ZA200509647B - Methods and compositions for treating amyloid-related diseases - Google Patents

Description

k WO 20047113275 PCT/IB2004/002375

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METHODS AND COMPOSITIONS FOR TIREATING

AMYLOID-RELATED DISEASES

Related _Applications

T his application claims priority to U.S. Patent Applicatiora No. 10/871,514, filed

June 18, 2004 (identified by Attorney Docket No. NBI-162A), U. S. Patent Application

No. 10/8771,365, filed June 18, 2004 (identified by Attorney Dock=et No. NBI-162B),

U.S. Prowisional Patent Application No. 60/512,047, filed Octobe=r 17, 2003, and U.S.

Provisioral Patent Application No. 60/480,906, filed June 23, 2003, all entitled Methods and Compositions for Treating Amyloid-Related Diseases.

This application is also related to U.S. Provisional Patent ~Application No. 60/512,017, filed October 17, 2003, U.S. Provisional Patent Application No. 60/480,918, filed June 23, 2003, and U.S. Patent Application No. 10/871,613, filed June 18,2004 (identified by Attorney Docket No. NBI-149), all entitled Methods for Treating

Protein A ggregation Disorders.

This application is related to U.S. Provisional Patent Application No. 60/512,116, filed October 17, 2003, U.S. Provisional Patent Appli_cation No. 60/480,984, filed June 23, 2003, and U.S. application 10/871,549, filed June 18, 2004 (identified by Attorney Docket No. NBI-152), all entitled Pharma ceutical Formulations of Amyloi d-Inhibiting Compounds.

This application is related to U.S. Provisional Patent Appli_cation No. 60/436,379, filed December 24, 2002, U.S. Provisional Patent Application No. 60/482,21 4, filed June 23 2003, entitled Combination Therapy for the Treatment of

Alzheimer's Disease, U.S. Patent Application No. 10/746,138, filed December 24, 2003,

International Patent Application No. PCT/CA2003/002011, and U .S. Patent Application

No.10/746,138, filed June 18, 2004 (identified by NBI-154CP), emtitled Therapeutic

Formulatgons for the Treatment of Beta-Amyloid Related Diseases .

Thais application is related to U.S. Provisional Patent Appliecation No. 60/512,13 5, filed October 17, 2003, U.S. Provisional Patent Application ‘No. 60/48 2,058, filed June 23, 2003, both entitled Synthetic Process for Preparing

Compounds for Treating Amyloidosis, and U.S. Patent Applicatiom No. 10/871,543, filed

June 18, 2.004 (identified by Attorney Docket No. NBI-156), entitl ed Improved

Pharmace=utical Drug Candidates and Method for Preparation Thezreof.

This application is related to U.S. Provisional Patent Application Serial No. 60/512,01 8, filed on October 17, 2003 and U.S. Provisional Patent Application Serial

No. 60/48€0,928, filed on June 23, 2003, and U.S. application 10/87 1,512, filed June 18, -1- Amende=d Sheet: 18 April 2008

2004 (identified by Attorney Docket No. NBI-163), all entitled Adethods and

Compositions for Treating Amyloid- and Epileptogenesis-Associaated Diseases.

This application is also related to Method for Treating Arayloidosis, U.S. Patent

Application No. 08/463,548, now U.S. Pat. No. 5,972,328.

The entire contents of each of these patent applications amd patents are hereby expressly incorporated herein by reference including without limitation the specification, claims, and abstract, as well as any figures, tables, or drawings thereof. : : Background

Amyloidosis refers to a pathological condition characterized by the presence of amyloid fibrils. Amyloid is a generic term referring to a group Of diverse but specific protein deposits (intracellular or extracellular) which are seen in_ a number of different diseases. Though diverse in their occurrence, all amyloid depos its have common morphologic properties, stain with specific dyes (e.g., Congo recl), and have a ’ characteristic red-green birefringent appearance in polarized light after staining. They also share common ultrastructural features and common X-ray Jiffraction and infrared spectra.

Amyloid-related diseases can either be restricted to one organ or spread to several organs. The first instance is referred to as “localized amyloidosis” while the second is referred to as “systemic amyloidosis.”

Some amyloid diseases can be idiopathic, but most of th_ese diseases appear as a complication of a previously existing disorder. For example, primary amyloidosis (AL amyloid) can appear without any other pathology or can follow plasma cell dyscrasia or multiple myeloma. :

C. 25 Secondary amyloidosis is usually seen associated with chronic infection (such as tuberculosis) or chronic inflammation (such as rheumatoid arthritis). A familial form of secondary amyloidosis is also seen in other types of familial anmyloidosis, e.g., Familial

Mediterranean Fever (FMF). This familial type of amyloidosis is genetically inherited and is found in specific population groups. In both primary andl secondary amyloidosis, deposits are found in several organs and are thus considered sysstemic amyloid diseases. “Localized amyloidoses” are those that tend to involve & single organ system.

Different amyloids are also characterized by the type of protein present in the deposit.

For example, neurodegenerative diseases such as scrapie, bovin_e spongiform encephalitis, Creutzfeldt-Jakob disease, and the like are characteerized 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 neuritic plaques and neurofibrillary tangles. In this case, the amyloid plaques found imn the parenchyma and the blood vessel is formed by the deposition of fibrillar AB amylokd protein. Other diseases such as adult-onset diabetes (type II diabetes) are characterized by the localized accumulation of amyloid fibrils in the pancreas.

Once these amyloids have formed, there i=s no known, widely accepted therapy or treatment which significantly dissolves amyloid Cleposits in situ, prevents further amyloid deposition or prevents the initiation of ammyloid deposition.

Each amyloidogenic protein has the ability to undergo a conformational change andto organize into B-sheets and form insoluble fibrils which may be deposited extracellularly or intracellularly. Each amyloido =genic protein, although different mm amino acid sequence, has the same property of forming fibrils and binding to other elements such as proteoglycan, amyloid P and cosmplement component. Moreover, each amyloidogenic protein has amino acid sequences: which, although different, show similarities such as regions with the ability to birmd to the glycosaminoglycan (GAG) portion of proteoglycan (referred to as the GAG Thinding site) as well as other regions which promote B-sheet formation. Proteoglycanss are macromolecules of various sizes and structures that are districuted almost everywhere in the body. They can be found in the intracellular compartment, on the surface of cells, and as part of the extracellular matrix. The basic structure of all proteoglycans -is comprised of a core protein and at . least one, but frequently more, polysaccharide chains (GAGs) attached to the core : protein. Many different GAGs have been discovered including chondroitin sulfate, dermatan sulfate, keratan sulfate, heparin, and hyaluronan.

In specific cases, amyloid fibrils, once deposited, can become toxic to the : surrounding cells. For example, the A fibrils organized as senile plaques have been shown to be associated with dead neuronal cells, dystrophic neurites, astrocytosis, and microgliosis in patients with Alzheimer’s disease. ‘When tested in vitro, oligomeric oo (soluble) as well as fibrillar AP peptide was shown to be capable of triggering an activation process of microglia (brain macrophagzes), which would explain the presence of microgliosis and brain inflammation found in the brain of patients with Alzheimer’s disease. Both oligomeric and fibrillar AB peptide can also induce neuronal cell death in vitro. See, e.g., MP Lambert, et al., Proc. Natl. Acad. Sci. USA 95, 6448-53 (1998).

In another type of amyloidosis seen in pzatients with type II diabetes, the amyloidogenic protein IAPP, when organized in_ oligomeric forms or in fibrils, has been shown to induce islet cell toxicity in vitro. Heence, appearance of IAPP fibrils in the pancreas of type II diabetic patients contributes to -the loss of the P islet cells (Langerhans) and organ dysfunction which can lea_d to insulinemia. :

Another type of amyloidosis is related to f= microglobulin and is found in long- term hemodialysis patients. Patients undergoing long term hemodialysis will develop Py-microglobulin fibrils in the carpal tunnel and ine the collagen rich tissues in several joints. This causes severe pains, joint stiffness anc swelling.

Amyloidosis is also characteristic of Alzhesimer’s disease. Alzheimer’s disease is a devastating disease of the brain that results in preogressive memory loss leading to dementia, physical disability, and death over a relatively long period of time. With the aging populations in developed countries, the number of Alzheimer’s patients is reaching epidemic proportions. :

People suffering from Alzheimer’s disease develop a pro gressive dementia in adulthood, accompanied by three main structural «changes in the brain: diffuse loss of neurons in multiple parts of the brain; accumulation of intracellular protein deposits termed neurofibrillary tangles; and accumulation «of extracellular protein deposits termed amyloid or senile plaques, surrounded by misshapen nerve terminals (dystrophic neurites) and activated microglia (microgliosis an_d astrocytosis). A main constituent of these amyloid plaques is the amyloid—p peptide (AB), a 39-43 amino-acid protein that is produced through cleavage of the f—amyloid preccursor protein (APP). Extensive research has been conducted on the relevance of #AB deposits in Alzheimer’s disease, see, e.g., Selkoe, Trends in Cell Biology 8, 447-453 (1998). AB naturally arises from the metabolic processing of the amyloid precursor preotein (“APP”) in the endoplasmic reticulum (“ER”), the Golgi apparatus, or the end _osomal-lysosomal pathway, and most is normally secreted as a 40 (“Ap1-40”) or 42 (“A p1-42") amino acid peptide (Selkoe,

Annu. Rev. Cell Biol. 10, 373-403 (1994)). A roles for AP as a primary cause for

Alzheimer’s disease is supported by the presence of extracellular AB deposits in senile plaques of Alzheimer’s disease, the increased prosduction of AP in cells harboring mutant Alzheimer’s disease associated genes, e.g", amyloid precursor protein, presenilin I and presenilin II; and the toxicity of extracellular soluble (oligomeric) or fibrillar AP to cells in culture. See, e.g., Gervais, _Eur. Biopharm. Review, 40-42 (Autumn 2001); May, DDT 6, 459-62 (2001). Although symptomatic treatments exist for Alzheimer’s disease, this disease cannot be prevented or cured at this time.

Alzheimer’s disease is characterized by d-iffuse and neuritic plaques, cercbral angiopathy, and neurofibrillary tangles. Plaque amd blood vessel amyloid is believed to be formed by the deposition of insoluble AB amy~loid protein, which may be described as diffuse or fibrillary. Both soluble oligomeric Af and fibrillar AP are also believed to be neurotoxic and inflammatory.

Another type of amyloidosis is cerebral amyloid angiopathy (CAA). CAA isthe specific deposition of amyloid-B £ibrils in the walls of leptomingeal and cortical arteries. arterioles and veins. It is commonly associated with Alzheimer’s disease, Down’s syndrome and normal aging, as well as with a variety of familial conditions related to stroke or dementia (see Frangione: ef al., Amyloid: J. Protein Folding Disord. 8, Suppl. L, 36-42 (2001)). .

Presently available therapies for treatment of B-amyloid diseases are almost entirely symptomatic, providing only temporary or partial clinical benefit. Although some pharmaceutical agents have been described that offer partial symptomatic relief, no comprehensive pharmacological therapy is currently available for the prevention or treatment of, for example, Alzheixmer’s disease. : - Summary of The Invention : ‘ The present invention relates to the use of certain compounds in the treatment of amyloid-related diseases. In particular, the invention relates to a method of treating or preventing an amyloid-related disease in a subject comprising administering to the subject a therapeutic amount of a compound of the invention. The invention also pertains to each of the novel comgpounds of the invention as described herein. Among the compounds for use in the invention are those according to the following Formulae, such that, when administered, amyloid fibril formation, organ specific dysfunction (e.g. , neurodegeneration), or cellular toxicity is reduced or inhibited

Tn one embodiment, the iryvention pertains, at least in part to compounds of

Formula I:

T

R! N Y wherein:

R! is a substituted or unsubstituted cycloalkyl, heterocyclic, aryl, arylcycloalkyl., bicyclic or tricyclic ring, a bicyclic or tricyclic fused ring group, or a substituted or unsubstituted C,-Cjy alkyl groupz

R?is selected from a group consisting of hydrogen, alkyl, mercaptoalkyl, alkenyl,

alkynyl, cycloalkyl, aryl, arylatkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, &and benzoimidazolyl;

Y is 80; X*, 0805 X', or S805 X';

X* is hydrogen, a cationic group, or an ester-forming group (i.e., as in a procimg, which are described elsewhere herezin); and each of L! and 1.2 is indepemndently a substituted or unsubstituted C,;-Cs alkyl group or absent, or a pharmaceuticzally acceptable salt thereof, provided that when RR is alkyl, L' is absent.

In another embodiment, the invention pertains, at least in part to compounds of Formula II:

RQ

N—(C)m—(CH2)i—Y a wherein:

R! is a substituted or unsubsstituted cyclic, bicyclic, tricyclic, or : benzoheterocyclic group or a substituted or unsubstituted C,-Cy alkyl group; : R%is hydrogen, alkyl, merc=aptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryE alkyl, thiazolyl, triazolyl, imidazolyl, bexazothiazolyl, benzoimidazolyl, or linked to R'to form a heterocycle;

Y is SOX}, 080; X', or SSO; X';

X* is hydrogen, a cationic _group, or an ester forming moiety; misOorl; nis 1,2,3,0r4;

L is substituted or unsubstituted C;-Cs alkyl group or absent, or a pharmaceutically acceptable szalt thereof, provided that when R! is alkyl, Lis absent.

In yet another embodiment, the invention pertains, at least in part to compo unds of Formula III:

RRS

Sa

RY R 0

R® 1 —(Ct4,),—S—A—R 7 6

R R78 REE (1) wherein:

A is nitrogen or oxygen;

R"! is hydrogen, salt-forming cation, ester forming group, —(CHp)x—QQ, or when

A is nitrogen, Ax and R"! taken together may be the residue of a natural or unmoatural amino acid or a salt or ester thereof;

Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolw/l; xis0,1,2,3,0r4; nis0,1 ,2,3,4,5,6,7,8,9,0r 10;

R3,R®, RY, RY RS, R* RS, R® R’ and R’® are each independently mydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylczarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, or two R groups on adjacent ring atoms taken together with the ring atoms form a double bond, provided that one of rR,

R® RY, R® RZ, R*® RS, R®, R’ and R™ is a moiety of Formula Illa: :

RA ww

R? (CHa) ) RC : RE ’

RP (Ila) wherein: misO, 1,2,3,0r4;

RA, RB_ RC, RP, and RE are independently selected from a group of h-ydrogen, halogen, hydroexyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyR, alkynyl, cycloalkyl, ary-1, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothia zolyl, and benzoimidazol yl; and pharmaceutically acceptable salts and esters thereof, provided that said compound is not 3-(4-phenyl-1, 2, 3, 6-tetrahydro-1-pyridyl)-1-propanessulfonic acid.

Tn yet another embodiment, the invention pertains at least in part to compounds of Formula IV = 9 8 RY RS

R R RE JF se 5 ll

R'0 (CH)n—N N—(CHy)—S—A—RY

R" R2 RT 7a 18 vy wherein:

A is nitreogen or oxygen;

R!! is hy=drogen, salt-forming cation, ester forming group, —(#CHz),—Q, or when

A is nitrogen, A. and R!! taken together may be the residue of a natur—al or unnatural amino acid or a salt or ester thereof;

Q is hydlrogen, thiazolyl, triazolyl, imidazolyl, benzothiazoly~1, or benzoimidazolyl; : xis0,1 ,2,3,0r4; ‘ nis0,1 2,3,4,5,6,7,8,9,0r10;

Co RY, R®, RS, R™ RS, R® R’, and R™ are each independently Ehydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, ary-lcarbonyl, : alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, R* and R’ taken together, with the ring atoms they. are attached to, form a double bond, or RS and R’ taken together, with the ring atoms ~they are attached to, form a double bond; mis0, 1,2,3,0r4;

RE: R®, R'%, RY, and R'? are independently selected from a group of hydrogen, halogen, hydroexyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyR, alkenyl, alkynyl, : cycloalkyl, ary=1, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, beenzothiazolyl, and benzoimidazokyl, and pharmaceutically acceptable salts and esters thereof.

In another embodiment, the invention includes compounds eof Formula Vv:

R15 0

IE

. wherein: . : } A is ni_trogen or oxygen,

R'! is Mydrogen, salt-forming cation, ester forming group, —(CH_.)x—Q, or when

A is nitrogen, A and R"! taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;

Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazo-1yl, or benzoimidazowlyl; xis 0, 1,2,3,0r4; nis0, 1,2,3,4,5,6,7,8,9,0r10; aa is a_ natural or unnatural amino acid residue; " misOs,1,2,0r3;

R™ is hydrogen or protecting group;

RY is hydrogen, alkyl or aryl, and pharmaceutically acceptable salts and prodrugs thereof.

In another embodiment, the invention includes comp ounds of the Formula VI:

R22

I Cl

ATT s RE RB R19 0 vD wherein: nis1,2,3,4,5,6,7,8,9,0r 10; . A is oxygen or nitrogen;

R!! is hydrogen, salt-forming cation, ester forming group, —(CH)x—Q, or when A is nitrogen, A and R"! taken together may De the residue of a natural or unnatural amino acid or a salt or ester thereof;

Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; xis0,1,2,3, 014; :

RY is hydrogen, alkyl or aryl;

Y! is oxygen, sulfur, or nitrogen;

Y? is carbon, nitrogen, or OXygen;

R? is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;

R? is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl,

Co arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazoly, benzothiazolyl, _ benzoimidazolyl, or absent if Y? is oxygen;

RZ is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazoly~1, benzothiazolyl, benzoimidazolyl; or R? is hydrogen, hydroxyl, alkoxy or aryloxy if Y'is : nitrogen; or R22 is absent if Y! is oxygen or sulfum;or R? and R* may be linked to form a cyclic moiety if Y! is nitrogen;

RZ is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidlazolyl, benzothiazolyl, or benzoimidazolyl, or absent if Y? is nitrogen or oxygen; or pharmaceutically acceptable salts thereof.

In another embodiment, the invention inclucles compounds of Formula VIL: oO

A ey” == La I (VID) wherein: nis2,3,or4;

A is oxygen or nitrogen;

R!! is hydrogen, salt-forming cation, ester £orming group, —(CH,)s—Q, or when } A is nitrogen, A and R!! taken together may be the residue ofa natural or unnatural amino acid or a salt or ester thereof;

Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; xis 0,1,2,3,0r4;

G is a direct bond or oxygen, nitrogen, or sulfur;

L5 zis0,1,2,3,4, or 5; misQorl; ’

R**is selected from a group consisting of hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, aroyl, alkylcarbonyl, aminoalkylcarbonyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl; each R* is independently selected from hycirogen, halogen, cyano, hydroxyl, alkoxy, thiol, amino, nitro, alkyl, aryl, carbocyclic, or heterocyclic, and pharmaceutically acceptable salts thereof.

In one embodiment, the compounds disclosed herein prevent or inhibit amyloid protein assembly into insoluble fibrils which, in vivo, are deposited in various organs, or it favors clearance of pre-formed deposits or slows deposition in patients already having deposits. In another embodiment, the compound may also prevent the amyloid protein, in its soluble, oligomeric form or in its fibrillar forrm, from binding or adhering to a cell surface and causing cell damage or toxicity. In yet: another embodiment, the compound may block amyloid-induced cellular toxicity or macrophage activation. In another embodiment, the compound may block amyloid-ineduced neurotoxicity or microglial activation. In another embodiment, the compound protects cells from amyloid induced cytotoxicity of B-islet cells. In another embodiment, the compound may enhance clearance from a specific organ, e.g., the brain or it- decreases concentration of the amyloid protein in such a way that amyloid fibril formation is prevented in the targeted x5 organ

The compounds of the invention may be administered therapeutically or prophylactically to treat diseases associated with armyloid fibril formation, aggregation or deposition. The compounds of the invention maey act to ameliorate the course of an amyloid related disease using any of the following mechanisms (this list is meant to be illustrative and not limiting): slowing the rate of armyloid fibril formation or deposition; lessening the degree of amyloid deposition; inhibiting, reducing, or preventing amyloid fibril formation; inhibiting neurodegeneration or cesllular toxicity induced by amyloid; inhibiting amyloid induced inflammation; enhancimg the clearance of amyloid; or favoring the degradation of amyloid protein prior tots organization in fibrils. : The compounds of the invention may be administered therapeutically or prophylactically to treat diseases associated with aayloid-p fibril formation, aggregation or deposition. The compounds of the invention maay act to ameliorate the course of an a. amyloid-P related disease using any of the following mechanisms (this list is meant to be illustrative and not limiting): slowing the rate of armyloid-p fibril formation or deposition; lessening the degree of amyloid-f deposition; inhibiting, reducing, or preventing amyloid-p fibril formation; inhibiting reurodegeneration or cellular toxicity induced by amyloid-B; inhibiting amyloid-p induc-ed inflammation; enhancing the clearance of amyloid- from the brain; or favoring the degradation of amyloid-f8 protein prior to its organization in fibrils.

Therapeutic compounds of the invention ray be effective in controlling amyloid-B deposition either following their entry into the brain (following penetration of the blood brain barrier) or from the periphery. When acting from the periphery, a compound may alter the equilibrium of AB between the brain and the plasma so as to favor the exit of AB from the brain. It may also in crease the catabolism of neuronal AS : 25 and change the rate of exit from the brain. An increase in the exit of AG from the brain . would result in a decrease in AS brain and cerebra 1 spinal fluid (CSF) concentration and : therefore favor a decrease in AS deposition. Alternatively, compounds that penetrate the brain could control deposition by acting directly om brain AB e.g., by maintaining itina non-fibrillar form, favoring its clearance from the brain, or by slowing down APP processing. These compounds could also prevent Af in the brain from interacting with the cell surface and therefore prevent neurotoxicity, neurodegeneration or inflammation.

They may also decrease AS production by activated microglia. The compounds may also increase degradation by macrophages or neur-onal cells.

In one embodiment, the method is used to treat Alzheimer’s disease (e.g., sporadic, familial, or early AD). The method can also be used prophylactically or therapeutically to treat other clinical occurrences of amyloid-f deposition, such as in

Down’s syndrome individuals and in patients with cerebral amyloid angiopathy (“CAA”) or hereditary cerebral hemorrhage. :

In another embodiment, the method is used to treat mild co gnitive impairment.

Mild Cognitive Impairment (“MCI”) is a condition characterized by a state of mild but measurable impairment in thinking skills, which is not necessarily associated with the : presence of dementia. MCI frequently, but not necessarily, precedes Alzheimer’s disease.

Additionally, abnormal accumulation of APP and of amyloid-B protein in muscle fibers has been implicated in the pathology of sporadic inclusion body myositis (IBM) (Askanas, et al., Proc. Natl. Acad. Sci. USA 93, 1314-1319 (1996); Askanas, et al.,

Current Opinion in Rheumatology 7, 486-496 (1 995)). Accordingly, the compounds of the invention can be used prophylactically or therapeutically in the treatment of disorders in which amyloid-beta protein is abnormally deposited at non-neurological locations, such as treatment of IBM. by delivery of the compounds to muscle fibers.

Additionally, it has been shown that AP is associated with abnormal extracellular deposits, known as drusen, that accumulate along the basal surface of the retinal : . pigmented epithelium in individuals with age-related macular degeneration (AMD).

AMD is a cause of irreversible vision loss in older individuals. It is believed that AB : deposition could be an important component of the local inflammatory events that contribute to atrophy of the retinal pigmented epithelium, drusen biogenesis, and the pathogenesis of AMD (Johnson, ez al., Proc. Natl. Acad. Sci. USA 99(18), 11830-5 : (2002)). : The present invention there fore relates to the use of compounds of Formulae I, IT,

IM, IV, V, VI, VII, or otherwise described herein in the prevention or treatment of amyloidrelated diseases, including, inter alia, Alzheimer’s disease, cerebral amyloid angiopathy, mild cognitive impairrment, inclusion body myositis, Down’s syndrome, macular degeneration, as well as other types of amyloidosis like IAPP- related amyloidosis (e.g., diabetes), primary (AL) amyloidosis, secondary (AA) amyloidosis and B, microglobulin-related (dialysis-related) amyloidosis.

In Type II diabetes related amyloidosis (IAPP), the amyloidogenic protein IAPP induces B-islet cell toxicity when Organized in oligomeric forms or in fibrils. Hence, . appearance of IAPP fibrils in the pancreas of type II diabetic patients contributes to the loss of the B islet cells (Langerhans) and organ dysfunction which leads to insulinemia,

Primary amyloidosis (AL amyloid) is usually found associated with plasma cell dyscrasia and multiple myeloma. It can also be found as an idiopathic disease.

Secondary (AA) amyloidosis is us ually seen associated with chronic infection (such as tuberculosis) or chronic inflammation (such as rheumatoid arthritis). A familial form of secondary amyloidosis is also seen in Familial Mediterranean Fever (FMF). f2 microglobulin-related (dialysis—related) amyloidosis is found in long—term hemodialysis patients. Patients undergoimg long term hemodialysis will develop f32- microglobulin fibrils in the carpal tunnel and in the collagen rich tissues in several joints.

This causes severe pains, joint stiffness amd swelling. These deposits are due to the inability to maintain low levels of §,M ira plasma of dialyzed patients. Increased plasma concentrations of 8M protein will inducee structural changes and may lead to the deposition of modified 8,M as insoluble fibrils in the joints.

Detailed Description of The Invention

The present invention relates to the use of compounds of Formulae LO0LIv,

V, VI, VII, or compounds otherwise des«cribed herein in the treatment of amyloid-related diseases. For convenience, some definitions of terms referred to herein are set forth below. Co _ : Amvyloid-Related Diseases

AA (Reactive) Amyloidosis

Generally, AA amyloidosis is a “manifestation of a number of diseases that provoke a sustained acute phase response. Such diseases include chronic inflammatory disorders, chronic local or systemic micsrobial infections, and malignant neoplasms. The . most common form of reactive or secorndary (AA) amyloidosis is seen as the result of long-standing inflammatory conditions For example, patients with Rheumatoid

Arthritis or Familial Mediterranean Fewer (which is a genetic disease) can develop AA amyloidosis. The terms “AA amyloidosis” and “secondary (AA) amyloidosis” are used interchangeably.

AA fibrils are generally compossed of 8,000 Dalton fragments (AA peptide or protein) formed by proteolytic cleavages of serum amyloid A protein (ApoSAA), a circulating apolipoprotein which is mainly synthesized in hepatocytes in response to ; such cytokines as IL-1, IL-6 and TNF. Once secreted, ApoSAA is complexed with

HDL. Deposition of AA fibrils can be widespread in the body, with a preference for parenchymal organs. The kidneys are -usually a deposition site, and the liver and the spleen may also be affected. Deposition is also seen in the heart, gastrointestinal tract, and the skin. -13- oo

Underlying diseases which can lead to the development of AA amyloidosis include, but are mot limited to inflammatory diseases, such as rheumatoid arthritis, juvenile chronic =arthritis, ankylosing spondylitis, psoriasis, psoriatic arthropathy, + : Reiter's syndrome, Adult Still’s disease, Behcet's syndrome, and Crohn’s disease. AA deposits are also produced asa result of chronic microbial infections, such as leprosy, tuberculosis, bronchiectasis, decubitus ulcers, chronic pyelonephritis, osteomyelitis, and

Whipple’s disease. Certain malignant neoplasms can also result in AA fibril amyloid deposits. These include such conditions as Hodgkin's lymphoma, renal carcinoma, carcinomas of gmt, lung and urogenital tract, basal cell carcinoma, and hairy cell : leukemia. Othe underlying copditions that may be associated with AA amyloidosis are

Castleman’s disease and Schnitzler’s syndrome.

AL Amyloidoses- (Primary Amyloidosis)

AL amyJoid deposition is generally associated with almost any dyscrasia of the B lymphocyte linesage, ranging from malignancy of plasma cells (multiple myeloma) to benign monoclonal gammopathy. At times, the presence of amyloid deposits may bea primary indicator of the underlying dyscrasia. AL amyloidosis is also described in detail in Current Drugs Targets, 2004, 5 159-171. : : Fibrils oef AL amyloid deposits are composed of monoclonal immunoglobulin to light chains or Fragments thereof. More specifically, the fragments are derived from the

N-terminal region of the light chain (kappa or lambda) and contain all or part of the variable (V1) domain thereof. Deposits generally occur in the mesenchymal tissues, causing peripheral and autonomic neuropathy, carpal tunnel syndrome, macxoglossia, restrictive cardiomyopathy, arthropathy of large joints, immune dyscrasias, xnyelomas, as well as occult dyscrasias. However, it should be noted that almost any tissue, particularly visceral organs such as the kidney, liver, spleen and heart, may be involved.

Hereditary Sysatemic Amyloidoses : } There are many forms of hereditary systemic amyloidoses. Although they are relatively rare conditions, adult onset of symptoms and their inheritance patterns (usually autososmal dominant) lead to persistence of such disorders in the general population. Generally, the syndromes are attributable to point mutations in the precursor protein leading to production of variant amyloidogenic peptides or proteins. Table 1 summarizes thee fibril composition of exemplary forms of these disorders.

TABLE I - Fibril Composi tion of Exemplary Amyloid-Related Diseases

Fibril Peptide/Protein Genetic Clinical Syndrome

Variant

ATTR protein from Transthyrettin Met30, many Familial amyloid polyneuropathy CFAP), and fragments others (Mainly peripheral nerves)

ATTR protein from Transthyre-tin Thrd5, Ala60, Cardiac involvement predominant wvithout and fragments Ser84, Met111, | neuropathy, familial amyloid polynevaropathy,

Tlel22 senile systemic amyloidosis, Tenosynovium

N-terminal fragment of Arg26 Familial amyloid polyneuropathy FAP),

Apolipoprotein Al (apoAl) (mainly peripheral nerves)

N-terminal fragment of Arg26, Arg50, | Ostertag-type, non-neuropathic (predeominantly

Apoliproprotein Al (AapoAN) Arg 60, others visceral involvement)

AapoAll from Apolipoprotein _All | Familial amyloidosis

Lysozyme (Alys) Thr56, His67 | Ostertag-type, non-neuropathic (predeominantly visceral involvement)

Fibrogen alpha chain fragmemt Leu554, Val Cranial neuropathy with lattic comeal 526 , dystrophy

Gelsolin fragment (Agel) ~ Asni87, Cranial neuropathy with lattice ceomeal

Az Tyr187 dystrophy

Cystatin C fragment (ACys) Glu68 Hereditary cerebral hemorrhage (cerebral amyloid angiopathy) - Icelandics type

B-amyloid protein (AB) derived from | GIn693 Hereditary cerebral hemorrhage (cerebral

Amyloid Precursor Protein (APP) amyloid angiopathy) - Dutch t=ype

B-amyloid protein (AB) derived from Nle717, Phe717, Familial Alzheimer’s Disease

Amyloid Precursor Protein (APP) Gly717

B-amyloid protein (AB) derived from Gln 618 Alzheimer’s disease, Down’s symdrome,

Amyloid Precursor Protein (APP), hereditary cerebral hemorrhages with e.g., bPP 695 amyloidosis, Dutch type

Fibril Peptid e/Protein Genetic Clinical Syndrome

Variant

B-amiyloid protein (AA) derived from Asn670, Familial Dementia — “probably Alzheimer’s

Amyloid Precursoxt Protein (APP) Leu671 Dis ease

Prion Protein (PrP, APP) derived Leu102, Familial Creutzfesldt-Jakob disease; from Prp precursom protein (51-91 |. Vall67, Gerstmann-Striusslex-Scheinker syndrome inser-t) Asnl78, (hereditary spongiform encephalopathies, prion

Lys200 disezases)

AA derived from Serum amyloid A Familial Mediterranesan fever, predominant protein (ApoSAA) renal involvement (autosomal recessive)

AA derived from Serum amyloid A Muckle-Well’s symdrome, nephropathy, protein (A_poSAA) deafness, urti<aria, limb pain

Unkn-own Cutaneous deposi ts (bullous, papular, pustul«dermal)

AH amyloid protein, derived from Ayl Myeloma associated amyloidosis immunoglobul&n heavy chain (gamrma I)

ACal amyloid. protein from (Pro) calcitonin Medullary carciraomas of the thyroid (pro)cal_citonin

AANF amyloid protein from atrial Isolated a trial amyloid natriuretic factor

Abri/ADan frozn ABri peptide British and Danish familial Dementia

Data derived from Tan SY, Pepys MB. Amyloidosis. Histopathology, 25(5), 403-414 (Nov 1994),

WHO/TUIS Nommenclature Subcommittee, Nomenclature of Amyloid and Amyloidossis. Bulletin of the ’

World Health Organisation 1993; 71: 10508; and Merlini et al, Clin Chem Lab Med 2001; 39(11): 1065- 75. :

The data provided in Table 1 are exemplary and are not intended to limit the scope of the Jnvention. For example, more than 40 separate point mu tations in the transthy~retin gene have been described, all of which give risse to clinically similar forms of familial amyloid polyneuropathy.

In general, any hereditary amyloid disorder can also= occur sporadically, and both hereditary and sporadic forms of a disease present with the same characteristics with regard to amyloid. For example, the most prevalent form o-f secondary AA amyloidosis occurs sporadically, e.g. as a result of ongoing inflammatio-n, and is not associated with }

Familiza] Mediterranean Fever. Thus general discussion rel ating to hereditary amyloid disordesrs below can also be applied to sporadic amyloidose=s.

Transthyretin (TTR) is a 14 kiloDalton protein that is also sometimes referred to as prea.dbumin. It is produced by the liver and choroid plexzus, and it functions in transporting thyroid hormones and vitamin A. At least 50 —variant forms of the protein, each characterized by a single amino acid change, are respeonsible for various forms of familizal amyloid polyneuropathy. For example, substitution of proline for leucine at ~ positiosn 55 results in a particularly progressive form of nevaropathy; substitution of methionine for leucine at position 111 resulted in a severe cardiopathy in Danish patients.

Amyloid deposits isolated from heart tissue of patients with systemic amyloidosis have revealed that the deposits are composed of a heterogeneous mixture of

TTR a.nd fragments thereof, collectively referred to as AT TR, the full length sequences of whi_ch have been characterized. ATTR fibril componemts can be extracted from such plaque=s and their structure and sequence determined accor—ding to the methods known in the art (e.g., Gustavsson, A., et al., Laboratory Invest. 73: 703-708, 1995; Kametani, F., et al, Biochem. Biophys. Res. Commun. 125: 622-628, 1984; Pras, M., et al., PNAS 80: 539-422, 1983).

Persons having point mutations in the molecule ap-olipoprotein Al (e.g.,

Gly—>-Arg26; Trp—>Arg50; Leu—>»Arg60) exhibit a form of amyloidosis (“Ostertag type” characterized by deposits of the protein apolipoprotein Al or fragments thereof (AApeoAl). These patients have low levels of high density lipoprotein (HDL) and preserat with a peripheral neuropathy or renal failure.

A mutation in the alpha chain of the enzyme lysozyme (e.g., Tle—>Thr56 or

Asp—>His57) is the basis of another form of Ostertag-type> non-neuropathic hereditary -. amyloid reported in English families. Here, fibrils of the Jmutant lysozyme protein (Alys)) are deposited, and patients generally exhibit impaimred renal function. This protei_n, unlike most of the fibril-forming proteins describsed herein, is usually present in wholes (unfragmented) form (Benson, M.D., ef al. CIBA F<dn. Symp. 199: 104-131, 1996.

Immunoglobulin light chains tend to form aggregates in various morphologies, including fibrillar (e.g., AL amyloidosis ancl AH amyloidosis), granular (e.g., light chain deposition disease (LCDD), heavy chain deposition disease (HCDD), and light-heavy chain deposition disease (LHCDD)), crystalline (e.g., Acquired Farconi’s Syndome), and microtubular (e.g., Cryoglobulinemia). AL and AH amyloidosis is indicated by the formation of insoluble fibrils of immunoglobulin light chains and heavy chain, respectively, and/or their fragments. In AIL fibrils, lambda (N) chains such as A V1 chains (\6 chains), are found in greater comcentrations than kappa (x) chains. NOI chains are also slightly elevated. Merlini et al., CLIN CHEM LAB MED 39(11):1065-75 (2001).

Heavy chain amyloidosis (AH) is generally characterized by aggregates of gamma chain amyloid proteins of the IgGl subclass. Eulitz et al., PROC NATL AcaD Sci USA 87:6542-46 (1990).

Comparison of amyloidogenic to non-amyloidogenic light chains has revealed that the former can include replacements or substitutions that appear to destabilize the folding of the protein and promote aggregation. AL and LCDD bave been distinguished : from other amyloid diseases due to their relatively small population monoclonal light chains, which are manufactured by neoplastic expansion of an antibody-producing B cell. AL aggregates typically are well-ordered fibrils of lambda chains. LCDD aggregates are relatively amorphous aggregations of both kappa and lambda chains, with a majority being kappa, in some cases kIV’. Bellotti et al., JOURNAL OF STRUCTURAL

BIOLOGY 13:280-89 (2000). Comparison of amyloidogenic and non-amyloidogenic heavy chains in patients having AH amyloidosis has revealed missing and/or altered components. Eulitz ef al., PROC NATL ACAD Sc1 USA 87:6542-46 (1990) (pathogenic heavy chain characterized by significantly’ lower molecular mass than non- amyloidogenic heavy chains); and Solomon et al. AMJHEMAT 45(2) 171-6 (1994) (amyloidogenic heavy chain characterized] as consisting solely of the VH-D portion of the non-amyloidogenic heavy chain).

Accordingly, potential methods off detecting and monitoring treatment of subjects having or at risk of having AL, LCDD, AH, and the like, include but are not limited to - 30 immunoassaying plasma or urine for the presence or depressed deposition of amyloidogenic light or heavy chains, e.g. , amyloid \, amyloid , amyloid IV, amyloid 4, or amyloid 1.

Brain Amyloidosis ’ 35 . The most frequent type of amyloid in the brain is composed primarily of

AP peptide fibrils, resulting in dementia associated with sporadic (non-hereditary)

Alzheimer’s disease. In fact, the incidence of sporadic Alzheimer’s disease greatly exceeds forms shown to be hereditary. INevertheless, fibril peptides forming plaques are very similar in both types. Brain amylo#&dosis includes those diseases, conditions, pathologies, and other abnormalities of the structure or function of the brain, including components thereof, in which the causative agent is amyloid. The area of the brain affected in an amyloid-related disease maay be the stroma including the vasculature or the parenchyma including functional or anaatomical regions, or neurons themselves. A subject need not have received a definitive diagnosis of a specifically recognized amyloid-related disease. The term “am yloid related disease” includes brain amyloidosis.

Amyloid peptide (“AB”) is a 39-43 amino acid peptide derived by proteolysis from a large protein known as Beta Amayloid Precursor Protein (“BAPP”). Mutations in . APP result in familial forms of AlzheXimer’s disease, Down’s syndrome, cerebral amyloid angiopathy, and senile dementia, characterized by cerebral deposition of plaques composed of Ap fibrils and other components, which are described in further detail below. Known mutations in APP® associated with Alzheimer’s disease occur proximate to the cleavage sites of B or ~y-secretase, or within AB. For example, position 717 is proximate to the site of gamma-secretase cleavage of APP in its processing to AB, "and positions 670/671 are proximate to» the site of B-secretase cleavage. Mutations at any of these residues may result in Alzheinner’s discase, presumably by causing an increase in the amount of the 42/43 amino acid form of AP generated from APP. The familial form of Alzheimer’s disease representss only 10% of the subject population. Most occurrences of Alzheimer’s disease ares sporadic cases where APP and Ap donot possess any mutation. The structure an d sequence of AB peptides of various lengths are well known in the art. Such peptides can be made according to methods known in the art, or extracted from the brain according to known methods (e.g., Glenner and Wong,

Biochem. Biophys. Res. Comm. 129, 885-90 (1984); Glenner and Wong, Biochem.

Biophys. Res. Comm. 122, 1131-35 (1984)). In addition, various forms of the peptides are commercially available. APP is expressed and constitutively catabolized in most cells. The dominant catabolic pathways appears to be cleavage of APP within the Af sequence by an enzyme provisionally €ermed c-secretase, leading to release of a soluble ectodomain fragment known as APPscx. This cleavage precludes the formation of Af peptide. In contrast to this non-amylodidogenic pathway, APP can also be cleaved by enzymes known as 8- and y-secretase at the N- and C-termini of the AB , respectively, followed by release of Ap into the extracellular space. To date, BACE has been identified as B-secretase (Vasser, ef al. , Science 286:735-741, 1999) and presenilins have been implicated in y-secretase activity (De Strooper, et al., Nature 391, 387-90 (1998)).

The 39-43 amino acid AP peptide is produced by sequential proteolytic cleavage of the amyloid precursor protein (APP) by th e 3 and v secretases enzyme. Although AB40 is the predominant form produced, 5-7%6 of total Ap exists as AP42 (Cappai et al., Int. J.

Biochem. Cell Biol. 31. 885-89 (1999).

The length of the AB peptide appears to dramatically alter its biochemical/biophysical properties. Specifically, the additional two amino acids at the

C-terminus of AP42 are very hydrophobic, presumably increasing the propensity of

APA42 to aggregate. For example, Jarrett, ef al. demonstrated that AB42 aggregates very rapidly in vitro compared to AP40, suggesting that the longer forms of Ap may be the important pathological proteins that ae involved in the initial seeding of the neuritic plaques in Alzheimer’s disease (Jarrett, et al., Biochemistry 32, 4693-97 (1993); Jarrett, etal, Ann. N.Y. Acad. Sci. 695, 144-48 (1993)). This hypothesis has been further _ substantiated by the recent analysis of the contributions of specific forms of A in cases of genetic familial forms of Alzheimer’s disease (“FAD”). For example, the “London” mutant form of APP (APPV717]) linked to FAD selectively increases the production of

AB 42/43 forms versus AB 40 (Suzuki, et al., Science 264, 1336-40 (1994)) while the “Swedish” mutant form of APP (APPK670N/M671L) increases levels of both AB40 and : AB42/43 (Citron, et al., Nature 360, 672-674 (1992); Cai, et al., Science 259, 514-16, oo (1993). Also, it has been observed thrat FAD-linked mutations in the Presenilin-1 (“PS1”) or Presenilin-2 (“PS2”) genes will lead to a selective increasc in AB42/43 production but not A840 (Borchelt, e# al., Neuron 17, 1005-13 (1996)). This finding was corroborated in transgenic mouse models expressing PS mutants that demonstrate a selective increase in brain AB42 (Borchelt, op cit.; Duff, et al., Neurodegeneration 5(4), 293-98 (1996)). Thus the leading hypothesis regarding the etiology of Alzheimer’s disease is that an increase in AB42 brain concentration due to an increased production and release of AB42 or a decrease in Clearance (degradation or brain clearance) is a causative event in the disease patholo gy.

Multiple mutation sites in eithier AP or the APP gene have been identified and are clinically associated with either dementia or cerebral hemorrhage. Exemplary CAA disorders include, but are not limited to, hereditary cerebral hemorrhage with amylaidosis of Icelandic type (HCHWA-I); the Dutch variant of HCHWA (HCHWA-D; amutation in AB); the Flemish mutation of Ag; the Arctic mutation of AB; the Italian mutation of AB; the Iowa mutation of Ag; familial British dementia; and familial Danish dementia. CAA may also be sporadic.

As used herein, the terms “B amyloid,” “amyloid—B,” and the like refer to amyloid B proteins or peptides, amyloid B precursor proteins or peptides, intermediates, and modifications and fragments thereof, unless otherwise specifically indicated. In particular, “AB” refers to any peptide produced by proteolytic processing of the APP gene product, especially peptides which are associated with amyloid pathologies,

including AB1-39, AB1-40, AB1-41, AB1-42, and AP 1-43. For convenience of nomenclature, “A31-42’> may be referred to herein as “AB(1-42)” or simply as “AB42” or “ABs” (and likewise for any other amyloid peptides discussed herein). As used herein, the terms “g amyloid,” “amyloid-g,” and “Ag” are synonymous.

Unless otherwise specified, the term “amyloid” refers to amyloidogenic proteims, peptides, or fragments thereof which can be soluble (e.g., monomeric or oligomeric) ox insoluble (e.g., having £ibrillary structure or in amyloid plaque). See, e.g., MP Lambert, et al., Proc. Nat'l Acad. Sci. USA 95, 6448-53 (1998). “Amyloidosis” or “amyloid disease” or “amyloid-related disease” refers to a pathological condition characterized by the presence of amyloid fibers. “Amyloid” is a generic term referring to a group of diverse but specific protein deposits (intracellular or extracellular) which are seenin a number of different diseases. Though diverse in their occurrence, ail amyloid deposits have common morphologic properties, stain with specific dyes (e.g., Congo red), and have a characteristic red-green birefringent appearance in polarized light after stainings.

They also share common ultrastructural features and common X-ray diffraction and infrared spectra. i

Gelsolin is a calcium binding protein that binds to fragments and actin filamemats.

Mutations at position 1 87 (e.g., Asp—>Asn; Asp—Tyr) of the protein result in a form of hereditary systemic amyloidosis, usually found in patients from Finland, as well as persons of Dutch or Japanese origin. In afflicted individuals, fibrils formed from gelsolin fragments (Agel), usually consist of amino acids 173-243 (68 kDa carboxyterminal fragment) and are deposited in blood vessels and basement membrarmes, resulting in corneal dystrophy and cranial neuropathy which progresses to peripheral : neuropathy, dystrophic skin changes and deposition in other organs. (Kangas, H., et al

Human Mol. Genet. 5(9): 1237-1243, 1996).

Other mutated proteins, such as mutant alpha chain of fibrinogen (AfibA) and. mutant cystatin C (Acys) also form fibrils and produce characteristic hereditary disorders. AfibA fibri 1s form deposits characteristic of a nonneuropathic hereditary amyloid with renal dis ease; Acys deposits are characteristic of a hereditary cerebral amyloid angiopathy resported in Iceland (Isselbacher, Harrison’s Principles of Internal

Medicine, McGraw-Hill, San Francisco, 1995; Benson, ef al.). In at least some cases., patients with cerebral amyloid angiopathy (CAA) have been shown to have amyloid fibrils containing a nom-mutant form of cystatin C in conjunction with amyloid beta protein (Nagai, A., ef «al. Molec. Chem. Neuropathol. 33: 63-78, 1998).

Certain forms ©f prion disease are now considered to be heritable, accounting; for up to 15% of cases, which were previously thought to be predominantly infectious in_

pature. (Baldwin, et al., in Research Advances in Alzheimer’s Disease and Related

Disorders, John Wiley and Sons, New York, 1995). In hereditary and sporadic prion disorders, patients develop plagues composed of abnormal isoforms of the normal priosn protein (PrP).

A predominant mutant isoform, PrP, also referred to as AScr, differs from the normal cellular protein in its resistance to protease degradation, insolubility after detergent extraction, deposition in secondary lysosomes, post-translational synthesis, and high B-pleated sheet content. Genetic linkage has been established for at least fives mutations resulting in Crewtzfeldt-Jacob disease (CID), Gerstmann-Striussler-Scheink=<er syndrome (GSS), and fatal familial insomnia (FFI). (Baldwin, supra) Methods for extracting fibril peptides fi-om scrapie fibrils, determining sequences and making sucha peptides are known in the art (e.g., Beekes, M., et al. J. Gen. Virol. 76: 2567-76, 1995s).

For example, one form of GSS has been linked to a PrP mutation at codon 102, while telencephalic GSS segregates with a mutation at codon 117. Mutations at codors 198 and 217 result in a form of GSS in which neuritic plaques characteristic of

Alzheimer’s disease contain PrP instead of AG peptide. Certain forms of familial CIID have been associated with mutations at codons 200 and 210; mutations at codons 129° and 178 have been found i n both familial CJD and FFI. (Baldwin, supra).

Cerebral Amyloidosis

Local deposition o f amyloid is common in the brain, particularly in elderly individuals. The most freqquent type of amyloid in the brain is composed primarily of” AG peptide fibrils, resulting ira dementia or sporadic (non-hereditary) Alzheimer’s diseas e.

The most common occurrences of cerebral amyloidosis are sporadic and not familial

For example, the incidence of sporadic Alzheimer’s disease and sporadic CAA greatly exceeds the incidence of familial AD and CAA. Moreover, sporadic and familial formms of the disease cannot be d_istinguished from each other (they differ only in the presenace or absence of an inherited genetic mutation); for example, the clinical symptoms andl the amyloid plaques formed in both sporadic and familial AD are very similar, if not identical.

Cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyRBoid fibrils in the walls of leptoomingeal and cortical arteries, arterioles and veins. Itis commonly associated with Alzheimer’s disease, Down’s syndrome and normal agin _g, as well as with a variety of Familial conditions related to stroke or dementia (see Frangione et al., Amyloid: J. Protein Folding Disord. 8, Suppl. 1, 36-42 (2001)). CAA can occur sporadically or be hereditary.

Senile Systemic Amyloidosis

Amyloid deposition, either systemic or focal, increases with agge. For example, fibrils «of wild type transthyretin (TTR) are commonly found in the heart tissue of elderly individuals. These may be asymptomatic, clinically silent, or may result in heart failure.

Asymptomatic fibrillar focal deposits may also occur in the brain (AS), corpora amylacea of the prostate (8, microglobulin), joints and seminal vesicles.

Dialys is-related Amyloidosis (DRA)

Plaques composed of 8; microglobulin (8;M) fibrils commonly develop in patien®s receiving long term hemodialysis or peritoneal dialysis. (> mmicroglobulin is a 11.8 kiiloDalton polypeptide and is the light chain of Class I MHC antigens, which are present on all nucleated cells. Under normal circumstances, 5,M is usually distributed in the extracellular space unless there is an impaired renal function, in wrhich case BM is transpeorted into tissues where it polymerizes to form amyloid fibrils. Failure of cleararice such as in the case of impaired renal function, leads to depowsition in the carpal tunnel and other sites (primarily in collagen-rich tissues of the joints). Unlike other fibril proteins, BM molecules are not produced by cleavage of a long er precursor : proteir and are generally present in unfragmented form. in the fibrils. (Benson, supra).

Retention and accumulation of this amyloid precursor has been showm to be the main pathogzenic process underlying DRA. DRA is characterized by peripheral joint osteoaTthropathy (e.g., joint stiffness, pain, swelling, etc.). Isoforms of 8,M, glycated

BM, or polymers of 8M in tissue are the most amyloidogenic form (as opposed to native FM). ‘Unlike other types of amyloidosis, $,M is confined larg-ely to osteoarticular sites. Visceral depositions are rare. Occasionally, these deposits may involv-e blood vessels and other important anatomic sites.

Despite improved dialysis methods for removal of 8;M, the mx ajority of patients have pelasmatic $,M concentrations that remain dramatically higher ttman normal. These elevatesd S,M concentrations generally lead to Diabetes-Related AmyJoidosis (DRA) and cormo-rbidities that contribute to mortality.

Islet Amyloid Polypeptide and Diabetes

Islet hyalinosis (amyloid deposition) was first described over =a century ago as the presemce of fibrous protein aggregates in the pancreas of patients witha severe hyperglycemia (Opie, EL., J Exp. Med. 5: 397-428, 1901). Today, islet amyloid, composed predominantly of islet amyloid polypeptide (APP), or amy/lin, is a characteristic histopathological marker in over 90% of all cases of Type II diabetes (also knowra as Non-Insulin Dependent Diabetes, or NIDDM). These fibrillar accumulations

Claims (110)

> v CLAIMS

1. Use of a compound in the treatment or prevention of an amyloid-related disease, wherein said compound is of Formula I: R2 RIL Y ~~ rd ~~ 2 M wherein: R! is a substituted or unsubstituted cycloalkyl, heterocyclic, aryl, arylcycloalkyl, bicyclic or tricyclic ring, a bicyclic or tricyclic fused ring group, or a substituted or unsubstituted C;-Cy alkyl group; R?is hydrogen or alkyl Y is SOX; X* is hydrogen or a cationic group; and L' is a substituted or unsubstituted C;-Cs alkyl group or absent, L? is a substituted or unsubstituted C,-Cs alkyl group; or a pharmaceutically acceptable salt, ester or prodrug thereof, provided that when. R'is alkyl, L' is absent; provided that when R? is hydrogen, L? is -(CH,)s-, L' is methylene, and Y is SOs X.*, R' is not phenyl, 1,3-benzodioxol-5-yl or 3, 4- dimethoxyphenyl, and pro-vided that when R? is hydrogen, L? is -(CH,)s-, L'is absent, and Y is SO+'X*, R'is not n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n— decyl, cyclohexyl, 1-hydroxy-2-propyl, 1-hydroxy-2-butyl, 2-hydroxy-1-propyl, 1-hydroxy-4-pentyl, 1-hydroxy-5-hexyl, 2-hydroxy-1-ethyl, 3-hydroxy-1-propyl, 4-hydroxy-1-butyl, S-hydr-oxy-1-pentyl, 6-hydroxy-1-hexyl, 3,5-dimethyl-1- adamantyl, 1-hydromethyl—1-cyclopentyl, 2-(2-deoxy-D-glucose), phenyl, 4- hydroxyphenyl or 4-pyridy], 1-hydroxy-2-pentyl, 3-methyl butyric acid, 4-methyl - pentanoic acid methyl ester or 2,2-diphenyl-ethyl.

2. The use of claim 1, wherein R” is hydrogen.

3. The use of any one of claims 1 and 2, wherein R! is straight chain alkyl. -202- Amended Sheet: 18 April 2008

‘a A) WO 2004/113275 PCT/1B2004/0023775

4. The use of claim 3, wherein R' is ethyl, n-pentyl, n-heptyl, n-octyl, or n-nonyl.

5. The use of claim 4, wherein R' is n-pentyl, n-heptyl or n-octyl.

6. The use of any one of claims 1 and 2, wherein R' is t-butyl.

7. The use of claim 6, wherein said compound is 3-(¢-butyl)amino-1-propanesulforic acid or a pharmaceutical ly acceptable salt, ester or prodrug thereof.

8. The use of any one of claims 1 and 2, wherein R' is carbocyclic.

9. The use of claim 8, wherein R' is a bicyclic or tricyclic fused ring group.

10. The use of claim 9, wherein R!is C;-Cyp bicycloalkyl.

11. The use of claim 9, wherein R' is tricycloalkyl.

12. The use of claim 11, wherein R' is tricyclo[3.3.1 0%")decyl or adamantyl.

13. The use of claim 10, wherein R' is bicyclo[2.1.2]heptyl.

14. The use of claim 12, wherein said compound is 3-(1-adamantyl)amino-1- propanesulfonic acid, or a pharmaceutically acceptable salt, ester or prodrug thereof.

15. The use of any one of claims 1 to 14, wherein Lis (CH»)s.

16. The use of any one of claims 1 to 14, wherein L? is a substituted C,-Cs alkyl group.

17. The use of claim 16, wherein L? is selected from -CH,CH,CH(CH3)- and -CH; CH(OH)CH;-.

18. The use of claim 1, wherein said compound is selected from the group consistingg of: -203 - Amended Sheet: 18 April 208

7s ! SOA ~~ SOH JIS wis i H H [>—N__~_SOsH [tensor (so OH E PO won TL I~ ~~ NP NG “X “T NGPA H NTN VN == I" ¢ g = - N SOSH 7 Non ; Se ANG FZ © 1 =r ~Y =r A aN H CH " § T NP g T ENG a Ir ING ad nT Nsom Y ~NSoH NENG

H . oN SoH H sou Nh NY ~~ N H H,C H,C HsCO. : HN 5" LEN Nadel jon (o] ‘0 y a VW ~ -204 - Amended Sheet: 18 April 2008

~ H Jo SO3H Ao Nm S01 Hi H Br ~~ 3 z CH,OH H HN SO ~N 0 iy SOM " ~TN ad AN NP ENG NP tas NG NG i HO NENG C HO HO OH H \ NNT Nsom : ’ .. ANG H ~TN CHa OH CH,OCH; R SO3H Hy ~TN 3 CH,0H —, CH,0 y “Wom LANG PON : y gl NW NNT Nsom Ohh H H H TH,0H lo] NH, 0 CH, H H N <_~_-SOH

SO.H CH,O a mo AN : : Y -205 - Amended Sheet: 18 April 2008 wv Pp: SO,H i BC Ag OH Na 0, ANP at 07 NH,

HCO. INGEN xs nN OH _OH HN HN ~N- QP fe) [e) 0 0 HN Sn, OH CH WNT TTS H ’ 7 OMe 0] H CH, H H 3 oF TNH, Ns OH H Pe Je Cr 0 ef 07 NH CL man 2 N Nsom 0) WOCH,Ph OCH,Ph H NT N""so -., NT "sou : H H oF OCH,CH, BE: H N SO,H No SOH NPE TY ~~ 3 A : CH,OH 9 x H H H , N SO.H } A Aso TY SINT Sse En OH CH,OH H 2 o> OMe - 206 - Amended Sheet: 18 April 2008

Y H ANSON : Ne -S0:H a 070 < NH, (0) H H H SNS 80H NSO JR som ~~ 5 : o OH o7 oH NF N i H i Na S051 : —0 PY —0 N S=— N S=— JY ~~ N “on ~~ N oH ZN 5 3 (0) NH, “0 No” H q H i H \ =0 \ =0 No S0sH AA Ae or TY H : OH z : OMe 0 on 07 H, lo} O [e] H H l_o H l_o Na -S0H Cy x NaS, 0” NH 07 “Nn, 0 n fo H 0 Na S0H \ Z | 2! TY RO O00: DORE: oO NH, 0 ag On 0” o] I Ilo N sZ 0 0 KY Nn LOH, PY LOH

N 5.0 iN qo HN _~_-S. HN. _~_-S. OH OH Tx Ts I oO 0] ~ Oo OH OH N 0 < On - 0 H 12 N I : N 1-9 HN _~_-S.

HN. Ls HN s OH ~~ “oH ~~ ‘on H CW Re NL = 20 N = H Ss! N HN _~_-S oH NO “ou INS -207 - Amended Sheet: 18 April 2008

L} « NH 90 0 x 0 2, NF 1.0 i NH, po HN _~-S. HN ~_-S. HAN _~_-5. OH OH OH 0 BN 4 R Me BE Me = Wo No CN fo HN S! HN S. HN S, ~~ N OH ~N OH } ~~ OH Oo 0] T Me Me Me N oe N 90 H N 90 H I, H 1 = Hl HN ~~. HN _~_-S. HN 5, OH OH OH 0] 0 Ix Me Na Y N06 = N Qo mA _E TP INGAAS "OH "OH 0] N | Lo HN j Lo HN ; © H N ~~ “oH ~~ “oH ~~ OH Hid i i.0 N° To IN fo . HN S. HN S! ~TN OH ~NOON OH ~NON OH (6) >— 0] jo] N 0 HN MH 8 0] Y Q N ~ Nl “oH ~~ “oH HN n Lo HN ; Lo HN J Lo ~~ “OH ~N “OH ~NTN “OH 0 o ) R No 0 NTQ N fo

H 1.0 : H 11-0 HN ~-S. HN MNS OH -208 - Amended Sheet: 18 April 2008

- Oo 0] 0 \ MeS MeS Dar “Ao, ~~ oo i, HO aN. HK 8 mn. HB 87 “ ~ ~~ N iN ~~ N oH ~TON oH oH 0 0 pe N 0 Or NT fo § TN fo 0 N HN _~_-S. N HN _~_-S. OH 1.0 OH 0 0] Ts AN 0 AA 0 I OH Ro HN iY 1° HN > 12° MNS, —_— “OH ~~ N “OH . 0 0 (0) Mes A MeS_~ o OH fl.0 IT "OH 0.0 \ x OH no HN S. HN 8? ~~ 0] z 0} A N ~~ HN Ss! HN s7 H OH —_— OH ~N OH MeS (eo Y 0 4 nl OH 11.0 i" OH 11,0 ENS ~~ N “oH —_— “OH MeS ~~ 0 . HN S HN Ss. H H H Ox. © H 04.0 H Og ~° NC Nao ~S~on NC No ~—Sou No~—S~on PY ® CN

H 0.0 HI NAY H 0x..0 N >s NC _NI >s NC _N >s? 0] \ O— : -209 - Amended Sheet: 18 April 2008

2° ne HN Oa iP ne Ho O° N Og” AN NaS rx NN TNomm H H Crs cS ow H H H 0s 0° Nw N— xg? N I H 04° N I H Ox 0 Na" omc \Y \ N° H N N N / TN 0 /N / TN NIH Oxo” N H le NAY N H 0+.-.° \ \S WR \ >~_% °N NS on lg 'N ANG NE 0] \ O— H 0) 0] H 0) 4 H Ox “ N— Na” Nd N N S N S N NS / N

N. .N N H H H Ox © H 0. 0 N— Sg” Ng” N N S N S Ne lH 0,0 HO No HO "0H H 0 \ O~ H 0s_0 H 0,0 0.0 N Ss HO N s N “57 "7s ~~ 0H Crs ~~ on eS, F H SN 0 Cl H *N 0 Br H Os 0 TDMA AIL, TAAIL, Noon

H O. 0 Me H ON 0 NaS N os J Os? OH So OH So Me oO 0 Cl [o] 0 N RA

MeO. o.,0 i" 57 TL ~ So vs” NNO TAS, TK OH OH -210- Amended Sheet: 18 April 2008

“

0.0 Br H Sg” H Og 0 , 0.0 ~~ No “OH ~~ “OH He ~Sly OH OH ora F H 0, 0 H Ov ° MeO H 0, 0 No~~Son NS 0H Ta OH OH OH o_.0 H (NIRA [o)] [o] N SJ H 0, 0 H NIRA AL ~~ —~""0H AO, QPL Son OMe OMe F H Oc 0 MeO H Os® u 0, 0 ~~ ~">on Son JQ OMe OMe Me Cl o. oO y Ss” 0,0 H 0, .0 LS Ie GEL s BE F CF OMe *

0.0 Ho 2 Ne ~SC H Os “gq on JAAS, OMe e Me 0. .,0 o.,0 H N [oR ,0 H N JOP AAS, SEAS, Br OMe OH 0, ,0 ¥ %s?° o0..,0 H N77 NN “OH H 4 OH OH Me= H *N BY H Oog?® H 0, 0 ATES . ~~ “OH oF Nason 3 OH OMe OMe H Os PY H Qo? H O. ,0 Noon Noon NaS on Cl MeO OH OMe Ole o_O H 0, Be F H 0, AY R 3 N s N S " N “oH B NON “OH ~NN “OH e oH OMe -211 - Amended Sheet: 18 Aapril 2008

H 0, 0 H Os? Cl a lo) [0] Ne ~S2 ~~ Son N pig OH OMe BH 0,0 ’ x 7 “on Oss? AZ) oN N. _ ~~" ~ OH OH GUL OH Or-1 I H Oy 0 Br H UN 0 OMe H O° N—~~ou No ~S~on N ~~ “OH OH OH Me H 0 2 [0] I H 0, 0 F H EN No —~"0on GE N_~"0ou OH OMIe CF, 0 o Me H Oy BY a H ON 0 H 7 Neon N~Son NS on OH OMe OMe H SN 0 = d H ON BY Br H 0) . 0 ~ S Nou a | NAS OH N ~~ “oH OH (0) (2 o_.,0 H NZ OO [0] NN S 4 ~N\ Me OMe M Cl € Me Me 4 o_O H O° H UN 7 ONES NONE OMe B MeO . r CF, H 0,..° H SNPS o_,0 H 7 N _~U-S5S NAS S OH AA “OH Key B MeO OMe Me cl OMe H 0. .0 H ANP = Og \7 Ea ~~ N “OH ~~ “OH OMe MeO CF, Br -212- Amended Sheet: M8 April 2008

“ wea) 2004/113275 PCT/IB2004/002375 H ANP H 0° H %° ~ NC “oH N ~~ “OH ~~ N “OH MeO F OMe I d O° H OP H O° MeO MeO CF, Me Br H *N 0 ua ANP H O° Noon ~~ N\ “OH ~~ TN “OH MeO MeO OMe CF, I H %P H O° H Oe? ~~" 0H ~~ N"N0H ~~ N""0H MeO F OMe Me H o_.0 o._.,0 Nd o_,0 H 0) NNN H NZ N ~~ on OH Noon Me MeO Cl Me CF, Me N 7’ § O57 Hd Cs? ~~ “OH ~TN “OH ~TN “OH MeO MeO Br F OMe o._.,0 H /

o_.0 o_,0 Ne” H ANd H No” N_~_-SN S S OH MeO MeO Me I Cl Me Me F Cl Br. H iN 0 H 0, 0 H ON 0 ra SNS = ~~ SNOET Zz Noon -213- Amnended Sheet: 18 April 2008

“ WW0 2004/113275 PCT/IB2004/002375 Me ll Me Me H Oy 0 Me H © 2 " o_,0 Age NaS on Ae Nay H A i.

Bir. F F H UN PY H Oo, py H 0, © NG No~SSon SZ Na ~—"~on Z “Na ~Son Me =! ct Nee H Oy PY H Oy 0 Me H 0, 0 VZ ~~—50n Ae NS AN SNoh Br Br La o__,0 o_O H Oy 0 Zz Ne FZ RAT, = ~~ ~on OH oOo 0 te Me H hd H On Ph 0 Me H 0,0 = SINAN OH = ~NS “OH NaS &Z OH O=Me x OMe

0._.0 0o_,0 ZY OH A Ne NPL ZN OH oO Oo H 0.0 H 0, 0 i 7 PANE NS = “No~"S>on Zz ~~ OH F F F H 0,0 H Oy 0 H ug z= on Ne SZ OH = Ki Neo~"Son = ~~ OH Ci Ch al -214 - Amended Sheet: 18 April 2008 P

H 05.20 0.0 H 05° TT areas: y OMe F H UN 0 H SN 0 = Nou ~~ Non “SK Cl OMe (o] ya AX ° _X POPP (} A “SK ANY o H 0 o H oa tp / ~~ o I Da Ne ° o o 0” rE Fo t HO ~~ 4 OO ° | © we f “y~K J AN & ° r~K.

0

~./ A i CA [e— 0 q [ J 1 BN ° 1 A > i salt ° =< Ones, 2 ~~ -215- Amended Sheet: 18 April 2008

Box ok } Bee IY \ Are ~TY Ao YY ~e SUS AAA, STK NeXORS XR, Or 5 v g YY N° LC NS A Jor PS AX Sama Ps [o] . o For X rd or NH Ll ~s0um oy or a pharmaceutically acceptable salt, ester or proedrug thereof. -216 ~ Amended Sheet: 18 April 2008

19. Use of a compound in the treatment ox prevention of an amyloid-related disease, wherein said compound is of Formula II: 9 ri NC (CH —Y (II) wherein: R?is linked to R' to form a heterocycle; Y is SO;"X", 0SO; X", or SSO3 XX; X" is hydrogen, a cationic group, ©r an ester forming moiety; m is 0; nis 2,3, or4; L is absent, or a pharmaceutically acceptable salt, ester or prodrug thereof, provided that whennis3or4,andY is SO;’X’, then the heterocycle formed by R! and R? is not phthalimido, 2-(1,2,3,4,5,6,7,8-oc tahydroisoquinolinyl), N-(1,2,3,4- tetrahydroisoquinolinyl), N-(6-methoxy-1,2,3,4-tetrahydroisoquinolinyl), N-(6,7- dimethoxy-1,2,3,4-tetrahydroisoquinolinyl) or 1,2,3,4-tetrahydro-9H-pyrido[3,4- blidol-2-yl; provided that when n is 3, and Y is SO3X", then the heterocycle formed by R' and R? is not N-isoindo1yl, N-(1,2,3,4-tetrahydroquinolinyl), N- (3- carboxy-1,2,3,4-tetrahydroisoquinolirayl), N-(6-chloro-1,2,3,4- tetrahydroisoquinolinyl), N-(6-dimethvylamino-1,2,3,4-tetrahydroisoquinolinyl), N-~(8-methoxy-1,2,3,4-tetrahydroisoquinolinyl), N-indolyl, N-saccharin, N-(4- benzylpiperidinyl), N-(1,2,3,6-tetrahy-dropyridinyl), N-(4-phenyl-1,2,3,6- tetrahydropyridinyl), N-(1,4-dihydropeyridinyl), pyridinium, N-(S)-nicotinium, or N-morpholino; provided that when n ds 2, and Y is SO5'X", then the heterocycle formed by R' and R? is not 1-(4-hydroxyethylpiperazinyl).

20. The use of claim 19, wherein n is 3.

21. The use of any one of claims 19 or 2Q, wherein the heterocycle formed by R' and R? is a substituted 1,2,3,4-tetrahydroisoquinolinyl group substituted with a group selected from the group consisting of bromo, nitro, amino, iodo, and N,N- diacetylamino. -217- Amended Sheet: 18 April 2008

22. The use of claim 19, wherein said compound is selected from the group consisting of: > dhe A I r \ 0 2 he PJOOUN bo] TE dol ; oC Oe ISOPN

0 . GS Com ° ¢ {=} ” 0 = < a AXA < oS oo iY ~~ A eval OJ or za pharmaceutically acceptable salt, ester or prodrugs thereof. -218 - Amended Sheet: 18 April 2008

23. Use of a compound in the treatment or paevention of an amyloid-related disease, wherein said compound is of Formula IIK: R4a RS 4 5a R R 0 R3 1 N—(CH;),—S—A—R R? RS R72 Roa (IID) wherein:

A is nitrogen or oxygen;

R'! is hydrogen, salt-forming cation, ester forming group, or (CH,),—Q;

Q is hydrogen, thiazolyl, triazolyl, imaidazolyl, benzothiazolyl, or benzoimidazolyl;

xis 0,1,2,3,0r4;

nis2 3,4,5,6,7,8,9,o0r 10;

R}, R*® R* R® R°, R™ RS R%® R’ and R™ are each independently hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, or two R groups on adjacent ring atoms taken together with the ring atoms form a double bond, provided that one of R}, R*® RS, R* R®, and R® is a moiety of Formula Illa:

RA ™ RE (CH2)m RC RE RO (11a)

wherein:

mis0,1,2,3,or4;

RA? RE RC, RP, and RF are independently selected from a group of hydrogen, halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothiazolyl, and benzoimid azolyl; and pharmaceutically acceptable salts, esters, and prodrugs thereof, provided that said compound is not 3-(4- phenyl-1, 2, 3, 6-tetrahydro-1-pyridyl)-1-propanesulfonic acid, and provided that

-219- Amended Sheet: 18 April 2008 when R* R*, R® R®, R™* R% R® R’ and R”* are hydrogen, then R? is not a moiety of Formula Illa.

24. The use of claim 23, wherein n is 2, 3 or 4.

25. The use of claim 23 or 2 4, wherein R'' is a salt-forming cation.

26. The use of claim 25, wherein said salt-forming cation is lithium, sodium, potassium, magnesium, <alcium, barium, zinc, iron, or ammonium.

27. The use of claim 23 or 2 4, wherein R'! is an ester-forming group.

28. The use of claim 27, wherein said ester-forming group is substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, or cycloalkyl.

29. The use of any one of claims 23-28, wherein R* and R* are taken together form a double bond.

30. The use of any one of claim 23-28, wherein R* R>, R®, and R’ are each hydrogen.

31. The use of any one of claims 23-30, wherein R* is hydroxyl, cyano, acyl, or hydroxyl.

32. The use of any one of claims 23-31, wherein R*, RE, RS, RP, and R" are each hydrogen.

33. The use of any one of claims 23-31, wherein RA RB, RP, and RE are each hydrogen, and RC is halogen.

34. The use of claim 33, wherein said halogen is fluorine, bromine, chlorine, or iodine.

35. The use of any one of claims 23-34, wherein mis O or 1.

36. The use of any one of claims 23-34, wherein mis 3.

37. The use of any one of claims 23-36, wherein A is oxygen.

38. The use of any one of claims 23-37, wherein R’ is a moiety of Formula Illa. -220- Amended Sheet: 18 April 2008

39. The use of claim 23, wherein said compound is selected from the group consisting of: cl { » 4 Nsom = NC Ve SOs N SO3H SMe -50s ~TNT = OH SAe we Ne -SOsH NH "504 ~ a Oso Md son ON NT" 50mH or a pharmaceutically acceptable salt, ester, or prodrug thereof.

40. Use of a compound in the txeatment or prevention of an amyloid-related disease, wherein said compound is of Formula IV: R® R® a R4a RS s R*, | ) _R"2 o Il R0 (CH2)m—N N—(CHp)s—S—A—R" rR {ree © R11 R12 R72 RS IV) wherein: A is nitrogen or oxygen ; R!' is hydrogen, salt-foxrming cation, ester forming group, or (CH),—Q; Q is hydrogen, thiazoly1, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; xis0,1,2,3,0r4, nis0,1,2,3,4,5,6,7, 8,9, or 10; R*, R* RR’, R*® R% R®_ R’, and R™ are each independently hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, -221- Amended Sheet: 18 April 2008 alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, R* and R® taken together, with the ring atoms they are attached to, form a double bond, or Réand R’ taken together, with the ring atoms they are attached to, form a double bondi; mis O,1, 2,3, or4,; R% R° R' R', and R'? are independently selected from a group «of hydrogen, halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothiazolyl, and benzoimidazolyl; or pharmaceutically acceptable salts, esters, and prodrugs thereof.

41. The use of claim 40, wherein mis 0.

42. The use of claim 40 or 41, wherein n is 2, 3, or 4.

43. The use of any one of claims 40-42, wherein R%, R’, R® and R’ are each hydrogen.

44, The use of any one of claims 40-42, wherein RR’, R'® R'" and R'? are each hydrogem.

45. The use of any one of claims 40-42, wherein R% R’, R!! and R'? are each hydrogen, and R' is fluorine, chlorine, nitro, or alkyl.

46. The use of any one of claims 40-42, wherein R’ R! R!" and R'? are each hydrogen, and R® is fluorine.

47. The use of claim 41, wherein said compound is: F o—( H- NN sos Hn NT "SOs _/ __/ and on) NT 7 sogH / or pharmaceutically acceptable salts, esters, or prodrugs thereof.

48. Use of a compound in the treatment or prevention of an amyloid-related disease, wherein said compound is of Formula V: -222. Amended Sheet: M8 April 2008

R's 0] Il FRY —(aa)n —N—(CHph—S—A—R" 0 v) wherein: A is mitrogen or oxygen; R'! iss hydrogen, salt-forming cation, ester forming group, —CCHa)x—Q, or when A is nitrogen, A and R'! taken together may be the residues of a natural or unnatura 1 amino acid or a salt or ester thereof, wherein A and R! ! taken together are not a leucine residue; Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazoly~1, or benzoimudazolyl; xis ?d,1,2,3,0r4; nis2 3,4,5,6,7,8,9, or 10; aa is anatural or unnatural amino acid residue; mis €,1, 2, or 3; R"is hydrogen or protecting group; R'® is hydrogen, alkyl or aryl; and pharmaceutically acceptable salts, esters, or prodrugs thesreof, wherein when m Ls 0, R'* and R" are both hydrogen, and A is oxygen, theen R'"isnota hydrogem or a salt-forming cation; provided that when A is oxyg-en, R' isa hydrogem or a salt-forming cation, nis 2, mis I, R' and R'’ are “both hydrogen, then aa is not a phenylalanine residue; provided that when A is oxygen, Risa hydrogem or a salt-forming cation, nis 2, 3 or 4, mis 2, R'* and R" are both hydrogem, then aa is not D-phenylalanine. 49, The use of claim 48, wherein nis 2, 3 or 4.

50. The use of claim 48, wherein n is 3.

51. The use of any one of claims 49-50, wherein m is 0.

52. The use of any one of claims 49-51, wherein A-R''is a residue o fa natural amino acid, or a salt or ester thereof.

53. The use of claims 52, wherein A-R'' is a phenylalanine residue. -223 - Amended Sheet: 18 April 2008

54. The use of any one of claims 48-53, wherein (aa)n is a residue of phenylalanine, glycine, or phe-phe.

35. The use of any one of claims 48-54, wherein R'> is hydrogen or substituted alkyl.

56. The use of claim 55, wherein R'? is arylalkyl.

57. The use of claim 48, wherein said compound is selected from the group consisting of: Ng hi . N~_SC o - HN NAS a © "oe wT HO : (2 ONa ¥ SNPS \ H —CO;Na “x i” MS Oo NTNN50,N +« fo) o ls} H lo) oy 0 Ie ~~ & o_ 0 S : Loe HN ~ Sy AO hoo and A or pharmaceutically acceptable salts, esters, or prodrugs thereof.

58. Use of a compound in the treatment or prevention of an amyloid-related disease, wherein said compound is of Formula VI: -224 - Amended Sheet: 18 April 2008

R22 R21 9 No N —C—N——{(CHp)y——S——A——R!! R R10 fo) (VD wherein:

nis2,3,4,5,6,7,8,9,o0r 10;

A is oxygen or nitrogen;

R'! is hydrogen, salt-forming cation, estemr forming group, —(CH,)—Q, or when A is nitrogen, A and R'' taken together- may be the residue of a natural or unnatural amino acid or a salt or ester thereof;

Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;

xis 0,1,2,3,0r4;

R'? is hydrogen, alkyl or aryl;

Y! is oxygen, sulfur, or nitrogen;

Y? is carbon, nitrogen, or oxygen;

R? is hydrogen, alkyl, amino, mercaptoallkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;

R?' is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imid azolyl, benzothiazolyl, benzoimidazolyl, or absent if Y? is oxygen;

R?? is hydrogen, alkyl, mercaptoalkyl, allzenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imid azolyl, benzothiazolyl, benzoimidazolyl; or R* is hydrogen, hydroxyl, alkoxy or aryloxy if Y's nitrogen; or R? is absent if Y' is oxygen or sulfur; or R*? and R?' may be linked to form a cyclic moiety if Y' is nitrogen;

R? is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl, or absent if Y? is nitrogen or oxygen;

or pharmaceutically acceptable salts, este=ts, or prodrugs thereof, provided that when n is 3, Y' is oxygen, Y? is oxygen, R?! isbenzyl, A is oxygen, R''isa hydrogen or a salt-forming cation, R'? is not hydrogen; provided that when n is 3,

-225 - Amended Sheet: 18 April 2008

A is oxygen, R'!is a hydrogen or a salt-form-ing cation, Y' is oxygen, Y?is carbon, each of R%, R?}, and R? is hydrogen_, R'? is not hydrogen, and provided that R*! and R*? are not linked to form an ary-1 ring; provided that when n is 3, A is oxygen, R'! is a hydrogen or a salt-forming c ation, Y' is oxygen, Y? is carbon, R?' is benzyl, R*? is hydrogen, R* is amino, A is oxygen, then R'is not hydrogen.

59. The use of claim 58, wherein R'! is hydrogem or a salt forming cation.

60. The use of claim 58 or 59, wherein A is oxygen.

61. The use of any one of claims 58-60, wherein Y' is oxygen or sulfur, and R? is absent.

62. The use of any one of claims 58-61, wherein “Y? is oxygen and R*' is absent.

63. The use of any one of claims 58-62, wherein RY js benzyl, aryl, alkyl, or cycloalkyl.

64. The use of any one of claims 58-61 and 57, Y~? is nitrogen.

65. The use of any one of claims 58-61, wherein IR?! is hydrogen.

66. The use of any one of claims 58-61, wherein RR? is benzyl.

67. The use of any one of claims 58-61 and 63-66=, wherein Y' is sulfur.

68. The use of claim 59, wherein said compound us selected from the group consisting of: fo) [0] a 0 NT souk PLN H OH N SOH H 0 o]

o—. NNO ~~ PY H aN 4 ) N N SO3H Oo g A Be J N NT SOM s I -226 - Amended Sheet: 18 April 2008

W O2004/113275 PCT/1B2004/002375 H 0] PR

N.__~_-SOsH STN NT 80H o) H H 0 VAN GP NG Nah N NNNS0H hooh som H H S NH SO3H PN TNT NH NH >" s0;H 0) A ~L, “A H je] ~~ amd pharmaceutically acceptable salts, esters, and perodrugs thereof.

69. Use of a compound in the treatment or prev-ention of an amyloid-related disease, wherein said compound is of Formula VII: 0 A (RSG), = Loa J z R Oo (VID) wherein: nis2,3,or4, A is oxygen or nitrogen; R'! is hydrogen, salt-forming cation, ester forming group, -(CH2)x—Q, or when A is nitrogen, A and R'! taken togeth er may be the residue of a natural or unnatural amino acid or a salt or ester there=of; Q is hydrogen, thiazolyl, triazolyl, imidlazolyl, benzothiazolyl, or benzoimidazolyl; xis 0,1, 2,3, or4, G is a direct bond or oxygen, nitrogen, or sulfur; -227 - Amended Sheet: 18 April 2008 zis0,1,2,3,4, or 5; misOor 1; R**is selected from a group consisting of hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, aroyl, alkylcarbonyl, aminoalkylcarbonyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl; each R? is independently selected from hydrogen, halogen, cyano, hydroxyl, alkoxy, thiol, amino, nitro, alkyl, aryl, carbocyclic, or heterocyclic; and pharmaceutically acceptable salts, esters, and prodrugs thereof, provided that when n is 3, A is oxygen, R''is a hydrogen or a salt-forming cation, mis 0 or 1, R?* is hydrogen, then z is not 0; and provided that when n is 3, A is oxygen, R'is a hydrogen or a salt-forming cation, mis O or 1, R? is hydrogen, zis 1, Gis a direct bond, then R* is not a 4-haydroxy group.

70. The use of claim 69, wherein R"' is hydrogen.

71. The use of claim 69 or 70, wherein A is oxygen.

72. The use of any one of claims 69-71, wherein n is 3.

73. The use of any one of claims 69-72, wherein R* is hydrogen.

74. The use of any one of claims 69-73, wherein R** is benzyl.

75. The use of any one of claims 69-74, wherein m is 1.

76. The use of any one of claims 69-75, wherein zis 0, 2, or 3.

717. The use of any one of claims 69-76, wherein R% is hydroxyl or alkoxy.

78. The use of claim 77, wherein said R* is methoxy.

79. The use of claim 69, wherein said compound is selected from the group consisting of: oT Sq NH >" s05H 0 o = - AN - 228 - Amended Sheet: 18 April 2008

Te / JT H / Oo — pg NN 80H ) © Bd gg — / o— of SG JT - BOSH Sears Se oT ’ H H No_—_SOH N._~_-SO;H 7 Ae H H ° N__~_-SOH ® NA -SOH H,N F and H or OH and pharmaceutically acceptable salts, esters, and prodrugs thereof.

80. Use of a compound in the treatment or prevention of an amyloid-related disease, wherein said cornpound is selected from the group consisting of: LN (some 4

[0] ne / le} A o NH o NN LAK HNN N3 SO;Na ) & “oH -229. Amended Sheet: 18 April 20808

HCI J CO.H PAN NTR 7 \ Oman OO Bm OH HzN SoH HN ~~~ 2 ~~ NT 3 SO3H N or a pharmaceutically acceptable salt, ester or prodrug thereof.

81. The use of any one of claims 1-80, wherein said compound is not a compourad of Table 2A.

82. The use of any one of claims 1-81, wherein said amyloid-related disease is Alzheimer’s disease, cerebral amyloid angiopathy, inclusion body myositis, macular degener ation, MCI, or Down’s syndrome.

83. A compound of Formula I as described in claim 1 or Formula II as described in claim 19, or a pharmaceutically acceptable salt, ester or prodrug thereof, wheerein said compound i s selected from the group consisting of: i : & 50 0H Sa Nel ~~ S

Jr. NSO A ! y y H H ANG ach NaN H as “TY Son H ING NP AN == SNS d =r SO3H N SoH i 4 Non H N 0 Rd = oF i! NON Neo OH -230 - Amended Sheet: 18 April 2008

OOhd X ~~ No (rT NGS Pa aN H Ne one Hi ~~ CH, } ANN NS SOM NN Nd SOsH H H,C Oo H,C HyCO H N SO,H INGEN H ~~ ’ €O,Bn PN N SO3H Ak SO,H on SoH . ~~ 0Me Br ~TS H CH,0H H iN SoH ~ ® 3! SOH H ~~ NT ahd N SO4H o ~~ GaN ANG NP R HO ANGE ° HO

HO. AN OH H N SO3H H ‘ com M5 ~NTON on CH,0CH, -231- Amended Sheet: 18 April 2008

SNIP i" CH,OH 2 CH,0 ou Hin So CH,

H.C % SO. INN NTN H N SOH N SOH 3 ~~ NT CHy0H 0 NH, HC” Ns 0H i SO,H A i SO.H CH.O Ne . ~~ NU0YE 3 07 NH, Hye < NP i SOM H ; ~~ NS Na _OH OH HN HN Sse QP ©0 oo HN ~~ Son __OH cH INT H ® oO No _~_-SC:H NT som 2 ~0Me 0} H CH, HyC Na _——_-SOH : oF TNH, NT som H RY of 0” wn Cann o NT sop @ -232- Amended Sheet: 18 April 2008

.OCH,Ph OCH,Ph H I Tr HON S0H NN NsoH “ NT "so H J N H 07 TOCHCH, Ax ; : i. y } N , Ne ~-SOH BG: ~~ SOH JY ~~ NTTs FZ : CH,OH ® “X H H H ; H AR son hh dhe SLR son = CH,OH : CH,0H o7 ome H H H,C Na S0:H H C J} NSH YY flO oN, 070 < NH

[8] 2 Hi H H ~ SO,H N SO,H . ~~ ~~ s . EN Nh MR son Pon Pon 4 i " i N SO,H ) —0 PY ) —0 NY ~~ NOY Ma, ZN H : o NH, oo al oN 0” PP ! : ! =0 N =0 Na SoH N s= N s= ~ ~~ “on rx ~ TN TY = : OMe 0% Now 0 H, ol 0} oO H H _o H lo -233. Amended Sheet: 18 April 2008

- H H i lo) H i 0

MN. _ ~~ SoH 0 = | ~ N S N S TX TI aT (0) NIH, o a0 oo" OH = Id Vd ~ H N" Do NN" 9g TN Qo IPA HN H lg HN H S! “OH ~~ “oH ~~ N “oH INAS oH (@n] (@] s LOH, LOH, N" 0 N 0 Ngo HN _~_-S. HN __~_-S. HN _~_-S. OH OH OH NR g PN Me INH, Ro NH, 0 NT .0 HN S. HN S. HN S! ~~" oH ~N oH ~~ NN OH (on 0] BE M e Me Me Y N° Op NT R.0 rN Do ND HN AS. HN _~_-S. ~~ “OH OH OH 2 M (0) 0] e NTO 0 AR Me ~Me wn HE TN fo No ~~ TN ‘OH HN. _~_-S. HN _~_-S. OH OH ? M e H N" Qo fo) 0 H H i. HN ~N ~ N [0] 0 x N Q 0 OH an. M4 we. M8 N ~~ ~~ 0u OH o) - lo} N Qo HN N 1. HN ; [1.0 wn A L° ~~ ‘OH ~N “OH OH 0 ¢) REY ¢) Y (eo Y 0 N SN ~~ 0u OH -234 - Amended Sheet: 18 April 2008

- - 0) HN i Lo HN i Lo HN ; [© ~~ ~~ T on ~Ton AEH NE lo) lo} 0) Dr ~~ 0 N 0.0 HILO I 2 HN Ss HN _~_-S.

HN _~_-S.

OH OH OH o) \ ? 0 \ Cry ge Se TH ap : H Il, H Sr Ng H < HN s HN Ss” HN S” NON “OH ~~ N OH ~ON OH (0) 6) 0] \ No § TX Re HN ; 1° NT EN AAS, NT EN ACSS NT on H OH H OH R FS fo} oH Qo > Lo HN iy 1% H (l., HN N SN MNS ~~ on OH 0 lo) 0 MeS MeS oH © ~NAon O oH Og © HN =O ) HN ~_S HN S! Z . ~T""on ~ on N OH i PON H : 0, . ; HN Ss N ~~ oH Pome ~~ ‘on H (0) MeS PN ~ on ©.0 OH f.0 TY" "OH 0 ANS HN S! HN Ss’ ~T OH ~N OH MeS ~~. HN _~_"5. HN Ss! HN Ss.

OH N Ton N TN -235- Amended Sheet: 18 April 2008

H Os 0 H Ox Oo H 05° A Gg NCS AN Sion SE “OH ( ) CN H Ox 0 H Ox 0 H Oa BY Dg” NC X NC. N Ss” lo] \ O—

H O. 0 H *N Be H Ox 0 N 7 (4 So SASL ASE dS, CN H H H Ox 0 N-— Nw ~ Hoes A ee? (eT “N H N N N =~M ~N / TN

N. | H Pe N, H Og o=° N, H Og° N OH N ~NN OH N ~~ T “OH 0 \ O— H H OL ° H 0s 0 N— N 35% N Ss? N, lw 0, 0 Ox TOH HO Non N No ] N

N. .N N H H H Os H 0. 0 N— N Ss’ N Ss? N, ln o, ,0 HO ~~ HO Non N N NaS H 0} (I) \ O— H Os 0 H Os 0 H Qs Pe N >s HO N Ss. N SZ N Ny ors on A, -236 - Amended Sheet: 18 April 2008

F H o, ,0 Cl H o>. .0 Br “ 0, ,0 QU ~~ on TIAA, QPL N ug? Me H 0, 0 0, 0 ~Son Nao~—-5 0H EN MeO oO .0 H ~ 7% Ne~-SS H A Neo ~-S OH TIAL, SVL > OH OH H Oo PB O Br. H oOo, 0 0 o ~~ TN0H N _~_-S ~OH PN OH OH OH " y 0, PY H <, % 0 MeO H 0, .° ~~ on Nao ~—"5~0H TAZ OH OH OH Oo, .,0 Ro ~%, R O° \ O° NTN “OH | NN “OH OMe OMe

F 0..0 MeO H NI H Os 0 0 fo) N So N S ~ H NI TL ~~ on TOL NTN Ton JAAS, OMe OMe Me “ H 0s © o.,0 0, ,0 . Nao ~-S H NL H (NR) oH JAAS, _OEASE, OMe : ! H 0...° H Og? o_,0 OK ~~ cl ~~ — “OH LAA, OMe MeO Me H Ou? o_ 0 H Os ?® ~~" ou JQ PL . ~~ 0m Br OMe OH

0.0 N Og H No N_~—u-5~ H 0, 0 Anon eo on JO IAZE, Cl Me OH OH OMe H °N ,0 H oO, 0 i °N 0 NN NaS on ~SS B H E CE OH 3 OH OMe OMe -237 - Amended Sheet: 18 April 2008 o_,0 Oo, .0 o, 0 H NZ) H “s ” 1 Sg” Nao ~Sou ~~ NT on ~~ on 1 Ci MeO OH OMe OMe H SPY o °° F y Cog? M Neo~S<on B ~~ TSNoH ~~ oH e OH OMe (0) 0 " o, 0 H Sa a o_,0 NR So H 2 Neon Ne _~— OH Ne ~_S CF; i OH OH OMe F CF Br H Oo. .0 i 5? ’ i 0% N ON NO S OH QPL “oH oH OH OH I H Oy? Br H oN 0 OMe i O° Nr “OH NN ~NS “CH OH OH Me o_,0 I F H N57 Zz H SN = H Os?° ~TN “OH a | N~SNon ~~ | “OH OH OMe CF, o © Me 00 cl f 0,0 S OH OH CAA “oH OH OMe OM B ° u 0 ,0 Qu Oy fH 0, 0 N ~~ on No _~_ ~OH Nao~Son OH OMe H ON BY O 0 N77 I H 7 N S o_..0 Ng” NNO H Neon Noon OH Me «OMe cl Me Me MMe H 0.0 H 0) Sg PY H Oy 0 /, Cet DED OR OMe MeO Br F -238- Amended Sheet: 18 April 2008

“ow Og 0 N 7 N 7? NG ~ON0N ~~ NS GG on OH OH OM MeO © Me Cl o._,0 0_,0 OMe H Oy py Ne ~~ 3 pid Nox OH ~TNS OH OMe MeO CF, Br H Ag? i! ANP H Og ~~ NS “OH ~~ N “OH ~~ TON ~oH MeO F OMe I H Oy py H ON 0 H 0) NP oO Nou Nao~"S~on Non MeO MeO CF, Me Br H (0) Ny 0 ’ On?° H 0) N “ 0 Non ~N “OH ~TN ~OH MeO MeO OMe CF, I H Os ?° H O° H One® ~TN “OH ~TNS “OH ~~ N “OH MeO F OMe Me H Os? 0, 0 H oN 0 No ~-SN H N No~"3>0n OH Noo~Ssop Me MeO Cl pr Me CF, e H O° H O° H 0,0 Nae" ~0n N "0H NS on MeO MeO Br F OMe -239- Amended Sheet: 18 April 2008 o._,0 H NZ H 0 2 O H e) 2 0 N ~NUAN N S N S OH ~~ “OH ~~ N “OH MeO MeO © Me 1 : Cl Me Me F Cl Br H Oy 0 H O. 0 H Oy, PY “Za Non a ~~ 0h a Neo~on Me Cl Me Me H ON 0 Me H 0,0 ne 0..0 Nat Sw oN >sL c H No AN ~NTNoH = ~~ 0H p ~~Son Br F F H Oag® H O° H Oy 2° = w- No “OH Zz N ~~ “OH ZF SNo~Son Me & Cl Me H SN PY H °N PY Me” YO u o, 0 FZ ~~ Non A eon OG

Br. Br

F 0. .0 H Oy 0 H (ON 0 H Ng? NSN IR NPONPAN Cp, Zz OH Zz oH Me H O° H 0, ,0

Me. \ i ol ; op = RYAN Ne “OH ZZ No~—% ou FZ Ne ~"50n OMe OMe HO H OP Ho wt ~ ow ~ = OH = Non = OH ~ 240 - Amended Shezet: 18 April 2008 o..0 o_,0 H NA H Oy 0 H Ng” WN Son geet Rae “OH — F F F o_,0 o_.0 H NZ

H 0. .0 H N77 Neo NL S — v OH Cl Cl Cl

Oo. 0 o._,0 H No Oo 0 H N N S H N72 N S = SIN “OH >s == ~~ “OH OMe F H Os ° H O° o> = N ~~ “OH Z ~NN “OH Ant, Ct OMe Ahn ~~K

He. H lo) H H ~ RD I ~ t- AY 0 Lor ~~~ Tes rr ~SE £ Crs o So ~ MEN a xX OOK ~ ° ~ -241- Amended Sheet: ¥ 8 April 2008

2, EP ad SN Ns ox fo” PN Ones oT ae? Bn ee CO Ae SAA he or a . TS <n Jive A eal <i os Jeasa lS PUSS

-»

84. The compound of claim 83, or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein said compound is selected from the group consisting of: ] : NPN OH SASH

HO. NN"50,H 7 & CH, " H Ne ol SO joy NGGPZ wef H,C “~K rE Ha, o Yo go H 0 H H {q_0° NE SIC aes 3° JE Ao < FUN S00 or -

85. A compound of Formula III as described in claim 23, wherein said compound is selected from the group consisting of: NC Cc NTT" 50H SO3H —~-) we NA so {HN nso 0 Hs HO OH cl NO s05H ao YW so H Son HPO -243 - Amended Sheet: 18 April 2008 v WO 2004/113275 PCT/1B2004/002375 and Or NH "so, “ ~ A or a pharmaceutically acceptable salt, ester, or prodrug thereof.

86. A compound of Formula IV as described in claim 40, wherein said compound is selected from the group consisting of: /\ /\ on) NT SoH NOW so / \__/ F ’ od _)- NOW sos __/ or pharmaceutically acceptable sa Its, esters, or prodrugs thereof.

87. A compound of Formula VV: R'® lo) li RY —(@@)n—N—(CH)—S—A—R" 0 v) wherein: A is nitrogen or oxygen; Ris hydrogen, salt-fo rming cation, ester forming group, —(CH.)x—Q, or when A is nitrogen, A and R'' taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof, wherein A and R!' taken together are not a leucine residue; Q is hydrogen, thiazoly 1, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; xis 0, 1,2, 3, ord; nis0,1,2,3,4,5,6,7, 8,9,0r10; aa is a natural or unnatu ral amino acid residue; mis0,1,2,0r3; -244 - Amended Sheet: 18 April 2008

~ WO 2004/113275 PCT/IB2004/002375 R'is hydro gen or protecting group; RY is hydrogen, alkyl or aryl; and pharmaceutically acceptable salts, est-ers, or prodrugs thereof, provided that when m is 0, R'* and R!® are both hydrogen, and A is oxygen, then R' is not a hydrogen or a salt-forming cation; provided that when A is oxygen, R'' isa hydrogen or a salt-forming cation, nis 2, mis 1, R'* and R" are both hydrogen, then aa is not a phenylalanine residue; provided that when A is oxygen, R'! is a hydrogen or a salt-forming cation, n is 2, 3 or 4, mis 2, R" and R'® are both hydrogen, then aa is not D-phenylalanine.

88. The compound of claim 87, wherein n is 2, 3 ©r4.

89. The compound of claim 87, wherein n is 3.

90. The compound of any one of claims 88-89, wherein m is 0.

91. The compound of any one of claims 88-90, wherein A-R'! is a residue of a natural amino acid, or a salt or ester thereof.

92. The compound of claims 91, wherein A-R'' is a phenylalanine residue.

93. The compound of any one of claims 87-92, wherein (aa), is a residue of phenylalanine, glycine, or phe-phe.

94. The compound of any one of claims 87-93, wh_erein R'® is hydrogen or substituted alkyl.

95. The compound of claim 94, wherein R' is aryl alkyl.

96. The compound of claim 87, wherein said comp-ound is selected from the group consisting of: H QQ, .° H H 0 Q 0 tse oy 0P I NY hy NS NSN o_- Dir x, a a! Ll 0 ; H cr -245 - Amended Sheet: 18 April 2008

© WO 2004/113275 PCT/IB2004/002375 C2 ONa 0 OP SN i coaia i 7 HN MSs o~ NTN"50,N7 oo H lo] A (en ] cy ® x cr or 4 rs ae °N PY HN _~SS EN : ; Hoo or pharmaceutically acceptable salts, esters, or prodrugs thereof.

97. A compound of Formula VI as described in claim 5s 8, wherein said compound is selected from the group consisting of: i i ol SO3H 0 N"~""50:Na 0 A, SL BY ANT A ~N N SO3H H H O Cl NH. NH sos J 0 | NT S00: 3 - H 9] I N__~_SOsH Ae so H H (TY A 0 Va Va Na Na NaN N"NsoH Lol Sa SO H H S NH SO3H NNT re NH" 80H Oo and ’ and pharmaceutically acceptable salts, esters, and prodrugs t_hereof. -246 - Aa mended Sheet: 18 April 2008

98. A compound of Formula VII as described in claim 69, wherein said compound is selected from the group consisting of: Oo— —0 \ NN Ns0H / NH 50.H H 0 / O —- N— TN" s0H - / o— Sola seace (0) al ~ and 06 Ge" red sears oT and pharmaceutically acceptable salts, esters, and prodrugs thereof.

9. A compound selected from the group consisting of: dA son CL N S NH» H H NH Morty SSS [e] 00 , L_~sou OH amd pharmaceutically acceptable salts, esters, and prodrugs thereof.

100. The compound of claim 83, wherein said compound is of ®he formula: o SUN o} -247 - Amended Sheet: 18 April 2008

© Pp J WQ 2004/113275 PCT/IB2004/002375 or apharmaceutically acceptable salt, ester, or prodrug thereof.

101. A pharmaceutical composition comprising a compoun«d according to any one of claims 83 to 100 together with a pharmaceutically acceptable carrier.

102. A compound according to any one of claims 83 to 100, for use in the treatment or prevention of an amyloid-related disease or condition.

103. A compound according to any one of claims 83 to 100, for use in the treatment or prevention of amyloid deposition.

104. The compound according to claim 102 or 103, whereim said disease or condition is related to amyloid-3 deposition.

105. A compound according to any one of claims 83 to 100,. for use in the treatment or prevention of a disease selected from the group consisting of Alzheimer’s disease, cerebral amyloid angiopathy, inclusion body myositis, macular degeneration, MCI, and Down’s syndrome.

106. The compound of claim 105, wherein said compound iss for use in the treatment of Alzheimer’s disease.

107. Use of a compound according to any one of claims 83 £0 100, in the manufacture of a medicament for the treatment or prevention of an aamyloid-related disease or condition.

108. The use of claim 107, wherein said disease or condition is related to amyloid-3 deposition.

109. Use of a compound according to any one of claims 83 to 100, in the manufacture of a medicament for the treatment or prevention of a dissease selected from the group consisting of Alzheimer’s disease, cerebral amyloid angiopathy, inclusion body myositis, macular degeneration, MCI, and Down’ s syndrome.

110. The use of claim 109, wherein said medicament is for tkae treatment of Alzheimer’s disease. - 248 - Ameended Sheet: 18 April 2008