+

WO1999008685A1 - Composes de phosphono-carboxylate conçus pour le traitement de l'amylose - Google Patents

Composes de phosphono-carboxylate conçus pour le traitement de l'amylose Download PDF

Info

Publication number
WO1999008685A1
WO1999008685A1 PCT/IB1998/000967 IB9800967W WO9908685A1 WO 1999008685 A1 WO1999008685 A1 WO 1999008685A1 IB 9800967 W IB9800967 W IB 9800967W WO 9908685 A1 WO9908685 A1 WO 9908685A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
aryl
hydrogen
formula
Prior art date
Application number
PCT/IB1998/000967
Other languages
English (en)
Inventor
Walter A. Szarek
Xiangi Kong
Gregory R. J. Thatcher
Boris Gorine
Original Assignee
Queen's University At Kingston
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 US08/912,574 external-priority patent/US5869469A/en
Application filed by Queen's University At Kingston filed Critical Queen's University At Kingston
Priority to JP2000509424A priority Critical patent/JP2001515039A/ja
Priority to IL13461998A priority patent/IL134619A0/xx
Priority to AU22431/99A priority patent/AU2243199A/en
Priority to CA002300910A priority patent/CA2300910C/fr
Priority to EP98966963A priority patent/EP1014994A1/fr
Publication of WO1999008685A1 publication Critical patent/WO1999008685A1/fr

Links

Classifications

    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4062—Esters of acids containing the structure -C(=X)-P(=X)(XR)2 or NC-P(=X)(XR)2, (X = O, S, Se)
    • C07F9/4065—Esters of acids containing the structure -C(=X)-P(=X)(XR)2, (X = O, S, Se)

Definitions

  • Amyloidosis refers to a pathological condition characterized by the presence of amyloid.
  • Amyloid is a generic term referring to a group of diverse but specific extracellular protein deposits which are seen in a number of different diseases. Though diverse in their occurrence, all amyloid deposits have common morphologic properties, stain with specific dyes (e.g., Congo red), and have a characteristic red-green birefringent appearance in polarized light after staining. They also share common ultrastructural features and common x-ray diffraction and infrared spectra.
  • specific dyes e.g., Congo red
  • Amyloidosis can be classified clinically as primary, secondary, familial and/or isolated. Primary amyloidosis appears de novo without any preceding disorder. Secondary amyloidosis is that form which appears as a complication of a previously existing disorder. Familial amyloidosis is a genetically inherited form found in particular geographic populations. Isolated forms of amyloidosis are those that tend to involve a single organ system. Different amyloids are also characterized by the type of protein present in the deposit.
  • 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.
  • AScr protease-resistant form of a prion protein
  • Alzheimer's disease another neurodegenerative disorder, is characterized by congophilic angiopathy, neuritic plaques and neurofibrillary tangles, all of which have the characteristics of amyloids.
  • the plaque and blood vessel amyloid is formed by the beta protein.
  • amyloids systemically. In each of these cases, a different amyloidogenic protein is involved in amyloid deposition.
  • This invention provides methods and compositions which are useful in the treatment of amyloidosis.
  • the methods of the invention involve administering to a subject a therapeutic compound which inhibits amyloid deposition.
  • the compositions and methods of the invention are useful for inhibiting amyloidosis in disorders in which amyloid deposition occurs.
  • the methods of the invention can be used therapeutically to treat amyloidosis or can be used prophylactically in a subject susceptible to amyloidosis. Without wishing to be bound by theory, it is believed that the methods of the invention are based, at least in part, on inhibiting an interaction between an amyloidogenic protein and a constituent of basement membrane to inhibit amyloid deposition.
  • the constituent of basement membrane can be a glycoprotein or proteoglycan, preferably heparan sulfate proteoglycan.
  • a therapeutic compound used in the method of the invention preferably can interfere with binding of a basement membrane constituent to a target binding site on an amyloidogenic protein, thereby inhibiting amyloid deposition.
  • the invention relates to phosphonocarboxylate compounds, i.e., compounds which include a phosphonate group and a carboxylate group, or a pharmaceutically acceptable salt or ester thereof.
  • the method of the invention involves administering to a subject an effective amount of a therapeutic compound having the formula (Formula I):
  • Z is XR 2 or R 4 ,
  • R 1 and R 2 are each independently hydrogen, a substituted or unsubstituted aliphatic group (preferably a branched or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain; or an unsubstituted or substituted cyclic aliphatic moiety having from 4 to 7 carbon atoms in the aliphatic ring; preferred aliphatic and cyclic aliphatic groups are alkyl groups, more preferably lower alkyl), an aryl group, a heterocyclic group, or a salt-forming cation;
  • R 3 is hydrogen, lower alkyl, aryl, or a salt-forming cation;
  • R 4 is hydrogen, lower alkyl, aryl or amino (including alkylamino, dialkylamino (including cyclic amino moieties), arylamino, diarylamino, and alkylarylamino);
  • X is, independently for each
  • therapeutic compounds of the invention prevent or inhibit amyloid deposition in a subject to which the therapeutic compound is administered.
  • Preferred therapeutic compounds for use in the invention include compounds in which both R 1 and R 2 are pharmaceutically acceptable salt-forming cations. It will be appreciated that the stoichiometry of an anionic compound to a salt- forming counterion (if any) will vary depending on the charge of the anionic portion of the compound (if any) and the charge of the counterion.
  • R 1 , R 2 and R 3 are each independently a sodium, potassium or calcium cation.
  • the aliphatic group has between 1 and 10 carbons atoms in the straight or branched chain, and is more preferably a lower alkyl group. In other embodiments in which at least one of R 1 and R 2 is an aliphatic group, the aliphatic group has between 10 and 24 carbons atoms in the straight or branched chain. In certain preferred embodiments, n is 0 or 1; more preferably, n is 0. In certain preferred embodiments of the therapeutic compounds, Y 1 and Y 2 are each hydrogen.
  • the therapeutic compound of the invention can be represented by the formula (Formula II):
  • the therapeutic compound of the invention can be represented by the formula (Formula III): X
  • R a and R ⁇ - are each hydrogen.
  • a compound of the invention comprises an ⁇ -amino acid (or ⁇ -amino acid ester), more preferably a L- ⁇ - amino acid or ester.
  • the compounds of the invention can be represented by the formula (Formula IV):
  • G represents hydrogen or one or more substituents on the aryl ring (e.g., alkyl, aryl, halogen, amino, and the like) and L is a substituted alkyl group (in certain embodiments, preferably a lower alkyl), more preferably a hydroxy-substituted alkyl or an alkyl substituted with a nucleoside base.
  • substituents on the aryl ring e.g., alkyl, aryl, halogen, amino, and the like
  • L is a substituted alkyl group (in certain embodiments, preferably a lower alkyl), more preferably a hydroxy-substituted alkyl or an alkyl substituted with a nucleoside base.
  • the therapeutic compounds of the invention are administered to a subject by a route which is effective for modulation of amyloid deposition.
  • Suitable routes of administration include oral, transdermal, subcutaneous, intravenous, intramuscular and intraperitoneal injection.
  • a preferred route of administration is oral administration.
  • the therapeutic compounds can be administered with a pharmaceutically acceptable vehicle.
  • the invention also provides methods for treating a disease state associated with amyloidosis by administering to a subject an effective amount of a therapeutic compound having the formula described supra, such that a disease state associated with amyloidosis is treated.
  • the invention provides methods for modulating amyloid deposition characterized by interaction between an amyloidogenic protein and a constituent of a basement membrane by administering to the subject an effective amount of a therapeutic compound having the formula described supra, such that modulation of amyloid deposition characterized by interaction between an amyloidogenic protein and a constituent of a basement membrane occurs.
  • the invention further provides pharmaceutical compositions for treating amyloidosis.
  • the pharmaceutical compositions include a therapeutic compound of the invention in an amount effective to modulate amyloid deposition and a pharmaceutically acceptable vehicle.
  • the invention also provides packaged pharmaceutical compositions for treating amyloidosis.
  • the packaged pharmaceutical compositions include a therapeutic compound of the invention and instructions for using the pharmaceutical composition for treatment of amyloidosis.
  • This invention pertains to methods and compositions useful for treating amyloidosis.
  • the methods of the invention involve administering to a subject a therapeutic compound which modulates amyloid deposition.
  • Modulation of amyloid deposition is intended to encompass prevention of amyloid formation, inhibition of further amyloid deposition in a subject with ongoing amyloidosis and reduction of amyloid deposits in a subject with ongoing amyloidosis. Modulation of amyloid deposition is determined relative to an untreated subject or relative to the treated subject prior to treatment. In certain embodiments, amyloid deposition can be modulated by modulating an interaction between an amyloidogenic protein and a constituent of basement membrane.
  • Basis membrane refers to an extracellular matrix comprising glycoproteins and proteoglycans, including laminin, collagen type IV, fibronectin chondroitan sulfate, and/or heparan sulfate proteoglycan (HSPG).
  • amyloid deposition is modulated by interfering with an interaction between an amyloidogenic protein and a sulfated glycosaminoglycan such as HSPG.
  • Sulfated glycosaminoglycans are known to be present in all types of amyloids (see Snow, A.D. et al. (1987) Lab. Invest.
  • amyloid deposition and HSPG deposition occur coincidentally in animal models of amyloidosis (see Snow, A.D. et al. (1987) Lab. Invest. 56:665-675).
  • molecules which have a similar structure to a sulfated glycosaminoglycan are used to modulate interaction between an amyloidogenic protein and basement membrane constituent.
  • the therapeutic compounds of the invention preferably comprise at least one phosphonate group (or phosphonic ester), or a functional equivalent thereof (including phosphorus- containing anionic groups including, but not limited to, phosphates, phosphate esters, phosphinates, and the like), and a carboxylate group or carboxylic ester (or a congener such as a thioacid, thiolester,or thionoester), provided that the compound includes, or is capable of having after reaction in vivo, at least one anionic group.
  • the anionic groups(s) can optionally be covalently bound to a carrier (e.g., an aliphatic group, peptide or peptidomimetic, or the like).
  • a carrier e.g., an aliphatic group, peptide or peptidomimetic, or the like.
  • the carrier molecule can enable the compound to traverse biological membranes and to be biodistributed without excessive or premature metabolism.
  • the method of the invention includes administering to the subject an effective amount of a therapeutic compound which has at least one phosphonate group or phosphonic ester group.
  • the therapeutic compound is preferably capable of modulating interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane to thus modulate amyloid deposition.
  • the therapeutic compound has the formula (Formula I):
  • Z is XR 2 or R 4 , R 1 and R 2 are each independently hydrogen, a substituted or unsubstituted aliphatic group (preferably a branched or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain; or an unsubstituted or substituted cyclic aliphatic moiety having from 4 to 7 carbon atoms in the aliphatic ring; preferred aliphatic and cyclic aliphatic groups are alkyl groups, more preferably lower alkyl), an aryl group, a heterocyclic group, or a salt-forming cation; R 3 is hydrogen, lower alkyl, aryl, or a salt-forming cation; X is, independently for each occurrence, O or S; R 4 is hydrogen, lower alkyl, aryl or amino; Y 1 and Y 2 are each independently hydrogen, halogen (e.g., F, Cl, Br, or I), lower alkyl, amino (including alkylamino
  • therapeutic compounds of the invention prevent or inhibit amyloid deposition in a subject to which the therapeutic compound is administered.
  • Preferred therapeutic compounds for use in the invention include compounds in which both R 1 and R 2 are pharmaceutically acceptable salt-forming cations. It will be appreciated that the stoichiometry of an anionic compound to a salt- forming counterion (if any) will vary depending on the charge of the anionic portion of the compound (if any) and the charge of the counterion.
  • R 1 , R 2 and R 3 are each independently a sodium, potassium or calcium cation.
  • the aliphatic group has between 1 and 10 carbons atoms in the straight or branched chain, and is more preferably a lower alkyl group. In other embodiments in which at least one of R 1 and R 2 is an aliphatic group, the aliphatic group has between 10 and 24 carbons atoms in the straight or branched chain. In certain preferred embodiments, n is 0 or 1 ; more preferably, n is 0. In certain preferred embodiments of the therapeutic compounds, Y 1 and Y 2 are each hydrogen. In certain preferred embodiments, the therapeutic compound of the invention can be represented by the formula (Formula II):
  • the therapeutic compound of the invention can be represented by the formula (Formula III):
  • R 1 , R 2 , R 3 , Y 1 , Y 2 , and X are as defined above
  • R a and R D are each independently hydrogen, alkyl, aryl, or heterocyclyl, or R a and Rt ⁇ , taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the ring, and n is an integer from 0 to 6.
  • R a and R D are each hydrogen.
  • a compound of the invention comprises an ⁇ -amino acid (or ⁇ -amino acid ester), more preferably a L- ⁇ - amino acid or ester.
  • the Z, Q, R 1 , R 2 , R 3 , Y 1 , Y 2 and X groups are each independently selected such that the biodistribution of the compound for an intended target site is not prevented while maintaining activity of the compound.
  • the number of anionic groups (and the overall charge on the therapeutic compound) should not be so great as to inhibit traversal of an anatomical barrier, such as a cell membrane, or entry across a physiological barrier, such as the blood-brain barrier, in situations where such properties are desired.
  • esters of phosphonoformate have biodistribution properties different from, and in some cases superior to, the biodistribution properties of phosphonoformate (see, e.g., U.S. Patent Nos.
  • At least one of R 1 and R 2 is an aliphatic group (more preferably an alkyl group), in which the aliphatic group has between 10 and 24 carbons atoms in the straight or branched chain.
  • the number, length, and degree of branching of the aliphatic chains can be selected to provide a desired characteristic, e.g., lipophilicity.
  • At least one of R 1 and R 2 is an aliphatic group (more preferably an alkyl group), in which the aliphatic group has between 1 and 10 carbons atoms in the straight or branched chain.
  • the number, length, and degree of branching of the aliphatic chains can be selected to provide a desired characteristic, e.g., lipophilicity or ease of ester cleavage by enzymes.
  • a preferred aliphatic group is an ethyl group.
  • the therapeutic compound includes a moiety selected from the group consisting of -P(S)(OR 1 )(OR 2 ), - P(S)(SRl)(OR 2 ), or -P(S)(SR l )(SR 2 ).
  • the compounds of the invention can be represented by the formula (Formula IV): in which G represents hydrogen or one or more substituents on the aryl ring (e.g., alkyl, aryl, halogen, amino, and the like) and L is a substituted alkyl group (in certain embodiments, preferably a lower alkyl), more preferably a hydroxy-substituted alkyl or an alkyl substituted with a nucleoside base.
  • G is hydrogen or an electron-donating group.
  • G is preferably an electron withdrawing group at the meta position.
  • electron- withdrawing group refers to a group which has a greater electron- withdrawing than hydrogen.
  • electron- withdrawing groups include halogens (e.g., fluoro, chloro, bromo, and iodo groups), nitro, cyano, and the like.
  • electron-donating group refers to a group which is less electron-withdrawing than hydrogen. In embodiments in which G is an electron donating group, G can be in the ortho, meta or para position.
  • L is a moiety selected from the group consisting of (Formulas IVa-IVg):
  • Table 1 lists data pertinent to the characterization of these compounds using art- recognized techniques.
  • the invention includes novel compounds useful for inhibiting amyloidosis, and/or compounds having antiviral activity.
  • the compounds of the invention can be represented by the structures of Formula IV, e.g., a compound of Formula IV in which G is hydrogen (e.g., the phenyl ring is unsubstituted) and L is any of the moieties of Formulas IVa-IVg.
  • G is hydrogen (e.g., the phenyl ring is unsubstituted)
  • L is any of the moieties of Formulas IVa-IVg.
  • a more preferred compound is the compound of Formula IVc.
  • the invention provides a method for preparing esters of phosphonates, e.g., phosphono-carboxylate compounds of the invention, e.g., a compound of Formula IV in which G is hydrogen and L is a moiety of Formula IVa - IVg.
  • the method includes the step of reacting a phosphonodichloridate (or other phosphonate diacid halide) with a disilylated diol under conditions such that a compound of Forumla IV is formed (see Example 2, infra).
  • the invention provides a method for preparing a compound represented by the Formula (Formula V):
  • the method includes the step of reacting an ester of a carbonylphosphono diacid halide (e.g., ROOC-P(O)(A)(A'), in which R is as described in Formula V, and A and A' are both halogen or other good leaving groups, e.g., chloro, iodo, bromo, pentafluorophenyl, and the like, which can be the same or different) with a disilylether of a vicinal diol, under conditions such that the compound of Formula V is prepared.
  • a carbonylphosphono diacid halide e.g., ROOC-P(O)(A)(A')
  • R is as described in Formula V
  • a and A' are both halogen or other good leaving groups, e.g., chloro, iodo, bromo, pentafluorophenyl, and the like, which can be the same or different
  • An anionic group (i.e., a phosphonate or carboxylate group) of a therapeutic compound of the invention is a negatively charged moiety that, in certain preferred embodiments, can modulate interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane to thus modulate amyloid deposition.
  • the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers (e.g., enantiomers and diastereomers) arising from such asymmetry are included within the scope of this invention. Such isomers can be obtained in substantially pure form by classical separation techniques and by sterically controlled synthesis. For the purposes of this application, unless expressly noted to the contrary, a compound shall be construed to include both the R or S stereoisomers at each chiral center.
  • an amyloidogenic protein e.g., serum amyloid A protein or ⁇ -amyloid precursor protein ( ⁇ -APP)
  • the solid support is washed extensively to remove unbound material.
  • the binding of the basement membrane constituent (e.g., HSPG) to the amyloidogenic protein (e.g., ⁇ -APP) is then measured using an antibody directed against the basement membrane constituent which is conjugated to a detectable substance (e.g., an enzyme, such as alkaline phosphatase) by detecting the detectable substance.
  • a detectable substance e.g., an enzyme, such as alkaline phosphatase
  • a compound which modulates an interaction between an amyloidogenic protein and a glycoprotein or proteoglycan constituent of a basement membrane will reduce the amount of substance detected (e.g., will inhibit the amount of enzyme activity detected).
  • a therapeutic compound of the invention interacts with a binding site for a basement membrane glycoprotein or proteoglycan in an amyloidogenic protein and thereby modulates the binding of the amyloidogenic protein to the basement membrane constituent.
  • Basement membrane glycoproteins and proteoglycans include laminin, collagen type IV, fibronectin and heparan sulfate proteoglycan (HSPG).
  • the therapeutic compound inhibits an interaction between an amyloidogenic protein and HSPG.
  • a therapeutic compound of the invention comprises a cation (i.e., in certain embodiments, at least one of R 1 , R 2 or R 3 is a cation).
  • R 1 , R 2 or R 3 can be a pharmaceutically acceptable alkali metal (e.g., Li, Na, or K), ammonium cation, alkaline earth cation (e.g., Ca 2+ , Ba + , Mg 2+ ), higher valency cation, or polycationic counter ion (e.g., a polyammonium cation).
  • alkali metal e.g., Li, Na, or K
  • ammonium cation e.g., alkaline earth cation
  • alkaline earth cation e.g., Ca 2+ , Ba + , Mg 2+
  • polycationic counter ion e.g., a polyammonium cation
  • esters can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent; either of which are methods known to those skilled in the art.
  • Carboxylic acids and phosphonic acids can be converted into esters according to methods well known to one of ordinary skill in the art, e.g., via treatment with an alcohol in the presence of a catalyst.
  • a preferred ester group (e.g., when R 3 is lower alkyl) is an ethyl ester group.
  • alkyl refers to the saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer.
  • preferred cycloalkyls 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 cycloalkyls having from 3 to 6 carbons in the ring structure.
  • alkyl (including “lower alkyl) as used throughout the specification and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoro
  • alkoxy refers to a moiety having the structure -O- alkyl, in which the alkyl moiety is described above.
  • aryl as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, unsubstituted or substituted benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like.
  • the aromatic ring can be substituted at one or more ring positions with such substituents, e.g., as described above for alkyl groups.
  • Preferred aryl groups include unsubstituted and substituted phenyl groups.
  • aryloxy refers to a group having the structure -O-aryl, in which the aryl moiety is as defined above.
  • amino refers to an unsubstituted or substituted moiety of the formula -NR a Rt ⁇ , in which R a and Rt ⁇ are each independently hydrogen, alkyl, aryl, or heterocyclyl, or R a and Rt ⁇ , 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 is intended to include cyclic amino moieties such as piperidinyl or pyrrolidinyl groups, unless otherwise stated.
  • An “amino-substituted amino group” refers to an amino group in which at least one of R a and R D , is further substituted with an amino group.
  • R 1 or R 2 can be (for at least one occurrence) a long-chain aliphatic moiety.
  • long-chain aliphatic moiety refers to a moiety having a straight or branched chain aliphatic moiety (e.g., an alkyl or alkenyl moiety) having from 10 to 24 carbons in the aliphatic chain, e.g., the long-chain aliphatic moiety is an aliphatic chain of a fatty acid (preferably a naturally-occurring fatty acid).
  • Representative long-chain aliphatic moieties include the aliphatic chains of stearic acid, oleic acid, linolenic acid, and the like.
  • the therapeutic compound of the invention can be administered in a pharmaceutically acceptable vehicle.
  • pharmaceutically acceptable vehicle includes any and all solvents, excipients, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like which are compatible with the activity of the compound and are physiologically acceptable to the subject.
  • An example of a pharmaceutically acceptable vehicle is buffered normal saline (0.15 molar NaCl).
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the therapeutic compound, use thereof in the compositions suitable for pharmaceutical administration is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • the therapeutic compound of the invention can be represented by the formula:
  • R 1 and R 2 are each independently hydrogen, an aliphatic group (preferably a branched or straight-chain aliphatic moiety having from 1 to 24 carbon atoms, more preferably 10-24 carbon atoms, in the chain; or an unsubstituted or substituted cyclic aliphatic moiety having from 4 to 7 carbon atoms in the aliphatic ring), an aryl group, a heterocyclic group, or a salt-forming cation;
  • R 3 is hydrogen, lower alkyl, aryl, or a salt- forming cation;
  • Y 1 and Y 2 are each independently hydrogen, halogen (e.g., F, Cl, Br, or I), lower alkyl, hydroxy, alkoxy, or aryloxy; and n is an integer from 0 to 12; such that amyloid deposition is modulated.
  • therapeutic compounds of the invention prevent or inhibit amyloid deposition in a subject to which the therapeutic compound is administered.
  • Preferred therapeutic compounds for use in the invention include compounds in which both R l and R 2 are pharmaceutically acceptable salt-forming cations.
  • R ⁇ R 2 and R 3 are each independently a sodium, potassium or calcium cation, and n is 0.
  • Y 1 and Y 2 are each hydrogen.
  • Particularly preferred therapeutic compounds are salts of phosphonoformate.
  • Trisodium phosphonoformate (foscarnet sodium or Foscavir®) is commercially available (e.g., from Astra), and its clinical pharmacology has been investigated (see, e.g., "Physician's Desk Reference", 51st Ed., pp. 541-545 (1997)).
  • a further aspect of the invention includes pharmaceutical compositions for treating amyloidosis.
  • the therapeutic compounds in the methods of the invention, as described hereinbefore, can be incorporated into a pharmaceutical composition in an amount effective to modulate amyloidosis in a pharmaceutically acceptable vehicle.
  • the invention further contemplates the use of prodrugs which are converted in vivo to the therapeutic compounds of the invention (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 compounds which would not typically cross the blood-brain barrier to cross the blood-brain barrier) or the pharmacokinetics of the therapeutic compound.
  • an anionic group e.g., a phosphonate or carboxylate
  • the ester When the phosphonic or carboxylic ester is administered to a subject, the ester can be cleaved, enzymatically or non-enzymatically, to reveal the anionic group.
  • an ester can be cyclic, e.g., a cyclic phosphonate, or two or more anionic moieties may be esterified through a linking group.
  • the prodrug is a phosphonate or carboxylate.
  • An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently decomposes to yield the active compound.
  • an anionic moiety e.g., a phosphonate or carboxylate
  • the ester can be selected to allow specific targeting of the therapeutic moieties to particular organs, as described below for carrier moieties.
  • compounds of the invention can have more than one phosphonic or carboxylic ester moiety, e.g., one phosphonic ester and one carboxylic ester, or a phosphonic diester.
  • the parent compound may include an anioic group and may be active; however, cleavage of any or all ester functionalities may result in an active compound.
  • the ester groups can be selected to permit selective cleavage of one or more ester functionalities, to unveil one or more anionic groups.
  • the relative ease of cleavage of ester groups is well known; for example, a tert-butyloxy ester is generally cleaved more slowly than an ethyl ester under certain conditions. Selection of appropriate moieties to provide a desired rate or order of ester cleavage willl be routine to the ordinarily-skilled artisan.
  • the number of anionic functionalities can be controlled to provide for a seelctive activity of a compound of the invention according to the rate or order of ester cleavage.
  • Carrier or substituent moieties useful in the present invention may also include moieties which allow the therapeutic compound to be selectively delivered to a target organ or organs.
  • the carrier molecule may include a moiety capable of targeting the therapeutic compound to the brain, by either active or passive transport (a "targeting moiety").
  • the carrier molecule may include a redox moiety, as described in, for example, U.S. Patents 4,540,564 and 5,389,623, both to Bodor. These patents disclose drugs linked to dihydropyridine moieties which can enter the brain, where they are oxidized to a charged pyridinium species which is trapped in the brain. Thus, drug accumulates in the brain.
  • carrier moieties include compounds, such as amino acids or thyroxine, which can be passively or actively transported in vivo. Such a carrier moiety can be metabolically removed in vivo, or can remain intact as part of an active compound. Structural mimics of amino acids (and other actively transported moieties), including peptidomimetics, are also useful in the invention.
  • peptidomimetic is intended to include peptide analogs which serve as appropriate substitutes for peptides in interactions with e.g., receptors and enzymes. The peptidomimetic must possess not only affinity, but also efficacy and substrate function. That is, a peptidomimetic exhibits function(s) of a peptide, without restriction of structure. Peptidomimetics, methods for their preparation and use are described in
  • targeting moieties include, for example, asialoglycoproteins (see, e.g. Wu, U.S. Patent 5,166,320) and other ligands which are transported into cells via receptor-mediated endocytosis (see below for further examples of targeting moieties which may be covalently or non-covalently bound to a carrier molecule).
  • the therapeutic compounds of the invention may bind to amyloidogenic proteins in the circulation and thus be transported to the site of action.
  • the targeting and prodrug strategies described above can be combined to produce a compound that can be transported as a prodrug to a desired site of action and then unmasked to reveal an active compound.
  • amyloid deposition e.g., deposition of ⁇ - amyloid
  • a therapeutic compound of the invention is modulated by administering a therapeutic compound of the invention to the subject.
  • subject is intended to include living organisms in which amyloidosis can occur. Examples of subjects include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof.
  • Administration of the compositions of the present invention to a subject to be treated can be carried out using known procedures, at dosages and for periods of time effective to modulate amyloid deposition in the subject.
  • an effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the amount of amyloid already deposited at the clinical site in the subject, the age, sex, and weight of the subject, and the ability of the therapeutic compound to modulate amyloid deposition in the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a non-limiting example of an effective dose range for a therapeutic compound of the invention e.g., phosphonoformic acid, trisodium salt
  • a therapeutic compound of the invention is between 0.5 and 500 mg/kg of body weight/per day.
  • preferred concentrations for the active compound are between 5 and 500 mM, more preferably between 10 and 100 mM, and still more preferably between 20 and 50 mM.
  • the therapeutic compounds of the invention can be effective when administered orally. Accordingly, a preferred route of administration is oral administration. Alternatively, the active compound may be administered by other suitable routes such as subcutaneous, intravenous, intramuscular or intraperitoneal administration, and the like (e.g. by injection). Depending on the route of administration, the active compound may be coated in a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound.
  • the compounds of the invention can be formulated to ensure proper distribution in vivo. For example, the blood-brain barrier (BBB) excludes many highly hydrophilic compounds. To ensure that the therapeutic compounds of the invention cross the BBB, they can be formulated, for example, in liposomes.
  • the liposomes may comprise one or more moieties which are selectively transported into specific cells or organs ("targeting moieties"), thus providing targeted drug delivery (see, e.g., V.V.
  • targeting moieties include folate or biotin (see, e.g., U.S. Patent 5,416,016 to Low et al.); mannosides (Umezawa et al., (1988) Biochem. Biophys. Res. Commun. 153:1038); antibodies (P.G. Bloeman et al.
  • the therapeutic compounds of the invention are formulated in liposomes; in a more preferred embodiment, the liposomes include a targeting moiety.
  • anionic groups such as phosphonate or carboxylate can be esterified to provide compounds with desirable pharmocokinetic, pharmacodynamic, biodistributive, or other properties.
  • anionic groups such as phosphonate or carboxylate can be esterified to provide compounds with desirable pharmocokinetic, pharmacodynamic, biodistributive, or other properties.
  • Exemplary compounds include phosphonoformate trisodium salt (Foscarnet, Foscavir), phosphonoacetate, trisodium salt, and pharmaceutically acceptable salts or esters thereof.
  • the therapeutic compound may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation.
  • the therapeutic compound may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
  • Pharmaceutically acceptable diluents include saline and aqueous buffer solutions.
  • Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al. , (1984) J Neuroimmunol. 7:27).
  • the therapeutic compound may also be administered parenterally (e.g., intramuscularly, intravenously, intraperitoneally, intraspinally, or intracerebrally).
  • parenterally e.g., intramuscularly, intravenously, intraperitoneally, intraspinally, or intracerebrally.
  • Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • 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.
  • 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 of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • Sterile injectable solutions can be prepared by incorporating the therapeutic compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization.
  • dispersions are prepared by incorporating the therapeutic compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic compound) plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the therapeutic compound can be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the therapeutic compound and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
  • the therapeutic compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the percentage of the therapeutic compound in the compositions and preparations may, of course, be varied. The amount of the therapeutic compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • 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 compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of amyloid deposition in subjects.
  • compositions can be administered in time-release or depot form, to obtain sustained release of the therapeutic compounds over time.
  • the therapeutic compounds of the invention can also be administered transdermally (e.g., by providing the therapeutic compound, with a suitable carrier, in patch form).
  • Active compounds are administered at a therapeutically effective dosage sufficient to modulate amyloid deposition (or amyloid load) in a subject.
  • a "therapeutically effective dosage” preferably modulates amyloid deposition by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects.
  • the ability of a compound to modulate amyloid deposition can be evaluated in model systems that may be predictive of efficacy in modulating amyloid deposition in human diseases, such as animal model systems known in the art (including, e.g., the method described in PCT Publication WO 96/28187) or by in vitro methods, e.g., the method of Chakrabartty, described in PCT Publication WO 97/07402, or the assay described in Example 1 , infra.
  • model systems that may be predictive of efficacy in modulating amyloid deposition in human diseases, such as animal model systems known in the art (including, e.g., the method described in PCT Publication WO 96/28187) or by in vitro methods, e.g., the method of Chakrabartty, described in PCT Publication WO 97/07402, or the assay described in Example 1 , infra.
  • the ability of a compound to modulate amyloid deposition can be evaluated by examining the ability of the compound to modulate an interaction between an amyloidogenic protein and a basement membrane constituent, e.g., using a binding assay such as that described hereinabove.
  • the amount or distribution of amyloid deposits in a subject can be non-invasively monitored in vivo, for example, by use of radiolabelled tracers which can associate with amyloid deposits, followed by scintigraphy to image the amyloid deposits (see, e.g., Aprile, C. et al., Eur. J. Nucl. Med. 22:1393 (1995); Hawkins, P.N., Baillieres Clin. Rheumatol.
  • amyloid load of a subject can be evaluated after a period of treatment according to the methods of the invention and compared to the amyloid load of the subject prior to beginning therapy with a therapeutic compound of the invention, to determine the effect of the therapeutic compound on amyloid deposition in the subject.
  • the ability of a compound of the invention to modulate amyloid deposition or amyloid load can, in certain embodiments, be evaluated by observation of one or more symptoms or signs associated with amyloid deposition or amyloid load in vivo.
  • the ability of a compound to decrease amyloid deposition or amyloid load may be associated with an observable improvement in a clinical manifestation of the underlying amyloid-related disease state or condition, or a slowing or delay in progression of symptoms of the condition.
  • monitoring of clinical manifestations of disease can be useful in evaluating the amyloid-modulating efficacy of a compound of the invention.
  • amyloidosis associated with any disease in which amyloid deposition occurs.
  • amyloidosis can be primary, secondary, familial or isolated.
  • Amyloids have been categorized by the type of amyloidogenic protein contained within the amyloid.
  • Non-limiting examples of amyloids which can be modulated, as identified by their amyloidogenic protein, are as follows (with the associated disease in parentheses after the amyloidogenic protein): ⁇ - amyloid (Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage amyloidosis [Dutch], cerebral angiopathy); amyloid A (reactive [secondary] amyloidosis, familial Mediterranean Fever, familial amyloid nephropathy with urticaria and deafness [Muckle- Wells syndrome]); amyloid K L-chain or amyloid ⁇ L-chain (idiopathic [primary], myeloma or macroglobulinemia-associated); A ⁇ 2M (chronic hemodialysis); ATTR (familial amyloid polyneuropathy [Portuguese, Japanese, Swedish], familial amyloid cardiomyopathy [Danish], isolated cardiac amyloid, systemic senile amyloidosis
  • phosphonic esters can be prepared from the corresponding phosphonic acid by standard methods.
  • carboxylic esters can be prepared from the free carboxylic acid by standard techniques (for a reference to esterification techniques, see, e.g., R. Larock, "Comprehensive Organic Transformations," VCH Publishers (1989)).
  • Carboxylic esters can be converted to thionoesters by known reactions, e.g., by treatment with Lawesson's reagent (2,4-bis(4-methoxyphenyl)-l ,3-dithia-2,4-diphosphetane-2,4-disulfide, which is commercially available, e.g., from Aldrich Chemical Co., Milwaukee, WI).
  • Lawesson's reagent 2,4-bis(4-methoxyphenyl)-l ,3-dithia-2,4-diphosphetane-2,4-disulfide, which is commercially available, e.g., from Aldrich Chemical Co., Milwaukee, WI).
  • Compounds of the present invention also can be prepared as described below. The following Examples further illustrate the present invention and are not intended to be further limiting in anyway.
  • Example 1 It is known that amyloidogenic peptides or proteins which have formed amyloid deposits or plaques have a significant amount of ⁇ -sheet secondary structure, while the unaggregated peptide or protein generally has less ⁇ -sheet structure. It is believed that the ability of a candidate therapeutic compound to prevent the formation of ⁇ -sheet secondary structure in vitro may be correlated with the ability of the compound to inhibit amyloidogenesis in vivo. Accordingly, phosphonate compounds were assayed for ability to prevent the formation of ⁇ -sheet secondary structure in assay systems including an in vitro circular dichroism (CD) assay.
  • CD in vitro circular dichroism
  • AB is a 40 amino acid protein associated with Alzheimer's disease.
  • AB peptide was prepared and purified as described in Fraser, P.E. et al., Biochemistry 31, 10716 (1992). Briefly, the peptide was synthesized by standard solid-phase techniques and purified by HPLC according to well known procedures.
  • a stock solution of purified peptide was made by dissolving the peptide in phosphate-buffered saline (PBS) to a concentration of 2 mg/ml.
  • PBS phosphate-buffered saline
  • a test solution was made for each potential therapeutic agent (test compound) as shown below: AB stock solution 25 ⁇ l
  • the control sample had no test compound, and a total of 5 ⁇ l distilled water was added.
  • the test solution was incubated for either 0 or 24 hours at 37°C before CD measurement.
  • the size minimum in the CD spectrum at 218 run is believed to be diagnostic of the presence of ⁇ -pleated sheet.
  • Comparison of the minimum at 218 nm of a candidate compound, compared to the minimum of a control sample, is believed to be indicative of the ability of the candidate compound to inhibit the formation of ⁇ -pleated sheet.
  • Phosphonoformate sodium salt was found to significantly and reproducibly reduce the amount of ⁇ -sheet formation, as measured by the CD assay.
  • Phosphonoacetate was also found to be active in this assay. Thus, phosphonoformate and phosphonoactetate are believed to be inhibitors of amyloid deposition. 2-carboxyethylphosphonic acid had a lower ability to prevent ⁇ -pleated sheet formation in this model system.
  • the neurotoxicity of phosphonoformate trisodium salt was investigated in cortical hippocampal neuronal cultures; no significant toxicity was noted at concentrations ranging from 10" 7 M to 10" 4 M.
  • the procedure has the advantage that the reactivity of the nucleophile (e.g., the hydroxyl groups of a diol which react with the phosphonic acid chloride) is attenuated by use of a silyl ether (e.g., a trimethylsilyl ether), which can improve selectivity.
  • a silyl ether e.g., a trimethylsilyl ether
  • TSC1 trimethylsilyltriflate
  • TMSOTf trimethylsilyltriflate
  • the compounds of Formula IVa, IVc and IVd (in salt forms, e.g., methylpyridinium salts and/or anilinium salts) were tested in at least one assay for their ability to inhibit amyloidosis. It was found that these compounds showed activity in at least one assay system indicative of their ability to be an inhibitor of amyloidosis in vivo in both free or salt forms.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Epidemiology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Diabetes (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Psychiatry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention se rapporte à des composés thérapeutiques, ainsi qu'aux méthodes associées, qui modulent le dépôt de plaques amyloïdes chez un patient, quel que soit son état clinique. On module le dépôt de plaques amyloïdes en administrant au sujet une quantité efficace d'un composé thérapeutique comportant un groupe phosphonate et un groupe carboxylate, un de ses congénères ou un sel ou un ester pharmaceutiquement acceptable de ce composé. Dans les réalisations préférées, on régule une interaction entre une protéine amyloïdogène et un constituant de membrane basale.
PCT/IB1998/000967 1997-08-18 1998-04-10 Composes de phosphono-carboxylate conçus pour le traitement de l'amylose WO1999008685A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2000509424A JP2001515039A (ja) 1997-08-18 1998-04-10 アミロイド症を治療するためのホスホノ−カルボキシレート化合物
IL13461998A IL134619A0 (en) 1997-08-18 1998-04-10 Phosphono-carboxylate compounds for treating amyloidosis
AU22431/99A AU2243199A (en) 1997-08-18 1998-04-10 Phosphono-carboxylate compounds for treating amyloidosis
CA002300910A CA2300910C (fr) 1997-08-18 1998-04-10 Composes de phosphono-carboxylate concus pour le traitement de l'amylose
EP98966963A EP1014994A1 (fr) 1997-08-18 1998-04-10 Composes de phosphono-carboxylate concus pour le traitement de l'amylose

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US08/912,574 1997-08-18
US08/912,574 US5869469A (en) 1997-08-18 1997-08-18 Phosphonocarboxylate compounds for treating amyloidosis
US7444598P 1998-02-11 1998-02-11
US60/074,445 1998-02-11

Publications (1)

Publication Number Publication Date
WO1999008685A1 true WO1999008685A1 (fr) 1999-02-25

Family

ID=26755679

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB1998/000967 WO1999008685A1 (fr) 1997-08-18 1998-04-10 Composes de phosphono-carboxylate conçus pour le traitement de l'amylose

Country Status (6)

Country Link
EP (1) EP1014994A1 (fr)
JP (1) JP2001515039A (fr)
CA (1) CA2300910C (fr)
IL (1) IL134619A0 (fr)
NZ (1) NZ550116A (fr)
WO (1) WO1999008685A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999040909A1 (fr) * 1998-02-11 1999-08-19 Neurochem, Inc. Methode de modulation de l'activation des macrophages
WO1999059571A1 (fr) * 1998-05-15 1999-11-25 Neurochem, Inc. Utilisation d'inhibiteurs d'amyloides pour une modulation de mort de cellules neuronales
WO2000064420A2 (fr) * 1999-04-28 2000-11-02 Queen's University At Kingston Compositions et procedes pour traiter l'amylose
US6310073B1 (en) 1998-07-28 2001-10-30 Queen's University At Kingston Methods and compositions to treat glycosaminoglycan-associated molecular interactions
WO2001085093A2 (fr) * 1999-12-23 2001-11-15 Neurochem, Inc. Composes et methodes permettant la modulation de l'angiopathie cerebrale amyloide
EP1233770A2 (fr) * 1999-12-03 2002-08-28 The Regents of The University of California at San Diego Composes de phosphonate
JP2003500350A (ja) * 1999-05-24 2003-01-07 クイーンズ ユニバーシティ アット キングストン アミロイド沈着物を阻害するための方法および化合物
US7244764B2 (en) 2003-06-23 2007-07-17 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
US7414076B2 (en) 2003-06-23 2008-08-19 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
US8372886B2 (en) 2005-12-22 2013-02-12 Kiacta Sarl Treatment of renal disorders, diabetic nephropathy and dyslipidemias
US8835654B2 (en) 2004-12-22 2014-09-16 Bhi Limited Partnership Method and compositions for treating amyloid-related diseases
US8993542B2 (en) 2008-01-25 2015-03-31 Chimerix Inc. Methods of treating viral infections
US9006218B2 (en) 2010-02-12 2015-04-14 Chimerix Inc. Nucleoside phosphonate salts
US9278135B2 (en) 2010-04-26 2016-03-08 Chimerix Inc. Methods of treating retroviral infections and related dosage regimes
US9499480B2 (en) 2006-10-12 2016-11-22 Bhi Limited Partnership Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US20240390336A1 (en) * 2022-02-11 2024-11-28 Tzerma Llc Methods for Preventing Ectopic Brain Mineralization in Alzheimer's Disease and Dementias

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0003275A1 (fr) * 1977-12-22 1979-08-08 Astra Läkemedel Aktiebolag Dérivés aromatiques de l'acide phosphonoformique, procédés pour leur préparation, compositions pharmaceutiques les contenant et leur utilisation pour combattre les infections virales
EP0434173A2 (fr) * 1989-12-04 1991-06-26 Schering Aktiengesellschaft Emploi des antagonistes des récepteurs NMDA dans le traitement des maladies neurodégénératives chroniques
WO1994022437A2 (fr) * 1993-03-29 1994-10-13 Queen's University At Kingston Procede de traitement de l'amyloïdose
WO1994027602A1 (fr) * 1993-06-01 1994-12-08 Cortex Pharmaceuticals, Inc. Utilisation d'agonistes des recepteurs metabotropiques pour le traitement de neurodegenerescences evolutives
WO1998011923A1 (fr) * 1996-09-20 1998-03-26 Baylor College Of Medicine Identification d'agents apportant une protection contre des lesions inflammatoires des neurones
WO1998013046A1 (fr) * 1996-09-27 1998-04-02 Guilford Pharmaceuticals Inc. Compositions de naaladase et methodes de traitement des anomalies du glutamate et de suscitation d'une activite neuronale chez l'animal
WO1998025938A1 (fr) * 1996-12-13 1998-06-18 Astra Aktiebolag (Publ) Nouveaux composes

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0003275A1 (fr) * 1977-12-22 1979-08-08 Astra Läkemedel Aktiebolag Dérivés aromatiques de l'acide phosphonoformique, procédés pour leur préparation, compositions pharmaceutiques les contenant et leur utilisation pour combattre les infections virales
EP0434173A2 (fr) * 1989-12-04 1991-06-26 Schering Aktiengesellschaft Emploi des antagonistes des récepteurs NMDA dans le traitement des maladies neurodégénératives chroniques
WO1994022437A2 (fr) * 1993-03-29 1994-10-13 Queen's University At Kingston Procede de traitement de l'amyloïdose
WO1994027602A1 (fr) * 1993-06-01 1994-12-08 Cortex Pharmaceuticals, Inc. Utilisation d'agonistes des recepteurs metabotropiques pour le traitement de neurodegenerescences evolutives
WO1998011923A1 (fr) * 1996-09-20 1998-03-26 Baylor College Of Medicine Identification d'agents apportant une protection contre des lesions inflammatoires des neurones
WO1998013046A1 (fr) * 1996-09-27 1998-04-02 Guilford Pharmaceuticals Inc. Compositions de naaladase et methodes de traitement des anomalies du glutamate et de suscitation d'une activite neuronale chez l'animal
WO1998025938A1 (fr) * 1996-12-13 1998-06-18 Astra Aktiebolag (Publ) Nouveaux composes

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
A. COPANI ET AL.: "ACTIVATION OF METABOTROPIC GLUTAMATE RECEPTORS PROTECTS CULTURED NEURONS AGAINST APOPTOSIS INDUCED BY beta-AMYLOID PEPTIDE", MOLECULAR PHARMACOLOGY, vol. 47, no. 5, 1995, pages 890 - 897, XP002079923 *
BRIGGS A D ET AL: "Acyloxymethyl and 4-Acyloxybenzyl Diester Prodrugs of Phosphonoformate", TETRAHEDRON, vol. 52, no. 47, 18 November 1996 (1996-11-18), pages 14937-14950, XP004105086 *
GORIN B I ET AL: "A Novel Esterification Procedure Applied to Synthesis of Biologically Active Esters of Foscarnet", TETRAHEDRON LETTERS, vol. 38, no. 16, 21 April 1997 (1997-04-21), pages 2791-2794, XP004058495 *
J.O. NOREN ET AL.: "synthesis of esters of phosphonoformic acid and their antiherpes activity", JOURNAL OF MEDICINAL CHEMISTRY, vol. 26, no. 2, 1983, pages 264 - 270, XP002079924 *
R. HUTCHINGS ET AL.: "THE EFFECT OF EXCITOTOXIN ANTAGONISTS ON IBOTENIC ACID-INDUCED ALTERATION OF APP MRNA HIPPOCAMPAL EXPRESSION", JOURNAL OF PHARMACY AND PHARMACOLOGY, vol. 47, no. 12B, 1995, pages 1131, XP002079922 *

Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999040909A1 (fr) * 1998-02-11 1999-08-19 Neurochem, Inc. Methode de modulation de l'activation des macrophages
WO1999059571A1 (fr) * 1998-05-15 1999-11-25 Neurochem, Inc. Utilisation d'inhibiteurs d'amyloides pour une modulation de mort de cellules neuronales
US6310073B1 (en) 1998-07-28 2001-10-30 Queen's University At Kingston Methods and compositions to treat glycosaminoglycan-associated molecular interactions
JP2003517458A (ja) * 1999-04-28 2003-05-27 クイーンズ ユニバーシティ アット キングストン アミロイドーシスを治療するための組成物および方法
WO2000064420A2 (fr) * 1999-04-28 2000-11-02 Queen's University At Kingston Compositions et procedes pour traiter l'amylose
JP4726304B2 (ja) * 1999-04-28 2011-07-20 ベルス ヘルス （インターナショナル） リミティッド アミロイドーシスを治療するための組成物および方法
KR100822525B1 (ko) * 1999-04-28 2008-04-16 뉴로겜 인터내셔널 리미티드 아밀로이드증 치료용 조성물 및 방법
WO2000064420A3 (fr) * 1999-04-28 2002-11-07 Univ Kingston Compositions et procedes pour traiter l'amylose
JP2003500350A (ja) * 1999-05-24 2003-01-07 クイーンズ ユニバーシティ アット キングストン アミロイド沈着物を阻害するための方法および化合物
US6716825B2 (en) 1999-12-03 2004-04-06 The Regents Of The University Of California Phosphonate compounds
US8889658B2 (en) 1999-12-03 2014-11-18 The Regents Of The University Of California Phosphonate compounds
US9649321B2 (en) 1999-12-03 2017-05-16 The Regents Of The University Of California Phosphonate compounds
AU2010257309B2 (en) * 1999-12-03 2014-04-10 The Regents Of The University Of California, San Diego Phosphonate compounds
US7034014B2 (en) 1999-12-03 2006-04-25 The Regents Of The University Of California Phosphonate compounds
US7094772B2 (en) 1999-12-03 2006-08-22 The Regents Of The University Of California Phosphonate compounds
US7098197B2 (en) 1999-12-03 2006-08-29 The Regents Of The University Of California Phosphonate compounds
US9206208B2 (en) 1999-12-03 2015-12-08 The Regents Of The University Of California Phosphonate compounds
EP1233770A2 (fr) * 1999-12-03 2002-08-28 The Regents of The University of California at San Diego Composes de phosphonate
EP1233770A4 (fr) * 1999-12-03 2003-04-16 Univ California At San Diego Composes de phosphonate
US7452898B2 (en) 1999-12-03 2008-11-18 The Regents Of The University Of California Phosphonate compounds
US8710030B2 (en) 1999-12-03 2014-04-29 The Regents Of The University Of California Phosphonate compounds
US7687480B2 (en) 1999-12-03 2010-03-30 The Regents Of The University Of California Phosphonate compounds
US7790703B2 (en) 1999-12-03 2010-09-07 The Regents Of The University Of California Phosphonate compounds
AU2006252074B2 (en) * 1999-12-03 2010-09-30 The Regents Of The University Of California, San Diego Phosphonate compounds
US10071110B2 (en) 1999-12-03 2018-09-11 The Regents Of The University Of California Phosphonate compounds
US8008308B2 (en) 1999-12-03 2011-08-30 The Regents Of The University Of California Phosphonate compounds
US8309565B2 (en) 1999-12-03 2012-11-13 The Regents Of The University Of California Phosphonate compounds
US6670399B2 (en) 1999-12-23 2003-12-30 Neurochem (International) Limited Compounds and methods for modulating cerebral amyloid angiopathy
WO2001085093A2 (fr) * 1999-12-23 2001-11-15 Neurochem, Inc. Composes et methodes permettant la modulation de l'angiopathie cerebrale amyloide
WO2001085093A3 (fr) * 1999-12-23 2002-08-29 Neurochem Inc Composes et methodes permettant la modulation de l'angiopathie cerebrale amyloide
US7598269B2 (en) 2003-06-23 2009-10-06 Bellus Health (International) Limited Methods and compositions for treating amyloid-related diseases
US7414076B2 (en) 2003-06-23 2008-08-19 Neurochem (International) Limited Methods and compositions for treating amyloid-related diseases
US7244764B2 (en) 2003-06-23 2007-07-17 Neurochem (International) Limited Methods 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
US8372886B2 (en) 2005-12-22 2013-02-12 Kiacta Sarl Treatment of renal disorders, diabetic nephropathy and dyslipidemias
US11020360B2 (en) 2006-10-12 2021-06-01 Bellus Health Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US10857109B2 (en) 2006-10-12 2020-12-08 Bellus Health, Inc. Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid
US9499480B2 (en) 2006-10-12 2016-11-22 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
US8993542B2 (en) 2008-01-25 2015-03-31 Chimerix Inc. Methods of treating viral infections
US9765100B2 (en) 2010-02-12 2017-09-19 Chimerix, Inc. Nucleoside phosphonate salts
US9006218B2 (en) 2010-02-12 2015-04-14 Chimerix Inc. Nucleoside phosphonate salts
US9956239B2 (en) 2010-04-26 2018-05-01 Chimerix, Inc. Methods of treating retroviral infections and related dosage regimes
US9694024B2 (en) 2010-04-26 2017-07-04 Chimerix, Inc. Methods of treating retroviral infections and related dosage regimes
US9278135B2 (en) 2010-04-26 2016-03-08 Chimerix Inc. Methods of treating retroviral infections and related dosage regimes
US20240390336A1 (en) * 2022-02-11 2024-11-28 Tzerma Llc Methods for Preventing Ectopic Brain Mineralization in Alzheimer's Disease and Dementias

Also Published As

Publication number Publication date
JP2001515039A (ja) 2001-09-18
NZ550116A (en) 2008-03-28
EP1014994A1 (fr) 2000-07-05
IL134619A0 (en) 2001-04-30
CA2300910C (fr) 2008-02-26
CA2300910A1 (fr) 1999-02-25

Similar Documents

Publication Publication Date Title
US20080004244A1 (en) Phosphono-carboxylate compounds for treating amyloidosis
US5869469A (en) Phosphonocarboxylate compounds for treating amyloidosis
CA2300910C (fr) Composes de phosphono-carboxylate concus pour le traitement de l'amylose
EP1276483B1 (fr) Compositions et procedes pour traiter l'amylose par des sulphonates
JP3623236B2 (ja) アミロイド症の治療法
JP4187072B2 (ja) アミロイド症の治療法
US6670399B2 (en) Compounds and methods for modulating cerebral amyloid angiopathy
US20020193395A1 (en) Methods and compositions to treat glycosaminoglycan-associated molecular interactions
AU4905000A (en) Methods and compounds for inhibiting amyloid deposits
EP2403859B1 (fr) Pincer moléculaire pour le traitement d'alzheimer
AU2005201716B2 (en) Phosphono-carboxylate compounds for treating amyloidosis
MXPA00001669A (en) Phosphono-carboxylate compounds for treating amyloidosis
AU2004202703A1 (en) Methods and compositions to treat glycosaminoglycan-associated molecular interactions
AU2006201445A1 (en) Compounds and methods for modulating cerebral amyloid angiopathy

Legal Events

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

Ref document number: 134619

Country of ref document: IL

AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BR CA CN HU ID IL JP MX NO NZ RU US YU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 2300910

Country of ref document: CA

Ref country code: CA

Ref document number: 2300910

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: PA/a/2000/001669

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 22431/99

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 503074

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 1998966963

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1998966963

Country of ref document: EP

WWR Wipo information: refused in national office

Ref document number: 1998966963

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1998966963

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载