deposition characterized by interaction between an amyloidogenic protein and a constituent of a basement membrane occurs. , In an additional preferred embodiment, the invention provides pharmaceutical compositions for treating a disease state associated with amyloidosis comprising a pharmaceutical composition for treating a disease state associated with amyloidosis, comprising a pharmaceutically acceptable vehicle and an effective amount of a therapeutic compound, wherein the therapeutic compound has the formula: O OR' Y1 Y2 -C(0)0Rv n in which R1 and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclyl group, or a salt-forming cation; R3 is hydrogen, lower alkyl, aryl or a salt-forming cation; Y1 and Y2 are each independently hydrogen, halogen, lower alkyl, —NRaRb, hydroxy, alkoxy, or aryloxy, wherein Ra and Rb are each independently hydrogen, alkyl, aryl, or heteroaryl, or Ra and Rb taken together with the nitrogen atom to which they are attached for a cyclic moiety having from 3 to 8 atoms in the cycle; and n is an integer from 0 to 12; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

INTELLECTUAL PROPERTY OFFICE OF N.Z. 21 DEC 2007 -4a- (Followed by page 4b) Also described are packaged pharmaceutical compositions for treating amyloidosis. The packaged pharmaceutical compositions include a therapeutic compound of the invention Mid instructions for using the pharmaceutical composition In a preferred embodiment, the invention provides a use, in the preparation of a medicament for modulating amyloid deposition in a subject, of a therapeutic compound of the formula: X -C(X)XR3 R1 in which Z is R4 or XR2; Rl and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; R^ is hydrogen, lower alkyl, aryl, or a salt-forming cation; R^ is hydrogen, lower alkyl, aryl or —NRaRb; X is, independently for each occurrence, O or S; yl and Y2 are each independently hydrogen, halogen, alkyl, —NRaRb, hydroxy, alkoxy, or aryloxy; n is an integer from 0 to 12; wherein in each occurrence RaandRb are each independently hydrogen, alkyl, aryl, or heteroaryl, or Ra andRb taken together with the nitrogen atom to which they are attached for a cyclic moiety having from 3 to 8 atoms in the cycle; and wherein when any of R1, R2, R3, R4, Y1, and Y2 is an aliphatic, an alkyl or an aryl group, then the aliphatic, alkyl or aryl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, -NH2, alkyl amino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, and an aromatic or heteroaromatic moiety; Tntellectualprop^" i office of n.Z. 1248378 l.DOC 2 I DEC 2007 pgr.FlVED -4b- (Foliowed by page 4c) wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

In an additional preferred embodiment, the invention provides a use, in the preparation of a medicament for modulating amyloid deposition in a subject, of a therapeutic compound of the formula: R1 OR2 Y C- J.

-CH(NRaRb)C(0)0R3 in which Rl and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; R^ is hydrogen, lower alkyl, aryl, or a salt-forming cation; X is, independently for each occurrence, O or S; Y* and Y2 are each independently hydrogen, halogen, alkyl, —NRaRb, hydroxy, alkoxy, or aryloxy; n is an integer from 0 to 12; wherein in each occurrence Ra and R^ are each independently hydrogen, alkyl, aryl, or heterocyclyl, or Ra and R]-,, taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the cycle; and wherein when any of R1, R2, R3, R4, Y1, and Y2 is an aliphatic, an alkyl or an aryl group, then the aliphatic, alkyl or aryl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, -NH2, alkyl amino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, and an aromatic or heteroaromatic moiety; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid. -4c- (Followed by page 4d) In yet another preferred embodiment, the invention provides a use, in the preparation of a medicament for treating a disease state associated with amyloidosis, of a therapeutic compound of the formula: R1 OR' Y1 Y2 -C(0)0R3 in which Rl and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclyl group, or a salt-forming cation; R^ is hydrogen, lower alkyl, aryl or a salt-forming cation; yl and Y2 are each independently hydrogen, halogen, lower alkyl, —NRaRb, hydroxy, alkoxy, or aryloxy, wherein RaandRb are each independently hydrogen, alkyl, aryl, or heteroaryl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a cyclic moiety having from 3 to 8 atoms in the cycle; and n is an integer from 0 to 12; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

In an additional preferred embodiment, the invention provide a use, in the preparation of a medicament for modulating amyloid deposition in a subject in which said amyloid deposition is characterized by interaction between an amyloidogenic protein and a constituent of a basement membrane, of a therapeutic compound of the formula: R1 OR' Y1 Y^ -C(0)0R in which R* and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclyl group, or a salt-forming cation; R^ is hydrogen, lower alkyl, aryl or a salt-forming cation; Y* and Y2 are each independently hydrogen, halogen, lower alkyl, —NRaRb, hydroxy, alkoxy, or aryloxy, wherein Ra and Rb are each independently hydrogen, alkyl, aryl, or heteroaryl, or Ra and Rb taken together with the nitrogen atom to which they are 1248378_1.doc intellectual property office of n.z. 21 DEC 2007 -4d- (Followed by page 4e) attached form a cyclic moiety having from 3 to 8 atoms in the cycle; and n is an integer from 0 to 12; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

In a further preferred embodiment, the invention provides a use, in the preparation of a medicament for reducing amyloid load in a human subject, of a therapeutic compound of the formula: X -C(X)XR3 R1 in which Z is R4 or XR2; R1 and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; R3 is hydrogen, lower alkyl, aryl, or a salt-forming cation; R4 is hydrogen, lower alkyl, aryl or —NRaRb; X is, independently for each occurrence, O or S; Y1 and Y2 are each independently hydrogen, halogen, alkyl, —NRaRb, hydroxy, alkoxy, or aryloxy; wherein in each occurrence Ra and Rb are each independently hydrogen, alkyl, aryl, or heteroaryl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a cyclic moiety having from 3 to 8 atoms in the cycle; and n is an integer from 0 to 12; and wherein when any of R1, R2, R3, R4, Y1, and Y2 is an aliphatic, an alkyl or an aryl group, then the aliphatic, alkyl or aryl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, -NH2, alkyl amino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, and an aromatic or heteroaromatic moiety; 1248378_1.DOC INTELLECTUAL PROPERTY OFFI6E OF N.Z. 2 I DEC 2007 qf^FIV ED -4e- (Followed by page 4f) wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid. preparation of a medicament for treating or preventing a neurodegenerative disorder in a human subject, of a therapeutic compound of the formula: Z is R4 or XR2; R1 and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; R3 is hydrogen, lower alkyl, aryl, or a salt-forming cation; R4 is hydrogen, lower alkyl, aryl or —NRaRt,; X is, independently for each occurrence, O or S; Y1 and Y2 are each independently hydrogen, halogen, alkyl, —NRaRb, hydroxy, alkoxy, or aryloxy; n is an integer from 0 to 12; wherein in each occurrence, Ra and Rb are each independently hydrogen, alkyl, aryl, or heteroaryl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a cyclic moiety having from 3 to 8 atoms in the cycle; and wherein when any of R1, R2, R3, R4, Y1, and Y2 is an aliphatic, an alkyl or an aryl group, then the aliphatic, alkyl or aryl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, -NH2, alkyl amino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, and an aromatic or heteroaromatic moiety; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

In yet another preferred embodiment the invention provides a use, in the X Y1 Z Y2 n in which INTELLECTUAL PROPERTY OFFICE OF N.Z. 1248378_1.DOC 2 1 DEC 2007 received -4f- (Followed by page 5) In a particular preferred embodiment, the invention provides a method for preparing a compound represented by the formula: O O I! II RO—C—P—O OH i M R' wherein R is alkyl or aryl; and R' is hydrogen, alkyl, or aryl; the method comprising: reacting an ester of a carbonylphosphono diacid halide with a silyl ether or an alcohol under conditions such that the compound is prepared.

In an additional preferred embodiment, the invention provides a compound and a method of synthesising a compound represented by the formula (Formula IV): O O /=\_ II H C-P-O—L G Q wherein G is hydrogen or one or more substituents on the aryl ring; and L is a substituted alkyl group.

This invention pertains to compositions useful for treating amyloidosis. Also described herein are methods useful for treating amyloiodosis. The methods described herein involve administering to a subject a therapeutic compound which modulates amyloid deposition. "Modulation of amyloid deposition" is intended to encompass prevention of amyloid formation, inhibition of further amyloid deposition in a subject with ongoing amyloidosis and reduction of amyloid deposits in a subject with ongoing amyloidosis. Modulation of amyloid deposition is determined relative to an untreated subject or relative to the treated subject prior to treatment In certain embodiments, amyloid deposition can be modulated by modulating an interaction between an amyloidogenic protein and a constituent of basement membrane. 1248378_1.doc Intellectual property office of n.z. 21 DEC 2007 received "Basement membrane" refers to an extracellular matrix comprising glycoproteins and proteoglycans, including laminin, collagen type IV, fibronectin chondroitan sulfate, and/or heparan sulfate proteoglycan (HSPG). In one embodiment, amyloid deposition is modulated by interfering with an interaction between an amyloidogenic protein and a 5 sulfated glycosaminoglycan such as HSPG. Sulfated glycosaminoglycans are known to be present in all types of amyloids (see Snow, A.D. et al. (1987) Lab. Invest. 56:120-123) and amyloid deposition and HSPG deposition occur coincidentally in animal models of amyloidosis (see Snow, A.D. et al. (1987) Lab. Invest. 56:665-675). In preferred embodiments of the methods described herein, molecules which have a similar 10 structure to a sulfated glycosaminoglycan are used to modulate interaction between an amyloidogenic protein and basement membrane constituent. In particular, the therapeutic compounds of the invention preferably comprise at least one phosphonate group (or phosphonic ester), or a functional equivalent thereof (including phosphorus-containing anionic groups including, but not limited to, phosphates, phosphate esters, 15 phosphinates, and the like), and a carboxylate group or carboxylic ester (or a congener such as a thioacid, thiolester,or thionoester), provided that the compound includes, or is capable of having after reaction in vivo, at least one anionic group. The anionic groups(s) can optionally be covalently bound to a carrier (e.g., an aliphatic group, peptide or peptidomimetic, or the like). In addition to functioning as a carrier for the 20 anionic functionality, the carrier molecule can enable the compound to traverse biological membranes and to be biodistributed without excessive or premature metabolism.

In one embodiment, the methods described herein include administering to the subject an effective amount of a therapeutic compound which has at least one 25 phosphonate group or phosphonic ester group. The therapeutic compound is preferably capable of modulating interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane to thus modulate amyloid deposition. The therapeutic compound has the formula (Formula I): X /P—(CY>Y2)nC(X)XR3 R1X I Z in which Z is XR2 or R4, R1 and R2 are each independently hydrogen, a substituted or unsubstituted aliphatic group (preferably a branched or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain; or an unsubstituted or substituted cyclic Intellectual hhurcni 7 office of n.z 2 1 DEC 2007 aliphatic moiety having from 4 to 7 carbon atoms in the aliphatic ring; preferred aliphatic and cyclic aliphatic groups are alkyl groups, more preferably lower alkyl), an aiyl group, a heterocyclic group, or a salt-forming cation; R3 is hydrogen, lower alkyl, aryl, or a salt-forming cation; X is, independently for each occurrence, O or S; R4 is 5 hydrogen, lower alkyl, aiyl or amino; Y1 and Y2 are each independently hydrogen, halogen (e.g., F, CI, Br, or I), lower alkyl, amino (including alkylamino, dialkylamino, arylamino, diaxyiamino, and alkylarylamino), hydroxy, alkoxy, or aryloxy; and n is an integer from 0 to 12 (more preferably 0 to 6, more preferably 0 or 1); such that amyloid deposition is modulated.

In preferred embodiments, therapeutic compounds of the invention prevent or inhibit amyloid deposition in a subject to which the therapeutic compound is administered. Preferred therapeutic compounds for use in the invention include compounds in which both R1 and R2 are pharmaceutically acceptable salt-forming cations. It will be appreciated that the stoichiometry of an anionic compound to a salt-15 forming counterion (if any) will vary depending on the charge of the anionic portion of the compound (if any) and the charge of the counterion. In a particularly preferred embodiment, R1, R2 and R3 are each independently a sodium, potassium or calcium cation. In certain embodiments in which at least one of R1 and R2 is an aliphatic group, the aliphatic group has between 1 and 10 carbons atoms in the straight or branched 20 chain, and is more preferably a lower alkyl group. In other embodiments in which at least one of R1 and R2 is an aliphatic group, the aliphatic group has between 10 and 24 carbons atoms in the straight or branched chain. In certain preferred embodiments, n is 0 or 1; more preferably, n is 0. In certain preferred embodiments of toe therapeutic compounds, Y1 and Y2 are each hydrogen. , In certain preferred embodiments, the therapeutic compound of the invention can be represented by the formula (Formula II): i .P—-(CY'Y2)nC(OpR3 R1X I ' XR2 in which R1, R2, R3, Y1, Y2, X and n are as defined above. In more preferred embodiments, the therapeutic compound of the invention can be represented by the 30 formula (Formula III): X (CYlY^CHfNRaRb^OORJ R ° OR2 in which Rl, R2, R3, Y], Y2, and X are as defined above, Ra and Rj, are each independently hydrogen, alkyl, aryl, or heterocyclyl, or Ra and R{,, taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the ring, and n is an integer from 0 to 6. In certain preferred embodiments, Ra 5 and Rj, are each hydrogen. In certain preferred embodiments, a compound of the invention comprises an a-amino acid (or a-amino acid ester), more preferably a L-a-amino acid or ester.

The Z, Q, Rl, R2, R3, Y1, Y2 and X groups are each independently selected such that the biodistribution of the compound for an intended target site is not prevented 10 while maintaining activity of the compound. For example, the number of anionic groups (and the overall charge on the therapeutic compound) should not be so great as to inhibit traversal of an anatomical barrier, such as a cell membrane, or entry across a physiological barrier, such as the blood-brain barrier, in situations where such properties are desired. For example, it has been reported that esters of phosphonoformate have 15 biodistribution properties different from, and in some cases superior to, the biodistribution properties of phosphonoformate (see, e.g., U.S. Patent Nos. 4,386,081 and 4,591583 to Helgstrand et al., and U.S. Patent Nos. 5,194,654 and 5,463,092 to Hostetler et al.). Thus, in certain embodiments, at least one of R1 and R2 is an aliphatic group (more preferably an alkyl group), in which the aliphatic group has between 10 and 20 24 carbons atoms in the straight or branched chain. The number, length, and degree of branching of the aliphatic chains can be selected to provide a desired characteristic, e.g., lipophilicity. In other embodiments, at least one of R1 and R2 is an aliphatic group (more preferably an alkyl group), in which the aliphatic group has between 1 and 10 carbons atoms in the straight or branched chain. Again, the number, length, and degree 25 of branching of the aliphatic chains can be selected to provide a desired characteristic, e.g., lipophilicity or ease of ester cleavage by enzymes. In certain embodiments, a preferred aliphatic group is an ethyl group.

It has also been reported that certain thiophosphate compounds have in vivo activity as anti-viral agents which is equal to or greater than the activity of the 30 corresponding oxy-phosphate compounds (possibly due to differences in bioavailability of the compounds). Accordingly, in certain preferred embodiments, the therapeutic compound includes a moiety selected from the group consisting of -P(S)(OR1)(OR2), -P(S)(SR1)(OR2), or -P(S)(SRl)(SR2).

In another embodiment, compounds useful in the methods described herein can 35 be represented by the formula (Formula IV): In another embodiment, the compounds of the invention can be represented by the formula (Formula IV): _ "tntfl lectual property office of fcl.z. 2 t DEC 2007 ocrFIVED * f C—P-—o—I I. o in which G represents hydrogen or one or more substituents on the aryl ring (e.g., alkyl, aiyl, halogen, amino, and the like) and L is a substituted alkyl group (in certain embodiments, preferably a lower alkyl), more preferably a hydroxy-substituted alkyl or an alkyl substituted with a nucleoside base. In certain embodiments, G is hydrogen or an electron-donating group. In embodiments in which G is an electron-withdrawing group, G is preferably an electron withdrawing group at the meta position. The term "electron-withdrawing group" is known in the art, and, as used herein, refers to a group which has a greater electron-withdrawing than hydrogen. A variety of electron-withdrawing groups are known, and include halogens (e.g., fluoro, chloro, bromo, and iodo groups), nitro, cyano, and the like. Similarly, the term "electron-donating group", as used herein, refers to a group which is less electron-withdrawing than hydrogen, in embodiments in which G is an electron donating group, G can be in the ortho, meta or para position.

In certain preferred embodiments, L is a moiety selected from the group consisting of (Formulas IVa-IVg): ,OH IVa NH2 —OH L-0C(0)C„H23 IVb —OH -SCXOA.H^ IVc —OH —SC(0)C7Hi5 IVd IVg Table 1 lists data pertinent to the characterization of these compounds using art-recognized techniques.

Table 1 lip NMR -6.33(DMSO-d6) llC NMR FAB- 60.97 CH20H(d, J=6Hz) 245.2 66.76 CHOH(d, J=7.8Hz) 121.65,121.78,121.99,125.71, 129.48,129.57,126.43 Aromatic CH 134.38 Aniline C-N 150.39 Phenyl C-0(d,J=7Hz) 171.57 P-C=0(d, J=234Hz) 13.94 CH3 456 22.11,24.40,28.56,28.72,28.99, 29.00,31.30,33.43, -(CH2)i(r 65.03 CH2-OC(0) 66.60 CH2-OP(d, J=5.6Hz) 67.71 CH2-OH(d, J=6 Hz) 121.73,121.10,125.64,126.57, 129.40,129.95, Aromatic CH 134.04 Aniline C-N 150.31 Phenyl C-0 171.44 P-C=0(d, J=6.7 Hz) 172.83 0-C=0 13.94 CH3 471 22.11,25.10,28.68,28.72, 28.85,29.00,30.76,31.31,32.10, -CCH2)IO" 43.36 CH2-S 68.43 CH2-OH 68.43 CH-OH(d, J=6.3 Hz) 68.76 P-0-CH2-9d, J=5.8 Hz) 121.75,122.03,125.62,126.37, 129.30,129.53, Aromatic CH 134.23 Aniline C-N 150.37 Phenyl C-0(d, J=6.7 Hz) 171.47 P-C=0(d, J=234.0 Hz) 198.47 S-C=0 COMPOUND MS0 IVa IVb -6.41(DMSO-d$) IVc -6.46(DMSO-d6) CQMPOUND iLP NMR liC NMR FAB« MS0 IVd -6.61(DMSO-d6) 13.94 CH3 22.06,25.14,28.24,28.35, 31.09,32.14 -CH2)6- 43.40 CH2-S 68.50 P-0-CH2-(d, J=5.8 Hz) 68.77 CH-OH(d, 6.4 Hz) 121.78,122.59,125.69,127.06, 129.43, 129.59 Aromatic CH 133,39 Aniline C-N 150.38 Phenyl C-0(d, J=6.7 Hz) 171.47 P-C=0(d, J=234.4 Hz) 198.54 S-CO 416 IVe -5.76(D20) N/A N/A IVf -7.00(DMSO-d6) N/A N/A IVg -6.60(DMSO-D6) 70.84 CH2-OH 72.17 CH-OH 121.68,121.79,121.85,125.71 127.10, 127.92,129.36,129.50,129.59 Aromatic CH 134.51 Aniline C-N 142.34 Aromatic C-CH 150.37 Phenyl C-0(d, J=6.2 Hz) 171.59 P-CO(d, J=232.6 Hz) 321 In another aspect, the invention includes novel compounds useful for inhibiting amyloidosis, and/or compounds having antiviral activity. The compounds of the invention can be represented by the structures of Formula IV, e.g., a compound of Formula IV in which G is hydrogen (e.g., the phenyl ring is unsubstituted) and L is any of the moieties of Formulas IVa-IVg. A more preferred compound is the compound of Formula IVc.

In another aspect, the invention provides a method for preparing esters of phosphonates, e.g., phosphono-carboxylate compounds of the invention, e.g., a compound of Formula IV in which G is hydrogen and L is a moiety of Formula IVa -IVg. Illustratively, the method includes the step of reacting a phosphonodichloridate (or other phosphonate diacid halide) with a disilylated diol under conditions such that a compound of Forumla IV is formed (see Example 2,infra).

Thus, in one embodiment, the invention provides a method for preparing a compound represented by the Formula (Formula V): in which R is alkyl or aryl, and R' is hydrogen, alkyl, or aryl (including heteroaromatic groups such as nucleosides). The method includes the step of reacting an ester of a carbonylphosphono diacid halide (e.g., ROOC-P(OXAXA'), in which R is as described in Formula V, and A and A' are both halogen or other good leaving groups, e.g., chloro, 10 iodo, bromo, pentafluorophenyl, and the like, which can be the same or different) with a disilylether of a vicinal diol, under conditions such that the compound of Formula V is prepared.

An anionic group (i.e., a phosphonate or carboxylate group) of a therapeutic compound of the invention is a negatively charged moiety that, in certain preferred 15 embodiments, can modulate interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane to thus modulate amyloid deposition.

It will be noted that the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers 20 (e.g., enantiomers and diastereomers) arising from such asymmetry are included within the scope of this invention. Such isomers can be obtained in substantially pure form by classical separation techniques and by sterically controlled synthesis. For the purposes of this application, unless expressly noted to the contrary, a compound shall be construed to include both the R or S stereoisomers at each chiral center. 25 The ability of a therapeutic compound of the invention to modulate interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane can be assessed by an in vitro binding assay, such as that described in the Exemplification or in U.S. Patent No. 5,164,295 by Kisilevsky et al. Briefly, a solid support such as a polystyrene microtiter plate is coated with an amyloidogenic 30 protein (e.g., serum amyloid A protein or p-amyloid precursor protein (p-APP)) and any residual hydrophobic surfaces are blocked. The coated solid support is incubated with various concentrations of a constituent of basement membrane, preferably HSPG, either in the presence or absence of a compound to be tested. The solid support is washed extensively to remove unbound material. The binding of the basement membrane constituent (e.g., HSPG) to the amyloidogenic protein (e.g., p-APP) is then measured using an antibody directed against the basement membrane constituent which is conjugated to a detectable substance (e.g., an enzyme, such as alkaline phosphatase) by detecting the detectable substance. A compound which modulates an interaction 5 between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane will reduce the amount of substance detected (e.g., will inhibit the amount of enzyme activity detected).

Preferably, a therapeutic compound of the invention interacts with a binding site for a basement membrane glycoprotein or proteoglycan in an amyloidogenic protein and 10 thereby modulates the binding of the amyloidogenic protein to the basement membrane constituent. Basement membrane glycoproteins and proteoglycans include laminin, collagen type IV, fibronectin and heparan sulfate proteoglycan (HSPG). In a preferred embodiment, the therapeutic compound inhibits an interaction between an amyloidogenic protein and H$PG.

IS In certain embodiments, a therapeutic compound of the invention comprises a cation (i.e., in certain embodiments, at least one of R1, R2 or R3 is a cation). If the cationic group is hydrogen, H+, then the compound is considered an acid, e.g., phosphonoformic acid. If hydrogen is replaced by a metal ion or its equivalent, the compound is a salt of the acid. Pharmaceutically acceptable salts of the therapeutic 20 compound are within the scope of the invention. For example, at least one of R1, R2 or R3 can be a pharmaceutically acceptable alkali metal (e.g., Li, Na, or K), ammonium cation, alkaline earth cation (e.g., Ca2+, Ba2+, Mg2+), higher valency cation, or polycationic counter ion (e.g., a polyammonium cation). (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J\ Pharm. Sci. 66:1 -19). It will be appreciated that the 25 stoichiometry of an anionic compound to a salt-forming counterion (if any) will vary depending on the charge of the anionic portion of the compound (if any) and the charge of the counterion. Preferred pharmaceutically acceptable salts include a sodium, potassium or calcium salt, but other salts are also contemplated within their pharmaceutically acceptable range.

Hie term "pharmaceutically acceptable esters" refers to the relatively non-toxic, esterified products of the compounds of the present invention. These esters can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free acid form or hydroxy! with a suitable esterifying agent; either of which are methods known to those skilled in the art. 35 Carboxylic acids and phosphonic acids can be converted into esters according to methods well known to one of ordinary skill in the art, e.g., via treatment with an alcohol in the presence of a catalyst. A preferred ester group (e.g., when R3 is lower alkyl) is an ethyl ester group.

The term "alkyl" refers to the saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cyctoalkyl (alicyclic) groups, alkyl 5 substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer. Likewise, preferred cycloalkyls have from 4-10 carbon atoms in their ring structure, and more preferably have 4-7 carbon atoms in the ring structure. 10 The term "lower alkyl" refers to alkyl groups having from 1 to 6 carbons in the chain, and to cycloalkyls having from 3 to 6 carbons in the ring structure.

Moreover, the term "alkyl" (including "lower alkyl") as used throughout the specification and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents 15 replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, 20 diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on 25 the hydrocarbon chain can themselves be substituted, if appropriate. Cycloalkyls can be further substituted, e.g., with the substituents described above. An "aralkyl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).

The term "alkoxy", as used herein, refers to a moiety having the structure -O-alkyl, in which the alkyl moiety is described above.

The term "aryl" as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, unsubstituted or substituted benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the 35 like. The aromatic ring can be substituted at one or more ring positions with such substituents, e.g., as described above for alkyl groups. Preferred aryl groups include unsubstituted and substituted phenyl groups.

The term "aryloxy", as used herein, refers to a group having the structure -O-aryl, in which the aryl moiety is as defined above.

The term "amino," as used herein, refers to an unsubstituted or substituted moiety of the formula -NRaRfc, in which Ra and Rb are each independently hydrogen, 5 alkyl, aryl, or heterocyclyl, or Ra and R|>, taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to & atoms in the ring.

Thus, the term "amino" is intended to include cyclic amino moieties such as piperidinyl or pyrrolidinyl groups, unless otherwise stated. An "amino-substituted amino group" refers to an amino group in which at least one of Ra and R^, is further substituted with 10 an amino group.

In a preferred embodiment of the compounds of Formulas Mil, R1 or R2 can be (for at least one occurrence) a long-chain aliphatic moiety. The term "long-chain aliphatic moiety" as used herein, refers to a moiety having a straight or branched chain aliphatic moiety (e.g., an alkyl or alkenyl moiety) having from 10 to 24 carbons in the 15 aliphatic chain, e.g., the long-chain aliphatic moiety is an aliphatic chain of a fatty acid (preferably a naturally-occurring fatty acid). Representative long-chain aliphatic moieties include the aliphatic chains of stearic acid, oleic acid, linolenic acid, and the like.

The therapeutic compound of the invention can be administered in a 20 pharmaceutically acceptable vehicle. As used herein "pharmaceutically acceptable vehicle" includes any and all solvents, excipients, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like which are compatible with the activity of the compound and are physiologically acceptable to the subject. An example of a pharmaceutically acceptable vehicle is ' 25 buffered normal saline (0.15 molar NaCl). The use of such media and agents for pharmaceutically active substances is well known in the art Except insofar as any conventional media or agent is incompatible with the therapeutic compound, use thereof in the compositions suitable for pharmaceutical administration is contemplated. Supplementary active compounds can also be incorporated into the compositions. 30 In certain embodiments, the therapeutic compound of the invention can be represented by the formula: Cf /P—(CYlY2)nCOOR3 R,°" in which Rland R2 are each independently hydrogen, an aliphatic group (preferably a branched or straight-chain aliphatic moiety having from 1 to 24 carbon atoms, more preferably 10-24 carbon atoms, in the chain; or an unsubstituted or substituted cyclic aliphatic moiety having from 4 to 7 carbon atoms in the aliphatic ring), an aiyl group, a 5 heterocyclic group, or a salt-forming cation; R3 is hydrogen, lower alkyl, aiyl, or a salt-forming cation; Y1 and Y2 are each independently hydrogen, halogen (e.g., F, CI, Br, or I), lower alkyl, hydroxy, alkoxy, or aryloxy; and n is an integer from 0 to 12; such that amyloid deposition is modulated. In one preferred embodiment, therapeutic compounds of the invention prevent or inhibit amyloid deposition in a subject to which the 10 therapeutic compound is administered. Preferred therapeutic compounds for use in the invention include compounds in which both R1 and R2 are pharmaceutically acceptable salt-forming cations. In a particularly preferred embodiment, R',R2 and R3 are each independently a sodium, potassium or calcium cation, and n is 0. In certain preferred embodiments of the therapeutic compounds, Y1 and Y2 are each hydrogen. Particularly 15 preferred therapeutic compounds are salts of phosphonoformate. Imodium phosphonoformate (foscarnet sodium or Foscavir®) is commercially available (e.g., from Astra), and its clinical pharmacology has been investigated (see, e.g., "Physician's Desk Reference", 51st Ed., pp. 541-545 (1997)). treating amyloidosis. The therapeutic compounds in the methods as described hereinbefore, can be incorporated into a pharmaceutical composition in an amount effective to modulate amyloidosis in a pharmaceutically acceptable vehicle.

Also described herein is the use of prodrugs which are converted in vivo to the therapeutic compounds of the invention (see, e.g., R.B. Silverman, 1992,, 25 "The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chp. 8). Such prodrugs can be used to alter the biodistribution (e.g., to allow compounds which would not typically cross the blood-brain barrier to cross the blood-brain barrier) or the pharmacokinetics of the therapeutic compound. For example, an anionic group, e.g., a phosphonate or carboxylate, can be esterified, e.g., with an ethyl group or a fatty group, 30 to yield a phosphonic or carboxylic ester. When the phosphonic or carboxylic ester is administered to a subject, the ester can be cleaved, enzymatically or non-enzymatically, to reveal the anionic group. Such an ester can be cyclic, e.g., a cyclic phosphonate, or two or more anionic moieties may be esterified through a linking group. In a preferred embodiment, the prodrug is a phosphonate or carboxylate. An anionic group can be 35 esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently decomposes to yield the active compound. Furthermore, an anionic moiety (e.g., a phosphonate or carboxylate) can be esterified to A further aspect of the invention includes pharmaceutical compositions for intellectual props office of n.z. 2 1 DEC 2007 a group which is actively transported in vivo, or which is selectively taken up by target organs. The ester can be selected to allow specific targeting of the therapeutic moieties to particular organs, as described below for carrier moieties. In certain embodiments, as described above, compounds of the invention can have more than one phosphonic or 5 carboxylic ester moiety, e.g., one phosphonic ester and one carboxylic ester, or a phosphonic diester. In such embodiments, the parent compound may include an anioic group and may be active; however, cleavage of any or all ester functionalities may result in an active compound. It will be appreciated that in a compound having multiple esterified moieties, the ester groups can be selected to permit selective cleavage of one 10 or more ester functionalities, to unveil one or more anionic groups. The relative ease of cleavage of ester groups is well known; for example, a tert-butyloxy ester is generally cleaved more slowly than an ethyl ester under certain conditions. Selection of appropriate moieties to provide a desired rate or order of ester cleavage willl be routine to the ordinarily-skilled artisan. Thus, the number of anionic functionalities can be 15 controlled to provide for a seelctive activity of a compound of the Invention according to the rate or order of ester cleavage.

Carrier or substituent moieties useful in the present invention may also include moieties which allow the therapeutic compound to be selectively delivered to a target organ or organs. For example, if delivery of a therapeutic compound to the brain is 20 desired, the carrier molecule may include a moiety capable of targeting the therapeutic compound to the brain, by either active or passive transport (a "targeting moiety"). Illustratively, the carrier molecule may include a redox moiety, as described in, for example, U.S. Patents 4,540,564 and 5,389,623, both to Bodor. These patents disclose drugs linked to dihydropyridine moieties which can enter the brain, where they are* 25 oxidized to a charged pyridinium species which is trapped in the brain. Thus, drug accumulates in the brain. Other carrier moieties include compounds, such as amino acids or thyroxine, which can be passively or actively transported in vivo. Such a carrier moiety can be metabolically removed in vivo, or can remain intact as part of an active compound. Structural mimics of amino acids (and other actively transported moieties), 30 including peptidomimetics, are also useful in the invention. As used herein, the term "peptidomimetic" is intended to include peptide analogs which serve as appropriate substitutes for peptides in interactions with e.g., receptors and enzymes. The peptidomimetic must possess not only affinity, but also efficacy and substrate function. That is, a peptidomimetic exhibits functions) of a peptide, without restriction of 35 structure. Peptidomimetics, methods for their preparation and use are described in Morgan et al., "Approaches to the discovery of non-peptide ligands for peptide receptors and peptidases," In Annual Reports in Medicinal Chemistry (Virick, F.J., ed.) pp. 243- 253, Academic Press, San Diego, CA (1989), the contents of which are incorporated herein by reference. Many targeting moieties are known, and include, for example, asialoglycoproteins (see, e.g. Wu, U.S. Patent 5,166,320) and other ligands which are transported into cells via receptor-mediated endocytosis (see below for further examples 5 of targeting moieties which may be covalently or non-covalently bound to a carrier molecule). Furthermore, the therapeutic compounds of the invention may bind to amyloidogenic proteins in the circulation and thus be transported to the site of action.

The targeting and prodrug strategies described above can be combined to produce a compound that can be transported as a prodrug to a desired site of action and 10 then unmasked to reveal an active compound.

In the methods described herein amyloid deposition (e.g., deposition of (3-amyloid) in a subject is modulated by administering a therapeutic compound of the ^ invention to the subject The term "subject" is intended to include living organisms^ which amyloidosis can occur. Examples of subjects include humans, monkeys, cows, 15 sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. Administration of the compositions of the present invention to a subject to be treated can be carried out using known procedures, at dosages and for periods of time effective to modulate amyloid deposition in the subject. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the amount of amyloid 20 already deposited at the clinical site in the subject the age, sex, and weight of the subject and the ability of the therapeutic compound to modulate amyloid deposition in the subject Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic , 25 situation. A non-limiting example of an effective dose range for a therapeutic compound of the invention (e.g., phosphonoformic acid, trisodium salt) is between 0.5 and 500 mg/kg of body weight/per day. In an aqueous composition, preferred concentrations for the active compound (i.e., the therapeutic compound that can modulate amyloid deposition) are between 5 and 500 mM, more preferably between 10 30 and 100 mM, and still more preferably between 20 and 50 mM.

The therapeutic compounds of the invention can be effective when administered orally. Accordingly, a preferred route of administration is oral administration. Alternatively, the active compound may be administered by other suitable routes such as subcutaneous, intravenous, intramuscular or intraperitoneal administration, and the like 35 (e.g. by injection). Depending on the route of administration, the active compound may be coated in a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound. intellectual propeh t t 1 office of n.z. i 2 1 DEC 2007 I o i= n fiv e di The compounds of the invention can be formulated to ensure proper distribution in vivo. For example, the blood-brain barrier (BBB) excludes many highly hydrophilic compounds. To ensure that the therapeutic compounds of the invention cross the BBB, they can be formulated, for example, in liposomes. For methods of manufacturing 5 liposomes, see, e.g., U.S. Patents 4,522,811; 5,374,548; and 5,399,331. The liposomes may comprise one or more moieties which are selectively transported into specific cells or organs ("targeting moieties"), thus providing targeted drug delivery (see, e.g., V.V. Ranade (1989) J. Clin. Pharmacol. 22-685). Exemplary targeting moieties include folate or biotin (see, e.g., U.S. Patent 5,416,016 to Low et al.); mannosides (Umezawa el 10 al., (1988) Biochem. Biophys. Res. Commun. 153:1038): antibodies (P.G. Bloeman et al (1995) FEBS Lett. 357:140: M. Owais et al. (1995) Antimicrob. Agents Chemother. 12:180); surfactant protein A receptor (Briscoe et al. (1995) Am. J. Physiol. 1233:134); gpl20 (Schreier et al. (1994) J. Biol. Chem. 262:9090); see also K. Keinanen; MX. Laukkanen (1994) FEBSLett. 346:123: J.J. Killion; IJ. Fidler (1994) Immunomethods 15 4:273. In a preferred embodiment, the therapeutic compounds of the invention are formulated in liposomes; in a more preferred embodiment, the liposomes include a targeting moiety.

Delivery and in vivo distribution can also be affected by alteration of an anionic group of compounds of the invention. For example, anionic groups such as phosphonate 20 or carboxylate can be esterified to provide compounds with desirable pharmacokinetic, pharmacodynamic, biodistributive, or other properties. Exemplary compounds include phosphonoformate trisodium salt (Foscamet, Foscavir), phosphonoacetate, trisodium salt, and pharmaceutically acceptable salts or esters thereof.

To administer the therapeutic compound by other than parenteral administration, 25 it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. For example, the therapeutic compound may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions as well as conventional 30 liposomes (Strejan et al., (1984) J. Neuroimmunol. 2:27).

The therapeutic compound may also be administered parenterally (e.g., intramuscularly, intravenously, intraperitoneally, intraspinally, or intracerebrally). Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations 35 may contain a preservative to prevent the growth of microorganisms.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In al l cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The 5 vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. 10 Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In some cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be brought 15 about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

Sterile injectable solutions can be prepared by incorporating the therapeutic compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Generally, 20 dispersions are prepared by incorporating the therapeutic compound 'Into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic compound) plus any 25 additional desired ingredient from a previously sterile-filtered solution thereof. * The therapeutic compound can be orally administered, for example, with an inert diluent or an assimilable edible carrier. The therapeutic compound and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet. For oral therapeutic administration, the 30 therapeutic compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The percentage of the therapeutic compound in the compositions and preparations may, of course, be varied. The amount of the therapeutic compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. 35 It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic 5 compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of amyloid deposition in subjects.

Therapeutic compositions can be administered in time-release or depot form, to obtain sustained release of the therapeutic compounds over time. The therapeutic 10 compounds of the invention can also be administered transdermally (e.g., by providing the therapeutic compound, with a suitable carrier, in patch form).

Active compounds are administered at a therapeutically effective dosage sufficient to modulate amyloid deposition (or amyloid load) in a subject A "therapeutically effective dosage" preferably modulates amyloid deposition by at least 15 about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects. The ability of a compound to modulate amyloid deposition can be evaluated in model systems that may be predictive of efficacy in modulating amyloid deposition in human diseases, such as animal model systems known in the art (including, e.g., the method 20 described in PCT Publication WO 96/28187) or by in vitro methods, e.g., the method of Chakrabartty, described in PCT Publication WO 97/07402, or the assay described in Example 1, infra. Alternatively, the ability of a compound to modulate amyloid deposition can be evaluated by examining the ability of the compound to moduUte an Interaction between an amyloidogenic protein and a basement membrane constituent, 25 e.g., using a binding assay such as that described hereinabove. Furthermore, the amount or distribution of amyloid deposits in a subject can be non-invasively monitored in vivo, for example, by use of radiolabelled tracers which can associate with amyloid deposits, followed by scintigraphy to image the amyloid deposits (see, e.g., Aprile, C. et al., Eur. J. Nucl. Med 22:1393 (1995); Hawkins, P.N., BaiUieres Clin. Rheumatol. 8:635 (1994); 30 and references cited therein). Thus, for example, the amyloid load of a subject can be evaluated after a period of treatment according to the methods of the invention and compared to the amyloid load of the subject prior to beginning therapy with a therapeutic compound of the invention, to determine the effect of the therapeutic compound on amyloid deposition in the subject.

It vail be appreciated that the ability of a compound of the invention to modulate amyloid deposition or amyloid load can, in certain embodiments, be evaluated by observation of one or more symptoms or signs associated with amyloid deposition or amyloid load in vivo. Thus, for example, the ability of a compound to decrease amyloid deposition or amyloid load may be associated with an observable improvement in a clinical manifestation of the underlying amyloid-related disease state or condition, or a slowing or delay in progression of symptoms of the condition. Thus, monitoring of 5 clinical manifestations of disease can be useful in evaluating the amyloid-modulating efficacy of a compound of the invention.

The methods described herein are useful for treating amyloidosis associated with any disease in which amyloid deposition occurs. Clinically, amyloidosis can be primary, secondaiy, familial or isolated. Amyloids have been categorized by the type of 10 amyloidogenic protein contained within the amyloid. Non-limiting examples of amyloids which can be modulated, as identified by their amyloidogenic protein, are as follows (with the associated disease in parentheses after the amyloidogenic protein): p-amyloid (Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage amyloidosis [Dutch], cerebral angiopathy); amyloid A (reactive (secondaiy] 15 amyloidosis, familial Mediterranean Fever, familial amyloid nephropathy with urticaria and deafness [Muckle-Wells syndrome]); amyloid tc L-chain or amyloid X L-chain (idiopathic [primary], myeloma or macroglobulinemia-associated); A02M (chronic hemodialysis); ATTR (familial amyloid polyneuropathy [Portuguese, Japanese, Swedish], familial amyloid cardiomyopathy [Danish], isolated cardiac amyloid, 20 systemic senile amyloidosis); AIAPP or amylin (adult onset diabetes, insulinoma); atrial naturetic factor (isolated atrial amyloid); procalcitonin (medullary carcinoma of the thyroid); gelsolin (familial amyloidosis [Finnish]); cystatin C (hereditary cerebral hemorrhage with amyloidosis [Icelandic]); AApoA-I (familial amyloidotic polyneuropathy [Iowa]); AApoA-II (accelerated senescence in mice); fibrinogen-25 associated amyloid; lysozyme-associated amyloid; and AScr or PrP-27 (Scrapie, Creutzfeldt-Jacob disease, Gerstmann-Straussler-Scheinker syndrome, bovine spongiform encephalitis).

Compounds for the use in the methods described herein are commercially available and/or can be synthesized by standard techniques known in the art. In general, 30 phosphonic esters can be prepared from the corresponding phosphonic acid by standard methods. Similarly, carboxylic esters can be prepared from the free carboxylic acid by standard techniques (for a reference to esterification techniques, see, e.g., R. Larock, "Comprehensive Organic Transformations," VCH Publishers (1989)). Carboxylic esters can be converted to thionoesters by known reactions, e.g., by treatment with Lawesson's 35 reagent (2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide, which is commercially available, e.g., from Aldrich Chemical Co., Milwaukee, WI). Compounds of the present invention also can be prepared as described below. intellectual property office of n.z. 2 I DEC 2007 ncrciwen -21a- (Followed by page 22) The term "comprising" as used in this specification means "consisting at least in part of'. When interpreting each statement in this specification that includes the term "comprising", features other than that or those prefaced by the term may also be present. Related terms such as "comprise" and "comprises" are to be interpreted in the same manner. The following Examples further illustrate the present Invention and are not intended to be further limiting in anyway. fixawl? I It is known that amyloidogenic peptides or proteins which have formed amyloid deposits or plaques have a significant amount of P-sheet secondary structure, while the unaggregated peptide or protein generally has less P-sheet structure. It is believed that the ability of a candidate therapeutic compound to prevent the formation of P-sheet secondary structure in vitro may be correlated with the ability of the compound to 10 Inhibit amyloidogenesis in vivo. Accordingly, phosphonate compounds were assayed for ability to prevent the formation of P-sheet secondary structure in assay systems including an in vitro circular dichroism (CD) assay.

Afl is a 40 amino acid protein associated with Alzheimer's disease. AB peptide was prepared and purified as described in Fraser, P.E. et al., Biochemistry 31,10716 15 (1992). Briefly, the peptide was synthesized by standard solid-phase techniques and purified by HPLC according to well known procedures.

All CD experiments were performed on a commercially available instrument. The cell was maintained at 2S°C using a circulating water bath. Computer-averaging of traces was performed to improve signal-to-noise ratios. The solvent signal was 20 subtracted. CD experiments were performed for each test compound according to the following procedure: A stock solution of purified peptide was made by dissolving the peptide in phosphate-buffered saline (PBS) to a concentration of 2 mg/ml. A test solution was made for each potential therapeutic agent (test compound) as shown below: « AB stock solution 25 pi Test compound (20 mg/ml) 2.5 jil Distilled water 2.5 \l\ mM Tris-HCl buffer, pH 7 370 ^1 The control sample had no test compound, and a total of 5 ill distilled water was added. The test solution was incubated for either 0 or 24 hours at 37°C before CD measurement The size minimum in the CD spectrum at 218 nm is believed to be diagnostic of the presence of P-pleated sheet. Comparison of the minimum at 218 nm of a candidate compound, compared to the minimum of a control sample, is believed to be 35 indicative of the ability of the candidate compound to inhibit the formation of P-pleated sheet.

Using this assay, several candidate compounds were tested. Phosphonoformate sodium salt (foscamet sodium) was found to significantly and reproducibly reduce the amount of P-sheet formation, as measured by the CD assay. Phosphonoacetate was also found to be active in this assay. Thus, phosphonoformate and phosphonoactetate are 5 believed to be inhibitors of amyloid deposition. 2-carboxyethylphosphonic acid had a lower ability to prevent P-pleated sheet formation in this model system.

In a preliminary result in a different assay system (in which the candidate compound and amyloid peptide were incubated together overnight, followed by centrifugation and determination of the amount of soluble peptide), phosphonoformate 10 trisodium salt was found to have little effect on amyloid peptide solubility; it is believed that the buffer composition may have interfered with the ability of the compound to inhibit amyloid deposition.

The neurotoxicity of phosphonoformate. trisodium salt was investigated in cortical/hippocampal neuronal cultures; no significant toxicity was noted at IS concentrations ranging from 10~7M to 10*4 M.

Example 2 The procedure described below is further described in Gorin et al., Tet. Lett. 1997,38:2791-2794, incorporated herein by reference. The procedure has the advantage 20 that the reactivity of the nucieophile (e.g., the hydroxyl groups of a diol which react with the phosphonic acid chloride) is attenuated by use of a silyl ether (e.g., a trimethylsilyl ether), which can improve selectivity.

To a solution of (phenoxycarbonyl)phosphoonodichloridate (5 mmol) in 10 ml dry THF cooled in an ice water bath under argon was added a vicinal bis-trimethylsifyl 25 ether (5 mmol) (prepared from the vic-diol, e.g., by treatment with trimethylsilylchloride (TMSC1) or trimethylsilyltriflate (TMSOTf), available from Aldrich Chemical Co., Milwaukee, WI) in 10 mL dry THF. After addition was complete, the reaction mixture was stirred for one hour at room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in dioxane containing 90 mg water (5 30 mmol), neutralized by adding 5 mmol aniline in 10 mL diozane, and the product precipitated by pouring into 200 mL 1:1 diethyl ether.hexanes. The solid product was filtered and washed with 1:1 diethyl ether:hexanes.

Compounds IVa - IVg were prepared by the above procedure using the corresponding diols, which are commercially available and/or can be readily prepared by 35 one of ordinary skill in the art using no more than routine experimentation.

Examvle 3 The compounds of Formula IVa, IVc and IVd (in salt forms, e.g., methyipyridinium salts and/or anilinium salts) were tested in at least one assay for their ability to inhibit amyloidosis. It was found that these compounds showed activity in at 5 least one assay system indicative of their ability to be an inhibitor of amyloidosis in vivo in both free or salt forms.

Equivalents The contents of all references, issued patents, and published patent applications 10 cited throughout this application are hereby incorporated by reference.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims.

In the description in this specification reference is made to subject matter which is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application. intellectual property office Of n.z. 2 1 DEC 2007 RECEIVED

Claims

WHAT WE CLAIM IS:

1. A pharmaceutical composition for modulating amyloid deposition in a subject, comprising a pharmaceutically acceptable vehicle and an effective amount of a therapeutic compound, wherein the therapeutic compound has the formula: X R1 Y1 Y2 -C(X)XR3 in which Z is R4 or XR2; R1 and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; R3 is hydrogen, lower alkyl, aryl, or a salt-forming cation; R4 is hydrogen, lower alkyl, aryl or -NRaRb; X is, independently for each occurrence, O or S; Y1 and Y2 are each independently hydrogen, halogen, alkyl, -NRaRb, hydroxy, alkoxy, or aryloxy; n is an integer from 0 to 12; wherein in each occurrence, Raand Rb are each independently hydrogen, alkyl, aryl, or heteroaryl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a cyclic moiety having from 3 to 8 atoms in the cycle; and wherein when any of R1, R2, R3, R4, Y1, and Y2 is an aliphatic, an alkyl or an aryl group, then the aliphatic, alkyl or aryl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, -NH2, alkyl amino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, and an aromatic or heteroaromatic moiety; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid. INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 1 DEC 2007 received -26-

2. The pharmaceutical composition of claim 1, wherein Z is XR2, and wherein X and R2 are as defined in claim 1.

3. The pharmaceutical composition of claim 1 or 2, wherein R1 and R2 are each a pharmaceutically acceptable salt-forming cation.

4. The pharmaceutical composition of claim 3, in which R1, R2 and R3 are each independently a sodium, potassium or calcium cation.

5. The pharmaceutical composition of claim 4, wherein n is 0.

6. The pharmaceutical composition of claim 1, wherein at least one of R1 and R2 is a long-chain aliphatic moiety.

7. The pharmaceutical composition of claim 6, wherein R3 is a lower alkyl group.

8. The pharmaceutical composition of claim 1, wherein Y1 and Y2 are each hydrogen.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the pharmaceutical composition is for oral administration.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the pharmaceutically acceptable vehicle comprises an aqueous solution.

11. The pharmaceutical composition of any one of claims 1 to 10, wherein the therapeutic compound inhibits amyloid deposition in a subject.

12. The pharmaceutical composition of claim 1, wherein X is, for each occurrence, O.

13. The pharmaceutical composition of claim 1, wherein the therapeutic compound is represented by the formula: X Y1 -C(0)0R3 R ^yr 1 21 2 XR2 Y2 wherein X, Y1, Y2, R1, R2, R3 and n are as defined in claim 1. INTELLECTUAL PROPERtY OFFICE OF N.Z. 2 1 DEC 2007 received. -27 -

14. A pharmaceutical composition for modulating amyloid deposition in a subject, comprising a pharmaceutically acceptable vehicle and an effective amount of a therapeutic compound, wherein the therapeutic compound has the formula: X Y1 3 -c— -CH(NRaRb)C(Q)OR3 OR2 Y2 R1 in which Rl and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; R3 is hydrogen, lower alkyl, aryl, or a salt-forming cation; X is, independently for each occurrence, O or S; Y1 and Y2 are each independently hydrogen, halogen, alkyl, NRaRb, hydroxy, alkoxy, or aryloxy; n is an integer from 0 to 12; and wherein in each occurrence Ra and R{, are each independently hydrogen, alkyl, aryl, or heterocyclyl, or Ra and R^, taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the cycle; wherein when any of R1, R2, R3, Y1, and Y2 is an aliphatic, an alkyl or an aryl group, then the aliphatic, alkyl or aryl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, -NH2, alkyl amino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, and an aromatic or heteroaromatic moiety; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

15. The pharmaceutical composition of claim 14, in which Ra and R^ are each hydrogen. INTELLECTUAL PROPERTY OFFICE OF N.Z 2 I DEC 2007 -28-

16. A pharmaceutical composition for treating a disease state associated with amyloidosis, comprising a pharmaceutically acceptable vehicle and an effective amount of a therapeutic compound, wherein the therapeutic compound has the formula: R1 0 Y p -c OR2 Y -C(0)0R3 in which R1 and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclyl group, or a salt-forming cation; R3 is hydrogen, lower alkyl, aryl or a salt-forming cation; Y1 and Y2 are each independently hydrogen, halogen, lower alkyl, —NRaRb, hydroxy, alkoxy, or aryloxy, wherein RaandRb are each independently hydrogen, alkyl, aryl, or heteroaryl, or Ra and Rb taken together with the nitrogen atom to which they are attached for a cyclic moiety having from 3 to 8 atoms in the cycle; and n is an integer from 0 to 12; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

17. The pharmaceutical composition of claim 16, wherein said amyloidosis is Alzheimer's disease.

18. The pharmaceutical composition of claim 16, wherein R1 and R2 are each a pharmaceutically acceptable salt-forming cation.

19. The pharmaceutical composition of claim 18, in which R1, R2 and R3 are each independently a sodium, potassium or calcium cation.

20. The pharmaceutical composition of claim 19, wherein n is 0.

21. The pharmaceutical composition of claim 16, wherein at least one of R1 and R2 is a long-chain aliphatic moiety.

22. The pharmaceutical composition of claim 21, wherein R3 is a lower alkyl group. intellectual property office of n.z. 2 t DEC 200? -29-

23. The pharmaceutical composition of claim 16, wherein Y1 and Y2 are each hydrogen.

24. The pharmaceutical composition of claim 16, wherein -NRaRb is -NH2.

25. The pharmaceutical composition of any one of claims 16 to 24, wherein the pharmaceutical composition is for oral administration.

26. The pharmaceutical composition of any one of claims 16 to 25, wherein the pharmaceutically acceptable vehicle comprises an aqueous solution.

27. A pharmaceutical composition for modulating amyloid deposition in a subject in which said amyloid deposition is characterized by interaction between an amyloidogenic protein and a constituent of a basement membrane, comprising a pharmaceutically acceptable vehicle and an effective amount of a therapeutic compound, wherein the therapeutic compound has the formula: O R1< OR' Y1 I -C- -2 -C(0)0R in which R1 and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclyl group, or a salt-forming cation; R3 is hydrogen, lower alkyl, aryl or a salt-forming cation; Y1 and Y2 are each independently hydrogen, halogen, lower alkyl, —NRaRb, hydroxy, alkoxy, or aryloxy, wherein Raand Rb are each independently hydrogen, alkyl, aryl, or heteroaryl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a cyclic moiety having from 3 to 8 atoms in the cycle; and n is an integer from 0 to 12; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

28. The pharmaceutical composition of claim 27, wherein R1 and R2 are each a pharmaceutically acceptable salt-forming cation. INTELLECTUAL PROPERTY OFFICE OF N.Z. 21 DEC 2007 received -30-

29. The pharmaceutical composition of claim 28, in which R1, R2 and R3 are each independently a sodium, potassium or calcium cation.

30. The pharmaceutical composition of claim 29, wherein n is 0.

31. The pharmaceutical composition of claim 27, wherein at least one of R1 and R2 is a long-chain aliphatic moiety.

32. The pharmaceutical composition of any one of claims 1 to 31, wherein said amyloidosis or disease in which amyloid deposition occurs is associated with a protein selected from the group consisting of P-amyloid, A£2M, AIAPP, amylin, amyloid A, amyloid k L-chain, amyloid I L-chain, ATTR, atrial natriuretic factor, procalcitonin, gelsolin, cystatin C, AApoA-I, AApoA-II, fibrinogen, lysozyme, AScr, and PrP-27.

33. The pharmaceutical composition of any one of claims 1 to 31, wherein the amyloidosis or disease in which amyloid deposition occurs is selected from the group consisting of Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage amyloidosis, cerebral angiopathy, chronic hemodialysis, adult onset diabetes, insulinoma, reactive [secondary] amyloidosis, familial Mediterranean Fever, familial amyloid nephrophathy with urticaria and deafness [Muckle-Wells syndrome], idiopathic [primary], myeloma-associated, macroglobulinemia-associated, familial amyloid polyneuropathy, familial amyloid cardiomyopathy, isolated cardiac amyloidosis, systemic senile amyloidosis, isolated atrial amyloidosis, medullary carcinoma of the thyroid, familial amyloidosis, hereditary cerebral hemorrhage with amyloidosis, familial amyloidotic polyneuropathy, accelerated senescence in mice, fibrinogen-associated amyloidosis, lysozyme-associated amyloidosis, Scrapie, Creutzfeldt-Jacob disease, Gerstmann-Straussler-Scheinker syndrome, and bovine spongiform encephalitis.

34. The pharmaceutical composition according to any one claims 1 to 33, wherein the composition prevents amyloid deposition.

35. The pharmaceutical composition according to any one claims 1 to 33, wherein the composition inhibits amyloid deposition.

36. The pharmaceutical composition according to any one claims 1 to 33, wherein the composition prevents and inhibits amyloid deposition. INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 I DEC 2007 received -31 -

37. Use, in the preparation of a medicament for modulating amyloid deposition in a subject, of a therapeutic compound of the formula: X R1 -c- -2 -C(X)XR in which Z is R4 or XR2; R* and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; R^ is hydrogen, lower alkyl, aryl, or a salt-forming cation; R4 is hydrogen, lower alkyl, aryl or—NRaRb; X is, independently for each occurrence, O or S; Y* and Y2 are each independently hydrogen, halogen, alkyl, —NRaRb, hydroxy, alkoxy, or aryloxy; n is an integer from 0 to 12; wherein in each occurrence RaandRb are each independently hydrogen, alkyl, aryl, or heteroaryl, or Raand Rb taken together with the nitrogen atom to which they are attached for a cyclic moiety having from 3 to 8 atoms in the cycle; and wherein when any of R1, R2, R3, R4, Y1, and Y2 is an aliphatic, an alkyl or an aryl group, then the aliphatic, alkyl or aryl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, -NH2, alkyl amino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, and an aromatic or heteroaromatic moiety; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

38. The use of claim 37, wherein Z is XR2. INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 I DEC 2007 received -32-

39. The use of claim 38, wherein and R2 are each a pharmaceutically acceptable salt-forming cation.

40. The use of claim 39, in which R^, R2 and R^ are each independently a sodium, potassium or calcium cation.

41. The use of claim 40, wherein n is 0.

42. The use of claim 37, wherein at least one of R^ and R2 is a long-chain aliphatic moiety.

43. The use of claim 42, wherein R^ is a lower alkyl group.

44. The use of claim 37, wherein and Y2 are each hydrogen.

45. The use of any one of claims 37 to 44, wherein the medicament is for oral administration.

46. The use of any one of claims 37 to 44, wherein the medicament is formulated for oral administration.

47. The use of any one of claims 37 to 44, wherein the medicament, when administered, is administered orally.

48. The use of any one of claims 37 to 44, wherein the medicament further comprises a pharmaceutically acceptable vehicle.

49. The use of claim 48, wherein the pharmaceutically acceptable vehicle comprises an aqueous solution.

50. The use of any one of claims 37 to 44, wherein the medicament inhibits amyloid deposition in a subject.

51. The use of claim 37, wherein X is, for each occurrence, O. INTELLECTUAL PROPERTY OFFICE OF N.2. 2 I DEC 2007 received -33 -

52. The use of claim 37, wherein the therapeutic compound is represented by the formula: r Y1 XR' C- I -C(0)0R wherein X, Y1, Y2, Rl, R2, r3 and n are as defined in claim 37.

53. The use of claim 37, wherein the therapeutic compound is represented by the formula: R1 0 Y1 I p 1 I -c— -C(0)0R3 1 2 OR2 i2 wherein Y1, Y2, R1, R2, R3 and n are as defined in claim 37.

54. Use, in the preparation of a medicament for modulating amyloid deposition in a subject, of a therapeutic compound of the formula: X R1 OR2 Y1 -C-Y2 -CH(NRaRb)C(0)0R3 in which R' and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; R^ is hydrogen, lower alkyl, aryl, or a salt-forming cation; X is, independently for each occurrence, O or S; Y* and Y2 are each independently hydrogen, halogen, alkyl, —NRaRb, hydroxy, alkoxy, or aryloxy; n is an integer from 0 to 12; wherein in each occurrence Ra and R^ are each independently hydrogen, alkyl, aryl, or heterocyclyl, or Ra and R^, taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the cycle; and INTELLECTUAL PROPERTY OFFICE OF N.2. 2 1 DEC 2007 RPCPiucn -34- wherein when any of R1, R2, R3, R4, Y1, and Y2 is an aliphatic, an alkyl or an aryl group, then the aliphatic, alkyl or aryl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, -NH2, alkyl amino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, and an aromatic or heteroaromatic moiety; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

55. The use of claim 54, in which Ra and R(-, are each hydrogen.

56. Use, in the preparation of a medicament for treating a disease state associated with amyloidosis, of a therapeutic compound of the formula: O R1( OR' Y1 -c- „2 -C(0)0R3 in which Rl and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclyl group, or a salt-forming cation; R^ is hydrogen, lower alkyl, aryl or a salt-forming cation; Y* and Y2 are each independently hydrogen, halogen, lower alkyl, —NRaRb, hydroxy, alkoxy, or aryloxy, wherein Ra and Rb are each independently hydrogen, alkyl, aryl, or heteroaryl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a cyclic moiety having from 3 to 8 atoms in the cycle; and n is an integer from 0 to 12; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

57. The use of claim 56, wherein said amyloidosis is Alzheimer's disease. intellectual property OFFICE OF N.2. 2 1 DEC 2007 -35 -

58. The use of claim 56 or 57, wherein R' and R2 are each a pharmaceutically acceptable salt-forming cation.

59. The use of claim 56, in which R', R2 and R^ are each independently a sodium, potassium or calcium cation.

60. The use of claim 59, wherein n is 0.

61. The use of claim 56, wherein at least one of R^ and R2 is a long-chain aliphatic moiety.

62. The use of claim 58, wherein R^ is a lower alkyl group.

63. The use of claim 56, wherein Y' and Y2 are each hydrogen.

64. The use of claim 56, wherein -NRaRb is -NH2-

65. The use of any one of claims 56 to 64, wherein the medicament is for oral administration.

66. The use of any one of claims 56 to 64, wherein the medicament is formulated for oral administration.

67. The use of any one of claims 56 to 64, wherein the medicament, when administered, is administered orally.

68. The use of any one of claims 56 to 65, wherein the medicament further comprises a pharmaceutically acceptable vehicle comprising an aqueous solution.

69. Use, in the preparation of a medicament for modulating amyloid deposition in a subject in which said amyloid deposition is characterized by interaction between an amyloidogenic protein and a constituent of a basement membrane, of a therapeutic compound of the formula: INTELLECTUAL PROPERTY OFFICE OF N.2. 2 I DEC 2007 received -36- R1 O OR2 -C- "2 -C(0)0R in which R' and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclyl group, or a salt-forming cation; R^ is hydrogen, lower alkyl, aryl or a salt-forming cation; and Y2 are each independently hydrogen, halogen, lower alkyl, —NRaRb, hydroxy, alkoxy, or aryloxy, wherein RaandRb are each independently hydrogen, alkyl, aryl, or heteroaryl, or RaandRb taken together with the nitrogen atom to which they are attached form a cyclic moiety having from 3 to 8 atoms in the cycle; and n is an integer from 0 to 12; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

70. The use of claim 69, wherein R^ and R2 are each a pharmaceutically acceptable salt-forming cation.

71. The use of claim 72, in which Rl, R2 and R^ are each independently a sodium, potassium or calcium cation.

72. The use of claim 71, wherein n is 0.

73. The use of claim 69, wherein at least one of R' and R2 is a long-chain aliphatic moiety.

74. The use according to any one of claims 37 to 73, wherein the amyloidosis or disease in which amyloid deposition occurs is associated with a protein selected from the group consisting of p-amyloid, A$2M, AIAPP, amylin, amyloid A, amyloid k L-chain, amyloid X L-chain, ATTR, atrial natriuretic factor, procalcitonin, gelsolin, cystatin C, AApoA-I, AApoA-II, fibrinogen, lysozyme, AScr, and PrP-27. INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 I DEC 2007 received -37-

75. The use according to any one of claims 37 to 73, wherein the amyloidosis or disease in which amyloid deposition occurs is selected from the group consisting of Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage amyloidosis, cerebral angiopathy, chronic hemodialysis, adult onset diabetes, insulinoma, reactive [secondary] amyloidosis, familial Mediterranean Fever, familial amyloid nephrophathy with urticaria and deafness [Muckle-Wells syndrome], idiopathic [primary], myeloma-associated, macroglobulinemia-associated, familial amyloid polyneuropathy, familial amyloid cardiomyopathy, isolated cardiac amyloidosis, systemic senile amyloidosis, isolated atrial amyloidosis, medullary carcinoma of the thyroid, familial amyloidosis, hereditary cerebral hemorrhage with amyloidosis, familial amyloidotic polyneuropathy, accelerated senescence in mice, fibrinogen-associated amyloidosis, lysozyme-associated amyloidosis, Scrapie, Creutzfeldt-Jacob disease, Gerstmann-Straussler-Scheinker syndrome, and bovine spongiform encephalitis.

76. The use according to any one of claims 37 to 75, wherein the medicament prevents amyloid deposition.

77. The use according to any one of claims 37 to 75, wherein the medicament inhibits amyloid deposition.

78. The use according to any one of claims 37 to 75, wherein the medicament prevents and inhibits amyloid deposition.

79. Use, in the preparation of a medicament for reducing amyloid load in a human subject, of a therapeutic compound of the formula: Z is R4 or XR2; R1 and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; X Y1 Z Y2 n in which -38- R3 is hydrogen, lower alkyl, aryl, or a salt-forming cation; R4 is hydrogen, lower alkyl, aryl or—NRaRt,; X is, independently for each occurrence, O or S; Y1 and Y2 are each independently hydrogen, halogen, alkyl, —NRaRb, hydroxy, alkoxy, or aryloxy; wherein in each occurrence Raand Rb are each independently hydrogen, alkyl, aryl, or heteroaryl, or Raand Rb taken together with the nitrogen atom to which they are attached form a cyclic moiety having from 3 to 8 atoms in the cycle; and n is an integer from 0 to 12; and wherein when any of R1, R2, R3, R4, Y1, and Y2 is an aliphatic, an alkyl or an aryl group, then the aliphatic, alkyl or aryl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, -NH2, alkyl amino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, and an aromatic or heteroaromatic moiety; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

80. Use, in the preparation of a medicament for treating or preventing a neurodegenerative disorder in a human subject, of a therapeutic compound of the formula: Y1 R1 -C- >'2 -C(X)XR in which Z is R4 or XR2; R1 and R2 are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation; R3 is hydrogen, lower alkyl, aryl, or a salt-forming cation; R4 is hydrogen, lower alkyl, aryl or —NRaRb; X is, independently for each occurrence, O or S; INTELLECTUAL PROPERTY OFFICE OF N.Z 2 I DEC 2007 received -39- Y1 and Y2 are each independently hydrogen, halogen, alkyl,—NRaRb, hydroxy, alkoxy, or aryloxy; n is an integer from 0 to 12; wherein in each occurrence, Ra and Rb are each independently hydrogen, alkyl, aryl, or heteroaryl, or Ra and Rb taken together with the nitrogen atom to which they are attached form a cyclic moiety having from 3 to 8 atoms in the cycle; and wherein when any of R1, R2, R3, R4, Y1, and Y2 is an aliphatic, an alkyl or an aryl group, then the aliphatic, alkyl or aryl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, —NH2, alkyl amino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, aralkyl, and an aromatic or heteroaromatic moiety; wherein said therapeutic compound is other than 2-amino-7-phosphonoheptanoic acid or 2-amino-5-phoshonopentanoic acid.

81. The use according to claim 80, wherein said neurodegenerative disorder is a P-amyloid disorder.

82. The use according to claim 80 or 81, wherein the neurodegenerative disorder is Alzheimer's disease.

83. The pharmaceutical composition of any one of claims 1 to 31, wherein said amyloidosis or disease in which amyloid deposition occurs is associated with P-amyloid.

84. The pharmaceutical composition of any one of claims 1 to 31, wherein the amyloidosis or disease in which amyloid deposition occurs is Alzheimer's disease.

85. The use according to any one of claims 37 to 73, wherein the amyloidosis or disease in which amyloid deposition occurs is associated with P-amyloid.

86. The use according to any one of claims 37 to 73, wherein the amyloidosis or disease in which amyloid deposition occurs is Alzheimer's disease. INTELLECTUAL PROPERTY OFFICE OF N.Z 2 1 DEC 2007 received -40-

87. A method for preparing a compound represented by the formula: O O II II II II RO—C—P—O OH I wherein R is alkyl or aryl; and R' is hydrogen, alkyl, or aryl; the method comprising: reacting an ester of a carbonylphosphono diacid halide with a silyl ether or an alcohol under conditions such that the compound is prepared.

88. The method of claim 87, wherein R is an alkyl or aryl group, R' is a substituted alkyl group, and the silyl ether of an alcohol is a silyl ether of a vicinal diol, such that the compound of Formula V is prepared.

89. The method of claim 87, wherein said carbonylphosphono diacid halide is a phosphonodichloridate.

90. A compound represented by the formula (Formula IV): wherein G is hydrogen or one or more substituents on the aryl ring; and L is a substituted alkyl group.

91. The compound of claim 90, wherein G is hydrogen, or an alkyl, aryl, halogen, or amino group.

92. The compound of claim 90, wherein L is a substituted lower alkyl group or an alkyl group substituted with a nucleoside base. O O O INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 I DEC 2007 received -41 -

93. The compound of claim 90, wherein Lisa hydroxy substituted alkyl group.

94. The compound of claim 90, wherein G is an electron withdrawing group in the meta position.

95. The compound of claim 94, wherein G is a fluoro, chloro, bromo, iodo, nitro, or cyano group.

96. The compound of claim 90, wherein G is an electron donating group in the ortho, meta, or para position.

97. The compound of claim 90, wherein L is selected from the following: oh OH IVa 1 00(0)0^23 IVb oh oh •SC(0)CUH23 IVc sc(0)c7h15 IVd OH IVe OH IVf oh and ^ IVg. INTELLECTUAL PROPER! V OFFICE OF N.Z. 2 I DEC 2007 -42-

98. A method of synthesizing a compound represented by the formula O O O—C—P—O—L G O wherein G is hydrogen or one or more substituents on the aryl ring and the L is a hydroxy substituted alkyl group; the method comprising reacting an ester of a carbonylphosphono diacid halide with a disilylether of a vicinal diol, under conditions such that the compound of said formula is prepared.

99. The method of claim 98, wherein G is hydrogen, or an alkyl, aryl, halogen, or amino group.

100. The method of claim 98, wherein L is a hydroxy substituted lower alkyl group.

101. The method of claim 98, wherein G is an electron withdrawing group in the meta position.

102. The method of claim 101, wherein G is a fluoro, chloro, bromo, iodo, nitro, or cyano group.

103. The method of claim 98, wherein G is an electron donating group in the ortho, meta, or para position.

104. The method of claim 98, wherein L is selected from the following oh OH IVa 0C(0)CnH23 IVb intellectual property officfc of Kl.z. 2 I DEC 2007 received -43 - -oh -SC(0)CHH23 IVc -oh -sc(0)c7h1s IVd NH, > OH IVe NH, IX) OH IVf ,oh and ffl IVg.

105. The method of claim 98, wherein said carbonylphosphono diacid halide is a phosphonodichloridate.

106. A therapeutic composition comprising a compound of claim 86 or a pharmaceutically acceptable salt.

107. A pharmaceutical composition as defined in claim 1 for modulating amyloid deposition in a subject, substantially as herein described with reference to any example thereof.

108. A pharmaceutical composition as defined in claim 14 for modulating amyloid deposition in a subject, substantially as herein described with reference to any example thereof. INTELLECTUAL PROPERTY OFFICE OP N.2. 21 DEC 2007 received -44-

109. A pharmaceutical composition as defined in claim 16 for treating a disease state associated with amyloidosis, substantially as herein described with reference to any example thereof.

110. A pharmaceutical composition as defined in claim 27 for modulating amyloid deposition in a subject, substantially as herein described with reference to any example thereof.

111. Use of a compound as defined in claim 37 substantially as herein described with reference to any example thereof.

112. Use of a compound as defined in claim 54 in the preparation of a medicament, substantially as herein described with reference to any example thereof.

113. Use of a compound as defined in claim 56 in the preparation of a medicament, substantially as herein described with reference to any example thereof.

114. Use of a compound as defined in claim 69 in the preparation of a medicament, substantially as herein described with reference to any example thereof.

115. Use of a compound as defined in claim 79 in the preparation of a medicament, substantially as herein described with reference to any example thereof.

116. A method of preparing a compound as defined in claim 87, substantially as herein described with reference to any example thereof.

117. A compound of formula IV as defined in claim 90, substantially as herein described with reference to any example thereof.

118. A method of synthesizing a compound as defined in claim 98, substantially as herein described with reference to any example thereof. INTELLECTUAL PROPERTY OFFICE OF N.2. 2 I DEC 200? received