| Phosphono-carboxylate compounds for treating amyloidosis -> Monitor Keywords |
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Phosphono-carboxylate compounds for treating amyloidosisRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Phosphorus Containing Other Than Solely As Part Of An Inorganic Ion In An Addition Salt Doai, Nitrogen Containing Hetero RingPhosphono-carboxylate compounds for treating amyloidosis description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060135479, Phosphono-carboxylate compounds for treating amyloidosis. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application is a continuation application of application Ser. No. 10/226,613 filed on Aug. 23, 2002, which in turn is a continuation application of application Ser. No. 09/860,255 filed on May 17, 2001, Granted, which in turn is a divisional application of application Ser. No. 09/288,583 filed on Apr. 8, 1999, Granted, which claims benefit of provisional application No. 60/081,402 filed on Apr. 10, 1998. The contents of all of the aforementioned application(s) are hereby incorporated by reference. BACKGROUND OF INVENTION [0002] 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. [0003] 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. 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 congophilic angiopathy, neuritic plaques and neurofibrillary tangles, all of which have the characteristics of amyloids. In this case, the plaque and blood vessel amyloid is formed by the beta protein. Other systemic or localized diseases such as adult-onset diabetes, complications of long-term hemodialysis and sequelae of long-standing inflammation or plasma cell dyscrasias are characterized by the accumulation of amyloids systemically. In each of these cases, a different amyloidogenic protein is involved in amyloid deposition. SUMMARY OF THE INVENTION [0004] 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. Accordingly, 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. In certain embodiments, 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. [0005] 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. In one embodiment, the method of the invention involves administering to a subject an effective amount of a therapeutic compound having the formula (Formula I): in which Z is XR.sup.2 or R.sup.4, R.sup.1 and R.sup.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.sup.3 is hydrogen, lower alkyl, aryl, or a salt-forming cation; R.sup.4 is hydrogen, lower alkyl, aryl or amino (including alkylamino, dialkylamino (including cyclic amino moieties), arylamino, diarylamino, and alkylarylamino); X is, independently for each occurrence, O or S; Y.sup.1 and Y.sup.2 are each independently hydrogen, halogen (e.g., F, Cl, Br, or I), alkyl (preferably lower alkyl), amino, hydroxy, alkoxy, or aryloxy; and n is an integer from 0 to 12 (more preferably 0 to 6, more preferably 0 or 1); such that amyloid deposition is modulated. [0006] In preferred embodiments, therapeutic compounds of the invention prevent or inhibit amyloid deposition in a subject to which the therapeutic compound is administered. Preferred therapeutic compounds for use in the invention include compounds in which both R.sup.1 and R.sup.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. In a particularly preferred embodiment, R.sup.1, R.sup.2 and R.sup.3 are each independently a sodium, potassium or calcium cation. In certain embodiments in which at least one of R.sup.1 and R.sup.2 is an aliphatic group, the aliphatic group has between 1 and 10 carbons atoms in the straight or branched chain, and is more preferably a lower alkyl group. In other embodiments in which at least one of R.sup.1 and R.sup.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.sup.1 and Y.sup.2 are each hydrogen. [0007] In certain preferred embodiments, the therapeutic compound of the invention can be represented by the formula (Formula II): in which R.sup.1, R.sup.2, R.sup.3, Y.sup.1, Y.sup.2, X and n are as defined above. In more preferred embodiments, the therapeutic compound of the invention can be represented by the formula (Formula III): in which R.sup.1, R.sup.2, R.sup.3, Y.sup.1, Y.sup.2, and X are as defined above, R.sub.a and R.sub.b are each independently hydrogen, alkyl, aryl, or heterocyclyl, or R.sub.a and R.sub.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, and n is an integer from 0 to 6. In certain preferred embodiments, R.sub.a and R.sub.b are each hydrogen. In certain preferred embodiments, a compound of the invention comprises an .alpha.-amino acid (or .alpha.-amino acid ester), more preferably a L-.alpha.-amino acid or ester. [0008] In another embodiment, 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. [0009] 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. [0010] 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. [0011] 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. [0012] 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. [0013] 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. DETAILED DESCRIPTION OF INVENTION [0014] 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. [0015] "Basement membrane" refers to an extracellular matrix comprising glycoproteins and proteoglycans, including laminin, collagen type IV, fibronectin chondroitan sulfate, and/or heparan sulfate proteoglycan (HSPG). In one embodiment, amyloid deposition is modulated by interfering with an interaction between an amyloidogenic protein and a sulfated glycosaminoglycan such as HSPG. Sulfated glycosaminoglycans are known to be present in all types of amyloids (see Snow, A. D. et al. (1987) Lab. Invest. 56:120-123) and amyloid deposition and HSPG deposition occur coincidentally in animal models of amyloidosis (see Snow, A. D. et al. (1987) Lab. Invest. 56:665-675). In preferred embodiments of the methods of the invention, molecules which have a similar structure to a sulfated glycosaminoglycan are used to modulate interaction between an amyloidogenic protein and basement membrane constituent. In particular, the therapeutic compounds of the invention preferably comprise at least one phosphonate group (or phosphonic ester), or a functional equivalent thereof (including phosphorus-containing anionic groups including, but not limited to, phosphates, phosphate esters, phosphinates, and the like), and a carboxylate group or carboxylic ester (or a congener such as a thioacid, thiolester, or thionoester), provided that the compound includes, or is capable of having after reaction in vivo, at least one anionic group. The anionic groups(s) can optionally be covalently bound to a carrier (e.g., an aliphatic group, peptide or peptidomimetic, or the like). In addition to functioning as a carrier for the anionic functionality, the carrier molecule can enable the compound to traverse biological membranes and to be biodistributed without excessive or premature metabolism. [0016] In one embodiment, 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): in which Z is XR.sup.2 or R.sup.4, R.sup.1 and R.sup.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.sup.3 is hydrogen, lower alkyl, aryl, or a salt-forming cation; X is, independently for each occurrence, O or S; R.sup.4 is hydrogen, lower alkyl, aryl or amino; Y.sup.1 and Y.sup.2 are each independently hydrogen, halogen (e.g., F, Cl, Br, or I), lower alkyl, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), hydroxy, alkoxy, or aryloxy; and n is an integer from 0 to 12 (more preferably 0 to 6, more preferably 0 or 1); such that amyloid deposition is modulated. [0017] In preferred embodiments, therapeutic compounds of the invention prevent or inhibit amyloid deposition in a subject to which the therapeutic compound is administered. Preferred therapeutic compounds for use in the invention include compounds in which both R.sup.1 and R.sup.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. In a particularly preferred embodiment, R.sup.1, R.sup.2 and R.sup.3 are each independently a sodium, potassium or calcium cation. In certain embodiments in which at least one of R.sup.1 and R.sup.2 is an aliphatic group, the aliphatic group has between 1 and 10 carbons atoms in the straight or branched chain, and is more preferably a lower alkyl group. In other embodiments in which at least one of R.sup.1 and R.sup.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.sup.1 and Y.sup.2 are each hydrogen. [0018] In certain preferred embodiments, the therapeutic compound of the invention can be represented by the formula (Formula II): in which R.sup.1, R.sup.2, R.sup.3, Y.sup.1, Y.sup.2, X and n are as defined above. In more preferred embodiments, the therapeutic compound of the invention can be represented by the formula (Formula III): in which R.sup.1, R.sup.2, R.sup.3, Y.sup.1, Y.sup.2, and X are as defined above, R.sub.a and R.sub.b are each independently hydrogen, alkyl, aryl, or heterocyclyl, or R.sub.a and R.sub.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, and n is an integer from 0 to 6. In certain preferred embodiments, R.sub.a and R.sub.b are each hydrogen. In certain preferred embodiments, a compound of the invention comprises an .alpha.-amino acid (or .alpha.-amino acid ester), more preferably a L-.alpha.-amino acid or ester. [0019] The Z, Q, R.sup.1, R.sup.2, R.sup.3, Y.sup.1, Y.sup.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. For example, the number of anionic groups (and the overall charge on the therapeutic compound) should not be so great as to inhibit traversal of an anatomical barrier, such as a cell membrane, or entry across a physiological barrier, such as the blood-brain barrier, in situations where such properties are desired. For example, it has been reported that esters of phosphonoformate have biodistribution properties different from, and in some cases superior to, the biodistribution properties of phosphonoformate (see, e.g., U.S. Pat. Nos. 4,386,081 and 4,591583 to Helgstrand et al., and U.S. Pat. Nos. 5,194,654 and 5,463,092 to Hostetler et al.). Thus, in certain embodiments, at least one of R.sup.1 and R.sup.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. In other embodiments, at least one of R.sup.1 and R.sup.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. Again, 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. In certain embodiments, a preferred aliphatic group is an ethyl group. [0020] It has also been reported that certain thiophosphate compounds have in vivo activity as anti-viral agents which is equal to or greater than the activity of the corresponding oxy-phosphate compounds (possibly due to differences in bioavailability of the compounds). Accordingly, in certain preferred embodiments, the therapeutic compound includes a moiety selected from the group consisting of --P(S)(OR.sup.1)(OR.sup.2), --P(S)(SR.sup.1)(OR.sup.2), or --P(S)(SR.sup.1)(SR.sup.2). Continue reading about Phosphono-carboxylate compounds for treating amyloidosis... Full patent description for Phosphono-carboxylate compounds for treating amyloidosis Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Phosphono-carboxylate compounds for treating amyloidosis patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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