WO2004113275A2 - Methodes et compositions pour traiter les maladies liees a l'amyloide - Google Patents

Methodes et compositions pour traiter les maladies liees a l'amyloide Download PDF

Info

Publication number
WO2004113275A2
WO2004113275A2 PCT/IB2004/002375 IB2004002375W WO2004113275A2 WO 2004113275 A2 WO2004113275 A2 WO 2004113275A2 IB 2004002375 W IB2004002375 W IB 2004002375W WO 2004113275 A2 WO2004113275 A2 WO 2004113275A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
amyloid
subject
pharmaceutical composition
ofthe
Prior art date
Application number
PCT/IB2004/002375
Other languages
English (en)
Other versions
WO2004113275A3 (fr
Inventor
Xianqi Kong
David Migneault
Isabelle Valade
Xinfu Wu
Francine Gervais
Original Assignee
Neurochem (International) Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/871,365 external-priority patent/US7244764B2/en
Priority claimed from US10/871,514 external-priority patent/US7414076B2/en
Priority to CN2004800242077A priority Critical patent/CN1839118B/zh
Priority to CA2529257A priority patent/CA2529257C/fr
Priority to KR1020057024647A priority patent/KR101124935B1/ko
Priority to JP2006516599A priority patent/JP5146714B2/ja
Priority to AU2004249529A priority patent/AU2004249529A1/en
Priority to EA200600078A priority patent/EA012429B1/ru
Application filed by Neurochem (International) Limited filed Critical Neurochem (International) Limited
Priority to UAA200600637A priority patent/UA96115C2/uk
Priority to MXPA05014166A priority patent/MXPA05014166A/es
Priority to EP04744034A priority patent/EP1644325A2/fr
Priority to NZ544684A priority patent/NZ544684A/en
Priority to BRPI0411743-3A priority patent/BRPI0411743A/pt
Publication of WO2004113275A2 publication Critical patent/WO2004113275A2/fr
Publication of WO2004113275A3 publication Critical patent/WO2004113275A3/fr
Priority to IL172194A priority patent/IL172194A/en
Priority to NO20055894A priority patent/NO335084B1/no

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C307/02—Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
    • C07C309/15—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton the nitrogen atom of at least one of the amino groups being part of any of the groups, X being a hetero atom, Y being any atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/45—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/46—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/69—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a carbon skeleton substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/31—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
    • C07C311/32—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/30—Isothioureas
    • C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C07C381/02—Thiosulfates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
    • C07F9/165—Esters of thiophosphoric acids
    • C07F9/1651—Esters of thiophosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • 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 deposits have common morphologic properties, stain with specific dyes ⁇ e.g., Congo red), and have a characteristic red-green birefiingent appearance in polarized light after staining. They also share common ultrastructural features and common X-ray diffraction 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.”
  • amyloid diseases can be idiopathic, but most of these diseases appear as a complication of a previously existing disorder.
  • primary amyloidosis (AL amyloid) can appear without any other pathology or can follow plasma cell dyscrasia or multiple myeloma.
  • 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 amyloidosis, e.g., Familial Mediterranean Fever (FMF). This familial type of amyloidosis is genetically inherited and is found in specific population groups. In both primary and secondary amyloidosis, deposits are found in several organs and are thus considered systemic amyloid diseases.
  • FMF Familial Mediterranean Fever
  • “Localized amyloidoses” are those that tend to involve a single organ system. Different amyloids are also characterized by the type of protein present in the deposit. For example, neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, Creutzfeldt- Jakob disease, and the like are characterized 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.
  • amyloid plaques found in the parenchyma and the blood vessel is formed by the deposition of fibrillar A ⁇ amyloid protein.
  • Other diseases such as adult-onset diabetes (type LT diabetes) are characterized by the localized accumulation of amyloid fibrils in the pancreas.
  • amyloids have formed, there is no known, widely accepted therapy or treatment which significantly dissolves amyloid deposits in situ, prevents further amyloid deposition or prevents the initiation of amyloid deposition.
  • Each amyloidogenic protein has the ability to undergo a conformational change and to organize into ⁇ -sheets and form insoluble fibrils which may be deposited extracellularly or intracellularly.
  • Each amyloidogenic protein although different in amino acid sequence, has the same property of forming fibrils and binding to other elements such as proteoglycan, amyloid P and complement component.
  • each amyloidogenic protein has amino acid sequences which, although different, show similarities such as regions with the ability to bind to the glycosaminoglycan (GAG) portion of proteoglycan (referred to as the GAG binding site) as well as other regions which promote ⁇ -sheet formation.
  • GAG glycosaminoglycan
  • Proteoglycans are macromolecules of various sizes and structures that are districuted almost everywhere in the body.
  • GAGs polysaccharide chains
  • amyloid fibrils once deposited, can become toxic to the surrounding cells.
  • 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.
  • oligomeric (soluble) as well as fibrillar A ⁇ peptide was shown to be capable of triggering an activation process of microglia (brain macrophages), which would explain the presence of microgliosis and brain inflammation found in the brain of patients with Alzheimer's disease.
  • Both oligomeric and fibrillar A ⁇ 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).
  • amyloidogenic protein LAPP when organized in oligomeric forms or in fibrils, has been shown to induce ⁇ -islet cell toxicity in vitro.
  • appearance of LAPP fibrils in the pancreas of type II diabetic patients contributes to the loss ofthe ⁇ islet cells (Langerhans) and organ dysfunction which can lead to insulinemia.
  • amyloidosis is related to ⁇ microglobulin and is found in long- term hemodialysis patients. Patients undergoing long term hemodialysis will develop ⁇ 2 -microglobulin fibrils in the carpal tunnel and in the collagen rich tissues in several joints. This causes severe pains, joint stiffness and swelling.
  • Amyloidosis is also characteristic of Alzheimer's disease. Alzheimer's disease is a devastating disease ofthe brain that results in progressive 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.
  • a main constituent of these amyloid plaques is the amyloid- ⁇ peptide (A ⁇ ), a 39-43 amino-acid protein that is produced through cleavage ofthe ⁇ -amyloid precursor protein (APP).
  • a ⁇ amyloid- ⁇ peptide
  • APP ⁇ -amyloid precursor protein
  • a ⁇ naturally arises from the metabolic processing ofthe amyloid precursor protein ("APP") in the endoplasmic reticulum ("ER"), the Golgi apparatus, or the endosomal-lysosomal pathway, and most is normally secreted as a 40 (“A ⁇ l-40") or 42 (“A ⁇ l-42”) amino acid peptide (Selkoe, Annu. Rev. Cell Biol. 10, 373-403 (1994)).
  • APP amyloid precursor protein
  • ER endoplasmic reticulum
  • Golgi apparatus the endosomal-lysosomal pathway
  • Alzheimer's disease is supported by the presence of extracellular A ⁇ deposits in senile plaques of Alzheimer's disease, the increased production of A ⁇ in cells harboring
  • Alzheimer's disease associated genes e.g., amyloid precursor protein, presenilin I and presenilin II; and the toxicity of extracellular soluble (oligomeric) or fibrillar A ⁇ to cells in culture. See, e.g., Gervais, Eur. Biopharm. Review, 40-42
  • Alzheimer's disease is characterized by diffuse and neuritic plaques, cerebral angiopathy, and neurofibrillary tangles.
  • Plaque and blood vessel amyloid is believed to be formed by the deposition of insoluble A ⁇ amyloid protein, which may be described as diffuse or fibrillary. Both soluble oligomeric A ⁇ and fibrillar A ⁇ are also believed to be neurotoxic and inflammatory.
  • CAA cerebral amyloid angiopathy
  • the present invention relates to the use of certain compounds in the treatment of amyloid-related diseases.
  • 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 ofthe invention.
  • the invention also pertains to each ofthe novel compounds ofthe invention as described herein.
  • 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
  • the invention pertains, at least in part to compounds of
  • R 1 is a substituted or unsubstituted cycloalkyl, heterocyclic, aryl, arylcycloalkyl, bicyclic or tricyclic ring, a bicyclic or tricyclic fused ring group, or a substituted or unsubstituted C 2 -C 10 alkyl group;
  • R is selected from a group consisting of hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl;
  • Y is SOAX ⁇ , OSO ⁇ , or SSOAX + ;
  • X* ⁇ is hydrogen, a cationic group, or an ester-forming group (t.e., as in a prodrug, which are described elsewhere herein); and each of L 1 and L 2 is independently a substituted or unsubstituted -Cs alkyl group or absent, or a pharmaceutically acceptable salt thereof, provided that when R 1 is alkyl, L 1 is absent.
  • the invention pertains, at least in part to compounds of Formula II:
  • R 1 is a substituted or unsubstituted cyclic, bicyclic, tricyclic, or benzoheterocyclic group or a substituted or unsubstituted C 2 -C 10 alkyl group;
  • R 2 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl, or linked to R 1 to form a heterocycle;
  • Y is SO 3 ⁇ X + , OSO 3 ⁇ X + , or SSO 3 ⁇ X + ;
  • X is hydrogen, a cationic group, or an ester forming moiety; m is O or 1; n is 1, 2, 3, or 4;
  • L is substituted or unsubstituted CrC 3 alkyl group or absent, or a pharmaceutically acceptable salt thereof, provided that when R 1 is alkyl, L is absent.
  • the invention pertains, at least in part to compounds of Formula ILL:
  • A is nitrogen or oxygen
  • R l is hydrogen, salt-forming cation, ester forming group, — (CH 2 ) X — Q, or when A is nitrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
  • Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;
  • x is O, 1, 2, 3, or 4;
  • n is 0, 1 ,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
  • R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 and R 7a are each independently hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, or two R groups on adjacent ring atoms taken together with the ring atoms form a double bond, provided that one of R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 and R 7a is a moiety of Formula LTIa:
  • m is O, 1, 2, 3, or 4;
  • R A , R B , R c , R D , and R E are independently selected from a group of hydrogen, halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothiazolyl, and benzoimidazolyl; and pharmaceutically acceptable salts and esters thereof, provided that said compound is not 3-(4-phenyl-l, 2, 3, 6-tetrahydro-l -pyridyl)- 1-propanesulfonic acid.
  • the invention pertains at least in part to compounds of Formula V:
  • A is nitrogen or oxygen
  • R 11 is hydrogen, salt-forming cation, ester forming group, — (CH 2 ) X — Q, or when A is nitrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
  • Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;
  • x is O, 1, 2, 3, or 4;
  • n is 0, 1 ,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
  • R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 , and R 7a are each independently hydrogen, alkyl, rnercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, R 4 and R 5 taken together, with the ring atoms they are attached to, form a double bond, or R and R taken together, with the ring atoms they are attached to, form a double bond; m is .O, 1, 2, 3, or 4; R 8 , R 9 , R 10 , R 11 , and R 12 are independently selected from a group of hydrogen, halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl, cyclo
  • the invention includes compounds of Formula V:
  • A is nitrogen or oxygen;
  • R 11 is hydrogen, salt-forming cation, ester forming group, — (CH 2 ) X — Q, or when
  • A is nitrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
  • Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;
  • x is O, 1, 2, 3, or 4;
  • n is 0, 1 ,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
  • aa is a natural or unnatural amino acid residue;
  • m is O, 1, 2, or 3;
  • R 14 is hydrogen or protecting group
  • R 15 is hydrogen, alkyl or aryl, and pharmaceutically acceptable salts and prodrugs thereof.
  • the invention includes compounds ofthe Formula VI:
  • n is i, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • A is oxygen or nitrogen;
  • R 11 is hydrogen, salt-forming cation, ester forming group, — (CH 2 ) X — Q, or when A is nifrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
  • Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; x is 0, 1, 2, 3, or 4;
  • R 19 is hydrogen, alkyl or aryl
  • Y 1 is oxygen, sulfur, or nitrogen
  • Y is carbon, mtrogen, or oxygen
  • R is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;
  • R 21 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl, or absent ifY 2 is oxygen;
  • R 22 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl; or R 22 is hydrogen, hydroxyl, alkoxy or aryloxy ifY 1 is
  • the invention includes compounds of Formula VLI:
  • n 2, 3, or 4;
  • A is oxygen or nitrogen;
  • R 11 is hydrogen, salt-forming cation, ester forming group, — (CH 2 ) X — Q, or when A is nifrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
  • Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; is O, 1, 2, 3, or 4;
  • G is a direct bond or oxygen, nitrogen, or sulfur; z is O, 1, 2, 3, 4, or 5; m is O or 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 25 is independently selected from hydrogen, halogen, cyano, hydroxyl, alkoxy, thiol, amino, nitro, alkyl, aryl, carbocyclic, or heterocyclic, and pharmaceutically acceptable salts thereof.
  • 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.
  • the compound may also prevent the amyloid protein, in its soluble, oligomeric form or in its fibrillar form, from binding or adhering to a cell surface and causing cell damage or toxicity.
  • the compound may block amyloid-induced cellular toxicity or macrophage activation.
  • the compound may block amyloid-induced neurotoxicity or microglial activation.
  • the compound protects cells from amyloid induced cytotoxicity of B-islet cells.
  • the compound may enhance clearance from a specific organ, e.g., the brain or it decreases concentration ofthe amyloid protein in such a way that amyloid fibril formation is prevented in the targeted organ.
  • the compounds ofthe invention may be administered therapeutically or prophylactically to treat diseases associated with amyloid fibril formation, aggregation or deposition.
  • the compounds ofthe invention may act to ameliorate the course of an amyloid related disease using any ofthe following mechanisms (this list is meant to be illustrative and not limiting): slowing the rate of amyloid fibril formation or deposition; lessening the degree of amyloid deposition; inhibiting, reducing, or preventing amyloid fibril formation; inhibiting neurodegeneration or cellular toxicity induced by amyloid; inhibiting amyloid induced inflammation; enhancing the clearance of amyloid; or favoring the degradation of amyloid protein prior to its organization in fibrils.
  • the compounds ofthe invention may be administered therapeutically or prophylactically to treat diseases associated with amyloid- ⁇ fibril formation, aggregation or deposition.
  • the compounds ofthe invention may act to ameliorate the course of an amyloid- ⁇ related disease using any ofthe following mechanisms (this list is meant to be illustrative and not limiting): slowing the rate of amyloid- ⁇ fibril formation or deposition; lessening the degree of amyloid- ⁇ deposition; inhibiting, reducing, or preventing amyloid- ⁇ fibril formation; inhibiting neurodegeneration or cellular toxicity induced by amyloid- ⁇ ; inhibiting amyloid- ⁇ induced inflammation; enhancing the clearance of amyloid- ⁇ from the brain; or favoring the degradation of amyloid- ⁇ protein prior to its organization in fibrils.
  • Therapeutic compounds ofthe invention may be effective in controlling amyloid- ⁇ deposition either following their entry into the brain (following penetration of the blood brain barrier) or from the periphery.
  • a compound When acting from the periphery, a compound may alter the equilibrium of A ⁇ between the brain and the plasma so as to favor the exit of A/? from the brain. It may also increase the catabolism of neuronal A ⁇ and change the rate of exit from the brain. An increase in the exit of A ⁇ from the brain would result in a decrease in A/3 brain and cerebral spinal fluid (CSF) concenfration and therefore favor a decrease in A ⁇ deposition.
  • CSF cerebral spinal fluid
  • compounds that penetrate the brain could confrol deposition by acting directly on brain A ⁇ e.g., by maintaining it in a non-fibrillar form, favoring its clearance from the brain, or by slowing down APP processing.
  • These compounds could also prevent A ⁇ in the brain from interacting with the cell surface and therefore prevent neurotoxicity, neurodegeneration or inflammation. They may also decrease A ⁇ production by activated microglia.
  • the compounds may also increase degradation by macrophages or neuronal cells.
  • 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- ⁇ deposition, such as in Down's syndrome individuals and in patients with cerebral amyloid angiopathy ("CAA”) or hereditary cerebral hemorrhage.
  • CAA cerebral amyloid angiopathy
  • the method is used to treat mild cognitive impairment.
  • Mild Cognitive Impairment 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.
  • 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 freatment of LBM by delivery ofthe compounds to muscle fibers. Additionally, it has been shown that A ⁇ is associated with abnormal extracellular deposits, known as drusen, that accumulate along the basal surface ofthe retinal pigmented epithelium in individuals with age-related macular degeneration (AMD). AMD is a cause of irreversible vision loss in older individuals.
  • AMD age-related macular degeneration
  • a ⁇ deposition could be an important component ofthe local inflammatory events that contribute to afrophy ofthe retinal pigmented epithelium, drusen biogenesis, and the pathogenesis of AMD (Johnson, et al, Proc. Natl. Acad. Sci. USA 99(18), 11830-5 (2002)).
  • the present invention therefore relates to the use of compounds of Formulae I, LI, III, LV, V, VL, VII, or otherwise described herein in the prevention or treatment of amyloid-related diseases, including, ter alia, Alzheimer's disease, cerebral amyloid angiopathy, mild cognitive impairment, inclusion body myositis, Down's syndrome, macular degeneration, as well as other types of amyloidosis like LAPP- related amyloidosis (e.g., diabetes), primary (AL) amyloidosis, secondary (AA) amyloidosis and ⁇ 2 microglobulin-related (dialysis-related) amyloidosis.
  • amyloid-related diseases including, ter alia, Alzheimer's disease, cerebral amyloid angiopathy, mild cognitive impairment, inclusion body myositis, Down's syndrome, macular degeneration, as well as other types of amyloidosis like LAPP- related amyloidosis (e.g., diabetes), primary (AL)
  • LAPP Ln Type II diabetes related amyloidosis
  • the amyloidogenic protein LAPP induces ⁇ -islet cell toxicity when organized in oligomeric forms or in fibrils.
  • appearance of LAPP fibrils in the pancreas of type LI diabetic patients contributes to the loss ofthe ⁇ islet cells (Langerhans) and organ dysfunction which leads to insulinemia.
  • a amyloidosis is usually found associated with plasma cell dyscrasia and multiple myeloma. It can also be found as an idiopathic disease. Secondary (AA) 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 Familial Mediterranean Fever (FMF). ⁇ 2 microglobulin-related (dialysis-related) amyloidosis is found in long-term hemodialysis patients. Patients undergoing long term hemodialysis will develop /3 2 - microglobulin fibrils in the carpal tunnel and in the collagen rich tissues in several joints.
  • FMF Familial Mediterranean Fever
  • the present invention relates to the use of compounds of Formulae I, IL, III, LV, V, VI, VII, or compounds otherwise described herein in the freatment of amyloid-related diseases.
  • compounds of Formulae I, IL, III, LV, V, VI, VII, or compounds otherwise described herein in the freatment of amyloid-related diseases.
  • some definitions of terms referred to herein are set forth below.
  • 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 microbial infections, and malignant neoplasms. The most common form of reactive or secondary (AA) amyloidosis is seen as the result of long-standing inflammatory conditions. For example, patients with Rheumatoid Aithritis or Familial Mediterranean Fever (which is a genetic disease) can develop AA amyloidosis.
  • AA amyloidosis and "secondary (AA) amyloidosis” are used interchangeably.
  • AA fibrils are generally composed of 8,000 Dalton fragments (AA peptide or protein) formed by proteolytic cleavage of serum amyloid A protein (ApoSAA), a circulating apolipoprotein which is mainly synthesized in hepatocytes in response to such cytokines as IL-1, LL-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.
  • ApoSAA serum amyloid A protein
  • AA amyloidosis Underlying diseases which can lead to the development of AA amyloidosis include, but are not 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 as a 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 gut, lung and urogenital tract, basal cell carcinoma, and hairy cell leukemia. Other underlying conditions that may be associated with AA amyloidosis are Castleman's disease and Schnitzler's syndrome.
  • AL amyloid deposition is generally associated with almost any dyscrasia ofthe B lymphocyte lineage, ranging from malignancy of plasma cells (multiple myeloma) to benign monoclonal gammopathy. At times, the presence of amyloid deposits may be a primary indicator ofthe underlying dyscrasia. AL amyloidosis is also described in detail in Current Drug Targets, 2004, 5 159-171.
  • Fibrils of AL amyloid deposits are composed of monoclonal immunoglobulin 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 (V L ) domain thereof. Deposits generally occur in the mesenchymal tissues, causing peripheral and autonomic neuropathy, carpal tunnel syndrome, macroglossia, restrictive cardiomyopathy, arthropathy of large joints, immune dyscrasias, myelomas, 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.
  • Table 1 The data provided in Table 1 are exemplary and are not intended to limit the scope ofthe invention. For example, more than 40 separate point mutations in the transthyretin gene have been described, all of which give rise to clinically similar forms of familial amyloid polyneuropathy.
  • 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.
  • the most prevalent form of secondary AA amyloidosis occurs sporadically, e.g. as a result of ongoing inflammation, and is not associated with Familial Mediterranean Fever.
  • general discussion relating to hereditary amyloid disorders below can also be applied to sporadic amyloidoses.
  • Transthyretin is a 14 kiloDalton protein that is also sometimes referred to as prealbumin. It is produced by the liver and choroid plexus, and it functions in transporting thyroid hormones and vitamin A. At least 50 variant forms ofthe protein, each characterized by a single amino acid change, are responsible for various forms of familial amyloid polyneuropathy. For example, substitution of proline for leucine at position 55 results in a particularly progressive form of neuropathy; substitution of methionine for leucine at position 111 resulted in a severe cardiopathy in Danish patients.
  • ATTR fibril components can be exfracted from such plaques and their structure and sequence determined according 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: 539-42, 1983). Persons having point mutations in the molecule apolipoprotein Al ⁇ e.g.,
  • Gly->Arg26; Trp-»Arg50; Leu-»Arg60 exhibit a fonri of amyloidosis ("Ostertag type") characterized by deposits ofthe protein apolipoprotein AL or fragments thereof (AApoAL). These patients have low levels of high density lipoprotein (HDL) and present with a peripheral neuropathy or renal failure.
  • Asp-»His57 is the basis of another form of Ostertag-type non-neuropathic hereditary amyloid reported in English families.
  • fibrils ofthe mutant lysozyme protein (Alys) are deposited, and patients generally exhibit impaired renal function.
  • This protein unlike most ofthe fibril-forming proteins described herein, is usually present in whole (unfragmented) form (Benson, M.D., et al. CLBA Fdn. Symp. 199: 104-131, 1996).
  • Immunoglobulin light chains tend to form aggregates in various morphologies, including fibrillar ⁇ e.g., AL amyloidosis and 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.
  • Ln AL fibrils lambda ( ⁇ ) chains such as ⁇ VI chains ( ⁇ 6 chains), are found in greater concenfrations than kappa (K) chains. MIL 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 ofthe IgGl subclass. Eulitz et al, PROC NATL ACAD Sci USA 87:6542-46 (1990).
  • AL and LCDD have 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 nTV. Bellotti et al, JOURNAL OF STRUCTURAL BIOLOGY 13:280-89 (2000).
  • amloidogenic heavy chain characterized as consisting solely ofthe VH-D portion of the non-amyloidogenic heavy chain.
  • potential methods of detecting and monitoring freatment of subjects having or at risk of having AL, LCDD, AH, and the like include but are not limited to immunoassaying plasma or urine for the presence or depressed deposition of amyloidogenic light or heavy chains, e.g., amyloid ⁇ , amyloid K, amyloid KLV, amyloid ⁇ , or amyloid ⁇ l.
  • amyloidogenic light or heavy chains e.g., amyloid ⁇ , amyloid K, amyloid KLV, amyloid ⁇ , or amyloid ⁇ l.
  • Brain Amyloidosis The most frequent type of amyloid in the brain is composed primarily of
  • Brain amyloidosis includes those diseases, conditions, pathologies, and other abnormalities ofthe structure or function ofthe brain, including components thereof, in which the causative agent is amyloid.
  • the area ofthe brain affected in an amyloid-related disease may be the sfroma including the vasculature or the parenchyma including functional or anatomical regions, or neurons themselves.
  • a subject need not have received a definitive diagnosis of a specifically recognized amyloid-related disease.
  • the term "amyloid related disease” includes brain amyloidosis.
  • Amyloid- ⁇ peptide is a 39-43 amino acid peptide derived by proteolysis from a large protein known as Beta Amyloid Precursor Protein (“ ⁇ APP"). Mutations in ⁇ APP result in familial forms of Alzheimer's disease, Down's syndrome, cerebral amyloid angiopathy, and senile dementia, characterized by cerebral deposition of plaques composed of A ⁇ fibrils and other components, which are described in further detail below.
  • APP Amyloid Precursor Protein
  • position 717 is proximate to the site of gamma-secretase cleavage of APP in its processing to A ⁇
  • positions 670/671 are proximate to the site of ⁇ -secretase cleavage. Mutations at any of these residues may result in Alzheimer's disease, presumably by causing an increase in the amount ofthe 42/43 amino acid form of A ⁇ generated from APP.
  • the familial form of Alzheimer's disease represents only 10% ofthe subject population. Most occurrences of Alzheimer's disease are sporadic cases where APP and A ⁇ do not possess any mutation.
  • the structure and sequence of A ⁇ peptides of various lengths are well known in the art.
  • Such peptides can be made according to methods known in the art, or exfracted from the brain according to known methods ⁇ e.g., Glenner and Wong, Biochem. Biophys. Res. Comm. 129, 885-90 (1984); Glenner and Wong, Biochem.
  • APP is expressed and constitutively catabolized in most cells.
  • the dominant catabolic pathway appears to be cleavage of APP within the A ⁇ sequence by an enzyme provisionally termed ⁇ -secretase, leading to release of a soluble ectodomain fragment known as APPs ⁇ . This cleavage precludes the formation of A ⁇ peptide.
  • APP can also be cleaved by enzymes known as ⁇ - and ⁇ -secretase at the N- and C-termini ofthe A ⁇ , respectively, followed by release of A ⁇ into the extracellular space.
  • BACE has been identified as ⁇ -secretase (Vasser, et al, Science 286:735-741, 1999) and presenilins have been implicated in ⁇ -secretase activity (De Strooper, et al, Nature 391, 387-90 (1998)).
  • the 39-43 amino acid A ⁇ peptide is produced by sequential proteolytic cleavage ofthe amyloid precursor protein (APP) by the ⁇ and ⁇ secretases enzyme.
  • a ⁇ 40 is the predominant form produced, 5-7% of total A ⁇ exists as A ⁇ 42 (Cappai et al, Int. J. Biochem. Cell Biol. 31. 885-89 (1999)).
  • the length ofthe A ⁇ peptide appears to dramatically alter its biochemical/biophysical properties. Specifically, the additional two amino acids at the C-terminus of A ⁇ 42 are very hydrophobic, presumably increasing the propensity of A ⁇ 42 to aggregate.
  • Jarrett, et al. demonstrated that A ⁇ 42 aggregates very rapidly in vitro compared to A ⁇ 40, suggesting that the longer forms of A ⁇ may be the important pathological proteins that are involved in the initial seeding ofthe neuritic plaques in Alzheimer's disease (Jarrett, et al, Biochemistry 32, 4693-97 (1993); Jarrett, et al. , Ann. N. Y. Acad. Sci. 695, 144-48 (1993)). This hypothesis has been further.
  • Presenilin-1 Presenilin-1
  • PS2 Presenilin-2
  • CAA disorders include, but are not limited to, hereditary cerebral hemorrhage with amyloidosis of Icelandic type (HCHWA-L); the Dutch variant of HCHWA (HCHWA-D; a mutation in A ⁇ ); the Flemish mutation of A ⁇ ; the Arctic mutation of A/3; the Ltalian mutation of A/3; the Lowa mutation of A/3; familial British dementia; and familial Danish dementia.
  • CAA may also be sporadic.
  • ⁇ amyloid As used herein, the terms " ⁇ amyloid,” “amyloid- ⁇ ,” and the like refer to amyloid ⁇ proteins or peptides, amyloid ⁇ precursor proteins or peptides, intermediates, and modifications and fragments thereof, unless otherwise specifically indicated.
  • A/3 refers to any peptide produced by proteolytic processing ofthe APP gene product, especially peptides which are associated with amyloid pathologies, including A ⁇ l-39, A ⁇ l-40, A ⁇ l-41, A ⁇ l-42, and A ⁇ l-43.
  • A/31-42 may be referred to herein as “A/3(l-42)” or simply as “A/342” or “A/3 42 " (and likewise for any other amyloid peptides discussed herein).
  • the terms "/3 amyloid,” “amyloid-/3,” and “A/3” are synonymous.
  • the term “amyloid” refers to amyloidogenic proteins, peptides, or fragments thereof which can be soluble ⁇ e.g., monomeric or oligomeric) or insoluble ⁇ e.g., having fibrillary structure or in amyloid plaque). See, e.g., MP Lambert, et al, Proc. Nat 'I Acad. Sci.
  • 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 seen in a number of different diseases. Though diverse in their occurrence, all amyloid deposits have common morphologic properties, stain with specific dyes ⁇ e.g., Congo red), and have a characteristic red-green birefringent appearance in polarized light after staining. They also share common ultrastructural features and common X-ray diffraction and infrared spectra.
  • Gelsolin is a calcium binding protein that binds to fragments and actin filaments. Mutations at position 187 ⁇ e.g., Asp ⁇ Asn; Asp— »Tyr) ofthe 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 membranes, resulting in corneal dystrophy and cranial neuropathy which progresses to peripheral neuropathy, dysfrophic skin changes and deposition in other organs. (Kangas, H., et al. Human Mol. Genet. 5(9): 1237-1243, 1996).
  • mutant alpha chain of fibrinogen (AfibA) and mutant cystatin C (Acys) also form fibrils and produce characteristic hereditary disorders.
  • AfibA fibrils form deposits characteristic of a nonneuropafhic hereditary amyloid with renal disease; Acys deposits are characteristic of a hereditary cerebral amyloid angiopathy reported in Iceland (Isselbacher, Harrison's Principles of Internal Medicine, McGraw-Hill, San Francisco, 1995; Benson, et al).
  • CAA cerebral amyloid angiopathy
  • PrP Sc abnormal isoforms ofthe normal prion protein
  • AScr normal prion protein
  • CJD Creutzfeldt- Jacob disease
  • GSS Gerstmann-Straussler-Scheinker syndrome
  • FFI fatal familial insomnia
  • GSS has been linked to a PrP mutation at codon 102, while telencephalic GSS segregates with a mutation at codon 117. Mutations at codons 198 and 217 result in a form of GSS in which neuritic plaques characteristic of
  • Alzheimer's disease contain PrP instead of A ⁇ peptide.
  • Certain forms of familial CJD have been associated with mutations at codons 200 and 210; mutations at codons 129 and 178 have been found in both familial CJD and FFI. (Baldwin, supra).
  • Cerebral Amyloidosis Local deposition of amyloid is common in the brain, particularly in elderly individuals. The most frequent type of amyloid in the brain is composed primarily of A ⁇ peptide fibrils, resulting in dementia or sporadic (non-hereditary) Alzheimer's disease. 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.
  • Cerebral amyloid angiopathy refers to the specific deposition of amyloid fibrils 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 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 increases with age. 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 (A/3), corpora amylacea ofthe prostate (/3 2 microglobulin), joints and seminal vesicles.
  • TTR transthyretin
  • DAA Dialysis-related Amyloidosis
  • /3 2 microglobulin j(3 2 M) fibrils commonly develop in patients receiving long term hemodialysis or peritoneal dialysis.
  • /3 2 microglobulin is a 11.8 kiloDalton polypeptide and is the light chain of Class I MHC antigens, which are present on all nucleated cells.
  • /3 2 M is usually distributed in the extracellular space unless there is an impaired renal function, in which case /3 2 M is transported into tissues where it polymerizes to form amyloid fibrils. Failure of clearance such as in the case of impaired renal function, leads to deposition in the carpal tunnel and other sites (primarily in collagen-rich tissues ofthe joints).
  • /3 2 M molecules are not produced by cleavage of a longer precursor protein and are generally present in unfragmented form in the fibrils. (Benson, supra). Retention and accumulation of this amyloid precursor has been shown to be the main pathogenic process underlying DRA.
  • DRA is characterized by peripheral joint osteoarthropathy (e.g., joint stiffness, pain, swelling, etc.). Lsoforms of /3 2 M, glycated j3 2 M, or polymers of /? 2 M in tissue are the most amyloidogenic form (as opposed to native /3 2 M).
  • /3 2 M is confined largely to osteoarticular sites. Visceral depositions are rare.
  • Islet Amyloid Polypeptide and Diabetes Islet hyalinosis was first described over a century ago as the presence of fibrous protein aggregates in the pancreas of patients with severe hyperglycemia (Opie, EL., JExp. Med. 5: 397-428, 1901).
  • islet amyloid composed predominantly of islet amyloid polypeptide (LAPP), or amylin
  • LAPP islet amyloid polypeptide
  • amylin is a characteristic histopa hological marker in over 90% of all cases of Type TL diabetes (also known as Non-Lnsulin Dependent Diabetes, or NLDDM).
  • LAPP islet amyloid polypeptide
  • amylin amylin
  • LAPP is co-secreted with insulin in response to ⁇ -cell secretagogues.
  • This pathological feature is not associated with insulin-dependent (Type L) diabetes and is a unifying characteristic for the heterogeneous clinical phenotypes diagnosed as NLDDM (Type II diabetes).
  • LAPP has also been shown to induce ⁇ -islet cell toxicity in vitro, indicating that appearance of LAPP fibrils in the pancreas of Type IL or Type L diabetic patients (post-islet fransplantation) could contribute to the loss ofthe ⁇ -cell islets (Langerhans) and organ dysfunction.
  • pancreatic LAPP leads to formation of oligomeric IAPP, leading to a buildup of IAPP-amyloid as insoluble fibrous deposits which eventually destroys the insulin-producing ⁇ cells ofthe islet, resulting in ⁇ cell depletion and failure (Westermark, P., Grimelius, L., Acta Path. Microbiol. Scand., sect. A. 81: 291-300,
  • LAPP which organizes into toxic oligomers. Toxic effects may result from intracellular and extracellular accumulation of fibril oligomers. The LAPP oligomers can form fibrils and become toxic to the cells in vitro.
  • LAPP fibrils are likely to continue to grow after the cells are transplanted and cause death or dysfunction ofthe cells. This may occur even when the cells are from a healthy donor and the patient receiving the fransplant does not have a disease that is characterized by the presence of fibrils.
  • compounds ofthe present invention may also be used in preparing tissues or cells for fransplantation according to the methods described in International Patent Application (PCT) number WO 01/003680.
  • the compounds ofthe invention may also stabilize the ratio ofthe concentrations of Pro-IAPP/IAPP, pro-Lnsulin Insulin and C-peptide levels.
  • Such class of drugs could be used together with other drugs targeting insulin resistance, hepatic glucose production, and insulin secretion.
  • Such compounds might prevent insulin therapy by preserving ⁇ -cell function and be applicable to preserving islet transplants.
  • Endocrine organs may harbor amyloid deposits, particularly in aged individuals.
  • Hormone-secreting tumors may also contain hormone-derived amyloid plaques, the fibrils of which are made up of polypeptide hormones such as calcitonin (medullary carcinoma ofthe thyroid), and atrial natriuretic peptide (isolated atrial amyloidosis). Sequences and structures of these proteins are well known in the art.
  • amyloid disease There are a variety of other forms of amyloid disease that are normally manifest as localized deposits of amyloid. In general, these diseases are probably the result ofthe localized production or lack of catabolism of specific fibril precursors or a predisposition of a particular tissue (such as the joint) for fibril deposition. Examples of such idiopathic deposition include nodular AL amyloid, cutaneous amyloid, endocrine amyloid, and tumor-related amyloid.
  • amyloid related diseases include those described in Table 1, such as familial amyloid polyneuropathy (FAP), senile systemic amyloidosis, Tenosynovium, familial amyloidosis, Ostertag-type, non-neuropathic amyloidosis, cranial neuropathy, hereditary cerebral hemorrhage, familial dementia, chronic dialysis , familial Creutzfeldt- Jakob disease; Gerstmann-Sfraussler-Scheinker syndrome, hereditary spongiform encephalopathies, prion diseases, familial Mediterranean fever, Muckle- Well's syndrome, nephropathy, deafness, urticaria, limb pain, cardiomyopathy, cutaneous deposits, multiple myeloma, benign monoclonal gammopathy, maccoglobulinaemia, myeloma associated amyloidosis, medullary carcinomas ofthe thyroid, isolated atrial amyloid, and diabetes.
  • FAP familial am
  • the compounds ofthe invention may be administered therapeutically or prophylactically to treat diseases associated with amyloid fibril formation, aggregation or deposition, regardless ofthe clinical setting.
  • the compounds ofthe invention may act to ameliorate the course of an amyloid related disease using any ofthe following mechanisms, such as, for example but not limited to: slowing the rate of amyloid fibril formation or deposition; lessening the degree of amyloid deposition; inhibiting, reducing, or preventing amyloid fibril formation; inhibiting amyloid induced inflammation; enhancing the clearance of amyloid from, for example, the brain; or protecting cells from amyloid induced (oligomers or fibrillar) toxicity.
  • the compounds of the invention may be administered therapeutically or prophylactically to treat diseases associated with amyloid- ⁇ fibril formation, aggregation or deposition.
  • the compounds ofthe invention may act to ameliorate the course of an amyloid- ⁇ related disease using any ofthe following mechanisms (this list is meant to be illustrative and not limiting): slowing the rate of amyloid- ⁇ fibril formation or deposition; lessening the degree of amyloid- ⁇ deposition; inhibiting, reducing, or preventing amyloid- ⁇ fibril formation; inhibiting neurodegeneration or cellular toxicity induced by amyloid- ⁇ ; inhibiting amyloid- ⁇ induced inflammation; enhancing the clearance of amyloid- ⁇ from the brain; or favoring greater catabolism of A/3.
  • Compounds ofthe invention may be effective in controlling amyloid- ⁇ deposition either following their entry into the brain (following penetration ofthe blood brain barrier) or from the periphery.
  • a compound When acting from the periphery, a compound may alter the equilibrium of A/3 between the brain and the plasma so as to favor the exit of A ⁇ from the brain.
  • An increase in the exit of Aj8 from the brain would result in a decrease in A ⁇ brain concenfration and therefore favor a decrease in A/3 deposition.
  • compounds that penetrate the brain may confrol deposition by acting directly on brain A/3, e.g., by maintaining it in a non-fibrillar form or favoring its clearance from the brain.
  • the compounds may slow down APP processing; may increase degradation of A ⁇ fibrils by macrophages or by neuronal cells; or may decrease A ⁇ production by activated microglia. These compounds could also prevent A/? in the brain from interacting with the cell surface and therefore prevent neurotoxicity, neurodegeneration, or inflammation.
  • the method is used to treat Alzheimer's disease ⁇ e.g., sporadic or familial AD).
  • the method can also be used prophylactically or therapeutically to treat other clinical occurrences of amyloid- ⁇ deposition, such as in Down's syndrome individuals and in patients with cerebral amyloid angiopathy ("CAA”), hereditary cerebral hemorrhage, or early Alzheimer's disease.
  • CAA cerebral amyloid angiopathy
  • the method is used to treat mild cognitive impairment.
  • Mild Cognitive Impairment 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.
  • the compounds of the invention can be used prophylactically or therapeutically in the freatment of disorders in which amyloid-beta protein is abnormally deposited at non-neurological locations, such as freatment of IBM by delivery ofthe compounds to muscle fibers.
  • a ⁇ is associated with abnormal extracellular deposits, known as drusen, that accumulate along the basal surface ofthe retinal pigmented epithelium in individuals with age-related macular degeneration (ARMD).
  • ARMD is a cause of irreversible vision loss in older individuals. It is believed that A ⁇ deposition could be an important component ofthe local inflammatory events that contribute to afrophy ofthe retinal pigmented epithelium, drusen biogenesis, and the pathogenesis of ARMD (Johnson, et al, Proc. Natl. Acad. Sci. USA 99(18), 11830-5 (2002)).
  • the invention also relates to a method of treating or preventing an amyloid-related disease in a subject (preferably a human) comprising administering to the subject a therapeutic amount of a compound according to the following Formulae or otherwise described herein, such that amyloid fibril formation or deposition, neurodegeneration, or cellular toxicity is reduced or inhibited.
  • the invention in another embodiment, relates to a method of treating or preventing an amyloid- related disease in a subject (preferably a human) comprising administering to the subject a therapeutic amount of a compound according to the following Formulae or otherwise described herein, such that cognitive function is improved or stabilized or further deterioration in cognitive function is prevented, slowed, or stopped in patients with brain amyloidosis, e.g., Alzheimer's disease, Down's syndrome or cerebral amyloid angiopathy.
  • brain amyloidosis e.g., Alzheimer's disease, Down's syndrome or cerebral amyloid angiopathy.
  • the therapeutic compounds ofthe invention may treat amyloidosis related to type II diabetes by, for example, stabilizing glycemia, preventing or reducing the loss of ⁇ cell mass, reducing or preventing hyperglycemia due to loss of ⁇ cell mass, and modulating (e.g., increasing or stabilizing) insulin production.
  • the compounds ofthe invention may also stabilize the ratio ofthe concentrations of pro-LAPP/LAPP.
  • the therapeutic compounds ofthe invention may treat AA (secondary) amyloidosis and/or AL (primary) amyloidosis, by stabilizing renal function, decreasing proteinuria, increasing creatinine clearance (e.g., by at least 50% or greater or by at least 100% or greater), by leading to remission of chronic diarrhea or weight gain (e.g., 10% or greater), or by reducing serum creatinine. Visceral amyloid content as determined, e.g., by SAP scintigraphy may also be reduced.
  • the present invention relates, at least in part, to the use of certain chemical compounds (and pharmaceutical formulations thereof) in the prevention or treatment of amyloid-related diseases, including, ter alia, Alzheimer's disease, cerebral amyloid angiopathy, inclusion body myositis, Down's syndrome, diabetes related amyloidosis, hemodialysis-related amyloidosis (/3 2 M), primary amyloidosis (e.g., ⁇ or K chain- related), familial amyloid polyneuropathy (FAP), senile systemic amyloidosis, familial amyloidosis, Ostertag-type non-neuropathic amyloidosis, cranial neuropathy, hereditary cerebral hemorrhage, familial dementia, chronic dialysis, familial Creutzfeldt- Jakob disease, Gerstmann-Sfraussler-Scheinker syndrome, hereditary spongiform encephalopafhies, prion diseases, familial Mediterranean fever, Muckle-
  • alkenes can include either the E- or Z- geometry, where appropriate.
  • the compounds ofthe present invention may exist in unsolvated as well as solvated forms with acceptable solvents such as water, THF, ethanol, and the like. Ln general, the solvated forms are considered equivalent to the unsolvated forms for the purposes ofthe present invention.
  • a "small molecule” refers to a compound that is not itself the product of gene transcription or translation ⁇ e.g., protein, RNA, or DNA) and preferably has a low molecular weight, e.g., less than about 2500 amu.
  • nucleophile is art-recognized to mean a chemical group having a reactive pair of elecfrons that reacts with a compound by displacing a leaving group (commonly another nucleophile), such as commonly occur in aliphatic chemistry as unimolecular (known as "S N I") or bimolecular (“S N 2") reactions.
  • nucleophiles include uncharged compounds such as amines, mercaptans, and alcohols, and charged groups such as alkoxides, thiolates, carbanions, and a variety of organic and inorga'nic anions.
  • Illustrative anionic nucleophiles include, inter alia, simple anions such as azide, cyanide, thiocyanate, acetate, formate, or chloroformate, and bisulfite.
  • Organometallic reagents such as organocuprates, organozincs, organolithiums, Grignard reagents, enolates, and acetylides, will under appropriate reaction conditions, be suitable nucleophiles.
  • an "electrophile” means an atom, molecule, or ion able to accept an elecfron pair, particularly a pair of electrons from a nucleophile, such as typically occurs during an electrophilic substitution reaction.
  • an electrophile binds to a substrate with the expulsion of another electrophile, e.g., the substitution of a proton by another electrophile such as a nitronium ion on an aromatic substrate ⁇ e.g., benzene).
  • Electrophiles include cyclic compounds such as epoxides, aziridines, episulfides, cyclic sulfates, carbonates, lactones, and lactams; and non-cyclic electrophiles include sulfates, sulfonates ⁇ e.g., tosylates), chlorides, bromides, and iodides.
  • an electrophile may be a saturated carbon atom ⁇ e.g., a methylene group) bonded to a leaving group; however, an electrophile may also be an unsaturated group, such as an aldehyde, ketone, ester, or conjugated (c ⁇ /3-unsaturated) analog thereof, which upon reaction with a nucleophile forms an adduct.
  • the term "leaving group” generally refers to a group that is readily displaced and substituted by a nucleophile ⁇ e.g., an amine, a thiol, an alcohol, or cyanide).
  • Such leaving groups are well known and include carboxylates, N-hydroxysuccinimide (" ⁇ HS”), N-hydroxybenzotriazole, a halogen (fluorine, chlorine, bromine, or iodine), alkoxides, and thioalkoxides.
  • alkane sulfonyloxy groups ⁇ e.g., C ⁇ -C 4 alkane such as methane sulfonyloxy, ethane sulfonyloxy, propane sulfonyloxy, and butane sulfonyloxy groups
  • halogenated analogs ⁇ e.g., halogeno(C 1 -C 4 alkane) sulfonyloxy groups, such as trifluoromethane sulfonyloxy ⁇ i.e., triflate), 2,2,2-trichloroethane sulfonyloxy, 3,3,3-tribromopropane sulfonyloxy, and
  • 4,4,4-trifluorobutane sulfonyloxy groups 4,4,4-trifluorobutane sulfonyloxy groups
  • arylsulfonyloxy groups ⁇ e.g., C ⁇ - o aryl optionally substituted with 1 to 3 C 1 -C 4 alkyl groups, such as benzene sulfonyloxy, ⁇ -naphthylsulfonyloxy, ⁇ -naphthylsulfonyloxy, ?-toluenesulfonyloxy ⁇ i.e., tosylates), 4-tert-butylbenzene sulfonyloxy, mesitylene sulfonyloxy, and 6-ethyl- onaphthylsulfonyloxy groups).
  • Activated esters may be represented by the formula -COL, where L is a leaving group, typical examples of which include N-hydroxysulfosuccinimidyl and N-hydroxysuccinimidyl groups; aryloxy groups substituted with electron-withdrawing groups ⁇ e.g.,p-mtio, pentafluoro, pentachloro,/?-cyano, and carboxylic acids activated by a carbodiimide to form an anhydride or mixed anhydride, e.g., -OCOR a or -OC ⁇ R a ⁇ HR , where R a and R are independently C C 6 alkyl, C 5 -C 8 alkyl ⁇ e.g., cyclohexyl), - perfluoroalkyl, or C C 6 alkoxy groups.
  • L is a leaving group, typical examples of which include N-hydroxysulfosuccinimidyl and N-hydroxysuccinimidyl groups;
  • An activated ester may be formed in situ or may be an isolable reagent.
  • Sulfosuccinimidyl esters, pentafluorothiophenol esters, and sulfotetrafluorophenol are preferred activated esters.
  • ester leaving group may be, for example, substituted or unsubstituted C ⁇ -C 6 alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .sec-butyl, tert-butyl, pentyl, or hexyl), or substituted or unsubstituted C 6 -C 14 aryl or heterocyclic groups, such as 2-fluoroethyl, 2-chloroefhyl, 2-bromoefhyl, 2,2-dibromoethyl, 2,2,2-trichloroefhyl, 3-fluoropropyl, 4-chlorobutyl, methoxymethyl, 1,1 -dimethyl- 1 -methoxymethyl, ethoxymethyl, N-propoxymefhyl, isopropoxymethyl, N-butoxymefhyl, tert-butoxymethyl, 1-ethoxyethyl
  • the term "electron-withdrawing group” is art-recognized and describes the ability of a substituent to attract valence electrons ⁇ e.g., pi-electrons) from neighboring atoms, e.g., the substituent is more electronegative than neighboring atoms, or it draws electrons to itself more than a hydrogen atom would at the same position.
  • the Hammett sigma value ( ⁇ ) is an accepted measure of a group's electron-donating and withdrawing ability, especially the sigma para value ( ⁇ p ). See, e.g., "Advanced Organic Chemistry” by J. March, 5 th Ed., John Wiley & Sons, Inc., New York, pp.368-75 (2001).
  • Exemplary electron-withdrawing groups include nitro, acyl (ketone), formyl (aldehyde), sulfonyl, trifluoromethyl, halogeno ⁇ e.g., chloro and fluoro), and cyano groups, among others.
  • an "electron-donating group” designates a substituent that contributes electrons more than hydrogen would if it occupied the same position in the molecule. Examples include amino (including alkylamino and dialkylamino), aryl, alkoxy (including aralkoxy), aryloxy, mercapto and alkylthio, and hydroxyl groups, among others.
  • alkyl groups include saturated hydrocarbons having one or more carbon atoms, including straight-chain alkyl groups ⁇ e.g., methyl, ethyl, pfopyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), cyclic alkyl groups (or “cycloalkyl” or “alicyclic” or “carbocyclic” groups) ⁇ e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, sec-butyl, isobutyl, etc.), and alkyl-substituted alkyl groups ⁇ e.g., alkyl-substituted cycloalkyl groups and
  • aliphatic group includes organic moieties characterized by sfraight or branched-chains, typically having between 1 and 22 carbon atoms. Ln complex structures, the chains may be branched, bridged, or cross-linked. Aliphatic groups include alkyl groups, alkenyl groups, and alkynyl groups.
  • a sfraight-chain or branched-chain alkyl group may have 30 or fewer carbon atoms in its backbone, e.g., C 1 -C 30 for straight-chain or C 3 -C 30 for branched-chain.
  • a sfraight-chain or branched-chain alkyl group may have 20 or fewer carbon atoms in its backbone, e.g., C1-C 20 for sfraight-chain or C 3 -C 20 for branched-chain, and more preferably 18 or fewer.
  • preferred cycloalkyl groups have from 4-10 carbon atoms in their ring structure, and more preferably have 4-7 carbon atoms in the ring structure.
  • lower alkyl refers to alkyl groups having from 1 to 6 carbons in the chain, and to cycloalkyl groups having from 3 to 6 carbons in the ring structure.
  • lower as in “lower aliphatic,” “lower alkyl,” “lower alkenyl,” etc. as used herein means that the moiety has at least one and less than about 8 carbon atoms.
  • a straight-chain or branched-chain lower alkyl group has 6 or fewer carbon atoms in its backbone ⁇ e.g., -C 6 for straight-chain, C 3 -C 6 for branched-chain), and more preferably 4 or fewer.
  • preferred cycloalkyl groups have from 3-8 carbon atoms in their ring structure, and more preferably have 5 " or 6 carbons in the ring structure.
  • C C ⁇ as in " -C ⁇ alkyl” means alkyl groups containing 1 to 6 carbon atoms.
  • alkyl includes both "unsubstituted alkyls" and “substituted alkyls,” the latter of which refers to alkyl groups having substituents replacing one or more hydrogens on one or more carbons ofthe hydrocarbon backbone.
  • substituents may include, for example, alkenyl, alkynyl, halogeno, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • alkylaryl moiety is an aryl group substituted with an alkyl group ⁇ e.g., j9-methylphenyl ⁇ i.e.,p-tol ⁇ )).
  • w-alkyl means a straight-chain ⁇ i.e., unbranched) unsubstituted alkyl group.
  • alkylene is a divalent analog ofthe corresponding alkyl group.
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous to alkyls, but which contain at least one double or triple carbon-carbon bond respectively. Suitable alkenyl and alkynyl groups include groups having 2 to about 12 carbon atoms, preferably from 2 to about 6 carbon atoms.
  • aromatic group or "aryl group” includes unsaturated and aromatic cyclic hydrocarbons as well as unsaturated and aromatic heterocycles containing one or more rings.
  • Aryl groups may also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic so as to form a polycycle ⁇ e.g., tefralin).
  • An "arylene” group is a divalent analog of an aryl group.
  • Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle ⁇ e.g., tefralin).
  • heterocyclic group includes closed ring structures analogous to carbocyclic groups in which one or more ofthe carbon atoms in the ring is an element other than carbon, for example, nifrogen, sulfur, or oxygen. Heterocyclic groups may be saturated or unsaturated. Additionally, heterocyclic groups (such as pyrrolyl, pyridyl, isoquinolyl, quinolyl, purinyl, and furyl) may have aromatic character, in which case they may be referred to as “heteroaryl” or “heteroaromatic” groups.
  • heteroaryl and heterocyclic (including heteroaryl) groups may also be substituted at one or more constituent atoms.
  • heteroaromatic and heteroalicyclic groups may have 1 to 3 separate or fused rings with 3 to about 8 members per ring and one or more N, O, or S heteroatoms.
  • heteroatom includes atoms of any element other than carbon or hydrogen, preferred examples of which include nifrogen, oxygen, sulfur, and phosphorus. Heterocyclic groups may be saturated or unsaturated or aromatic.
  • heterocycles include, but are not limited to, acridinyl; azocinyl; benzimidazolyl; benzofuranyl; benzothiofuranyl; benzothiophenyl; benzoxazolyl; benzthiazolyl; benztriazolyl; benztefrazolyl; benzisoxazolyl; benzisothiazolyl; benzimidazolinyl; carbazolyl; 4aH-carbazolyl; carbolinyl; chromanyl; chromenyl; cinnolinyl; decahydroquinolinyl; 2H,6H-l,5,2-dithiazinyl; d ydrofuro[2,3-b]tetrahydrofuran; furanyl; furazanyl; imidazolidinyl; imidazolinyl; imidazolyl; lH-indazolyl; indolenyl
  • 1,2,4-thiadiazolyl 1,2,5-fhiadiazolyl; 1,3,4-thiadiazolyl; thianthrenyl; thiazolyl; thienyl; thienothiazolyl; thienooxazolyl; thienoimidazolyl; fhiophenyl; triazinyl; 1,2,3-triazolyl; 1,2,4-triazolyl; 1,2,5-triazolyl; 1,3,4-triazolyl; and xanthenyl.
  • Preferred heterocycles include, but are not limited to, pyridinyl; furanyl; thienyl; pyrrolyl; pyrazolyl; pyrrolidinyl; imidazolyl; indolyl; benzimidazolyl; lH-indazolyl; oxazolidinyl; benzotriazolyl; benzisoxazolyl; oxindolyl; benzoxazolinyl; and isatinoyl groups. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
  • a common hydrocarbon aryl group is a phenyl group having one ring.
  • Two-ring hydrocarbon aryl groups include naphthyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, pentalenyl, and azulenyl groups, as well as the partially hydrogenated analogs thereof such as indanyl and tefrahydronaphthyl.
  • Exemplary three- ring hydrocarbon aryl groups include acephfhylenyl, fluorenyl, phenalenyl, phenanthrenyl, and anthracenyl groups.
  • Aryl groups also include heteromonocyclic aryl groups, i.e., single-ring heteroaryl groups, such as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl groups; and oxidized analogs thereof such as pyridonyl, oxazolonyl, pyrazolonyl, isoxazolonyl, and thiazolonyl groups.
  • heteromonocyclic aryl groups i.e., single-ring heteroaryl groups, such as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl groups
  • oxidized analogs thereof such as pyridonyl,
  • the corresponding hydrogenated ⁇ i.e., non-aromatic) heteromonocylic groups include pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl and piperidino, piperazinyl, and mo ⁇ holino and morpholinyl groups.
  • Aryl groups also include fused two-ring heteroaryls such as indolyl, isoindolyl, indolizinyl, indazolyl, quinolinyl, isoquinolinyl, ph halazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromenyl, isochromenyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolizinyl, isoquinolonyl, quinolonyl, naphthyridinyl, and pteridinyl groups, as well as the partially hydrogenated analogs such as chromanyl, isochromanyl, indolinyl, isoindolinyl, and tetrahydroindolyl groups.
  • heteroaryls such as indolyl, isoindolyl, indolizinyl, indazo
  • Aryl groups also include fused three-ring groups such as phenoxathiinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, pheno hiazinyl, phenoxazinyl, and dibenzofuranyl groups.
  • aryl groups include substituted or unsubstituted 5- and 6- membered single-ring groups.
  • each Ar group maybe selected from the group consisting of substituted or unsubstituted phenyl, pyrrolyl, furyl, thienyl, thiazolyl, isothiaozolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl groups.
  • Further examples include substituted or unsubstituted phenyl, 1 -naphthyl, 2-naphfhyl, biphenyl, 1 -pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-
  • amine refers to an unsubstituted or substituted moiety ofthe formula -NR a R , in which R a and R b are each independently hydrogen, alkyl, aryl, or heterocyclyl, or R a and R b , taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the ring.
  • amino includes cyclic amino moieties such as piperidinyl or pyrrolidinyl groups, unless otherwise stated.
  • alkylamino as used herein means an alkyl group having an amino group attached thereto.
  • Suitable alkylamino groups include groups having 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms.
  • amino includes compounds or moieties in which a nifrogen atom is covalently bonded to at least one carbon or heteroatom.
  • dialkylamino includes groups wherein the nitrogen atom is bound to at least two alkyl groups.
  • arylamino and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
  • alkylarylamino refers to an amino group which is bound to at least one alkyl group and at least one aryl group.
  • alkaminoalkyl refers to an alkyl, alkenyl, or alkynyl group substituted with an alkylamino group.
  • amide or "aminocarbonyl” includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group.
  • alkylthio refers to an alkyl group, having a sulfhydryl group attached thereto. Suitable alkylthio groups include groups having 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms.
  • alkylcarboxyl as used herein means an alkyl group having a carboxyl group attached thereto.
  • alkoxy as used herein means an alkyl group having an oxygen atom attached thereto.
  • Representative alkoxy groups include groups having 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms, e.g., methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocafbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc., as well as perhalogenated alkyloxy groups.
  • acylamino includes moieties wherein an amino moiety is bonded to an acyl group.
  • the acylamino group includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • alkoxyalkyl examples include alkyl groups, as described above, which further include oxygen, nifrogen or sulfur atoms replacing one or more carbons ofthe hydrocarbon backbone.
  • carbonyl or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
  • ether or “ethereal” includes compounds or moieties which contain an oxygen bonded to two carbon atoms.
  • an ether or ethereal group includes "alkoxyalkyl” which refers to an alkyl, alkenyl, or alkynyl group substituted with an alkoxy group.
  • a “sulfonate” group is a -SO 3 H or -SO 3 " X + group bonded to a carbon atom, where X* is a cationic counter ion group.
  • a "sulfonic acid” compound has a -SO 3 H or -SO ⁇ X* group bonded to a carbon atom, where X+ is a cationic group.
  • a “sulfate” as used herein is a -OSO 3 H or -OSO 3 " X + group bonded to a carbon atom, and a “sulfuric acid” compound has a -SO 3 H or -OSO 3 " X + group bonded to a carbon atom, where X is a cationic group.
  • a suitable cationic group may be a hydrogen atom. In certain cases, the cationic group may actually be another group on the therapeutic compound that is positively charged at physiological pH, for example an amino group.
  • a "counter ion" is required to maintain electroneufrality.
  • anionic counter ions include halide, triflate, sulfate, nitrate, hydroxide, carbonate, bicarbonate, acetate, phosphate, oxalate, cyanide, alkylcarboxylate, N-hydroxysuccinimide , N-hydroxybenzotriazole, alkoxide, thioalkoxide, alkane sulfonyloxy, halogenated alkane sulfonyloxy, arylsulfonyloxy, bisulfate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, citrate, maleate, fumarate, succinate, tarfrate, naphfhylate mesylate, glucoheptonate, or lactobionate.
  • acyl refers to a carbonyl group that is attached through its carbon atom to a hydrogen ⁇ i.e., a formyl), an aliphatic group ⁇ e.g., acetyl), an aromatic group ⁇ e.g., benzoyl), and the like.
  • substituted acyl includes acyl groups where one or more ofthe hydrogen atoms on one or more carbon atoms are replaced by, for example, an alkyl group, alkynyl group, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), imino,
  • the chemical moieties ofthe compounds ofthe invention may be "substituted or unsubstituted.”
  • substituted means that the moiety has substituents placed on the moiety other than hydrogen ⁇ i.e., in most cases, replacing a hydrogen), which allow the molecule to perform its intended function.
  • substituents include moieties selected from sfraight or branched alkyl (preferably -C 5 ), cycloalkyl (preferably C 3 -C 8 ), alkoxy (preferably -C ⁇ ), tbioalkyl (preferably C ⁇ -C 6 ), alkenyl (preferably C -C 6 ), alkynyl (preferably C 2 -C 6 ), heterocyclic, carbocyclic, aryl ⁇ e.g., phenyl), aryloxy ⁇ .g, phenoxy), aralkyl ⁇ e.g., benzyl), aryloxyalkyl ⁇ e.g., phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl group, heteroarylcarbonyl, and heteroaryl groups, as well as (CR'R") 0-3 NR'R" ⁇ e.
  • R' and R" are each independently hydrogen, a -C 5 alkyl, C 2 -C 5 alkenyl, C -C 5 alkynyl, or aryl group; or the side chain of any naturally occurring amino acid.
  • a substituent may be selected from straight or branched alkyl (preferably -C 5 ), cycloalkyl (preferably C 3 -C 8 ), alkoxy (preferably -C ⁇ ), tbioalkyl (preferably Ci-C 6 ), alkenyl (preferably C 2 -C 6 ), alkynyl (preferably C 2 -C 6 ), heterocyclic, carbocyclic, aryl ⁇ e.g., phenyl), aryloxy (e.g., phenoxy), aralkyl ⁇ e.g., benzyl), aryloxyalkyl ⁇ e.g., phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl group, heteroarylcarbonyl, or heteroaryl group, (CR'R") 0 - 10 NR'R" ⁇ e.g., -
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with the permitted valence ofthe substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted is meant to include all permissible substituents of organic compounds. Ln a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more.
  • a "substituent" may be selected from the group consisting of, for example, halogeno, trifluoromefhyl, nitro, cyano, -C ⁇ alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C-i-Ce alkylcarbonyloxy, arylcarbonyloxy, -C ⁇ alkoxycarbonyloxy, aryloxycarbonyloxy, Ci-C ⁇ alkylcarbonyl, C C ⁇ alkoxycarbonyl, d-C 6 alkoxy,
  • R 1 is a substituted or unsubstituted cycloalkyl, heterocyclic, aryl, arylcycloalkyl, bicyclic or tricyclic ring, a bicyclic or tricyclic fused ring group, or a substituted or unsubstituted C 2 -C 10 alkyl group;
  • R 2 is selected from a group consisting of hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl;
  • Y is SOfX", OSO 3 " X + , or SSO 3 " X + ;
  • X* is hydrogen, a cationic group, or ester-forming group; and each of L 1 and L 2 is independently a substituted or unsubstituted -C 5 alkyl group or absent, or a pharmaceutically acceptable salt thereof, provided that when R t is alkyl, L 1 is absent.
  • the invention pertains to compounds of Formula II:
  • R 1 is a substituted or unsubstituted cyclic, bicyclic, tricyclic, or benzoheterocyclic group or a substituted or unsubstituted C 2 -C 10 alkyl group;
  • R 2 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl, or linked to R 1 to form a heterocycle;
  • Y is SOA?C ⁇ OSO 3 " X ⁇ , or SSOA ⁇ ;
  • X* is hydrogen, a cationic group, or an ester forming moiety; m is O or 1; n is i, 2, 3, or 4;
  • L is substituted or unsubstituted -C 3 alkyl group or absent, or a pharmaceutically acceptable salt thereof, provided that when R 1 is alkyl, L is absent.
  • R 2 is hydrogen.
  • R 1 is sfraight chain alkyl, for example, ethyl, n-pentyl, n-heptyl, or n-octyl. Ln another embodiment, R 1 is t-butyl.
  • R 1 is C 7 -C 10 bicycloalkyl or tricycloalkyl, such as, for example, tricyclo[3.3.1.0 ' jdecyl (or adamantyl), bicyclo[2.1.2]heptyl, or indolyl.
  • R 1 is tefrahydronaphthyl. 0
  • L is -(CH 2 ) 3 -. In another further embodiment, L is - (CH 2 ) 4 - or -(CH 2 ) 5 -. In yet another further embodiment, is -(CH 2 ) 2 -. Ln yet another further embodiment, L 2 is substituted alkyl, e.g., -CH 2 -(CHOH)-CH 2 -. Ln another embodiment, L 1 is CH 2 CH 2 or absent.
  • R 1 is branched alkyl, e.g., t-butyl. In another embodiment, R 1 is adamanyl. In another embodiment, R 1 is cyclic alkyl, e.g., cyclopropyl, cyclohexyl, cycloheptyl, cyclo-octyl, etc. The cycloalkyl moieties may be substituted further, e.g., with additional alkyl groups or other groups which allow the molecule to perform its intended function. In another embodiment, R 1 is alkyl substituted with a propargyl moiety (e.g., HC ⁇ C-). Ln another embodiment, R 1 is cyclohexyl substituted withone or more methyl or propargyl groups.
  • R 1 is cyclohexyl substituted withone or more methyl or propargyl groups.
  • L 1 is a -C 2 alkyl linker group (e.g., -CH(CH 3 )- or - (CH 2 ) 2 -.
  • R 1 is phenyl.
  • R 1 is substituted with a methoxy group.
  • L 1 is C 3 , e.g., -(CH 2 ) 3 - or
  • the ester group is a methyl , ethyl, propyl, butyl, cyclohexyl, or benzyl ester. In other embodiments, the ester group may be propenyl.
  • L 1 is substituted with a carboxylate group.
  • R 1 is substituted with a subsituted amido group, wherein the amido group is substituted with an alkyl, e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl group.
  • the amido group is substituted with an alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclohexyl, etc.), a benzyl or an aryl group.
  • the amido group is substituted with a -CH(CH 2 ) 2 group.
  • R 1 itself may be substituted with a phenyl or may be branched or sfraight chain alkyl. Ln certain embodiments, R 1 may also be substituted with a thioether moiety. Examples of fhioethers include S-Me, S-Et, etc.
  • the alkyl R 1 moiety is substituted with both an aryl or a thioether moiety and an amido moiety. In other embodiments, the alkyl R 1 moiety may be substituted with both a thioether and a carboxylate moiety. In other embodiments, alkyl R 1 groups are substituted with hydroxyl. R 1 groups, e.g., alkyl R 1 groups, may also be substituted with both thioether and hydroxyl groups. Ln other embodiments, R 1 groups, e.g., alkyl R groups are substituted with cyano groups. Examples of R 1 groups including -CN moieties include - C(CH 3 ) 2 CN, cyclohexyl substituted with one or more cyano groups, etc.
  • alkyl R 1 groups are substituted with aryl groups.
  • the aryl groups may be substituted phenyl, for example.
  • the substituted phenyl may be substituted with one or more substituents such as hydroxy, cyano and alkoxy.
  • alkyl R 1 groups are substituted with tetrazolyl or substituted or unsubstituted benzyl.
  • L 1 is -C(CH 3 ) 2 -(CH )-.
  • Ln another embodiment L 1 is - (C(CH 3 ) 2 -CHOH-.
  • L 1 is -(C(CH 3 ) 2 CH(OMe)-.
  • R 1 is substituted or unsubstituted phenyl.
  • R 1 is jrara-substituted phenyl. Examples of substitutuents include but are not limited to fluorine, chlorine, bromine, iodine, methyl, t-butyl, alkoxy, methoxy, etc. In other embodiment, R 1 is substituted at the meta position.
  • substituents include methoxy, chloro, methyl, t-butyl, fluoro, alkyl, alkoxy, iodo, trifluoroalkyl, methoxy, etc.
  • R 1 is phenyl substituted in the ortho position, with similar substituents.
  • Ln another embodiment, L 1 comprises a cycloalkyl moiety, e.g., cyclopentyl.
  • Ln another embodiment, L 1 comprises an alkyenyl group and, optionally, a substituted aryl group, with substittuents similar to those described about.
  • R 1 is cyclopropyl or cyclohexyl.
  • the cyclopropyl or cyclohexyl group is subsituted with an ether group or an alkyl group.
  • the ether group is a benzyl ether group.
  • R 1 is alkyl, it is substituted with groups such as phenyl, or hydroxy.
  • the compound ofthe invention is selected from the group consisting of:
  • A is nifrogen or oxygen
  • R 11 is hydrogen, salt-forming cation, ester forming group, — (CH ) X — Q, or when A is nifrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
  • Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;
  • x is O, 1, 2, 3, or 4;
  • n is 0, 1 ,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
  • R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 and R 7a are each independently hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, or two R groups on adjacent ring atoms taken together with the ring atoms form a double bond, provided that one of R 3 , R 3a , R 4 , R 4a , R 5 , R 5a , R 6
  • m 0, 1, 2, 3, or 4;
  • R A , R B , R c , R D , and R E are independently selected from a group of hydrogen, halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothiazolyl, and benzoimidazolyl; and pharmaceutically acceptable salts and esters thereof, provided that said compound is not 3-(4-phenyl-l, 2, 3, 6-tetrahydro-l -pyridyl)- 1-propanesulfonic acid.
  • n 2, 3 or 4.
  • R 11 is a salt-forming cation.
  • salt forming cations include pharmaceutically acceptable salts described herein as well as lithium, sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammonium.
  • R 11 is an ester-forming group.
  • An ester-forming group includes groups which when bound form an ester. Examples of such groups include substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, or cycloalkyl.
  • A is oxygen.
  • R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a double bond.
  • R A , R B , R c , R D , and R E are each hydrogen.
  • R A , R B , R D , and R E are each hydrogen and R c is a halogen, such as fluorine, chlorine, iodine, or bromine.
  • R 3 or R 5a is a moiety of Formula ILLa.
  • R 4 , R 5 , R 6 , and R 7 are each hydrogen.
  • R 4a , R 5a , R 6a , and R 7a are each hydrogen.
  • R 3a is hydroxyl, cyano, acyl, or hydroxyl.
  • R 11 and A taken together are a natural or unnatural amino acid residue or a pharmaceutically acceptable salt or ester thereof.
  • amino acid residues include esters and salts of phenylalanine and leucine.
  • n 0, 1, or 3.
  • Examples of compounds of Formula IH include, but are not limited to:
  • the invention pertains to compounds of Formula LV:
  • A is nifrogen or oxygen
  • R 11 is hydrogen, salt-forming cation, ester forming group, — (CH 2 ) X — Q, or when A is nifrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
  • Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;
  • x is O, 1, 2, 3, or 4;
  • n is 0, 1 ,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
  • R 4 , R 4a , R 5 , R 5a , R 6 , R 6a , R 7 , and R 7a are each independently hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, cyano, halogen, amino, tetrazolyl, R 4 and R 5 taken together, with the ring atoms they are attached to, form a double bond, or R 6 and R 7 taken together, with the ring atoms they are attached to, form a double bond;
  • m is O, 1, 2, 3, or 4;
  • R 8 , R 9 , R 10 , R u , and R 12 are independently selected from a group of hydrogen, halogen, hydroxyl, alkyl, alkoxyl, halogenated alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, cyano, thiazolyl, triazolyl, imidazolyl, tetrazolyl, benzothiazolyl, and benzoimidazolyl, and pharmaceutically acceptable salts and esters thereof.
  • R 11 is a salt-forming cation.
  • R 11 is an ester-forming group.
  • An ester-forming group includes groups which when bound form an ester. Examples of such groups include substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, or cycloalkyl.
  • A is oxygen.
  • m is 0 or 1.
  • n is 2, 3, or 4.
  • R 4 , R 5 , R 6 and R 7 are each hydrogen.
  • R 4a , R 5a , R 6a , and R 7a also may be hydrogen.
  • Examples of R 8 , R 9 , R 10 , R 11 , and R 12 include hydrogen.
  • R 8 , R 9 , R 11 , R 12 are each hydrogen, and R 10 is a halogen, (e.g., fluorine, chlorine, bromine, or iodine), nitro, or alkyl (e.g., methyl, ethyl, butyl).
  • A-R 11 maybe the residue of an amino acid, e.g., a phenylalanine residue.
  • R 9 , R 10 , R 11 and R 12 are each hydrogen, and R 8 is not hydrogen, e.g., halogen, e.g., fluorine, bromine, chlorine, or iodine.
  • the compound is:
  • the invention pertains to compounds of Formula V: R 5 O
  • A is nifrogen or oxygen;
  • R 11 is hydrogen, salt-forming cation, ester forming group, — (CH 2 ) X — Q, or when A is nitrogen, A and R u taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
  • Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;
  • x is O, 1, 2, 3, or 4;
  • n is 0, 1 ,2 ,3, 4, 5, 6, 7, 8, 9, or 10;
  • aa is a natural or unnatural amino acid residue;
  • m is O, 1, 2, or 3;
  • R 14 is hydrogen or protecting group;
  • R 15 is hydrogen, alkyl or aryl, and pharmaceutically acceptable salts, esters and prodrugs thereof.
  • R 11 is a salt-forming cation.
  • salt forming cations include pharmaceutically acceptable salts described herein as well as lithium, sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammonium.
  • R 11 is an ester-forming group.
  • An ester-forming group includes groups which when bound form an ester. Examples of such groups include substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, or cycloalkyl.
  • A is oxygen.
  • n is 2, 3 or 4.
  • m is 0.
  • A-R 11 is a residue of a natural amino acid, or a salt or ester thereof
  • amino acid residues include, but are not limited to, leucine or phenylalanine residues, and pharmaceutically acceptable salts and esters thereof.
  • examples of possible esters include methyl,, ethyl, and t-butyl.
  • m is 1.
  • Examples of aa include natural and unnatural amino acid residues such as phenylalanine, glycine, and leucine.
  • (aa) m is a residue of phe-phe, or an ester thereof.
  • R is hydrogen or substituted alkyl, e.g., arylalkyl.
  • the term ''unnatural amino acid refers to any derivative of a natural amino acid including D forms, and - and /3-amino acid derivatives. It is noted that certain amino acids, e.g., hydroxyproline, that are classified as a non-natural amino acid herein, may be found in nature within a certain organism or a particular protein. Amino acids with many different protecting groups appropriate for immediate use in the solid phase synthesis of peptides are commercially available.
  • non-natural amino acids and amino acid derivatives may be used according to the invention (common abbreviations in parentheses): /3-alanine ⁇ -ALA), ⁇ -aminobutyric acid (GAB A), 2-aminobutyric acid (2-Abu), acid (8-AU), 1-aminocyclopropane-l -carboxylic acid (ACPC), aminoisobutyric acid (Aib), 2-amino- thiazoline-4-carboxylic acid, 5-aminovaleric acid (5-Ava), 6-aminohexanoic acid (6-Ahx), 8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-aminododecanoic acid (12-Ado), 2-aminobenzoic acid (2-Abz), 3-aminobenzoic acid (3-Abz), 4-aminobenzoic acid(
  • 3-nitrotyrosine (3-NO 2 -Tyr), norleucine (Nle); norvaline (Nva), ornithine (Orn), ortAo-phosphotyrosine (H 2 PO 3 -Tyr), octahydroindole-2-carboxylic acid (Oic), penicillamine (Pen), pentafluorophenylalanine (F -Phe), phenylglycine (Phg), pipecolic acid (Pip), propargylglycine (Pra), pyroglutamic acid (PGLU), sarcosine (Sar), tetrahydroisoquinoline-3-carboxylic acid (Tic), thienylalanine, and thiazolidine-
  • N-alkylated amino acids may be used, as well as amino acids having amine-containing side chains (such as Lys and Orn) in which the amine has been acylated or or alkylated. o are not limited to:
  • the invention pertains, at least in part, to compounds of Formula VI:
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • A is oxygen or nifrogen;
  • R 11 is hydrogen, salt-foiming cation, ester forming group, — (CH 2 ) X — Q, or when A is nifrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
  • Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;
  • x is O, 1, 2, 3, or 4;
  • R 19 is hydrogen, alkyl or aryl;
  • Y 1 is oxygen, sulfur, or nifrogen;
  • Y 2 is carbon, nitrogen, or oxygen;
  • R 20 is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tefrazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl;
  • R 21 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tefrazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl, or absent ifY 2 is oxygen;
  • R 22 is hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tefrazolyl, imidazolyl, benzothiazolyl, benzoimidazolyl; or
  • R is hydrogen, hydroxyl, alkoxy or aryloxy ifY is nifrogen; or R is absent ifY is oxygen or sulfur;or R 22 and R 21 may be linked to form a cyclic moiety ifY 1 is mtrogen;
  • R 23 is hydrogen, alkyl, amino, mercaptoalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl, or absent ifY 2 is nitrogen or oxygen; or pharmaceutically acceptable salts thereof.
  • R 11 is a salt-forming ,cation.
  • salt forming cations include pharmaceutically acceptable salts described herein as well as lithium, sodium, potassium, magnesium, calcium, barium, zinc, iron, and ammonium.
  • the salt is a sodium salt.
  • A is oxygen.
  • Y 1 is oxygen or sulfur, and R 22 is absent.
  • Y 2 is oxygen and R 21 is absent.
  • R 20 include benzyl, aryl (e.g., phenyl), alkyl, cycloalkyl (e.g., adamantyl), etc.
  • Y 2 is nifrogen and R 21 is hydrogen.
  • R 21 is benzyl.
  • R 20 and R 21 are linked to form a pyridyl ring.
  • Y 1 is sulfur.
  • n 2, 3, or 4;
  • A is oxygen or nifrogen;
  • R 11 is hydrogen, salt-forming cation, ester forming group, — (CH ) X — Q, or when A is nifrogen, A and R 11 taken together may be the residue of a natural or unnatural amino acid or a salt or ester thereof;
  • Q is hydrogen, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, or benzoimidazolyl; x is 0, 1, 2, 3, or 4; G is a direct bond or oxygen, nifrogen, or sulfur; z is O, 1, 2, 3, 4, or 5; m is 0 or 1;
  • R 24 is selected from a group consisting of hydrogen, alkyl, mercaptoalkyl, alkenyl, alkynyl, aroyl, alkylcarbonyl, aminoalkylcarbonyl, cycloalkyl, aryl, arylalkyl, thiazolyl, triazolyl, imidazolyl, benzothiazolyl, and benzoimidazolyl; each R 25 is independently selected from hydrogen, halogen, cyano, hydroxyl, alkoxy, thiol, amino, nitro, alkyl, aryl, carbocyclic, or heterocyclic, and pharmaceutically acceptable salts, esters, and prodrugs thereof.
  • R 11 is hydrogen.
  • A is oxygen.
  • n may be 3 and m may be 1.
  • R 24 is hydrogen or benzyl.
  • Ln certain embodiments, z is 0, 2, or 3.
  • R 25 is hydroxyl or alkoxy, e.g., methoxy, ethoxy, etc.
  • two or more R 25 substituents can be linked to form a fused ring (e.g., to form a methylendioxyphenyl moiety). Examples of compounds ofthe invention include: r ⁇ ⁇ A ⁇ s ⁇ 3H
  • the invention pertains to both salt forms and acid/base forms ofthe compounds ofthe invention.
  • the invention pertains not only to the particular salt forms of compounds shown herein as salts, but also the invention includes other pharmaceutically acceptable salts, and the acid and/or base form ofthe compound.
  • the invention also pertains to salt forms of compounds shown herein.
  • the invention does not pertain to the compounds described in WO 00/64420 and W0 96/28187. Ln this embodiment, the invention does not pertain to methods of using the compounds described in WO 00/64420 and W0 96/28187 for the freatment of diseases or disorders described therein. In a further embodiment, the invention pertains to methods of using the compounds described in WO 00/64420 and WO 96/28187 for methods described in this application, which are not described in WO 00/64420 and W0 96/28187. Both of WO 00/64420 and WO 96/28187 are incorporated by reference herein in their entirety.
  • the invention pertains to methods ofthe invention which use and pharmaceutical compositions comprising, the compounds of Table 2A.
  • the compounds ofthe invention do not include the compounds of Table 2A.
  • subject includes living organisms in which amyloidosis can occur, or which are susceptible to amyloid diseases, e.g., Alzheimer's disease, Down's syndrome!, CAA, dialysis-related (j8 2 M) amyloidosis, secondary (AA) amyloidosis, primary (AL) amyloidosis, hereditary amyloidosis, diabetes, etc.
  • amyloid diseases e.g., Alzheimer's disease, Down's syndrome!, CAA, dialysis-related (j8 2 M) amyloidosis, secondary (AA) amyloidosis, primary (AL) amyloidosis, hereditary amyloidosis, diabetes, etc.
  • subjects include humans, chickens, ducks, peking ducks, geese, monkeys, deer, cows, rabbits, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof.
  • compositions ofthe present invention to a subject to be freated can be carried out using known procedures, at dosages and for periods of time effective to modulate amyloid aggregation or amyloid-induced toxicity in the subject as further described herein.
  • An effective amount ofthe therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the amount of amyloid already deposited at the clinical site in the subject, the age, sex, and weight ofthe subject, and the ability ofthe therapeutic compound to modulate amyloid aggregation in the subject.
  • Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies ofthe therapeutic situation.
  • the subject is in need of treatment by the methods ofthe invention, and is selected for freatment based on this need.
  • a subject in need of freatment is art-recognized, and includes subjects that have been identified as having a disease or disorder related to amyloid-deposition or amyloidosis, has a symptom of such a disease or disorder, or is at risk of such a disease or disorder, and would be expected, based on diagnosis, e.g., medical diagnosis, to benefit from freatment (e.g., curing, healing, preventing, alleviating, relieving, altering, remedying, ameliorating, improving, or affecting the disease or disorder, the symptom ofthe disease or disorder, or the risk ofthe disease or disorder).
  • the subject is a human.
  • the subject may be a human over 30 years old, human over 40 years old, a human over 50 years old, a human over 60 years old, a human over 70 years old, a human over 80 years old, a human over 85 years old, a human over 90 years old, or a human over 95 years old.
  • the subject may be a female human, including a postmenopausal female human, who may be on hormone (estrogen) replacement therapy.
  • the subject may also be a male human.
  • the subject is under 40 years old.
  • a subject may be a human at risk for Alzheimer's disease, e.g., being over the age of 40 or having a predisposition for Alzheimer's disease.
  • Alzheimer's disease predisposing factors identified or proposed in the scientific literature include, among others, a genotype predisposing a subject to Alzheimer's disease; environmental factors predisposing a subject to Alzheimer's disease; past history of infection by viral and bacterial agents predisposing a subject to Alzheimer's disease; and vascular factors predisposing a subject to Alzheimer's disease.
  • a subject may also have one or more risk factors for cardiovascular disease ⁇ e.g., atherosclerosis ofthe coronary arteries, angina pectoris, and myocardial infarction) or cerebro vascular disease ⁇ e.g., atherosclerosis of the infracranial or extracranial arteries, sfroke, syncope, and transient ischemic attacks), such as hypercholesterolemia, hypertension, diabetes, cigarette smoking, familial or previous history of coronary artery disease, cerebro vascular disease, and cardiovascular disease.
  • Hypercholesterolemia typically is defined as a serum total cholesterol concenfration of greater than about 5.2 mmol/L (about 200 mg/dL).
  • genotypes such as presenilin- 1, presenilin-2, and amyloid precursor protein (APP) missense mutations associated with familial Alzheimer's disease, and ⁇ -2-macroglobulin and LRP-1 genotypes, which are thought to increase the risk of acquiring sporadic (late-onset) Alzheimer's disease.
  • APP amyloid precursor protein
  • Another genetic risk factor for the development of Alzheimer's disease are variants of ApoE, the gene that encodes apolipoprotein E (particularly the apoE4 genotype), a constituent ofthe low-density lipoprotein particle. WJ Strittmatter, et al, Annu. Rev. Neurosci. 19, 53-77 (1996).
  • the molecular mechanisms by which the various ApoE alleles alter the likelihood of developing Alzheimer's disease are unknown, however the role of ApoE in cholesterol metabolism is consistent with the growing body of evidence linking cholesterol metabolism to Alzheimer's disease. For example, chronic use of cholesterol-lowering drugs such as statins has recently been associated with a lower incidence of Alzheimer's disease, and cholesterol-lowering drugs have been shown to reduce pathology in APP fransgenic mice.
  • Alzheimer's disease has been suggested to alter A ⁇ trafficking (in and out ofthe brain), and favor retention of A ⁇ in the brain. ApoE4 has also been suggested to favor APP processing toward A ⁇ formation.
  • Environmental factors have been proposed as predisposing a subject to Alzheimer's disease, including exposure to aluminum, although the epidemiological evidence is ambiguous.
  • prior infection by certain viral or bacterial agents may predispose a subject to Alzheimer's disease, including the herpes simplex virus and chlamydia pneumoniae.
  • other predisposing factors for Alzheimer's disease can include risk factors for cardiovascular or cerebrovascular disease, including cigarette smoking, hypertension and diabetes.
  • “At risk for Alzheimer's disease” also encompasses any other predisposing factors not listed above or as yet identified and includes an increased risk for Alzheimer's disease caused by head injury, medications, diet, or lifestyle.
  • the methods ofthe present invention can be used for one or more ofthe following: to prevent Alzheimer's disease, to treat Alzheimer's disease, or ameliorate symptoms of Alzheimer's disease, or to regulate production of or levels of amyloid ⁇ (A ⁇ ) peptides.
  • the human carries one or more mutations in the genes that encode /3-amyloid precursor protein, presenilin- 1 or presenilin-2.
  • the human carries the Apolipoprotein 64 gene.
  • the human has a family history of Alzheimer's Disease or a dementia illness.
  • the human has trisomy 21 (Down's Syndrome).
  • the subject has a normal or low serum total blood cholesterol level.
  • the serum total blood cholesterol level is less than about 200 mg/dL, or less than about 180, and it can range from about 150 to about 200 mg/dL.
  • the total LDL cholesterol level is less than about 100 mg/dL, or less than about 90 mg/dL and can range from about 30 to about 100 mg dL.
  • the subject has an elevated serum total blood cholesterol level.
  • the serum total cholesterol level is at least about 200 mg/dL, or at least about 220 mg/dL and can range from about 200 to about 1000 mg/dL.
  • the subject has an elevated total LDL cholesterol level.
  • the total LDL cholesterol level is greater than about 100 mg dL, or even greater than about 110 mg/dL and can range from about 100 to about 1000 mg dL.
  • the human is at least about 40 years of age. In another embodiment, the human is at least about 60 years of age. Ln another embodiment, the human is at least about 70 years of age. In another embodiment, the human is at least about 80 years of age.
  • the human is at least about 85 years of age. In one embodiment, the human is between about 60 and about 100 years of age. In still a further embodiment, the subject is shown to be at risk by a diagnostic brain imaging technique, for example, one that measures brain activity, plaque deposition, or brain afrophy.
  • the subject is shown to be at risk by a cognitive test such as Clinical Dementia Rating (“CDR”), Alzheimer's Disease Assessment Scale- Cognition (“ADAS-Cog”), or Mini-Mental State Examination (“MMSE”).
  • CDR Clinical Dementia Rating
  • ADAS-Cog Alzheimer's Disease Assessment Scale- Cognition
  • MMSE Mini-Mental State Examination
  • the subject may exhibit a below average score on a cognitive test, as compared to a historical confrol of similar age and educational background.
  • the subject may also exhibit a reduction in score as compared to previous scores ofthe subject on the same or similar cognition tests.
  • a subject In determining the CDR, a subject is typically assessed and rated in each of six cognitive and behavioural categories: memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care.
  • the assessment may include historical information provided by the subject, or preferably, a corroborator who knows the subject well.
  • the subject is assessed and rated in each of these areas and the overall rating, (0, 0.5, 1.0, 2.0 or 3.0) determined.
  • a rating of 0 is considered normal.
  • a rating of 1.0 is considered to correspond to mild dementia.
  • a subject with a CDR of 0.5 is characterized by mild consistent forgetfulness, partial recollection of events and "benign" forgetfulness.
  • the subject is assessed with a rating on the CDR of above 0, of above about 0.5, of above about 1.0, of above about 1.5, of above about 2.0, of above about 2.5, or at about 3.0.
  • MMSE Mini-Mental State Examination
  • the MMSE evaluates the presence of global intellectual deterioration. See also Folstein "Differential diagnosis of dementia. The clinical process.” Psychiatr Clin North Am. 20:45-57, 1997.
  • the MMSE is a means to evaluate the onset of dementia and the presence of global intellectual deterioration, as seen in Alzheimer's disease and multi-infart dementia.
  • the MMSE is scored from 1 to 30.
  • the MMSE does not evaluate basic cognitive potential, as, for example, the so-called IQ test.
  • the subject scores below 30 at least once on the MMSE. In another embodiment, the subject scores below about 28, below about 26, below about 24, below about 22, below about 20, below about 18, below about 16, below about 14, below about 12, below about 10, below about 8, below about 6, below about 4, below about 2, or below about 1.
  • ADAS-Cog Alzheimer's Disease Assessment Scale
  • SAD AS Standardized Alzheimer's Disease Assessment Scale
  • the ADAS-cog is designed to measure, with the use of questionnaires, the progression and the severity of cognitive decline as seen in AD on a 70- point scale.
  • the ADAS-cog scale quantifies the number of wrong answers. Consequently, a high score on the scale indicates a more severe case of cognitive decline.
  • a subject exhibits a score of greater than 0, greater than about 5, greater than about 10, greater than about 15, greater than about 20, greater than about 25, greater than about 30, greater than about 35, greater than about 40, greater than about 45, greater than about 50, greater than about 55, greater than about 60, greater than about 65, greater than about 68, or about 70.
  • the subject exhibits no symptoms of Alzheimer's Disease. In another embodiment, the subject is a human who is at least 40 years of age and exhibits no symptoms of Alzheimer's Disease. In another embodiment, the subject is a human who is at least 40 years of age and exhibits one or more symptoms of Alzheimer's Disease.
  • the subject has Mild Cognitive Impairment. In a further embodiment, the subject has a CDR rating of about 0.5. In another embodiment, the subject has early Alzheimer's disease. In another embodiment, the subject has cerebral amyloid angiopathy.
  • the levels of amyloid ⁇ peptides in a subject's plasma or cerebrospinal fluid (CSF) can be reduced from levels prior to freatment from about 10 to about 100 percent, or even about 50 to about 100 percent.
  • the subject can have an elevated level of amyloid A ⁇ 40 and A ⁇ 42 peptide in the blood and CSF prior to treatment, according to the present methods, of greater than about 10 pg/mL, or greater than about 20 pg/mL, or greater than about 35 pg/mL, or even greater than about 40 pg/mL.
  • the elevated level of amyloid A ⁇ 2 peptide can range from about 30 pg/mL to about 200 pg/mL, or even to about 500 pg/mL.
  • the measurable levels of amyloid ⁇ peptide in the CSF may decrease from elevated levels present before onset ofthe disease. This effect is attributed to increased deposition, i.e., trapping of A ⁇ peptide in the brain instead of normal clearance from the brain into the CSF.
  • the subject can have an elevated level of amyloid A ⁇ 40 peptide in the blood and CSF prior to treatment, according to the present methods, of greater than about 5 pg A ⁇ 2 /mL or greater than about 50 pg A ⁇ 40 /mL, or greater than about 400 pg/mL.
  • the elevated level of amyloid A ⁇ 40 peptide can range from about 200 pg/mL to about 800 pg/mL, to even about 1000 pg/mL.
  • the subject can have an elevated level of amyloid A ⁇ 4 peptide in the CSF prior to freatment, according to the present methods, of greater than about 5 pg/mL, or greater than about 10 pg/mL, or greater than about 200 pg/mL, or greater than about 500 pg/mL.
  • the level of amyloid ⁇ peptide can range from about 10 pg/mL to about 1 ,000 pg/mL, or even about 100 pg/mL to about 1,000 pg/mL.
  • the subject can have an elevated level of amyloid A ⁇ 0 peptide in the CSF prior to freatment according to the present methods of greater than about 10 pg/mL, or greater than about 50 pg/mL, or even greater than about 100 pg/mL.
  • the level of amyloid ⁇ peptide can range from about 10 pg/mL to about 1,000 pg/mL.
  • the amount of amyloid ⁇ peptide in the brain, CSF, blood, or plasma of a subject can be evaluated by enzyme-linked immunosorbent assay ("ELISA") or quantitative immunoblotting test methods or by quantitative SELDI-TOF which are well known to those skilled in the art, such as is disclosed by Zhang, et al, J. Biol Chem. 274, 8966-72 (1999) and Zhang, et al, Biochemistry 40, 5049-55 (2001). See also, A.K.Vehmas, et al, DNA Cell Biol. 20(11), 713-21 (2001), P.Lewczuk, et al, Rapid Commun. Mass Spectrom.
  • EIA Europium immunoassay
  • the methods ofthe invention may be applied as a therapy for a subject having Alzheimer's disease or a dementia, or the methods ofthe invention may be applied as a prophylaxis against Alzheimer's disease or dementia for subject with such a predisposition, as in a subject, e.g., with a genomic mutation in the APP gene, the ApoE gene, or a presenilin gene.
  • the subject may have (or may be predisposed to developing or may be suspected of having) vascular dementia, or senile dementia, Mild Cognitive Impairment, or early Alzheimer's disease.
  • the subject may have another amyloid-related disease such as cerebral amyloid angiopathy, or the subject may have amyloid deposits, especially amyloid— ⁇ amyloid deposits in the brain.
  • the present invention pertains to methods of using the compounds and pharmaceutical compositions thereof in the freatment and prevention of amyloid-related diseases.
  • the pharmaceutical compositions ofthe invention may be administered therapeutically or prophylactically to treat diseases associated with amyloid ⁇ e.g., AL amyloid protein ( ⁇ or ⁇ -chain related, e.g., amyloid ⁇ , amyloid K, amyloid KTV, amyloid ⁇ VI, amyloid ⁇ , amyloid ⁇ l), A ⁇ , LAPP, /3 2 M, AA, or AH amyloid protein) fibril formation, aggregation or deposition.
  • AL amyloid protein ⁇ or ⁇ -chain related, e.g., amyloid ⁇ , amyloid K, amyloid KTV, amyloid ⁇ VI, amyloid ⁇ , amyloid ⁇ l
  • a ⁇ , LAPP, /3 2 M, AA, or AH amyloid protein fibril formation, aggregation or deposition.
  • compositions ofthe invention may act to ameliorate the course of an amyloid-related disease using any ofthe following mechanisms (this list is meant to be illustrative and not limiting): slowing the rate of amyloid fibril formation or deposition; lessening the degree of amyloid deposition; inhibiting, reducing, or preventing amyloid fibril formation; inhibiting neurodegeneration or cellular toxicity induced by amyloid; inhibiting amyloid induced inflammation; enhancing the clearance of amyloid from the brain; enhancing degradation of A ⁇ in the brain; or favoring clearance of amyloid protein prior to its organization in fibrils.
  • “Modulation" of amyloid deposition includes both inhibition, as defined above, and enhancement of amyloid deposition or fibril formation.
  • modulating is intended, therefore, to encompass prevention or stopping of amyloid formation or accumulation, inhibition or slowing down of further amyloid formation or accumulation in a subject with ongoing amyloidosis, e.g., already having amyloid deposition, and reducing or reversing of amyloid formation or accumulation in a subject with ongoing amyloidosis; and enhancing amyloid deposition, e.g., increasing the rate or amount of amyloid deposition in vivo or in vitro.
  • Amyloid-enhancing compounds may be useful in animal models of amyloidosis, for example, to make possible the development of amyloid deposits in animals in a shorter period of time or to increase amyloid deposits over a selected period of time.
  • Amyloid-enhancing compounds may be useful in screening assays for compounds which inhibit amyloidosis in vivo, for example, in animal models, cellular assays and in vitro assays for amyloidosis. Such compounds may be used, for example, to provide faster or more sensitive assays for compounds. Modulation of amyloid deposition is determined relative to an unfreated subject or relative to the treated subject prior to freatment.
  • “Inhibition" of amyloid deposition includes preventing or stopping of amyloid formation, e.g., fibrillogenesis, clearance of amyloid, e.g., soluble A ⁇ from brain, inhibiting or slowing down of further amyloid deposition in a subject with amyloidosis, e.g., already having amyloid deposits, and reducing or reversing amyloid fibrillogenesis or deposits in a subject with ongoing amyloidosis.
  • Inhibition of amyloid deposition is determined relative to an unfreated subject, or relative to the treated subject prior to freatment, or, e.g., determined by clinically measurable improvement, e.g., or in the case of a subject with brain amyloidosis, e.g., an Alzheimer's or cerebral amyloid angiopathy subject, stabilization of cognitive function or prevention of a further decrease in cognitive function ⁇ i.e., preventing, slowing, or stopping disease progression), or improvement of parameters such as the concenfration of A ⁇ or tau in the CSF.
  • “freatment" of a subject includes the application or administration of a composition ofthe invention to a subject, or application or administration of a composition ofthe invention to a cell or tissue from a subject, who has an amyloid-related disease or condition, has a symptom of such a disease or condition, or is at risk of (or susceptible to) such a disease or condition, with the purpose of curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving, or affecting the disease or condition, the symptom ofthe disease or condition, or the risk of (or susceptibility to) the disease or condition.
  • treating refers to any indicia of success in the freatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the subject; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a subject's physical or mental well-being; or, in some situations, preventing the onset of dementia.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, a psychiatric evaluation, or a cognition test such as CDR, MMSE, ADAS-Cog, or another test known in the art.
  • the methods ofthe invention successfully treat a subject's dementia by slowing the rate of or lessening the extent of cognitive decline.
  • the term “treating” includes maintaining a subject's CDR rating at its base line rating or at 0.
  • the term treating includes decreasing a subject's CDR rating by about 0.25 or more, about 0.5 or more, about 1.0 or more, about 1.5 or more, about 2.0 or more, about 2.5 or more, or about 3.0 or more.
  • the term “treating” also includes reducing the rate ofthe increase of a subject's CDR rating as compared to historical controls.
  • the term includes reducing the rate of increase of a subject's CDR rating by about 5% or more, about 10% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100%, ofthe increase of the historical or unfreated controls.
  • the term “treating” also includes maintaining a subject's score on the MMSE.
  • the tenn “treating” includes increasing a subject's MMSE score by about 1, about 2, about 3, about 4, about 5, about 7.5, about 10, about 12.5, about 15, about 17.5, about 20, or about 25 points.
  • the term also includes reducing the rate ofthe decrease of a subject's MMSE score as compared to historical controls.
  • the term includes reducing the rate of decrease of a subject's MMSE score by about 5% or less, about 10% or less, about 20% or less, about 25% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less or about 100% or less, ofthe decrease ofthe historical or unfreated controls.
  • the term “treating” includes maintaining a subject's score on the ADAS-Cog.
  • the term “treating” includes decreasing a subject's ADAS- Cog score by about 1 point or greater, by about 2 points or greater, by about 3 points or greater, by about 4 points or greater, by about 5 points or greater, by about 7.5 points or greater, by about 10 points or greater, by about 12.5 points or greater, by about 15 points or greater, by about 17.5 points or greater, by about 20 points or greater, or by about 25 points or greater.
  • the term also includes reducing the rate ofthe increase of a subject's ADAS-Cog score as compared to historical controls.
  • the term includes reducing the rate of increase of a subject's ADAS-Cog score by about 5% or more, about 10% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more or about 100% ofthe increase ofthe historical or unfreated controls.
  • the term "treating" e.g., for AA or AL amyloidosis, includes an increase in serum creatinine, e.g., an increase of creatinine clearance of 10% or greater, 20% or greater, 50% or greater, 80% or greater, 90% or greater, 100% or greater, 150% or greater, 200% or greater.
  • the term "treating” also may induce remission of nephrotic syndrome (NS). It may also include remission of chronic diarrhea and/or a gain in body weight, e.g., by 10% or greater, 15% or greater, or 20% or greater.
  • the pharmaceutical compositions ofthe invention contain a compound that prevents or inhibits amyloid fibril formation, either in the brain or other organ of interest (acting locally) or throughout the entire body (acting systemically).
  • Pharmaceutical compositions ofthe invention may be effective in controlling amyloid deposition either following their entry into the brain (following penetration ofthe blood brain barrier) or from the periphery.
  • a compound of a pharmaceutical composition may alter the equilibrium of amyloidogenic peptide between the brain and the plasma so as to favor the exit of amyloidogenic peptide from the brain.
  • amyloid protein soluble
  • amyloid fibril formation and deposition due to a reduction ofthe amyloid protein pool in a specific organ, e.g., liver, spleen, pancreas, kidney, joints, brain, etc.
  • An increase in the exit of amyloidogenic peptide from the brain would result in a decrease in amyloidogenic peptide brain concenfration and therefore favor a decrease in amyloidogenic peptide deposition.
  • an agent may lower the levels of amyloid ⁇ peptides, e.g., both A ⁇ 40 and A ⁇ 42 in the CSF and the plasma, or the agent may lower the levels of amyloid ⁇ peptides, e.g., A ⁇ 40 and A ⁇ 42 in the CSF and increase it in the plasma.
  • compounds that penefrate the brain could confrol deposition by acting directly on brain amyloidogenic peptide e.g., by maintaining it in a non-fibrillar form or favoring its clearance from the brain, by increasing its degradation in the brain, or protecting brain cells from the detrimental effect of amyloidogenic peptide.
  • an agent can also cause a decrease ofthe concenfration ofthe amyloid protein (i.e., in a specific organ so that the critical concentration needed to trigger amyloid fibril formation or deposition is not reached).
  • the compoxmds described herein may inhibit or reduce an interaction between amyloid and a cell surface constituent, for example, a glycosaminoglycan or proteoglycan constituent of a basement membrane, whereby inhibiting or reducing this interaction produces the observed neuroprotective and cell- protective effects.
  • the compound may also prevent an amyloid peptide from binding or adhering to a cell surface, a process which is known to cause cell damage or toxicity.
  • the compound may block amyloid-induced cellular toxicity or microglial activation or amyloid-induced neurotoxicity, or inhibit amyloid induced inflammation.
  • the compound may also reduce the rate or amount of amyloid aggregation, fibril formation, or deposition, or the compound lessens the degree of amyloid deposition.
  • amyloid- ⁇ disease may be used for mild cognitive impairment; vascular dementia; early Alzheimer's disease; Alzheimer's disease, including sporadic (non-hereditary) Alzheimer's disease and familial (hereditary) Alzheimer's disease; age- related cognitive decline; cerebral amyloid angiopathy ("CAA”); hereditary cerebral hemorrhage; senile dementia; Down's syndrome; inclusion body myositis (“IBM”); or age-related macular degeneration (“ARMD”).
  • amyloid- ⁇ is a peptide having 39-43 amino-acids
  • amyloid- ⁇ is an amyloidogenic peptide produced from ⁇ APP.
  • Mild cognitive impairment 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. It is a diagnosis that has most often been associated with mild memory problems, but it can also be characterized by mild impairments in other thinking skills, such as language or planning skills. However, in general, an individual with MCI will have more significant memory lapses than would be expected for someone of their age or educational background. As the condition progresses, a physician may change the diagnosis to "Mild-to-Moderate Cognitive Impairment," as is well understood in this art.
  • Cerebral amyloid angiopathy refers to the specific deposition of amyloid fibrils in the walls of leptomingeal and cortical arteries, arterioles and in capillaries 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 sfroke or dementia (see Frangione, et al, Amyloid: J. Protein Folding Disord. 8,
  • CAA can occur sporadically or be hereditary. Multiple mutation sites in either A ⁇ 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 amyloidosis of Icelandic type (HCHWA-L); the Dutch variant of HCHWA (HCHWA-D; a mutation in A ⁇ ); the
  • Cerebral amyloid angiopathy is known to be associated with cerebral hemorrhage (or hemorrhagic sfroke).
  • LBM sporadic inclusion body myositis
  • Askanas, et al Proc. Natl. Acad. Sci. USA 93, 1314-19 (1996); Askanas, et al, Current Opinion in Rheumatology 7, 486-96 (1995)
  • the compounds ofthe invention can be used prophylactically or therapeutically in the freatment of disorders in which amyloid- ⁇ protein is abnormally deposited at non- neurological locations, such as treatment of LBM by delivery ofthe compounds to muscle fibers.
  • a ⁇ is associated with abnormal extracellular deposits, known as drusen, that accumulate along the basal surface ofthe retinal pigmented epithelium in individuals with age-related macular degeneration (ARMD).
  • ARMD is a cause of irreversible vision loss in older individuals. It is believed that A ⁇ deposition could be an important component ofthe local inflammatory events that contribute to atrophy ofthe retinal pigmented epithelium, drusen biogenesis, and the pathogenesis of ARMD (Johnson, et al, Proc. Natl Acad. Sci. USA 99(18), 11830-5 (2002)). Therefore, the invention also relates to the treatment or prevention of age- related macular degeneration.
  • the invention relates to a method for preventing or inhibiting amyloid deposition in a subject.
  • a method for preventing or inhibiting amyloid deposition in a subject comprises administering to a subject a therapeutically effective amount of a compound capable of reducing the concentration of amyloid ⁇ e.g., AL amyloid protein ( ⁇ or K-chain related, e.g., amyloid ⁇ , amyloid K, amyloid KTV, amyloid XVI, amyloid ⁇ , amyloid ⁇ l), A ⁇ , LAPP, ⁇ M, AA, AH amyloid protein, or other amyloids), such that amyloid accumulation or deposition is prevented or inhibited.
  • AL amyloid protein ⁇ or K-chain related, e.g., amyloid ⁇ , amyloid K, amyloid KTV, amyloid XVI, amyloid ⁇ , amyloid ⁇ l
  • the invention in another aspect, relates to a method for preventing, reducing, or inhibiting amyloid deposition in a subject.
  • a method for preventing, reducing, or inhibiting amyloid deposition in a subject comprises administering to a subject a therapeutically effective amount of a compound capable of inhibiting amyloid ⁇ e.g., AL amyloid protein ( ⁇ or /.-chain related, e.g., amyloid ⁇ , amyloid K, amyloid KLV, amyloid XVI, amyloid ⁇ , amyloid ⁇ l), A ⁇ , LAPP, 2 M, AA, AH amyloid protein, or other amyloids), such that amyloid deposition is prevented, reduced, or inhibited.
  • AL amyloid protein ⁇ or /.-chain related, e.g., amyloid ⁇ , amyloid K, amyloid KLV, amyloid XVI, amyloid ⁇ , amyloid ⁇ l
  • the invention also relates to a method for modulating, e.g., minimizing, amyloid-associated damage to cells, comprising the step of administering a compound capable of reducing the concenfration of amyloid ⁇ e.g., AL amyloid protein ( ⁇ or K-chain related, e.g., amyloid ⁇ , amyloid K, amyloid KTV, amyloid XVI, amyloid % amyloid ⁇ l), A ⁇ , LAPP, ⁇ 2 M, AA, AH amyloid protein, or another amyloid), such that said amyloid- associated damage to cells is modulated.
  • the methods for modulating amyloid-associated damage to cells comprise a step of administering a compound capable of reducing the concentration of amyloid or reducing the interaction of an amyloid with a cell surface.
  • the invention also includes a method for directly or indirectly preventing cell death in a subject, the method comprising administering to a subject a therapeutically effective amount of a compound capable of preventing amyloid ⁇ e.g., AL amyloid protein ( ⁇ or K-chain related, e.g., amyloid ⁇ , amyloid K, amyloid KTV, amyloid ⁇ VI, amyloid ⁇ , amyloid ⁇ l), A ⁇ , LAPP, 3 2 M, AA, AH amyloid protein, or other amyloid) mediated events that lead, directly or indirectly, to cell death.
  • AL amyloid protein ⁇ or K-chain related, e.g., amyloid ⁇ , amyloid K, amyloid KTV, amyloid ⁇ VI, amyloid ⁇ , amyloid ⁇ l
  • a ⁇ , LAPP, 3 2 M, AA, AH amyloid protein, or other amyloid mediated events that lead, directly or indirectly, to cell death.
  • the method is used to treat Alzheimer's disease (e.g. sporadic or familial AD).
  • the method can also be used prophylactically or therapeutically to treat other clinical occurrences of amyloid- ⁇ deposition, such as in Down's syndrome individuals and in patients with cerebral amyloid angiopathy ("CAA”) or hereditary cerebral hemorrhage.
  • CAA cerebral amyloid angiopathy
  • the compounds ofthe invention may be used prophylactically or therapeutically in the freatment of disorders in which amyloid-beta peptide is abnormally deposited at non-neurological locations, such as treatment of LBM by delivery ofthe compounds to muscle fibers, or freatment of macular degeneration by delivery ofthe compound(s) of the invention to the basal surface ofthe retinal pigmented epithelium.
  • the present invention also provides a method for modulating amyloid-associated damage to cells, comprising the step of administering a compound capable of reducing the concentration of A ⁇ , or capable of mimimizing the interaction of A ⁇ (soluble oligomeric or fibrillary) with the cell surface, such that said amyloid-associated damage to cells is modulated.
  • the methods for modulating amyloid-associated damage to cells comprise a step of administering a compound capable of reducing the concentration of A ⁇ or reducing the interaction of A ⁇ with a cell surface.
  • a method for preventing cell death in a subject comprising administering to a subject a therapeutically effective amount of a compound capable of preventing A/3-mediated events that lead, directly or indirectly, to cell death.
  • the present invention also provides a method for modulating amyloid-associated damage to cells, comprising the step of administering a compound capable of reducing v the concenfration of LAPP, or capable of mimimizing the interaction of LAPP (soluble oligomeric or fibrillary) with the cell surface, such that said amyloid-associated damage to cells is modulated,
  • the methods for modulating amyloid-associated damage to cells comprise a step of administering a compound capable of reducing the concenfration of LAPP or reducing the interaction of LAPP with a cell surface.
  • a method for preventing cell death in a subject comprising administering to a subject a therapeutically effective amount of a compound capable of preventing IAPP-mediated events that lead, directly or indirectly, to cell death.
  • This invention also provides methods and compositions which are useful in the treatment of amyloidosis.
  • the methods ofthe invention involve administering to a subject a therapeutic compound which inhibits amyloid deposition.
  • the compositions and methods ofthe invention are useful for inhibiting amyloidosis in disorders in which amyloid deposition occurs.
  • the methods ofthe invention can be used therapeutically to treat amyloidosis or can be used prophylactically in a subject susceptible to (hereditary) amyloidosis or identified as being at risk to develop amyloidosis, e.g., hereditary, or identified as being at risk to develop amyloidosis.
  • the invention includes a method of inhibiting an interaction between an amyloidogenic protein and a constituent of basement membrane to inhibit amyloid deposition.
  • the constituent of basement membrane is a glycoprotein or proteoglycan, preferably heparan sulfate proteoglycan.
  • a therapeutic compound used in this method may interfere with binding of a basement membrane constituent to a target binding site on an amyloidogenic protein, thereby inhibiting amyloid deposition.
  • the methods ofthe invention involve administering to a subject a therapeutic compound which inhibits amyloid deposition.
  • “Inhibition of amyloid deposition,” includes the prevention of amyloid formation, inhibition of further amyloid deposition in a subject with ongoing amyloidosis and reduction of amyloid deposits in a subject with ongoing amyloidosis. Inhibition of amyloid deposition is determined relative to an unfreated subject or relative to the freated subject prior to freatment. In an embodiment, amyloid deposition is inhibited by inhibiting an interaction between an amyloidogenic protein and a constituent of basement membrane.
  • Basis membrane refers to an extracellular matrix comprising glycoproteins and proteoglycans, including laminin, collagen type LV, fibronectin, perlecan, agrin, dermatan sulfate, and heparan sulfate proteoglycan (HSPG).
  • Sulfated glycosaminoglycans are known to be present in all types of amyloids (see Snow, et al. Lab. Invest.
  • the ability of a compound to prevent or block the formation or deposition of amyloid may reside in its ability to bind to non-fibrillar, soluble amyloid protein and to maintain its solubililty.
  • the ability of a therapeutic compound ofthe invention to inhibit an interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane can be assessed by an in vitro binding assay, such as that described in US 5,164,295, the contents of which are hereby incorporated by reference.
  • the ability of a compound to bind to an amyloidogenic protein or to inhibit the bindmg of a basement membrane constituent (e.g. HSPG) to an amyloidogenic protein e.g.
  • a ⁇ can be measured using a mass spectrometry assay where soluble protein, e.g.A ⁇ , LAPP, ⁇ 2 M is incubated with the compoxind.
  • a compound which binds to, e.g. A ⁇ will induce a change in the mass spectrum ofthe protein.
  • Exemplary protocols for a mass spectrometry assay employing A ⁇ and LAPP can be found in the Examples, the results of which are provided in Table 3. The protocol can readily be modified to adjust the sensitivity ofthe data, e.g., by adjusting the amount of protein and/or compound employed. Thus, e.g., binding might be detected for test compounds noted as not having detectable binding employing less sensitive test protocols.
  • test compoxmds to bind to, e.g., fibrillar A ⁇ .
  • One such screening assay is an ultraviolet abso ⁇ tion assay.
  • a test compound (20 ⁇ M) is incubated with 50 ⁇ M A ⁇ (l-40) fibers for 1 hour at 37°C in Tris buffered saline (20 mM Tris, 150 mM NaCl, pH 7.4 containing 0.01 sodium azide). Following incubation, the solution is centrifuged for 20 minutes at 21,000 g to sediment the A ⁇ (l-40) fibers along with any bound test compound.
  • test compound remaining in the supernatant can then be determined by reading the absorbance.
  • fraction of test compound bound can then be calculated by comparing the amoxint remaining in the supernatants of incubations with A ⁇ to the amount remaining in control incubations which do not contain A ⁇ fibers.
  • Thiofiavin T and Congo Red both of which are known to bind to A ⁇ fibers, may be included in each assay run as positive controls.
  • test compounds can be diluted to 40 ⁇ M, which would be twice the concenfration in the final test, and then scanned using the Hewlett Packard 8453 UV/VIS spectrophotometer to determine if the absorbance is sufficient for detection.
  • the invention in another embodiment, pertains to a method for improving cognition in a subject suffering from an amyloid-related disease.
  • the method includes administering an effective amount of a therapeutic compound ofthe invention, such that the subject's cognition is improved.
  • the subject's cognition can be tested using methods known in the art such as the Clinical Dementia Rating (“CDR”), Mini-Mental State Examination (“MMSE”), and the Alzheimer's Disease Assessment Scale- Cognition (“ADAS-Cog”).
  • CDR Clinical Dementia Rating
  • MMSE Mini-Mental State Examination
  • ADAS-Cog Alzheimer's Disease Assessment Scale- Cognition
  • the invention pertains to a method for treating a subject for an amyloid-related disease.
  • the method includes administering a cognitive test to a subject prior to administration of a compound ofthe invention, administering an effective amount of a compound ofthe invention to the subject, and administering a cognitive test to the subject subsequent to administration ofthe compound, such that the subject is freated for the amyloid-related disease, wherein the subject's score on said cognitive test is improved.
  • a subject's CDR is maintained at 0.
  • a subject's CDR is decreased (e.g., improved) by about 0.25 or more, about 0.5 or more, about 1.0 or more, about 1.5 or more, about 2.0 or more, about 2.5 or more, or about 3.0 or more.
  • the rate of increase of a subject's CDR rating is reduced by about 5% or more, about 10% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more of the increase of the historical or unfreated controls.
  • a subject's score on the MMSE is maintained.
  • the subject's score on the MMSE may be increased by about 1, about 2, about 3, about 4, about 5, about 7.5, about 10, about 12.5, about 15, about 17.5, about 20, or about 25 points, h another alternative, the rate ofthe decrease of a subject's MMSE score as compared to historical controls is reduced.
  • the rate ofthe decrease of a subject's MMSE score may be reduced by about 5% or more, about 10% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, or about 100% or more ofthe decrease ofthe historical or unfreated controls.
  • the invention pertains to a method for treating, slowing or stopping an amyloid-related disease associated with cognitve impairment, by administering to a subject an effective amount of a therapeutic compound ofthe invention, wherein the annual deterioration ofthe subject's cognition as measured by ADAS-Cog is less than 8 points per year, less the 6 points per year, less than 5 points per year, less than 4 points per year, or less than 3 points per year.
  • the invention pertains to a method for treating, slowing or stopping an amyloid-related disease associated with cognition by administering an effective amount of a therapeutic compound ofthe invention such that the subject's cognition as measured by ADAS-Cog remains constant over a year.
  • Constant includes fluctuations of no more than 2 points. Remaining constant includes fluctuations of two points or less in either direction.
  • the subject's cognition improves by 2 points or greater per year, 3 points or greater per year, 4 point or greater per year, 5 points or greater per year, 6 points or greater per year, 7 points or greater per year, 8 points or greater per year, etc. as measured by the ADAS-Cog.
  • the rate of the increase of a subject's ADAS-Cog score as compared to historical controls is reduced.
  • the rate ofthe increase of a subject's ADAS-Cog score may be reduced by about 5% or more, about 10% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more or about 100% ofthe increase ofthe historical or unfreated controls.
  • the ratio of A ⁇ 42 : A ⁇ 40 in the CSF dr plasma of a subject decreases by about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45 % or more, or about 50% or more.
  • the levels of A ⁇ in the subject's cerebrospinal fluid decrease by about 15% or more, about 25% or more, about 35% or more, about 45% or more, about 55% or more, about 75% or more, or about 90% or more.
  • the invention pertains to any novel chemical compound described herein. That is, the invention relates to novel compounds, and novel methods of their use as described herein, which are within the scope ofthe Formulae disclosed herein, and which are not disclosed in the cited Patents and Patent Applications.
  • the compounds ofthe present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. Ln these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
  • Functional and structural equivalents ofthe compounds described herein and which have the same general properties, wherein one or more simple variations of substituents are made which do not adversely affect the essential nature or the utility ofthe compound are also included.
  • the compounds ofthe present invention may be readily prepared in accordance with the synthesis schemes and protocols described herein, as illusfrated in the specific procedures provided. However, those skilled in the art will recognize that other synthetic pathways for forming the compounds of this invention maybe used, and that the following is provided merely by way of example, and is not limiting to the present invention. See, e.g., "Comprehensive Organic Transformations” by R. Larock, VCH Publishers (1989). It will be further recognized that various protecting and deprotecting strategies will be employed that are standard in the art (See, e.g., "Protective Groups in Organic Synthesis” by Greene and Wuts). Those skilled in the relevant arts will recognize that the selection of any particular protecting group ⁇ e.g., amine and carboxyl protecting groups) will depend on the stability ofthe protected moiety with regards to the subsequent reaction conditions and will understand the appropriate selections.
  • protecting group ⁇ e.g., amine and carboxyl protecting groups
  • Suitable solvents are liquids at ambient room temperature and pressure or remain in the liquid state under the temperature and pressure conditions used in the reaction.
  • Useful solvents are not particularly restricted provided that they do not interfere with the reaction itself (that is, they preferably are inert solvents), and they dissolve a certain amount ofthe reactants.
  • solvents may be distilled or degassed.
  • Solvents maybe, for example, aliphatic hydrocarbons ⁇ e.g., hexanes, heptanes, ligroin, pefroleum ether, cyclohexane, or methylcyclohexane) and halogenated hydrocarbons ⁇ e.g., methylenechloride, chloroform, carbontetrachloride, dichloroethane, chlorobenzene, or dichlororbenzene); aromatic hydrocarbons ⁇ e.g., benzene, toluene, tefrahydronaphthalene, ethylbenzene, or xylene); ethers ⁇ e.g., diglyme, methyl-tert-butyl ether, methyl-tert-amyl ether, ethyl-tert-butyl ether, diethylether, diisopropylether, tetrahydrofuran or methyltetrahydrofur
  • diethyleneglycol dimethylether diethyleneglycol dimethylether
  • nitriles ⁇ e.g., acetonitrile
  • ketones ⁇ e.g., acetone
  • esters ⁇ e.g., methyl acetate or ethyl acetate
  • the product is isolated from the reaction mixture according to standard techniques. For example, the solvent is removed by evaporation or filtration if the product is solid, optionally under reduced pressure.
  • water may be added to the residue to make the aqueous layer acidic or basic and the precipitated compound filtered, although care should be exercised when handling water-sensitive compounds.
  • water may be added to the reaction mixture with a hydrophobic solvent to extract the target compound.
  • the organic layer may be washed with water, dried over anhydrous magnesium sulphate or sodium sulphate, and the solvent is evaporated to obtain the target compound.
  • the target compound thus obtained may be purified, if necessary, e.g., by recrystallization, reprecipitation, chromatography, or by converting it to a salt by addition of an acid or base.
  • the compounds ofthe invention may be supplied in a solution with an appropriate solvent or in a solvent-free form ⁇ e.g., lyophilized).
  • the compoxmds and buffers necessary for carrying out the methods ofthe invention may be packaged as a kit, optionlly including a container.
  • the kit may be commercially used for treating or preventing amyloid-related disease according to the methods described herein and may include instructions for use in a method ofthe invention.
  • Additional kit components may include acids, bases, buffering agents, inorganic salts, solvents, antioxidants, preservatives, or metal chelators.
  • the additional kit components are present as pure compositions, or as aqueous or organic solutions that inco ⁇ orate one or more additional kit components. Any or all ofthe kit components optionally further comprise buffers.
  • the term "container” includes any receptacle for holding the therapeutic compound.
  • the container is the packaging that contains the compound.
  • the container is not the packaging that contains the compound, i.e., the container is a receptacle, such as a box or vial that contains the packaged compound or unpackaged compound and the instructions for use ofthe compound.
  • packaging techniques are well known in the art. It should be understood that the instructions for use ofthe therapeutic compound may be contained on the packaging containing the therapeutic compound, and as such the instructions form an increased functional relationship to the packaged product.
  • the present invention relates to pharmaceutical compositions comprising agents according to any ofthe Formulae herein for the freatment of an amyloid-related disease, as well as methods of manufacturing such pharmaceutical compositions.
  • the agents ofthe present invention may be prepared by the methods illusfrated in the general reaction schemes as, for example, in the patents and patent applications refered to herein, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. Ln these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
  • Functional and structural equivalents ofthe agents described herein and which have the same general properties, wherein one or more simple variations of substituents are made which do not adversely affect the essential nature or the utility of the agent are also included.
  • the agents ofthe invention may be supplied in a solution with an appropriate solvent or in a solvent-free form ⁇ e.g., lyophilized).
  • the agents and buffers necessary for carrying out the methods ofthe invention may be packaged as a kit.
  • the kit may be commercially used according to the methods described herein and may include instructions for use in a method ofthe invention.
  • Additional kit components may include acids, bases, buffering agents, inorganic salts, solvents, antioxidants, preservatives, or metal chelators.
  • the additional kit components are present as pure compositions, or as aqueous or organic solutions that inco ⁇ orate one or more additional kit components. Any or all ofthe kit components optionally further comprise buffers.
  • the therapeutic agent may also be administered parenterally, intraperitoneally, intraspinally, or infracerebrally.
  • Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • the agent may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
  • suitable diluents include saline and aqueous buffer solutions.
  • Liposomes include water-in-oil-in- water CGF emulsions as well as conventional liposomes (Sfrejan et al, J. Neuroimmunol 7, 27 (1984)).
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or, dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • Suitable pharmaceutically acceptable vehicles include, without limitation, any non-immunogenic pharmaceutical adjuvants suitable for oral, parenteral, nasal, mucosal, transdermal, intravascular ⁇ TV), infraarterial (IA), intramuscular (LM), and subcutaneous (SC) administration routes, such as phosphate buffer saline (PBS).
  • the vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use of surfactants.
  • a coating such as lecithin
  • surfactants for example, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium mannitol and sorbitol, in the composition.
  • Prolonged abso ⁇ tion ofthe injectable compositions can be brought about by including in the composition an agent which delays abso ⁇ tion, for example, aluminum monostearate or gelatin.
  • Sterile injectable solutions can be prepared by inco ⁇ orating the therapeutic agent in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by inco ⁇ orating the therapeutic agent into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the methods of preparation are vacuum drying and freeze-drying which yields a powder ofthe active ingredient ⁇ i.e., the therapeutic agent) plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the therapeutic agent can be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the therapeutic agent and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or inco ⁇ orated directly into the subject's diet.
  • the therapeutic agent maybe inco ⁇ orated with excipients and used in the form of ingestible tablets, buccal tablets, froches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the percentage ofthe therapeutic agent in the compositions and preparations may, of course, be varied.
  • the amount ofthe therapeutic agent in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of therapeutic agent calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • the specification for the dosage unit forms ofthe invention are dictated by and directly dependent on (a) the unique characteristics ofthe therapeutic agent and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic agent for the freatment of amyloid deposition in subjects.
  • the present invention therefore includes pharmaceutical formulations comprising the agents ofthe Formulae described herein, including pharmaceutically acceptable salts thereof, in pharmaceutically acceptable vehicles for aerosol, oral and parenteral administration.
  • the present invention includes such agents, or salts thereof, which have been lyophilized and which may be reconstituted to form pharmaceutically acceptable formulations for administration, as by intravenous, intramuscular, or subcutaneous injection. Administration may also be infradermal or transdermal.
  • an agent ofthe Formulae described herein, and pharmaceutically acceptable salts thereof may be administered orally or through inhalation as a solid, or may be administered intramuscularly or intravenously as a solution, suspension or emulsion. Alternatively, the agents or salts may also be administered by inhalation, infravenously or inframuscularly as a liposomal suspension.
  • compositions are also provided which are suitable for administration as an aerosol, by inhalation. These formulations comprise a solution or suspension ofthe desired agent of any Formula herein, or a salt thereof, or a plurality of solid particles ofthe agent or salt.
  • the desired formulation may be placed in a small chamber and nebulized. Nebulization may be accomplished by compressed air or by ultrasonic energy to form a plurality of liquid droplets or solid particles comprising the agents or salts.
  • the liquid droplets or solid particles should have a particle size in the range of about 0.5 to about 5 microns.
  • the solid particles can be obtained by processing the solid agent of any Formula described herein, or a salt thereof, in any appropriate manner known in the art, such as by micronization.
  • the size ofthe solid particles or droplets will be, for example, from about 1 to about 2 microns. Ln this respect, commercial nebulizers are available to achieve this pu ⁇ ose.
  • a pharmaceutical formulation suitable for administration as an aerosol may be in the form of a liquid, the formulation will comprise a water-soluble agent of any Formula described herein, or a salt thereof, in a carrier which comprises water.
  • a surfactant may be present which lowers the surface tension ofthe formulation sufficiently to result in the formation of droplets within the desired size range when subjected to nebulization.
  • Peroral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • the pharmaceutically acceptable vehicles suitable for preparation of such compositions are well known in the art.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, tragacanth, and sodium alginate;
  • typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
  • compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject agent is released in the gastrointestinal fract in the vicinity ofthe desired topical application, or at various times to extend the desired action.
  • dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, waxes, and shellac.
  • compositions useful for attaining systemic delivery ofthe subject agents include sublingual, buccal and nasal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • compositions of this invention can also be administered topically to a subject, e.g., by the direct laying on or spreading ofthe composition on the epidermal or epithelial tissue ofthe subject, or fransdermally via a "patch".
  • Such compositions include, for example, lotions, creams, solutions, gels and solids.
  • These topical compositions may comprise an effective amount, usually at least about 0.1%, or even from about 1% to about 5%, of an agent ofthe invention.
  • Suitable carriers for topical administration typically remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water.
  • the carrier is organic in nature and capable of having dispersed or dissolved therein the therapeutic agent.
  • the carrier may include pharmaceutically acceptable emolients, emulsifiers, thickening agents, solvents and the like.
  • active agents are administered at a therapeutically effective dosage sufficient to inhibit amyloid deposition in a subject.
  • a "therapeutically effective" dosage inhibits amyloid deposition by, for example, at least about 20%, or by at least about 40%), or even by at least about 60%, or by at least about 80% relative to untreated subjects.
  • a "therapeutically effective" dosage stabilizes cognitive function or prevents a further decrease in cognitive function ⁇ i.e., preventing, slowing, or stopping disease progression).
  • the present invention accordingly provides therapeutic drugs.
  • terapéutica an agent having a beneficial ameliorative or prophylactic effect on a specific disease or condition in a living human or non-human animal.
  • the agent may improve or stabilize specific organ function.
  • renal function may be stabilized or improved by 10% or greater, 20% or greater, 30% or greater, 40% or greater, 50% or greater, 60% or greater, 70% or greater, 80% or greater, or by greater than 90%.
  • the agent may maintain or increase ⁇ -islet cell function, as determined by insulin concentration or the Pro-LAPP/LAPP ratio.
  • the Pro-LAPP/LAPP ratio is increased by about 10% or greater, about 20% or greater, about 30% or greater, about 40% or greater, or by about 50%.
  • the ratio is increased up to 50%.
  • a therapeutically effective amount ofthe agent may be effective to improve glycemia or insulin levels.
  • the active agents are administered at a therapeutically effective dosage sufficient to treat AA (secondary) amyloidosis and/or AL (primary) amyloidosis, by stabilizing renal function, decreasing proteinuria, increasing creatinine clearance (e.g., by at least 50% or greater or by at least 100% or greater), remission of chronic diarrhea, or by weight gain (e.g., 10% or greater).
  • the agents may be administered at a therapeutically effective dosage sufficient to improve nephrotic syndrome.
  • active agents may be administered at a therapeutically effective dosage sufficient to decrease deposition in a subject of amyloid protein, e.g., A/340 or A/342.
  • a therapeutically effective dosage decreases amyloid deposition by, for example, at least about 15%, or by at least about 40%, or even by at least 60%, or at least by about 80% relative to untreated subjects.
  • active agents are administered at a therapeutically effective dosage sufficient to increase or enhance amyloid protein, e.g., A/340 or A/342, in the blood, CSF, or plasma of a subject.
  • a therapeutically effective dosage increases the concentration by, for example, at least about 15%, or by at least about 40%, or even by at least 60%, or at least by about 80% relative to unfreated subjects.
  • active agents are administered at a therapeutically effective dosage sufficient to maintain a subject's CDR rating at its base line rating or at 0. Ln another embodiment, the active agents are administered at a therapeutically effective dosage sufficient to decrease a subject's CDR rating by about 0.25 or more, about 0.5 or more, about 1.0 or more, about 1.5 or more, about 2.0 or more, about 2.5 or more, or about 3.0 or more. In another embodiment, the active agents are administered at a therapeutically effective dosage sufficient to reduce the rate ofthe increase of a subject's CDR rating as compared to historical or unfreated controls.
  • the therapeutically effective dosage is sufficient to reduce the rate of increase of a subject's CDR rating (relative to untreated subjects) by about 5% or greater, about 10% or greater, about 20% or greater, about 25% or greater, about 30% or greater, about 40% or greater, about 50% or greater, about 60% or greater, about 70% or greater, about 80% or greater, about 90% or greater or about 100% or greater.
  • active agents are administered at a therapeutically effective dosage sufficient to maintain a subject's score on the MMSE.
  • the active agents are administered at a therapeutically effective dosage sufficient to increase a subject's MMSE score by about 1, about 2, about 3, about 4, about 5, about 7.5, about 10, about 12.5, about 15, about 17.5, about 20, or about 25 points.
  • the active agents are administered at a therapeutically effective dosage sufficient to reduce the rate ofthe decrease of a subject's MMSE score as compared to historical controls.
  • the therapeutically effective dosage is sufficient to reduce the rate of decrease of a subject's MMSE score may be about 5% or less, about 10% or less, about 20% or less, about 25% or less, about 30% or less, about 40% or less, about 50% or less, about 60% or less, about 70% or less, about 80% or less, about 90% or less or about 100% or less, ofthe decrease ofthe historical or unfreated controls.
  • active agents are administered at a therapeutically effective dosage sufficient to maintain a subject's score on the ADAS-Cog.
  • the active agents are administered at a therapeutically effective dosage sufficient to decrease a subject's ADAS-Cog score by about 2 points or greater, by about 3 points or greater, by about 4 points or greater, by about 5 points or greater, by about 7.5 points or greater, by about 10 points or greater, by about 12.5 points or greater, by about 15 points or greater, by about 17.5 points or greater, by about 20 points or greater, or by about 25 points or greater.
  • the active agents are administered at a therapeutically effective dosage sufficient to reduce the rate ofthe increase of a subject's ADAS-Cog scores as compared to historical or unfreated controls.
  • the therapeutically effective dosage is sufficient to reduce the rate of increase of a subject's ADAS-Cog scores (relative to unfreated subjects) by about 5% or greater, about 10% or greater, about 20% or greater, about 25% or greater, about 30% or greater, about 40% or greater, about 50% or greater, about 60% or greater, about 70% or greater, about 80% or greater, about 90% or greater or about 100% or greater.
  • active agents are administered at a therapeutically effective dosage sufficient to decrease the ratio of A ⁇ 42:A ⁇ 40 in the CSF or plasma of a subject by about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 35% or more, about 40% or more, about 45% or more, or about 50% or more.
  • active agents are administered at a therapeutically effective dosage sufficient to lower levels of A ⁇ in the CSF or plasma of a subject by about 15% or more, about 25% or more, about 35% or more, about 45% or more, about 55% or more, about 75% or more, or about 95% or more.
  • Toxicity and therapeutic efficacy of such agents can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% ofthe population) and the ED50 (the dose therapeutically effective in 50% ofthe population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED50, and usually a larger therapeutic index is more efficacious. While agents that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such agents to the site of affected tissue in order to rninimize potential damage to unaffected cells and, thereby, reduce side effects.
  • doses depend upon a number of factors within the ken ofthe ordinarily skilled physician, veterinarian, or researcher.
  • the dose(s) ofthe small molecule will vary, for example, depending upon the identity, size, and condition ofthe subject or sample being freated, further depending upon the route by which the composition is to be admimstered, if applicable, and the effect which the practitioner desires the small molecule to have upon the subject.
  • Exemplary doses include milligram or microgram amounts ofthe small molecule per kilogram of subject or sample weight ⁇ e.g., about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram).
  • appropriate doses depend upon the potency. Such appropriate doses may be determined using the assays described herein. When one or more of these compounds is to be administered to an animal ⁇ e.g., a human), a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained.
  • the specific dose level for any particular animal subject will depend upon a variety of factors including the activity ofthe specific agent employed, the age, body weight, general health, gender, and diet ofthe subject, the time of administration, the route of administration, the rate of excretion, and any drug combination.
  • an agent to inhibit amyloid deposition can be evaluated in an animal model system that may be predictive of efficacy in inhibiting amyloid deposition in human diseases, such as a fransgenic mouse expressing human APP or other relevant animal models where A ⁇ deposition is seen or for example in an animal model of AA amyloidosis.
  • the ability of an agent to prevent or reduce cognitive impairment in a model system may be indicative of efficacy in humans.
  • the ability of an agent can be evaluated by examining the ability ofthe agent to inhibit amyloid fibril formation in vitro, e.g., using a fibrillogenesis assay such as that described herein, including a ThT, CD, or EM assay.
  • binding of an agent to amyloid fibrils may be measured using a MS assay as described herein.
  • the ability ofthe agent to protect cells from amyloid induced toxicity is determined in vitro using biochemical assays to determine percent cell death induced by amyloid protein.
  • the ability of an agent to modulate renal function may also be evaluated in an appropriate animal model system.
  • the therapeutic agent ofthe invention may be also be administered ex vivo to inhibit amyloid deposition or freat certain amyloid-related diseases, such as ⁇ 2 M amyloidosis and other amyloidoses related to dialysis.
  • Ex vivo administration ofthe therapeutic agents ofthe invention can be accomplished by contacting a body fluid (e.g., blood, plasma, etc.) with a therapeutic compound ofthe invention such that the therapeutic compound is capable of performing its intended function and administering the body fluid to the subject.
  • the therapeutic compound ofthe invention may perform its function ex vivo (e.g., dialysis filter), in vivo (e.g., admimstered with the body fluid), or both.
  • a therapeutic compound ofthe invention may be used to reduce plasma ⁇ 2 M levels and/or maintain ⁇ 2 M in its soluble form ex vivo, in vivo, or both.
  • the compound prevents or treats amyloid-related diseases, such as for example Alzheimer's disease, CAA, diabetes related amyloidosis, AL amyloidosis, Down's syndrome, or /3 M amyloidosis.
  • amyloid-related diseases such as for example Alzheimer's disease, CAA, diabetes related amyloidosis, AL amyloidosis, Down's syndrome, or /3 M amyloidosis.
  • the compound may reverse or favor deposition of amyloid or the compound may favor plaque clearance or slow deposition.
  • the compound may decrease the amyloid concenfration in the brain of a subject versus an unfreated subject.
  • the compound may penetrate into the brain by crossing the blood-brain barrier ("BBB”) to exert its biological effect.
  • BBB blood-brain barrier
  • the compound may maintain soluble amyloid in a non-fibrillar form, or alternatively, the compound may increase the rate of clearance of soluble amyloid from the brain of a subject versus an unfreated subject.
  • the compound may also increase the rate of degradation of A ⁇ in the brain prior to organization into fibrils.
  • a compound may also act in the periphery, causing a change in the equilibrium ofthe amyloid protein concenfration in the two compartments ⁇ i.e., systemic vs. central), in which case a compound may not be required to penetrate the brain to decrease the concentration of A ⁇ in the brain (a "sink" effect).
  • Agents ofthe invention that exert their physiological effect in vivo in the brain may be more useful if they gain access to target cells in the brain.
  • brain cells are neurons, glial cells (astrocytes, oligodendrocytes, microglia), cerebrovascular cells (muscle cells, endothelial cells), and cells that comprise the meninges.
  • the blood brain barrier (“BBB”) typically restricts access to brain cells by acting as a physical and functional blockade that separates the brain parenchyma from the systemic circulation ⁇ see, e.g., Pardridge, et al, J. Neurovirol 5(6), 556-69 (1999); Rubin, et al, Rev. Neurosci. 22, 11-28 (1999)). Circulating molecules are normally able to gain access to brain cells via one of two processes: lipid-mediated transport through the BBB by free diffusion, or active (or catalyzed) transport.
  • the agents ofthe invention maybe formulated to improve distribution in vivo, for example as powdered or liquid tablet or solution for oral administration or as a nasal spray, nose drops, a gel or ointment, through a tube or catheter, by syringe, by packtail, by pledget, or by submucosal infusion.
  • the blood-brain barrier excludes many highly hydrophilic agents.
  • they may be formulated, for example, in liposomes.
  • liposomes see, e.g., U.S. Pat. Nos. 4,522,811; 5,374,548; and 5,399,331.
  • the liposomes may comprise one or more moieties which are selectively transported into specific cells or organs ("targeting moieties” or “targeting groups” or “transporting vectors”), thus providing targeted drug delivery ⁇ see, e.g., V.V. RanadeJ. Clin. Pharmacol. 29, 685 (1989)).
  • the agents may be linked to targeting groups that facilitate penetration ofthe blood brain barrier.
  • the method ofthe present invention employs a naturally occurring polyamine linked to an agent that is a small molecule and is useful for inhibiting e.g., A ⁇ deposition.
  • fransport vectors include cationized albumin or the OX26 monoclonal antibody to the fransferrin receptor; these proteins undergo abso ⁇ tive-mediated and receptor-mediated transcytosis through the BBB, respectively.
  • Natural cell metabolites that may be used as targeting groups include, ter alia, putrescine, spermidine, spermine, or DHA.
  • Other exemplary targeting moieties include folate or biotin ⁇ see, e.g. , U.S.
  • BBB transport vectors examples include factors such as insulin, insulin-like growth factors ("IGF-I,” and “LGF-II”), angiotensin TL, atrial and brain natriuretic peptide ("ANP,” and “BNP”), interleukin I (“LL-1”) and fransferrin. Monoclonal antibodies to the receptors that bind these factors may also be used as BBB fransport vectors.
  • BBB fransport vectors targeting mechanisms for abso ⁇ tive-mediated transcytosis include cationic moieties such as cationized LDL, albumin or horseradish peroxidase coupled with polylysine, cationized albumin or cationized immunoglobuhns.
  • Small basic oligopeptides such as the dyno ⁇ hin analogue E-2078 and the ACTH analogue ebiratide may also cross the brain via abso ⁇ tive-mediated transcytosis and are potential fransport vectors.
  • Other BBB fransport vectors target systems for transporting nutrients into the brain.
  • BBB transport vectors examples include hexose moieties, e.g., glucose and monocarboxylic acids, e.g., lactic acid and neutral amino acids, e.g., phenylalanine and amines, e.g., choline and basic amino acids, e.g., arginine, nucleosides, e.g., adenosine and purine bases, e.g., adenine, and thyroid hormone, e.g., triiodothyridine.
  • Antibodies to the extracellular domain of nutrient transporters may also be used as fransport vectors.
  • Other possible vectors include angiotensin II and AMP, which may be involved in regulating BBB permeability.
  • the bond linking the therapeutic agent to the transport vector may be cleaved following fransport into the brain in order to liberate the biologically active agent.
  • exemplary linkers include disulfide bonds, ester-based linkages, thioether linkages, amide bonds, acid-labile linkages, and Schiff base linkages.
  • Avidin/biotin linkers in which avidin is covalently coupled to the BBB drug transport vector, may also be used. Avidin itself may be a drug transport vector.
  • Transcytosis including receptor-mediated fransport of compositions across the blood brain barrier, may also be suitable for the agents ofthe invention.
  • Transferrin receptor-mediated delivery is disclosed in U.S. Pat. Nos. 5,672,683; 5,383,988;
  • Transferrin-mediated fransport is also known.
  • EGF receptor-mediated delivery is disclosed in Y. Deguchi, et al, Bioconjug. Chem. 10, 32-37 (1999), and franscytosis is described in
  • U.S. Pat. No. 6,024,977 discloses covalent polar lipid conjugates for targeting to brain and central nervous system.
  • U.S. Pat. No. 5,017,566 discloses cyclodextrin derivatives comprising inclusion complexes of lipoidal forms of dihydropyridine redox targeting moieties.
  • 5,023,252 discloses the use of pharmaceutical compositions comprising a neurologically active drug and a compound for facilitating transport ofthe drug across the blood-brain barrier including a macrocyclic ester, diester, amide, diamide, amidine, diamidine, thioester, dithioester, thioamide, ketone or lactone.
  • U.S. Pat. No. 5,024,998 discloses parenteral solutions of aqueous-insoluble drugs with cyclodextrin derivatives.
  • U.S. Pat. No. 5,039,794 discloses the use of a metastatic tumor-derived egress factor for facilitating the fransport of compounds across the blood-brain barrier.
  • U.S. Pat. No. 5,124,146 discloses a method for delivery of therapeutic agents across the blood-brain barrier at sites of increase permeability associated with brain lesions.
  • U.S. Pat. No. 5,153,179 discloses acylated glycerol and derivatives for use in a medicament for improved penetration of cell membranes.
  • U.S. Pat. No. 5,177,064 discloses the use of lipoidal phosphonate derivatives of nucleoside antiviral agents for delivery across the blood-brain barrier.
  • 5,254,342 discloses receptor- mediated franscytosis of the blood-brain barrier using the fransferrin receptor in combination with pharmaceutical compounds that enhance or accelerate this process.
  • U.S. Pat. No. 5,258,402 discloses freatment of epilepsy with imidate derivatives of anticonvulsive sulfamate.
  • U.S. Pat. No. 5,270,312 discloses substituted piperazines as central nervous system agents.
  • U.S. Pat. No. 5,284,876 discloses fatty acid conjugates of dopamine drugs.
  • U.S. Pat. No. 5,389,623 discloses the use of lipid dihydropyridine derivatives of anti-inflammatory steroids or steroid sex hormones for delivery across the blood-brain barrier.
  • U.S. Pat. No. 5,405,834 discloses prodrug derivatives of thyrotropin releasing hormone.
  • U.S. Pat. No. 5,413,996 discloses acyloxyalkyl phosphonate conjugates of neurologically-active drugs for anionic sequestration of such drugs in brain tissue.
  • U.S. Pat. No. 5,434,137 discloses methods for the selective opening of abnormal brain tissue capillaries using bradykinin infused into the carotid artery.
  • 5,442,043 discloses a peptide conjugate between a peptide having a biological activity and incapable of crossing the blood-brain barrier and a peptide which exhibits no biological activity and is capable of passing the blood-brain barrier by receptor- mediated endocytosis.
  • U.S. Pat. No. 5,466,683 discloses water soluble analogues of an anticonvulsant for the treatment of epilepsy.
  • compositions for differential uptake and retention in brain tissue comprising a conjugate of a narcotic analgesic and agonists and antagonists thereof with a lipid form of dihydropyridine that forms a redox salt upon uptake across the blood-brain barrier that prevents partitioning back to the systemic circulation.
  • Nitric oxide is a vasodilator ofthe peripheral vasculature in normal tissue ofthe body. Increasing generation of nitric oxide by nitric oxide synthase causes vasodilation without loss of blood pressure. The blood-pressure-independent increase in blood flow through brain tissue increases cerebral bioavailability of blood-born compositions. This increase in nitric oxide may be stimulated by administering L-arginine. As nitric oxide is increased, cerebral blood flow is consequently increased, and drugs in the blood stream are carried along with the increased flow into brain tissue.
  • L-arginine may be used in the pharmaceutical compositions ofthe invention to enhance delivery of agents to brain tissue after introducing a pharmaceutical composition into the blood stream of the subject substantially contemporaneously with a blood flow enhancing amount of L-arginine, as described in WO 00/56328. Still further examples of modifications that enhance penetration ofthe blood brain barrier are described in International (PCT) Application Publication Number WO 85/02342, which discloses a drug composition comprising a glycerolipid or derivative thereof.
  • PCT Publication Number WO 089/11299 discloses a chemical conjugate of an antibody with an enzyme which is delivered specifically to a brain lesion site for activating a separately-administered neurologically-active prodrug.
  • WO 91/04014 discloses methods for delivering therapeutic and diagnostic agents across the blood-brain barrier by encapsulating the drugs in liposomes targeted to brain tissue using transport-specific receptor ligands or antibodies.
  • PCT Publication Number WO 91/04745 discloses transport across the blood-brain barrier using cell adhesion molecules and fragments thereof to increase the permeability of tight junctions in vascular endothelium.
  • PCT Publication Number WO 91/14438 discloses the use of a modified, chimeric monoclonal antibody for facilitating transport of substances across the blood-brain barrier.
  • PCT Publication Number WO 94/01131 discloses lipidized proteins, including antibodies.
  • PCT Publication Number WO 94/03424 discloses the use of amino acid derivatives as drug conjugates for facilitating transport across the blood-brain barrier.
  • PCT Publication Number WO 94/06450 discloses conjugates of neurologically-active drugs with a dihydropyridine-type redox targeting moiety and comprising an amino acid linkage and an aliphatic residue.
  • PCT Publication Number WO 94/02178 discloses antibody-targeted liposomes for delivery across the blood-brain barrier.
  • PCT Publication Number WO 95/07092 discloses the use of drug- growth factor conjugates for delivering drugs across the blood-brain barrier.
  • PCT Publication Number WO 96/00537 discloses polymeric microspheres as injectable drug- delivery vehicles for delivering bioactive agents to sites within the central nervous system.
  • PCT Publication Number WO 96/04001 discloses omega-3-fatty acid conjugates of neurologically-active drugs for brain tissue delivery.
  • PCT WO 96/22303 discloses fatty acid and glycerolipid conjugates of neurologically-active drugs for brain tissue delivery.
  • a carboxylic acid- containing compound, or a reactive equivalent thereof may be reacted with a hydroxyl- containing compound, or a reactive equivalent thereof, so as to provide the corresponding ester.
  • a carboxylic acid- containing compound, or a reactive equivalent thereof may be reacted with a hydroxyl- containing compound, or a reactive equivalent thereof, so as to provide the corresponding ester.
  • the present invention is also related to prodrugs ofthe agents ofthe Formulae disclosed herein.
  • Prodrugs are agents which are converted in vivo to active forms ⁇ see, e.g., R.B. Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action,” Academic Press, Chp. 8).
  • Prodrugs can be used to alter the biodistribution ⁇ e.g., to allow agents which would not typically enter the reactive site ofthe protease) or the pharmacokinetics for a particular agent.
  • a carboxylic acid group can be esterified, e.g., with a methyl group or an ethyl group to yield an ester.
  • the ester When the ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically, to reveal the anionic group.
  • An anionic group can be esterified with moieties ⁇ e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate agent which subsequently decomposes to yield the active agent.
  • the prodrug moieties may be metabolized in vivo by esterases or by other mechanisms to carboxylic acids. Examples of prodrugs and their uses are well known in the art ⁇ see, e.g., Berge, et al, "Pharmaceutical Salts", J. Pharm. Sci.
  • the prodrugs can be prepared in situ during the final isolation and purification ofthe agents, or by separately reacting the purified agent in its free acid form with a suitable derivatizing agent.
  • Carboxylic acids can be converted into esters via freatment with an alcohol in the presence of a catalyst.
  • cleavable carboxylic acid prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties, ⁇ e.g., ethyl esters, propyl esters, butyl esters, pentyl esters, cyclopentyl esters, hexyl esters, cyclohexyl esters), lower alkenyl esters, dilower alkyl-amino lower-alkyl esters ⁇ e.g., dimethylaminoethyl ester), acylamino lower alkyl esters, acyloxy lower alkyl esters ⁇ e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters ⁇ e.g., benzyl ester), substituted ⁇ e.g., with methyl, halo, or methoxy substituents) aryl and
  • compositions ofthe present agents can contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of agents ofthe present invention. These salts can be prepared in situ during the final isolation and purification ofthe agents ofthe invention, or by separately reacting a purified agent ofthe invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrohalide (including hydrobromide and hydrochloride), sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tarfrate, napthylate, mesylate, glucoheptonate, lactobionate, 2-hydroxyethanesulfonate, and laurylsulphonate salts and the like. See, e.g., Berge et al, "Pharmaceutical Salts", J. Pharm. Sci. 66, 1-19 (1977).
  • the agents ofthe present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of agents ofthe present invention.
  • salts can likewise be prepared in situ during the final isolation and purification ofthe agents, or by separately reacting the purified agent in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary a ine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary a ine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, .piperazine and the like.
  • “Pharmaceutically acceptable salts” also includes, for example, derivatives of agents modified by making acid or base salts thereof, as described further below and elsewhere in the present application.
  • Examples of pharmaceutically acceptable salts include mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts ofthe parent agent formed, for example, from non-toxic inorganic or organic acids.
  • Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfiiric, sulfamic, phosphoric, and nitric acid; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic acid.
  • inorganic acids such as hydrochloric, hydrobromic, sulfiiric, sulfamic, phosphoric, and nitric acid
  • organic acids such as acetic, propionic, succinic, glycolic, ste
  • salts may be synthesized from the parent agent which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts may be prepared by reacting the free acid or base forms of these agents with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture ofthe two.
  • All acid, salt, base, and other ionic and non-ionic forms ofthe compounds described are included as compounds ofthe invention.
  • the salt forms ofthe compound are also included.
  • the acid and/or basic forms are also included.
  • test compounds were synthesized and screened by mass spectrometry ("MS") assays, except for selected compounds which were purchased from a commercial source.
  • MS assay gives data on the ability of compounds to bind to proteins, in this example, to ⁇ -amyloid and LAPP.
  • samples were prepared as aqueous solutions (adding 20% ethanol if necessary to solubilize in water), 200 ⁇ M of a test compound and 20 ⁇ M of solubilized A ⁇ 40, or 400 ⁇ M of a test compound and 40 ⁇ M of solubilized A ⁇ 40.
  • the pH value of each sample was adjusted to 7.4 ( ⁇ 0.2) by addition of 0.1% aqueous sodium hydroxide.
  • the solutions were then analyzed by elecfrospray ionization mass spectrometry using a Waters ZQ 4000 mass spectrometer. Samples were introduced by direct infusion at a flow-rate of 25 ⁇ L/min within 2 hr. after sample preparation.
  • the source temperature was kept at 70 °C and the cone voltage was 20 V for all the analysis.
  • Data were processed using Masslynx 3.5 software.
  • the MS assay gives data on the ability of compoxmds to bind to soluble A ⁇ , whereas the ThT, EM and CD assays give data on inhibition of fibrillogenesis.
  • the results from the assay for binding to A ⁇ are summarized in Table 3.
  • Table 3 a blank box means that a value was not determined for that compound in that assay.
  • the assay for LAPP was conducted under the same conditions except that 200 ⁇ M of test compound and 20 ⁇ M of solubilized LAPP were employed.
  • the key below describes the codes used in Table 3 to quantify the binding based on the intensity ofthe abso ⁇ tion.
  • Transgenic mice TgCRND8, expressing the human amyloid precursor protein (hAPP) develop a pathology resembling Alzheimer's disease.
  • hAPP human amyloid precursor protein
  • high levels of A ⁇ 40 and A ⁇ 42 have been documented in the plasma and the brain of these animals at 8-9 weeks of age, followed by early accumulation of amyloid plaques similar to the senile plaques observed in AD patients.
  • These animals also display progressive cognitive deficits that parallel the appearance of degbnerative changes. See, e.g., (Chishti, et al, J. Biol. Chem. 276, 21562-70 (2001).
  • mice from the 3 rd and 4 th B6C3F1 generations were used in this example and given daily subcutaneous or oral administrations of one of a series of compounds for 14 or 28 days.
  • the following abbreviations are used to designate these animals from the 3 rd and 4th generation backcross in the present protocol: TgCRND8-2.B6C3Fl(N 3 ); TgCR D8-2.B6C3Fl(N 4 ).
  • Baseline animals (Group 1) consisted of naive TgCRND8-2. B6C3F1(N 3 ) at 11 ⁇ 1 weeks of age. These mice were used to deterrnine the A ⁇ levels in the plasma and brain of naive transgenic animals at the initiation of treatment.
  • animals received daily administration of their respective freatment for a period of 14 or 28 days (groups 2-21), at a dose of 250 mg/kg at 10 ml/kg or of vehicle only (water; group 2) or 1% methyl cellulose only (group 21).
  • the route of adminisfration was subcutaneous for water-soluble compounds and oral for compounds solubilized in methylcellulose 1% (MC 1%).
  • MC 1% methylcellulose 1%
  • mice used in this study were derived from a breeding colony at Institut Armand Frappier, and were well-acclimated to the animal facility environment prior to initiation ofthe study. Animals were assigned, according to age and gender, into the following experimental groups:
  • Brains were weighted frozen and homogenized with 4 volumes of ice cold 50 mM Tris-Cl pH 8.0 buffer with protease inhibitor cocktail (4mL of buffer for lg of wet brain). Samples were spun at 15000g for 20 minutes and the supernatants were transferred to fresh tubes. One hundred fifty (150) ⁇ l from each supernatant were mixed with 250 ⁇ l of 8M guanidine-HCL/50mM Tris-HCLpH 8.0 (ratio of 0.6 vol supernatant: 1 vol 8M guanidium/Tris-HCL 50mM pH8.0) and 400 ⁇ L 5 M guanidium/Tris-HCL 50mM pH8.0 were added.
  • A/340 and A/342 Fluorometric ELISA kits from Biosource (Cat. No. 89-344 and 89-348) according to manufacturer's recommended procedures. In short, samples were thawed at room temperature, sonicated for 5 minutes at 80°C (sonication for brain homogenates; no sonication for plasma samples) and kept on ice. A ⁇ peptides were captured using 100 ⁇ l ofthe diluted samples to the plate and incubated without shaking at 4°C overnight. The samples were aspirated and the wells were rinsed 4 times with wash buffer obtained from the Biosource ELISA kit.
  • the anti-A ⁇ 40 or anti-A ⁇ 42 rabbit polyclonal antiserum (specific for the A ⁇ 40 or A ⁇ 42 peptide) was added (100 ⁇ l) and the plate was incubated at room temperature for 2 hours with shaking. The wells were aspirated and washed 4 times before adding 100 ⁇ l ofthe alkaline phosphatase labeled anti-rabbit antibody and incubating at room temperature for 2 hours with shaking. The plates were then rinsed 5 times and the fluorescent substrate (100 ⁇ l) was added to the plate. The plate was incubated for 35 minutes at room temperature and the plate was read using a titer plate reader at an excitation wavelength of 460 nm and emission at 560 nm.
  • the tables show levels of A/3 peptides in the plasma and brain of TgCRND8 mice freated for 14 and 28 days with compounds ofthe invention.
  • Tables 6A and 6C show the data from Day 14 and Day 28 for the Plasma Vehicle group, respectively.
  • Tables 6B and 7 show the data for the Plasma Methylcellulose group on Days 14 and 28, respectively.
  • Tables 8 and 10 show the data on Days 14 and 28 for the Brain homogenate vehicle group, respectively.
  • Tables 9 and 11 show the data for brain homogenate for the Methylcellulose group on Days 14 and 28, respectively.
  • TABLE 6A Plasma Vehicle Group, Day 14
  • Transgenic mice as those used in the short term treatment, overexpress a human APP gene with the Swedish and Indiana mutations leading to the production of high levels ofthe amyloid peptides and to the development of an early- onset, aggressive development of brain amyloidosis.
  • the high levels of A ⁇ peptides and the relative overabundance of A/3 42 compared to A/3 4 o are believed to be associated with the severe and early degenerative pathology observed.
  • the pattern of amyloid deposition, presence of dystrophic neuritis, and cognitive deficit has been well documented in this fransgenic mouse line.
  • the levels of A/3 peptides in the brain of these mice increase dramatically as the animals age. While the total amyloid peptide levels increase from ⁇ 1.6 x 10 pg/g of brain to ⁇ 3.8 x 10 between 9 and 17 weeks of age.
  • mice used in the study consisted of animals bearing one copy ofthe hAPP gene (+/-) from the 2 nd and 3 rd generation progenies (N 2 and N 3 ) derived from backcrosses from TgCRND8.FVB(N 2 )AJ(N 3 ) with B6AF1/J hybrid animals.
  • N ⁇ TgCRND8.FVB(N 2 )AJ(N 3 ) x B6AF1/J
  • N 2 TgCRND8.FVB(N 2 )AJ(N 3 ).B6AFl/J(N 1 ) x B6AF1/J
  • N 3 TgCRND8.FVB(N 2 )AJ(N 3 ).B6AFl/J(N 2 ) " x
  • B6AF1/J The following abbreviations are used to designate these animals in the present study: TgCRND8.B6AFl/J(N 2 ); TgCRND8.B6AFl/J(N 3 ).
  • Baseline animals consisted of 9 ⁇ 1 week old naive TgCRND8.B6AFl/J animals from the 2 n and 3 r generations. These mice were used to determine the extent of cerebral amyloid deposits and A ⁇ levels in the plasma and brain of naive fransgenic animals at the initiation of treatment.
  • mice received daily adminisfration of their respective freatment for a period of 8 or 16 weeks, at a dose of 30 or 100 mg/kg at 10 ml/kg.
  • the route of adminisfration was subcutaneous for water-soluble compounds (Compound BX) and oral for compounds solubilized in methylcellulose 1% (MC 1%) (Compounds BW and BZ).
  • MC 1%) methylcellulose 1%
  • adminisfration of compound BX generally resulted in a dramatic decrease in the amount of A/3 in the brain at both 8 and 16 weeks.
  • Compound BW also resulted in a dramatic decrease in brain and plasma levels of A/3 at 8 weeks and plasma levels at 16 weeks.
  • NAC non-amyloid component
  • ⁇ -synuclein has also been described as the second most abundant component of amyloid plaques in the brain of AD patients, after.
  • Alpha-synuclein has been shown to form fibrils in vitro. Futhermore it binds to A ⁇ and promotes its aggregation (Yoshimoto, et al. 1995. Proc Natl Acad Sci USA 92:9141). It was in fact originally identified as the precursor ofthe non-amyloid beta (A ⁇ ) component (NAD) of AD plaques (Ueda, et al. 1993. Proc Natl Acad Sci USA 90:11282; Iwai.
  • NAC is a 35 amino acid long peptide with highly hydrophobic stretches which can self-aggregate and form fibrils in vitro. Moreover, these fibrils can efficiently seed the formation of A ⁇ fibrils in vitro (Han, et al. 1995. Chem Biol.2: 163-169; Iwai, et al. 1995. Biochemistry 34:10139). It is in fact through its NAC domain that alpha-synuclein retains its fibrillogenic properties.
  • Modulating the properties of NAC or targeting NAC with the compounds ofthe invention could therefore be a valid therapeutic avenue to inhibit the formation of protein aggregates and inclusions associated with alpha-synucleopathies, as well as the formation of aggregates between the beta-amyloid peptide and NAC of alpha-synuclein.
  • the ability ofthe compounds ofthe present invention to bind to NAC peptide in aqueous solution was evaluated.
  • the binding ability conelates to the intensities ofthe peptide-compound complex peaks observed by the Elecfrospray Mass Spectrum.
  • Millipore distilled deionized water was used to prepare all aqueous solutions.
  • pH determination a Beckman ⁇ 36 pH meter fitted with a Coming Semi-Micro Combination pH Electrode was employed.
  • NAC (MW 3260.6 Da) at 20 ⁇ M was first analyzed at pH 7.40 and the usual sodium clusters was observed at 4-2, +3 and 4-4 at m/z 1335.5, 1116.7 and 843.4 respectively.
  • the optimal cone voltage was determined to be 20V.
  • Mass spectrometry- Mass specfrometric analysis was performed using a Waters ZQ 4000 mass spectrometer equipped with a Waters 2795 sample manager. MassLynx 4.0 (earlier by MassLynx 3.5) was used for data processing and analysis. Test compounds were mixed with disaggregated peptides in aqueous media ⁇ 6.6% EtOH) at a 5:1 ratio (20 ⁇ M NAC : 100 ⁇ M of test compound or 40 ⁇ M NAC : 200 ⁇ M of test compound). The pH ofthe mixture was adjusted to 7.4 ( ⁇ 0.2) using 0.1% NaOH (3-5 ⁇ L). Periodically, NAC peptide solution at 20 ⁇ M or 40 ⁇ M was also prepared in the same fashion and run as confrol.
  • the spectra were obtained by introducing the solutions to the elecfrospray source by direct infusion using a syringe pump at a flow rate of 25 ⁇ l/min, and scanning from 100 to 2100 Da in the positive mode.
  • the scan time was 0.9 sec per scan with an inter-scan delay of 0.1 sec and the run time was 5 min for each sample. All the mass spectra were sum of 300 scans.
  • the desolvation and source temperature was 70°C and the cone and capillary voltage were maintained at 20 V and 3.2 kV respectively.
  • the present invention also relates to novel compounds and the synthesis thereof. Accordingly, the following examples are presented to illustrate how some of those compounds may be prepared. Synthesis of Compounds of the Invention
  • Cyclopentylamine (3.95 mL, 40 mmol) was added to a solution of 1,3-propane sultone (5.5 g, 45 mmol) in THF (80 mL). The mixture was heated at reflux with an oil- bath for 4 hours. Stirring was difficult, some acetone and ethanol were added to restore stirring. The mixture was cooled to room temperature. The solid was collected by filfration, dried in a vacuum oven for 1 hour at 60 °C (5.47 g). The solid material was dissolved in methanol/water (35 mL/2.5 mL, v/v) at reflux. The mixture was cooled slowly to room temperature overnight, and further cooled in a fridge.
  • the product was collected by filtration, rinsed with methanol (15 mL), air-dried for 15 minutes, and further dried in a vacuum oven at 60 °C overnight.
  • the product, Compound CJ was obtained as long fine white needles (4.79 g).
  • a second crop was obtained from the combined crude and first recrystallization mother liquor (0.84 g). Both crops were pure and were combined, total 5.63 g, 68% yield, m.p. 280-82 °C.
  • Cycloheptylamine (3.9 mL, 30 mmol) was added to a solution of 1,3-propane sultone (4.1 g, 33 mmol) in THF (65 mL). The mixture was heated at reflux for 5 hours with a heating mantle. The mixture was cooled to room temperature and the solid was collected by filtration, and then dried in a vacuum oven for 1 hour at 60 °C (6.21 g). The solid material was dissolved in methanol/water (30 mL/3 mL, v/v). The solution was cooled slowly to room temperature, and further cooled with an ice-bath.
  • Component 1 L-(N-Boc)-Phe-L-Phe
  • Component 2 3-aminol-propanesulfonic acid isobutyl ester
  • Step 1 3-azido- 1-propanesulfonic acid, sodium salt (5)
  • 1,3-propane sultone 4 (6.12 g, 49.1 mmol) in acetone (30 mL) was added to a mixture of sodium azide (3.22 g, 49.1 mmol) in water / acetone (70 mL, 20 to 50).
  • the clear solution was stirred at room temperature.
  • the reaction was completed within 1 hour.
  • the solvent was removed by evaporation under reduced pressure.
  • the solid obtained was rinsed with hot ether (50 mL) and then with ether at room temperature (150 ml). The solid was then dried in the vacuum oven at 40 °C for overnight.
  • the title compound 5 was obtained as a white solid (8.69 g, 46.4 mmol, 95% yield).
  • Step 2 3-azido-l-propanesulfonyl chloride 3-Azidopropanesulfonic acid, sodium salt 5 (1.87 g, 10.0 mmol) was suspended in dry benzene (20 mL), and PCI 5 (2.3 g, 10.5 mmol) was added to the suspension. The mixture was stirred at room temperature for 30 minutes, then at gentle reflux for about 1 hour. The benzene and P(O)C13 were removed by evaporation under reduced pressure. Benzene was added to the crude mixture and the solvent was removed again under reduced pressure. The residue was dried in vacuo.
  • Step 4 3 -amino- 1-propanesulfonic acid isobutyl ester A solution of isobutyl 3-azidopropanesulfonate (1.13 g, 5.11 mmol) in isobutanol
  • the mixture was heated under refluxed for 30 minutes and then was cooled to room temperature.
  • the white solid was collected by filfration, washed with ether, then dried in the vacuum oven for 45 minutes.
  • the resulting solid (423.1 mg) was dissolved in a mixture of water/tert-butanol (7:3, 5 mL) and treated with Amberlite LR- 120 plus (washed, 15 g dry weight) for 2 minutes at room temperature.
  • the resin was removed by filfration and washed 3 times with the mixed solvents of water and tert- butanol (10 mL). Concentrated HCl (4 mL) was added. The solvents were removed under reduced pressure, and the resulting solid was dried in vacuum.
  • the azide (2.70 g, 7.94 mmol) was stined under H 2 (40 psi) with 10% Pd/C (348 mg) in ethanol (16 mL) at room temperature overnight. The solid was removed by filfration over Celite. The filtrate was treated with TMSCl/EtOH in attempt to obtain a crystalline hydrochloride salt ofthe product. The solvent was evaporated to give a thick residue (2.2 g, 6.27 mmol, 79%) that crystallized xxnder none ofthe conditions tried.
  • the crude hydrochloric acid salt was dissolved in dichloromethane and washed once with saturated sodium bicarbonate. The organic layer was recovered and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure.
  • the hydrolysis was done by the conventional LiOH/MeOH method.
  • the product was purified by recrystallization from EtO Ac and Hexanes.
  • the L-(N-Boc)- Phe- (3-amino ⁇ ropane-l-sulfonyl)-L-Phe-OH (203 mg, 0.382 mmol) was dissolved in methanol (4 mL) and the solution was cooled to 0 °C. Concentrated HCl (0.35 mL) was added and the mixture was stined for 2 hours at 0 °C and for 2.5h at room temperature. The volatile solvents were removed under reduced pressure. The aqueous residue was freeze-dried to give the product as a white solid (171.4 mg).
  • the NMR and MS showed to product to be a mixtxire ofthe free acid and the methyl ester.
  • the MS showed also a sfrong association ofthe peptide.
  • the dimer was the major species on the MS.
  • the solid was dissolved into methanol and freated with HCl overnight at room temperature. The solvent was evaporated and the residue was dried in vacuo. The product was obtained as a white foamy solid (180.4 mg, 97%).
  • the 1H and 13 C NMR were consistent with the structure of compound AB.
  • the solid (1.96 g, 5.8 mmol) was dissolved in a minimum amount of water. To the solution was added aqueous NH 4 OH (28-30%, 15 mL). The reaction mixture was stirred at room temperature over weekend. The solvent was removed under reduced pressure and EtO Ac (15 mL) was added. The mixture was heated under reflux. The hot solution was filtered. The filtrate was cooled to room temperature and was stored in the fridge. The solid was collected by filfration, washed with EtO Ac, to give 4- iodophenylalanine amide.
  • the amide (1.3 g, 4.4 mmol) was dissolved in 15 mL of 2-butanone with a few drops of DMF before 1,3-propane sultone (560 mg, 4.9 mmol) was added.
  • the reaction mixture was stined at reflux for 2 hours. The mixture was cooled to room temperature.
  • the solid was collected by filtration, washed with acetone (2 x 20 mL) and dried in vacuo. The solid was suspended in MeOH (25 mL) and a small amount Of water (1 mL).
  • the suspension was stined at reflux.
  • the solid material was collected by filfration while the mixture was still hot.
  • the solid was washed with hot MeOH (2 x 10 mL).
  • the 4-(4-fluorophenyl)-l,2,3,6-tetrahydropyridine hydrochloride (2.58 g, 14.5 mmol) was treated with IN NaOH (20 mL). The aqueous mixtxire was extracted with CH C1 2 (20 mL). The organic layer was separated and dried over MgSO 4 . The solvents were removed by evaporation under reduced pressure.
  • the 4-(4-chlorophenyl)-l,2,3,6-tefrahydropyridine hydrochloride (2.52 g , 10.9 mmol) was treated with IN NaOH (20 mL); and aqueous mixture was exfracted with CH 2 C1 2 (20 mL). The organic layer was separated, dried over Na 2 SO 4 , and filtered. The solvent was removed under reduced pressure.
  • the l-(4-chlorophenyl)piperazine dihydrochloride (2.5g , 9.3 mmol) was freated with IN NaOH (40 mL); and the aqueous mixture was exfracted with CH 2 C1 2 (40 mL). The organic layer was separated, dried over Na 2 SO 4 , filtered and solvent was removed under reduced pressure.
  • the 4-cyano-4-phenylpiperidine hydrochloride (2.0 g, 9.0 mmol) was freated with IN NaOH (20 mL) and the aqueous phase was exfracted with CH 2 C1 2 (20 mL). The organic layer was separated, dried over MgSO 4 , filtered and solvent was removed under reduced pressure.
  • the 4-phenyl-l,2,3,6-tefrahydropyridine hydrochloride (2.01 g , 10.2 mmol) was treated with IN NaOH (20 mL) and the aqueous phase wa extracted with CH C1 2 (20 mL). The organic layer was separated, dried over MgSO 4 , filtered and solvent was removed under reduced pressure. The resulting 4-phenyl-l,2,3,6-tetrahydropyridine (1.55 g, 9.7 mmol) was dissolved in 20 mL of 2-butanone. To this solution was added potassium carbonate (2.02 g, 14.6 mmol).
  • the solid (1.94 g, 6.7 mmol) was dissolved hydrobromic acid (48%, 27 mL). The solution was stined at 100 °C for 4h. The solvent was removed xmder reduced pressure. The residue was dissolved in water (20 mL). The aqueous phase was washed with CH 2 C1 2 (3 x 20 mL), and evaporated under educed pressure. The solid residue was suspended in hot MeOH (75 mL). The suspension was stined at reflux for 30 sec; the solid was collected by filfration, washed with 50%
  • Tetrahydrofuran (THF, 800 mL) was placed a 3 neck 2-L flask (equipped with a condenser) and cooled to 5 C with an ice-bath.
  • aqueous ethylamine 70 wt. % solution in water, 85 mL, 1.07 mol
  • 1,3-propane sultone 25.08 g, 201 mmol
  • THF THF
  • the mixture was stined, while cooled with an ice— bath, for lh. The ice-bath was removed and the mixture was stined at room temperature overnight.
  • the 1-adamantanamine hydrochloride (80 g, 0.426 mol) was treated with NaOH (10%, 400 mL) in water.
  • the aqueous mixture was exfracted with dichloromethane (1 x 400 mL, 2 x 100 mL).
  • the combined organic layers were washed with brine (50 mL) and dried over sodium sulfate (10 g).
  • Solvent was removed under reduced pressure.
  • the resulting white waxy solid was co-evaporated with acetonitrile (50 mL).
  • the wet solid was suspended in acetonitrile (200 mL).
  • the suspension mixture was added dropwise over 20 min to a solution of 1,3-propane sultone (53 g, 0.426 mol) in acetonitrile (300 mL) and THF (200 mL). The thick mixture was stined for 2 hours under reflux with a mechanical stiner. The suspension was then cooled to 13 °C. The solid was collected by suction-filtration, rinsed with acetonitrile ( 2 x 100 mL) and ether (1 x 100 mL), air- dried for 30min, and further dried in vacuo at 60 °C overnight (104.17g for crop 1). Another crop was collected from the filtrate and dried in vacuo in the same manner (3.39 g for crop 2). Both crops gave identical proton NMR spectrum. The two batches were combined for further purification.
  • the solid was suspended in methanol (720 mL) and the mixture was heated to reflux. Water (490 mL) was added dropwise over 45 min, while maintaining reflux. After complete dissolution ofthe solid, the solution was kept under reflux for 30 minute. The mixture, was left in the power-off heating mantle and allowed to cool slowly. After 90 min, the temperature reached 40 °C. The heating mantle was replaced by a thermostated water bath. The mixture was cooled to 5 °C and stined overnight at this temperature. The white flaky solid was collected by filtration, rinsed with cold (0 °C) methanol (2 x 125 mL), air-dried for 60 minutes, and then dried in the vacuum oven at 60 °C overnight.
  • the 2-aminoadamantane hydrochloride (2 x 5g) was freated with NaOH in water.
  • 3-amino-l-propanesulfonic acid (2.0 g, 14.4 mmol) was dissolved a NaOH (1.2 g, 30.2 mmol) solution in a mixture of 1,4-dioxane (5mL) and water(15 mL). The mixture was cooled to 0°C before pivaloyl chloride (2.8 mL, 21.6 mmol) in 1,4-dioxane (5 mL) was added dropwise. The reaction mixture was allowed to warm up to room temperature and it was stined at 65 °C for 4h. The solvent was evaporated under reduced pressure. The resulting solid was dissolved in water (30 mL), and freated with Dowex 50WX8 resin.
  • L-valinamide hydrochloride (2.50 g, 16.4 mmol) was freated with a saturated solution of K 2 CO 3 (75 mL). The mixture was extracted with EtOAc (3 x 75 mL). The organic extracts were combined, dried over Na 2 SO 4 . The solid material was removed by filfration, and the filtrate was concentrated to dryness under reduced pressure. The residual material was dried in vacuo.
  • Isobutylamine (2.4 mL, 24 mmol) was added to a solution of 1,3-propane sultone (3.04g, 24.5 mmol) in 2-butanone (20 mL). The mixture was heated to reflux. After about 10 minutes, the mixture had turned into a lump. It was cooled to room temperature. Acetone was added and the lump was crushed. The solid was collected by filfration and dried in-vacuo (2.2 g). The white solid was suspended in ethanol (10 mL) and the mixture brought to reflux. A significant amount of the solid dissolved. Water was added slowly until a clear pink solution was obtained. The solution was left at room temperature overnight. The flask was placed in a fridge for 2 hours.
  • total 12 mL was added over 6 hours to a 42 °C solution of t-butylamine (10 mL, 94 mmol) in a mixture of water (10 mL) and 1,4-dioxane (10 mL). The mixture was stirred at 42 ° for 18 hours. The mixture was then heated to 60 °C for 24h. By proton NMR, 30 % of elimination product (vinylsulfonic acid) was observed. The mixture was concentrated to dryness and freated with ethanol at refluxing temperature. The solid material was collected (crop 1). The mother liquor was concentrated to dryness and the solid was again treated with ethanol at refluxing temperature, and the solid material was collected (crop 2).
  • the mixture was then cooled to room temperature and the solid was collected by suction filfration, rinsed with ethanol (2 x 5 mL), air-dried for 10 min, and further dried in a vacuum oven at 60 °C overnight (cropl, 7.10g).
  • the combined mother liquors were stined overmght at room temperature. There was a lot of solid.
  • the solid was collected by filtration, rinsed with acetone (3 x 5 mL), air-dried for 30 minutes, and then suspended in ethanol (12 mL). The suspension was heated at reflux for 1 hour.
  • the solid was collected by suction filfration, air-dried for 30 minutes, and further dried in a vacuum oven at 60 °C for 40 hours (crop 1, 4.47 g).
  • the combined mother liquor was stored at -20 °C for 40 hours.
  • a second crop ofthe solid was collected by filtration, rinsed with acetone (2 x 15 mL), air-dried (1 hour), and further dried in a vacuum oven at 60 °C for 24 hours.
  • Compound DY was obtained in two crops (total 7.82 g, 42% yield).
  • Mexiletine hydrochloride (2.45 g, 11.3 mmol) was freed with IN NaOH (50 mL), exfracted with ethyl acetate (2 x 50 mL). The combined extract was dried over sodium sulfate. The solvent was evaporated. A solution of 1,3-propane sultone (1.46 g, 11.9 mmol) in THF (35 mL) was added to the free amine. The mixture was heated at reflux for 4 hours. The mixture was cooled to room temperature; and the resultant solid material was collected by filfration, rinsed with THF (5 mL). The solid was dried overnight at 40 °C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Neurosurgery (AREA)
  • Biochemistry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Psychiatry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Hospice & Palliative Care (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)
  • Indole Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des méthodes, des composés, des compositions pharmaceutiques et des trousses pour traiter ou prévenir les maladies liées à l'amyloïde.
PCT/IB2004/002375 2003-06-23 2004-06-21 Methodes et compositions pour traiter les maladies liees a l'amyloide WO2004113275A2 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
NZ544684A NZ544684A (en) 2003-06-23 2004-06-21 Methods and compositions for treating amyloid-related diseases
BRPI0411743-3A BRPI0411743A (pt) 2003-06-23 2004-06-21 método e composições para tratar doenças relacionadas a amilóides
UAA200600637A UA96115C2 (uk) 2003-06-23 2004-06-21 Спосіб і композиція для лікування амілоїдогенних захворювань
KR1020057024647A KR101124935B1 (ko) 2003-06-23 2004-06-21 아밀로이드 관련 질환의 치료 방법 및 조성물
JP2006516599A JP5146714B2 (ja) 2003-06-23 2004-06-21 アミロイド関連疾患を治療するための方法および組成物
AU2004249529A AU2004249529A1 (en) 2003-06-23 2004-06-21 Methods and compositions for treating amyloid-related diseases
EA200600078A EA012429B1 (ru) 2003-06-23 2004-06-21 Способы и композиции для лечения амилоидных заболеваний
CN2004800242077A CN1839118B (zh) 2003-06-23 2004-06-21 治疗淀粉样相关疾病用的方法与组合物
CA2529257A CA2529257C (fr) 2003-06-23 2004-06-21 Methodes et compositions pour traiter les maladies liees a l'amyloide
MXPA05014166A MXPA05014166A (es) 2003-06-23 2004-06-21 Metodos y composiciones para tratar enfermedades relacionadas con amiloide.
EP04744034A EP1644325A2 (fr) 2003-06-23 2004-06-21 Methodes et compositions pour traiter les maladies liees a l'amyloide
IL172194A IL172194A (en) 2003-06-23 2005-11-24 A compound and pharmaceutical composition containing it for the treatment or prevention of amyloid-dependent diseases
NO20055894A NO335084B1 (no) 2003-06-23 2005-12-12 Forbindelser og preparater og deres anvendelse for behandling av amyloidrelaterte sykdommer

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US48090603P 2003-06-23 2003-06-23
US60/480,906 2003-06-23
US51204703P 2003-10-17 2003-10-17
US60/512,047 2003-10-17
US10/871,365 US7244764B2 (en) 2003-06-23 2004-06-18 Methods and compositions for treating amyloid-related diseases
US10/871,514 2004-06-18
US10/871,514 US7414076B2 (en) 2003-06-23 2004-06-18 Methods and compositions for treating amyloid-related diseases
US10/871,365 2004-06-18

Publications (2)

Publication Number Publication Date
WO2004113275A2 true WO2004113275A2 (fr) 2004-12-29
WO2004113275A3 WO2004113275A3 (fr) 2005-10-27

Family

ID=33545555

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/IB2004/002337 WO2004113277A2 (fr) 2003-06-23 2004-06-21 Procedes et compositions de traitement de maladies associees aux amyloides
PCT/IB2004/002375 WO2004113275A2 (fr) 2003-06-23 2004-06-21 Methodes et compositions pour traiter les maladies liees a l'amyloide

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/IB2004/002337 WO2004113277A2 (fr) 2003-06-23 2004-06-21 Procedes et compositions de traitement de maladies associees aux amyloides

Country Status (12)

Country Link
EP (2) EP1644325A2 (fr)
JP (2) JP2007516938A (fr)
KR (1) KR101124935B1 (fr)
AU (2) AU2004249529A1 (fr)
BR (1) BRPI0411743A (fr)
CA (2) CA2529257C (fr)
EA (1) EA012429B1 (fr)
MX (2) MXPA05013977A (fr)
NO (1) NO335084B1 (fr)
NZ (1) NZ544684A (fr)
UA (1) UA96115C2 (fr)
WO (2) WO2004113277A2 (fr)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007063428A2 (fr) * 2005-09-30 2007-06-07 Neurochem (International) Limited Méthodes et compositions pharmaceutiques comprenant des acides carboxyalkylsulfoniques
KR100883132B1 (ko) 2006-10-24 2009-02-10 재단법인서울대학교산학협력재단 아밀로이드 형성 펩타이드 또는 단백질의 가용성 회합체에선택적으로 작용하는 절단제
WO2009019534A2 (fr) * 2006-10-12 2009-02-12 Bellus Health (International) Limited Procédés, composés, compositions et véhicules permettant de délivrer l'acide 3-amino-1-propane sulfonique
WO2010014943A2 (fr) * 2008-08-01 2010-02-04 Bioxiness Pharmaceutics, Inc. Analogues de méthionine, et procédés d'utilisation de ceux-ci
US20100150804A1 (en) * 2007-04-02 2010-06-17 University Of South Alabama Carbon Dioxide Scrubbing Using Ionic Materials
US20120015911A1 (en) * 2004-12-22 2012-01-19 Bellus Health Inc. Method and compositions for treating amyloid-related diseases
US8187887B2 (en) 2009-10-06 2012-05-29 Massachusetts Institute Of Technology Method and apparatus for determining radiation
US8212132B2 (en) 2007-03-07 2012-07-03 Massachusetts Institute Of Technology Functionalization of nanoscale articles including nanotubes and fullerenes
US8456073B2 (en) 2009-05-29 2013-06-04 Massachusetts Institute Of Technology Field emission devices including nanotubes or other nanoscale articles
US8476510B2 (en) 2010-11-03 2013-07-02 Massachusetts Institute Of Technology Compositions comprising and methods for forming functionalized carbon-based nanostructures
US8642801B2 (en) 2003-06-23 2014-02-04 Bhi Limited Partnership Methods and compositions for treating amyloid-related diseases
US8735313B2 (en) 2008-12-12 2014-05-27 Massachusetts Institute Of Technology High charge density structures, including carbon-based nanostructures and applications thereof
US8951473B2 (en) 2008-03-04 2015-02-10 Massachusetts Institute Of Technology Devices and methods for determination of species including chemical warfare agents
US9051248B2 (en) 2009-08-10 2015-06-09 Bhi Limited Partnership Methods, compounds, and compositions for delivering 1,3-propanedisulfonic acid
AU2013206030B2 (en) * 2003-06-23 2016-05-12 Bhi Limited Partnership Methods and compositions for treating amyloid-related diseases
US9556301B1 (en) 2015-12-02 2017-01-31 King Fahd Universoty of Petroleum and Minerals Cyclopolymer containing residues of methionine and synthesis and uses thereof
EP3135683A1 (fr) * 2015-08-28 2017-03-01 Sysmex Corporation Procédé de libération de peptide, procédé de récupération de peptide et agent de libération de peptide
US11053192B2 (en) 2015-08-10 2021-07-06 Alzheon, Inc. Compositions and methods for treating and preventing neurodegenerative disorders
EP2247558B1 (fr) 2008-02-14 2022-02-02 Eli Lilly and Company Nouveaux agents d'imagerie pour la détection d'une dysfonction neurologique
EP3992182A1 (fr) 2020-10-28 2022-05-04 Cisbio Bioassays Complexes d'europium(iii) en tant que capteurs de ph
US11505467B2 (en) 2017-11-06 2022-11-22 Massachusetts Institute Of Technology High functionalization density graphene
WO2023212289A1 (fr) 2022-04-28 2023-11-02 Alzheon, Inc. Tramiprosate pour le traitement de maladies liées à apoe4

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA96115C2 (uk) * 2003-06-23 2011-10-10 Беллас Хелс (Інтернешнл) Лімітед Спосіб і композиція для лікування амілоїдогенних захворювань
AU2005310979A1 (en) * 2004-11-16 2006-06-08 Bellus Health (International) Limited Compounds for the treatment of CNS and amyloid associated diseases
CA2683756A1 (fr) 2006-04-14 2007-10-25 Prana Biotechnology Limited Procede de traitement de la degenerescence maculaire liee a l'age (amd)
WO2010025375A1 (fr) * 2008-08-29 2010-03-04 Treventis Corporation Procédés de traitement d’une maladie amyloïde utilisant des analogues de 1-(4-nitrophényl)pipérazine
KR101173677B1 (ko) 2009-12-11 2012-08-13 한국과학기술연구원 Ｅｐｐｓ를 유효성분으로 함유하는 베타아밀로이드 집적 관련 질환의 예방 또는 치료용 약학적 조성물
WO2012015019A1 (fr) * 2010-07-28 2012-02-02 住友化学株式会社 Procédé pour la fabrication de l'acide thiosulfurique d'aminoalkyle
EP3424502B1 (fr) * 2016-03-04 2022-10-19 Niigata University Activateur de la fonction de l'aquaporine 4 et composition pharmaceutique pour troubles neurologiques
RU2657844C1 (ru) * 2017-01-09 2018-06-15 Федеральное государственное бюджетное образовательное учреждение высшего образования "Северо-Осетинская государственная медицинская академия" Министерства здравоохранения Российской Федерации Способ лечения экспериментальной амилоидной кардиопатии у крыс
JP7268049B2 (ja) 2018-03-08 2023-05-02 インサイト・コーポレイション ＰＩ３Ｋ－γ阻害剤としてのアミノピラジンジオール化合物
WO2020010003A1 (fr) 2018-07-02 2020-01-09 Incyte Corporation DÉRIVÉS D'AMINOPYRAZINE UTILISÉS EN TANT QU'INHIBITEURS DE PI3K-γ
US20210165001A1 (en) * 2018-08-03 2021-06-03 The University Of Hong Kong Compositions and methods for detection and imaging of amyloid fibrils, amyloid plaques, rna, and nucleoli
JP2022059674A (ja) * 2020-10-02 2022-04-14 国立大学法人高知大学 アミロイドβの凝集抑制剤、アミロイドβ凝集疾患用医薬組成物、およびその用途
US20240092737A1 (en) * 2021-01-11 2024-03-21 Helios Huaming Biopharma Co., Ltd. Substituted salicylamide compounds and use thereof
CN113433325A (zh) * 2021-06-07 2021-09-24 西安市第一医院 血清vitronectin在AL型淀粉样变的诊断及疾病分期中的应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4085134A (en) * 1974-02-15 1978-04-18 Petrolite Corporation Amino-phosphonic-sulfonic acids
WO1996028187A1 (fr) * 1995-03-15 1996-09-19 Queen's University At Kingston Procedes de traitement de l'amylose
WO1997014306A1 (fr) * 1995-10-17 1997-04-24 Dovetail Technologies, Inc. Stimulants a faible poids moleculaire des cellules de la moelle osseuse et du systeme immunitaire
WO2000064420A2 (fr) * 1999-04-28 2000-11-02 Queen's University At Kingston Compositions et procedes pour traiter l'amylose
WO2000071101A2 (fr) * 1999-05-24 2000-11-30 Queen's University At Kingston Procedes et composes permettant d'inhiber les depots amyloides
WO2001003680A2 (fr) * 1999-07-09 2001-01-18 Isis Innovation Limited Composes destines a l'inhibition de maladies et a la preparation de cellules a transplanter

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2376911A (en) * 1941-12-24 1945-05-29 Swiss Company Of Soc Of Chemic Derivatives of sulphonated amines and process of preparing same
DE927992C (de) * 1952-07-27 1955-05-23 Hoechst Ag Verfahren zur Herstellung von Salzen des 1, 2-Dimethyl-3-phenyl-4-amino-5-pyrazolons
US3453309A (en) * 1966-10-14 1969-07-01 Parke Davis & Co Phenylalkylaminoethyl thiosulfates
DE2140278A1 (en) * 1970-01-19 1972-03-09 Crompton and Knowles Corp., Worcester, Mass. (V.St.A.) Water-soluble dyes and dye intermediates
JPS60184564A (ja) * 1984-03-05 1985-09-20 Mitsui Toatsu Chem Inc 液晶に使用するジスアゾ系二色性染料、該染料を含む液晶組成物及び表示装置
DD287256A5 (de) * 1989-08-21 1991-02-21 Akademie Der Wissenschaften Der Ddr,De Verfahren zur herstellung von chiralen wasserloeslichen ammoniumalkansulfonsaeuren sowie deren salzen und sulfobetainen
JP3070687B2 (ja) * 1990-07-19 2000-07-31 日本臓器製薬株式会社 心疾患治療剤
JP3068841B2 (ja) * 1990-08-23 2000-07-24 日本臓器製薬株式会社 アミノアルカンスルホン酸誘導体を有効成分として含有する心疾患治療剤
FR2665444B1 (fr) * 1990-08-06 1992-11-27 Sanofi Sa Derives d'amino-benzofuranne, benzothiophene ou indole, leur procede de preparation ainsi que les compositions les contenant.
JPH0995444A (ja) * 1995-10-02 1997-04-08 Teijin Ltd アミロイド蛋白凝集阻害剤
AU7237198A (en) * 1997-05-21 1998-12-11 Shionogi & Co., Ltd. Remedies for dementia of alzheimer type containing gamma-sultam derivatives
CN1348442A (zh) * 1999-02-26 2002-05-08 默克公司 新的磺胺化合物及其应用
JP4440446B2 (ja) * 1999-10-05 2010-03-24 花王株式会社 皮膚外用剤
JP2004500354A (ja) * 1999-11-29 2004-01-08 ニューロケム　インコーポレーティッド 全ｄ体ペプチドを含む、アルツハイマー病およびアミロイド関連疾患の予防および処置のためのワクチン
US20020094335A1 (en) * 1999-11-29 2002-07-18 Robert Chalifour Vaccine for the prevention and treatment of alzheimer's and amyloid related diseases
BR0016652A (pt) * 1999-12-23 2002-11-19 Neurochem Inc Métodos para inibir angiopatia amilóide cerebral, para tratar um estado de doença caracterizado por angiopatia amilóide cerebral em um indivìduo, e para diagnosticar angiopatia amilóide cerebral em um indivìduo
US20020115717A1 (en) * 2000-07-25 2002-08-22 Francine Gervais Amyloid targeting imaging agents and uses thereof
EP1585520A1 (fr) * 2002-12-24 2005-10-19 Neurochem (International) Limited Formulations therapeutiques pour le traitement de maladies liees a la beta-amyl0ide
UA96115C2 (uk) * 2003-06-23 2011-10-10 Беллас Хелс (Інтернешнл) Лімітед Спосіб і композиція для лікування амілоїдогенних захворювань

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4085134A (en) * 1974-02-15 1978-04-18 Petrolite Corporation Amino-phosphonic-sulfonic acids
WO1996028187A1 (fr) * 1995-03-15 1996-09-19 Queen's University At Kingston Procedes de traitement de l'amylose
WO1997014306A1 (fr) * 1995-10-17 1997-04-24 Dovetail Technologies, Inc. Stimulants a faible poids moleculaire des cellules de la moelle osseuse et du systeme immunitaire
WO2000064420A2 (fr) * 1999-04-28 2000-11-02 Queen's University At Kingston Compositions et procedes pour traiter l'amylose
WO2000071101A2 (fr) * 1999-05-24 2000-11-30 Queen's University At Kingston Procedes et composes permettant d'inhiber les depots amyloides
WO2001003680A2 (fr) * 1999-07-09 2001-01-18 Isis Innovation Limited Composes destines a l'inhibition de maladies et a la preparation de cellules a transplanter

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314317 Database accession no. BRN 4261672 & ISKANDER MN ET AL.: EUR. J. MED. CHEM. CHIM. THER., vol. 26, no. 2, 1991, pages 129-136, *
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314318 Database accession no. BRN 7023352 & CAMPAGNA F. ET AL.: FARMACO, vol. 49, no. 10, 1994, pages 653-58, *
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314319 Database accession no. BRN 8919306 & KILLDAY K. B. ET AL.: J. NAT. PROD., vol. 64, no. 4, 2001, pages 525-526, *
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314320 Database accession no. BRN 6023409 & TOMSON ET AL.: J. APPL. CHEM. USSR, ENGL. TRANSL., vol. 57, no. 9, 1984, pages 1885-91, *
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314321 Database accession no. BRN 2272192 & WOOD. J. M. ET AL.: J. CHEM. SOC. PERKIN TRANS 2, 5, 2002, pages 938-46, *
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314322 Database accession no. BRN 3948718 & HELFERICH B. ET AL.: JUSTUS LIEBIGS ANN. CHEM., 651, 1962, pages 33-42, *
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314323 Database accession no. BRN 1712477 & ABDERHALDEN; RIESZ: FERMENTFORSCHUNG, 12, 1930, page 198, *
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314324 Database accession no. BRN 2972476 & DORN, WALTER: Z. CHEM., 7, 1967, page 151, *
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314325 Database accession no. BRN 2434022 & JUSTUS LIEBIGS ANN. CHEM., 647, 1961, pages 37-40, *
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314326 Database accession no. BRN 5620601 & IENAGA, KAZUHARA ET AL.: CHEM. PHARM. BULL., vol. 36, no. 8, 1988, pages 2796-2801, *
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314327 Database accession no. BRN 2846394 & IIDA ET AL.: KOGYO KAGAKU ZASSHI, 72, 1969, page 887, *
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314328 Database accession no. BRN 3952462, 3935697 & ALLEN ET AL.: ANAL. CHEM., 37, 1965, page 156, *
DATABASE BEILSTEIN BEILSTEIN INSTITUT ZUR FÖRDERUNG DER CHEMISCHEN WISSENSCHAFTEN, FRANKFURT AM MAIN, DE; XP002314329 Database accession no. BRN5568774 & IENAGA, KAZUHARA ET AL.: CHEM. PHARM. BULL., vol. 36, no. 1, 1988, pages 70-77, *
See also references of EP1644325A2 *

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2013206030B2 (en) * 2003-06-23 2016-05-12 Bhi Limited Partnership Methods and compositions for treating amyloid-related diseases
US8642801B2 (en) 2003-06-23 2014-02-04 Bhi Limited Partnership Methods and compositions for treating amyloid-related diseases
US20120015911A1 (en) * 2004-12-22 2012-01-19 Bellus Health Inc. Method and compositions for treating amyloid-related diseases
US8835654B2 (en) * 2004-12-22 2014-09-16 Bhi Limited Partnership Method and compositions for treating amyloid-related diseases
WO2007063428A3 (fr) * 2005-09-30 2008-01-17 Neurochem Int Ltd Méthodes et compositions pharmaceutiques comprenant des acides carboxyalkylsulfoniques
WO2007063428A2 (fr) * 2005-09-30 2007-06-07 Neurochem (International) Limited Méthodes et compositions pharmaceutiques comprenant des acides carboxyalkylsulfoniques
JP2010514674A (ja) * 2006-10-12 2010-05-06 ベラス ヘルス （インターナショナル） リミテッド ３−アミノ−１−プロパンスルホン酸を送達するための方法、化合物、組成物および媒体
KR101742179B1 (ko) * 2006-10-12 2017-05-31 비에이치아이 리미티드 파트너쉽 3-아미노-1-프로판설폰산을 전달하기 위한 방법, 화합물, 조성물 및 비히클
US11020360B2 (en) 2006-10-12 2021-06-01 Bellus Health Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
EP2862581A3 (fr) * 2006-10-12 2015-08-12 BHI Limited Partnership Procédés, composés, compositions et véhicules pour l'administration d'acide 3-amino-1-propanesulfonique
US10857109B2 (en) 2006-10-12 2020-12-08 Bellus Health, Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
EA016568B1 (ru) * 2006-10-12 2012-05-30 Беллус Хелс (Интернэшнл) Лимитед Способы, соединения, композиции и носители для доставки 3-амино-1-пропансульфоновой кислоты
US20210386693A1 (en) * 2006-10-12 2021-12-16 Bellus Health Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
AU2007357451B2 (en) * 2006-10-12 2012-11-15 Bhi Limited Partnership. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US10238611B2 (en) 2006-10-12 2019-03-26 Bellus Health Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
CN106946748B (zh) * 2006-10-12 2019-02-05 Bhi有限合资公司 递送3-氨基-1-丙磺酸的方法、化合物、组合物和载体
CN106946748A (zh) * 2006-10-12 2017-07-14 Bhi有限合资公司 递送3‑氨基‑1‑丙磺酸的方法、化合物、组合物和载体
EP3851447A1 (fr) * 2006-10-12 2021-07-21 BHI Limited Partnership Procédés, composés, compositions et véhicules pour l'administration d'acide 3-amino-1-propanesulfonique
CN103787927B (zh) * 2006-10-12 2017-03-01 Bhi有限合资公司 递送3‑氨基‑1‑丙磺酸的方法、化合物、组合物和载体
WO2009019534A3 (fr) * 2006-10-12 2009-08-13 Bellus Health Int Ltd Procédés, composés, compositions et véhicules permettant de délivrer l'acide 3-amino-1-propane sulfonique
CN103787927A (zh) * 2006-10-12 2014-05-14 Bhi有限合资公司 递送3-氨基-1-丙磺酸的方法、化合物、组合物和载体
JP2016222671A (ja) * 2006-10-12 2016-12-28 ビーエイチアイ リミテッド パートナーシップ ３−アミノ−１−プロパンスルホン酸を送達するための方法、化合物、組成物および媒体
US8748656B2 (en) 2006-10-12 2014-06-10 Bhi Limited Partnership Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
WO2009019534A2 (fr) * 2006-10-12 2009-02-12 Bellus Health (International) Limited Procédés, composés, compositions et véhicules permettant de délivrer l'acide 3-amino-1-propane sulfonique
KR20160039309A (ko) * 2006-10-12 2016-04-08 비에이치아이 리미티드 파트너쉽 3-아미노-1-프로판설폰산을 전달하기 위한 방법, 화합물, 조성물 및 비히클
JP2015007047A (ja) * 2006-10-12 2015-01-15 ビーエイチアイ リミテッド パートナーシップ ３−アミノ−１−プロパンスルホン酸を送達するための方法、化合物、組成物および媒体
KR100883132B1 (ko) 2006-10-24 2009-02-10 재단법인서울대학교산학협력재단 아밀로이드 형성 펩타이드 또는 단백질의 가용성 회합체에선택적으로 작용하는 절단제
US8212132B2 (en) 2007-03-07 2012-07-03 Massachusetts Institute Of Technology Functionalization of nanoscale articles including nanotubes and fullerenes
US8952193B2 (en) 2007-04-02 2015-02-10 University Of South Alabama Carbon dioxide scrubbing using ionic materials
US20140170054A1 (en) * 2007-04-02 2014-06-19 University Of South Alabama Carbon Dioxide Scrubbing Using Ionic Materials
US20100150804A1 (en) * 2007-04-02 2010-06-17 University Of South Alabama Carbon Dioxide Scrubbing Using Ionic Materials
US8536371B2 (en) 2007-04-02 2013-09-17 University Of South Alabama Carbon dioxide scrubbing using ionic materials
EP2247558B1 (fr) 2008-02-14 2022-02-02 Eli Lilly and Company Nouveaux agents d'imagerie pour la détection d'une dysfonction neurologique
US9267908B2 (en) 2008-03-04 2016-02-23 Massachusetts Institute Of Technology Devices and methods for determination of species including chemical warfare agents
US8951473B2 (en) 2008-03-04 2015-02-10 Massachusetts Institute Of Technology Devices and methods for determination of species including chemical warfare agents
US9695119B2 (en) 2008-08-01 2017-07-04 Bioxiness Pharmaceuticals, Inc. Methionine analogs and methods of using same
WO2010014943A2 (fr) * 2008-08-01 2010-02-04 Bioxiness Pharmaceutics, Inc. Analogues de méthionine, et procédés d'utilisation de ceux-ci
WO2010014943A3 (fr) * 2008-08-01 2011-01-13 Bioxiness Pharmaceutics, Inc. Analogues de méthionine, et procédés d'utilisation de ceux-ci
US8580859B2 (en) 2008-08-01 2013-11-12 Bioxiness Pharmaceuticals, Inc. Methionine analogs and methods of using same
US8735313B2 (en) 2008-12-12 2014-05-27 Massachusetts Institute Of Technology High charge density structures, including carbon-based nanostructures and applications thereof
US9114377B2 (en) 2008-12-12 2015-08-25 Massachusetts Institute Of Technology High charge density structures, including carbon-based nanostructures and applications thereof
US8456073B2 (en) 2009-05-29 2013-06-04 Massachusetts Institute Of Technology Field emission devices including nanotubes or other nanoscale articles
US9051248B2 (en) 2009-08-10 2015-06-09 Bhi Limited Partnership Methods, compounds, and compositions for delivering 1,3-propanedisulfonic acid
US8426208B2 (en) 2009-10-06 2013-04-23 Massachusetts Institute Of Technology Method and apparatus for determining radiation
US8187887B2 (en) 2009-10-06 2012-05-29 Massachusetts Institute Of Technology Method and apparatus for determining radiation
US8476510B2 (en) 2010-11-03 2013-07-02 Massachusetts Institute Of Technology Compositions comprising and methods for forming functionalized carbon-based nanostructures
US9770709B2 (en) 2010-11-03 2017-09-26 Massachusetts Institute Of Technology Compositions comprising functionalized carbon-based nanostructures and related methods
US11053192B2 (en) 2015-08-10 2021-07-06 Alzheon, Inc. Compositions and methods for treating and preventing neurodegenerative disorders
US10053488B2 (en) 2015-08-28 2018-08-21 Sysmex Corporation Method of liberating peptide and method of recovering peptide
EP3135683A1 (fr) * 2015-08-28 2017-03-01 Sysmex Corporation Procédé de libération de peptide, procédé de récupération de peptide et agent de libération de peptide
US9556301B1 (en) 2015-12-02 2017-01-31 King Fahd Universoty of Petroleum and Minerals Cyclopolymer containing residues of methionine and synthesis and uses thereof
US11505467B2 (en) 2017-11-06 2022-11-22 Massachusetts Institute Of Technology High functionalization density graphene
EP3992182A1 (fr) 2020-10-28 2022-05-04 Cisbio Bioassays Complexes d'europium(iii) en tant que capteurs de ph
WO2022090284A1 (fr) 2020-10-28 2022-05-05 Cisbio Bioassays Complexes d'europium (iii) utilisés comme capteurs de ph
WO2023212289A1 (fr) 2022-04-28 2023-11-02 Alzheon, Inc. Tramiprosate pour le traitement de maladies liées à apoe4

Also Published As

Publication number Publication date
WO2004113277A3 (fr) 2005-10-13
AU2004249527A1 (en) 2004-12-29
WO2004113277A2 (fr) 2004-12-29
WO2004113275A3 (fr) 2005-10-27
EA200600078A1 (ru) 2006-08-25
MXPA05014166A (es) 2006-03-13
NZ544684A (en) 2009-10-30
AU2004249529A1 (en) 2004-12-29
JP5146714B2 (ja) 2013-02-20
CA2529257A1 (fr) 2004-12-29
EP1644325A2 (fr) 2006-04-12
UA96115C2 (uk) 2011-10-10
KR101124935B1 (ko) 2012-04-12
EP1658264A2 (fr) 2006-05-24
JP2007516938A (ja) 2007-06-28
JP2007516939A (ja) 2007-06-28
WO2004113277A8 (fr) 2005-07-14
CA2529257C (fr) 2013-04-23
NO335084B1 (no) 2014-09-08
KR20060023172A (ko) 2006-03-13
NO20055894L (no) 2006-03-21
MXPA05013977A (es) 2006-03-09
BRPI0411743A (pt) 2006-08-08
CA2529256A1 (fr) 2004-12-29
EA012429B1 (ru) 2009-10-30

Similar Documents

Publication Publication Date Title
CA2529257C (fr) Methodes et compositions pour traiter les maladies liees a l'amyloide
US7244764B2 (en) Methods and compositions for treating amyloid-related diseases
US8642801B2 (en) Methods and compositions for treating amyloid-related diseases
US8835654B2 (en) Method and compositions for treating amyloid-related diseases
US7414076B2 (en) Methods and compositions for treating amyloid-related diseases
US20050038000A1 (en) Methods and compositions for the treatment of amyloid-and epileptogenesis-associated diseases
AU2004251717B2 (en) Treatment of amyloid- and epileptogenesis-associated diseases
AU2011250847B2 (en) Methods and compositions for treating amyloid-related diseases

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200480024207.7

Country of ref document: CN

AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 172194

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2005/09647

Country of ref document: ZA

Ref document number: 200509647

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 2004249529

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2529257

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2005/014166

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2004249529

Country of ref document: AU

Date of ref document: 20040621

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1020057024647

Country of ref document: KR

Ref document number: 12005502335

Country of ref document: PH

WWP Wipo information: published in national office

Ref document number: 2004249529

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2006516599

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 544684

Country of ref document: NZ

REEP Request for entry into the european phase

Ref document number: 2004744034

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2004744034

Country of ref document: EP

Ref document number: 242/CHENP/2006

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 200600078

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: a200600637

Country of ref document: UA

WWP Wipo information: published in national office

Ref document number: 1020057024647

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 2004744034

Country of ref document: EP

ENP Entry into the national phase

Ref document number: PI0411743

Country of ref document: BR