JP2001515039A - Phosphono-carboxylate compounds for treating amyloidosis - Google Patents

Abstract

  (57) [Summary] Described are therapeutic compounds and methods that modulate amyloid deposition in a subject, regardless of clinical situation. Amyloid deposition is modulated by administering to a subject an effective amount of a therapeutic compound comprising a phosphonate group and a carboxylate group, a homologue thereof, or a pharmaceutically acceptable salt or ester thereof. In a preferred embodiment, the interaction between amyloidogenic protein and basement membrane components is modulated.

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION Amyloidosis refers to a pathological condition characterized by the presence of amyloid. Amyloid is a general term that refers to a group of diverse but specific extracellular protein deposits found in many different diseases. Although their origins vary widely, all amyloid deposits have common morphological characteristics, are colored with specific dyes (eg Congo Red), and have a characteristic red-green birefringence when viewed under polarized light after coloring Present. They further have common ultrastructural features and common X-ray diffraction and infrared spectra.

[0002] Amyloidosis can be classified clinically as primary, secondary, familial, and / or solitary. Primary amyloidosis appears to have arisen without any prior abnormalities. Secondary amyloidosis is such a form that appears to be a complication of the preceding abnormality. Familial amyloidosis is a genetically inherited form found in certain geographical populations. Solitary amyloidosis tends to involve a single organ system. Further distinct amyloids are characterized by the type of protein present in the deposit. For example, neurodegenerative diseases such as scrapie, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, etc., are characterized by the appearance and accumulation in the central nervous system of prion proteins in a protease-resistant form (called Ascr or PrP-27). Similarly, Alzheimer's disease and other neurodegenerative diseases are characterized by congophilic vascular disorders, neuritic plaques and neurofibrillary tangles, all of which are characteristic of amyloid. In this case, plaques and vascular amyloid are formed by beta proteins. Other systemic or local diseases, such as adult-onset diabetes, complications of long-term hemodialysis, and the sequelae of long-term inflammation or plasma cell disease, are characterized by systemic amyloid accumulation. In each of these cases, different amyloidogenic proteins are involved in amyloid deposition.

SUMMARY OF THE INVENTION [0003] The present invention provides methods and compositions useful for treating amyloidosis.
The method of the invention comprises administering to a subject a therapeutic compound that inhibits amyloid deposition. Accordingly, the compositions and methods of the present invention are useful for inhibiting amyloidosis in abnormalities in which amyloid deposition occurs. The methods of the invention may be used therapeutically to treat amyloidosis, or used prophylactically in subjects susceptible to amyloidosis. Without wishing to be bound by theory, the methods of the present invention are based, at least in part, on the inhibition of amyloid deposition by inhibiting the interaction between amyloidogenic proteins and basement membrane components. Things. The component of the basement membrane may be a glycoprotein or a proteoglycan, but is preferably a heparan sulfate proteoglycan. In some embodiments, the therapeutic compound used in the methods of the invention preferably inhibits amyloid deposition by interfering with the binding of basement membrane components to target binding sites on amyloidogenic proteins. Good to be.

[0004] The present invention relates to phosphonocarboxylate compounds, ie, compounds containing a phosphonate group and a carboxylate group, or a pharmaceutically acceptable salt or ester thereof. In one embodiment, the method of the present invention comprises administering to a subject an amyloid deposit of formula (formula I):

Embedded image Wherein Z is XR ² or R ⁴ , wherein R ¹ and R ² are each independently hydrogen, one substituted or unsubstituted aliphatic (Preferably one branched or straight-chain aliphatic moiety having 1 to 24 carbon atoms in the chain, or 4 to 7 carbon atoms in the aliphatic ring, One unsubstituted or substituted cycloaliphatic moiety; preferred aliphatic and cycloaliphatic groups are alkyl groups, more preferably lower alkyl), one aryl group, one A heterocyclic group or a cation forming one salt, R ³ is hydrogen, lower alkyl, aryl, or a cation forming one salt; R ⁴ is hydrogen, lower alkyl, aryl or Amino (alkylamino, dialkylamino (cyclic Including amino component), an arylamino include, diarylamino, and alkylaryl amino), X each time is present are individually O or S, Y ¹ and Y ² are each independently hydrogen, halogen, ( For example, 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 to 6). Or 1).

[0005] In a preferred embodiment, a therapeutic compound of the present invention prevents or inhibits amyloid deposition in a subject receiving the therapeutic compound. Therapeutic compounds suitable for use in the present invention include those in which both R ¹ and R ² are cations that form pharmaceutically acceptable salts. The stoichiometry of an anionic compound to a single salt forming counterion (if present) is determined by the anionic portion of the compound (if present)
It will be appreciated that will vary depending on the charge of the and its counterions. In a particularly preferred embodiment, R ¹ , R ² and R ³ are each individually one sodium, potassium or calcium cation. In some embodiments, where at least one of R ¹ and R ² is an aliphatic group, the aliphatic group may have from 1 to 10 carbon atoms in its straight or branched chain. And more preferably one lower alkyl group. In other embodiments, where at least one of R ¹ and R ² is an aliphatic group, the aliphatic group has 10 to 24 carbon atoms in its straight or branched chain. In some preferred embodiments, n is 0 or 1, more preferably n
Is 0. In some preferred embodiments of the therapeutic compounds, Y ¹ and Y ² are each hydrogen.

[0006] In some preferred embodiments, the therapeutic compounds of the present invention have the formula (Formula II):

Embedded image Where R ¹ , R ² , R ³ , Y ¹ , Y ² , X and n are as defined above. In a more preferred embodiment, the therapeutic compound of the invention has the formula (Formula III):

Embedded image Wherein R ¹ , R ² , R ³ , Y ¹ , Y ² , and X are as defined above, and _Ra and R _b are each independently hydrogen, alkyl, aryl, Or heterocyclyl, or _Ra and _Rb , taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the ring, with n from 0 to 6 Is an integer. In some preferred embodiments, _Ra and _Rb are each hydrogen. In some preferred embodiments, the compounds of the present invention comprise a single -amino acid (or-
Amino acid ester) and more preferably comprises one L-amino acid or ester.

In another embodiment, the compounds of the present invention have the formula (Formula IV):

Embedded image Where G is hydrogen or one or more substituents on the aryl ring (eg, alkyl, aryl, halogen, amino, etc.) and L is one substituted An alkyl group (in some embodiments, preferably one lower alkyl), more preferably one hydroxy-substituted alkyl or one alkyl substituted with a nucleoside base.

[0008] The therapeutic compounds of the present invention are administered to a subject by a route effective in modulating amyloid deposition. Suitable routes of administration include oral, transdermal, subcutaneous, intravenous, intramuscular, and intraperitoneal injection. The preferred route of administration is trend administration. The therapeutic compound may be administered together with a pharmaceutically acceptable excipient.

[0009] The present invention further comprises administering to a subject a disease state associated with amyloidosis such that an effective amount of a therapeutic compound having the formula described above is treated such that the disease state associated with amyloidosis is treated. It also provides a way to treat.

[0010] The present invention relates to amyloid deposition characterized by the interaction between amyloid-forming protein and basement membrane components, and to the regulation of amyloid deposition characterized by the interaction between amyloid-forming protein and basement membrane components. Provided is a method of modulating a subject by administering to a subject an effective amount of a therapeutic compound having the formula described above.

The present invention further provides a pharmaceutical composition for treating amyloidosis. The pharmaceutical composition comprises an effective amount of a therapeutic compound of the invention to modulate amyloid deposition and a pharmaceutically acceptable excipient.

[0012] The present invention further provides a packaged pharmaceutical composition for treating amyloidosis. The packaged pharmaceutical composition contains the therapeutic compound of the present invention and instructions for using the pharmaceutical composition to treat amyloidosis.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to methods and compositions useful for treating amyloidosis. The methods of the invention include administering to a subject a therapeutic compound that modulates amyloid deposition. "Regulation of amyloid deposition" refers to prevention of amyloid formation,
It is intended to include the inhibition of further amyloid deposition in a subject with advanced amyloidosis and the reduction of amyloid deposits in a subject with advanced amyloidosis. Modulation of amyloid deposition is determined relative to an untreated subject prior to treatment or as compared to a subject receiving treatment. In some embodiments, amyloid deposition can be modulated by modulating the interaction between amyloidogenic protein and basement membrane components.

“Basement membrane” refers to an extracellular matrix containing glycoproteins and proteoglycans, including laminin, collagen type IV, fibronectin chondroitin, and / or heparan sulfate proteoglycan (HSPG). In one embodiment,
Modulates amyloid deposition by interfering with the interaction between amyloidogenic protein and sulfated glycosaminoglycans such as HSPG. Sulfated glycosaminoglycans are known to be present in all types of amyloid (Snow, A.
D. et al. (1987) Lab. Invest. 56: 120-123), amyloid deposition and HSPG deposition occur simultaneously in animal models of amyloidosis (Snow, AD et al. (1
987) Lab. Invest. 56: 665-675). In a preferred embodiment of the method of the present invention, a molecule having a structure similar to sulfated glycosaminoglycan is used to modulate the interaction between amyloidogenic protein and basement membrane components. In particular, it is preferred that the therapeutic compounds of the present invention have at least one phosphonate group (or phosphonate group), provided that the compound contains or can have at least one anionic group after reaction in vivo. Acid ester) or (phosphate,
Including, but not limited to, phosphate esters, phosphinates, and the like.
It may include its functional equivalents (including phosphorus-containing anionic groups) and a carboxylate group or carboxylate ester (or homologs such as, for example, a thioacid, thiol ester, or thionoester). . The anionic group may optionally be covalently linked to a carrier (eg, an aliphatic group, a peptide or peptidomimetic, etc.). In addition to functioning as an anionic functional carrier, the carrier molecule may allow the compound to cross the biological membrane and be biodistributed without encountering excessive or premature metabolism.

In one embodiment, the method of the invention comprises administering to a subject an effective amount of a therapeutic compound having at least one phosphonate or phosphonate group. The therapeutic compound is preferably capable of modulating amyloid deposition by modulating the interaction between amyloidogenic protein and a basement membrane glycoprotein or proteoglycan component. The therapeutic compound has a formula (Formula I) such that amyloid deposition is modulated.

Embedded image Wherein Z is XR ² or R ⁴ , wherein R ¹ and R ² are each independently hydrogen, one substituted or unsubstituted aliphatic group (preferably one A branched or straight-chained aliphatic moiety having from 24 to 24 carbon atoms or one unsubstituted or substituted cyclic having from 4 to 6 carbon atoms in the aliphatic ring Preferred aliphatic and cyclic aliphatic groups are alkyl groups, more preferably lower alkyl), one aryl group, one heterocyclic group, or one salt. R ³ is hydrogen, lower alkyl, aryl, or a cation forming one salt, and X is
O or S, R ⁴ is hydrogen, lower alkyl, aryl or amino; Y ¹ and Y ² are each independently hydrogen, halogen, (eg, F, Cl, Br, or I), lower alkyl, amino ( Alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), hydroxy, alkoxy, or aryloxy, and n is an integer from 0 to 12 (more preferably 0 to 12).
Up to 6, more preferably 0 or 1).

In a preferred embodiment, a therapeutic compound of the invention prevents or inhibits amyloid deposition in a subject receiving the therapeutic compound. Therapeutic compounds suitable for use in the present invention include those in which both R ¹ and R ² are cations that form pharmaceutically acceptable salts. The stoichiometry of an anionic compound to a single salt forming counterion (if present) is determined by the anionic portion of the compound (if present)
It will be appreciated that will vary depending on the charge of the and its counterions. In a particularly preferred embodiment, R ¹ , R ² and R ³ are each individually one sodium, potassium or calcium cation. In some embodiments, where at least one of R ¹ and R ² is an aliphatic group, the aliphatic group may have from 1 to 10 carbon atoms in its straight or branched chain. And more preferably one lower alkyl group. In other embodiments, where at least one of R ¹ and R ² is an aliphatic group, the aliphatic group has 10 to 24 carbon atoms in its straight or branched chain. In some preferred embodiments, n is 0 or 1, more preferably n
Is 0. In some preferred embodiments of the therapeutic compounds, Y ¹ and Y ² are each hydrogen.

In some preferred embodiments, the therapeutic compounds of the present invention have the formula (Formula II):

Embedded image Where R ¹ , R ² , R ³ , Y ¹ , Y ² , X and n are as defined above. In a more preferred embodiment, a therapeutic compound of the present invention has the formula (Formula III):

Embedded image Wherein R ¹ , R ² , R ³ , Y ¹ , Y ² , and X are as defined above, and _Ra and R _b are each independently hydrogen, alkyl, aryl, Or heterocyclyl, or _Ra and _Rb , taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the ring, with n from 0 to 6 Is an integer. In some preferred embodiments, _Ra and _Rb are each hydrogen. In some preferred embodiments, the compounds of the present invention comprise one α-amino acid (or α-amino acid ester), more preferably one L-α-amino acid or ester.

[0018] Z, Q, R¹, R^Two, R^Three, Y¹, Y^Two And the group X are such that the biodistribution of the compound to the intended target site is not impeded while the activity of the compound is maintained.
Each is selected individually. For example, the number of anionic groups (and the totality of the therapeutic compound)
Electrical charge) can pass through anatomical barriers, such as cell membranes, or physiology, such as the blood-brain barrier.
Inhibits cross-barrier entry when such properties are desirable
Should not be as large. For example, in vivo in the phosphonoformate ester
The distribution characteristics may be different from, and in some cases, the biodistribution characteristics of phosphonoformate.
(Eg, Helgstrand et al., U.S. Pat. Nos. 4,386,081 and 4,591583; and Hostetler et al., U.S. Pat. No. 5,194,941).
No., 654 and 5,463,092). Thus, in some embodiments, R ¹ And R^Two At least one is an aliphatic group (more preferably, an alkyl group), provided that the aliphatic group has from 10 to 24 carbon atoms.
In a straight or branched chain. The number, length, and degree of branching of the aliphatic chains is
It can be chosen to provide a property, such as lipophilicity. In another embodiment,
, R¹ And R^Two Is at least one aliphatic group (more preferably, one
This aliphatic group has from 1 to 10 carbon atoms in its straight or branched chain. Again, the number, length, and degree of branching of this aliphatic chain is also desired.
Properties such as lipophilicity or ease of enzymatic ester cleavage are provided.
You can choose. In some embodiments, a preferred aliphatic group is ethyl
Group.

In addition, certain thiophosphate compounds may equate to the activity of the corresponding oxy-phosphate compound (possibly due to differences in the bioavailability of the compound) or may be more active as antiviral agents. It has been reported to have body activity. Thus, in some preferred embodiments, the therapeutic compound comprises -P
A component selected from any of (S) (OR ¹ ) (OR ² ), -P (S) (SR ¹ ) (OR ² ), or -P (S) (SR ¹ ) (SR ² ) including.

In another embodiment, compounds useful in the methods of the invention can be represented by formula (Formula IV):

In another embodiment, a compound of the present invention has the formula (Formula IV):

Embedded image Wherein G represents hydrogen or one or more substituents on the aryl ring (eg, alkyl, aryl, halogen, amino, etc.), and L represents one substituted group It is an alkyl group (in some embodiments, preferably one lower alkyl), but more preferably one hydroxy-substituted alkyl or one alkyl substituted with a nucleoside base. In some embodiments, G is hydrogen or an electron donating group. In embodiments where G is an electron withdrawing group, G is preferably an electron withdrawing group at the meta position. The term "electron withdrawing group" is well known in the art and, as used herein, refers to a group that is more electron withdrawing than hydrogen. A variety of electron withdrawing groups are known, including halogens such as fluoro, chloro, bromo, and iodo groups, nitro, cyano, and the like. Similarly, the term “electron donating group” as used herein refers to a group that is less electron-withdrawing than hydrogen. In embodiments where G is an electron donating group, G may be in the ortho, meta or para position.

In some preferred embodiments, L is of the formula (IVa-IVg):

Embedded image A component selected from any of the above.

Table 1 lists data on the characterization of these compounds using techniques known in the art.

[Table 1]

In another aspect, the invention includes novel compounds useful for inhibiting amyloidosis and / or compounds having antiviral activity. Compounds of the present invention can be represented by the structure of Formula IV, for example, Formula IV wherein G is hydrogen (eg, the phenyl ring is unsubstituted) and L is any of the components of Formulas IVa-IVg. Is a compound of More preferred compounds are compounds of formula IVc.

In another embodiment, the present invention provides an ester of a phosphonate, such as a phosphono-carboxylate compound of the present invention, for example a compound of formula IV wherein G is hydrogen and L is a component of formulas IVa-IVg. Methods for preparing compounds and the like are provided. Illustratively, the method involves the use of phosphonodichloridate (or other phosphonate diacid halides (ph
osphonate diacid halide) to the disilylated diol under conditions such that a compound of formula IV is formed (see Example 2 below).
.

Thus, in one embodiment, the present invention provides a compound of formula (Formula V):

Embedded image Wherein R is alkyl or aryl, and R ′ is hydrogen, alkyl, or aryl (including heteroaromatic groups such as nucleosides). ). The method is based on the ester of carbonyl phosphono diacid halide (
For example, ROOC-P (O) (A) (A ′), where R is as described for Formula V, and A and A ′ are both halogen or, for example, chloro, iodo, Bromo, pentafluorophenyl, etc., and other good leaving groups which may be the same or different) to the disilyl ether of vicinal diol under conditions such that the compound of formula V is prepared. Including steps.

The anionic group (ie, the phosphonate or carboxylate group) of the therapeutic compound according to the present invention is a negatively charged component, which in some preferred embodiments is amyloidogenic and basement membrane Amyloid deposition can be regulated by controlling the interaction between the glycoprotein and the proteoglycan component.

It will be noted that the structures of some compounds according to the invention contain asymmetric carbon atoms. Thus, it is to be understood that isomers (eg, enantiomers and diastereomers) resulting from such asymmetries are within the scope of the invention.
Such isomers can be obtained in substantially pure form by traditional separation techniques or sterically controlled synthesis. For the purposes of this application, unless otherwise stated, a compound is to be understood as including both the R or S stereoisomer of each chiral center.

The ability of a therapeutic compound according to the present invention to modulate the interaction between amyloidogenic proteins and glycoprotein or proteoglycan components of the basement membrane is described in this section and in Kislevev et al., US Pat. No. 5,164,295. Can be assessed by in vitro binding assays such as those described in Briefly, a solid support such as a polystyrene microtiter plate is coated with an amyloid-forming protein (eg, serum amyloid A protein or β-amyloid precursor protein (β-APP)) and the remaining hydrophobic Block all surfaces. The coated solid support is incubated with various concentrations of a basement membrane component, preferably HSPG, in the presence or absence of the test compound. The solid support is thoroughly washed to remove unbound material. Thus, the binding of the basement membrane component (eg, HSPG) to the amyloid-forming protein (eg, β-APP) is determined by using an antibody that targets the basement membrane component bound to a detectable substance (eg, an enzyme such as alkaline phosphatase). It measures by detecting this detectable substance. Any compound that modulates the interaction between amyloidogenic protein and a basement membrane glycoprotein or proteoglycan component will reduce the amount of substance detected (eg, the amount of enzyme activity detected). Will be inhibited).

Preferably, the therapeutic compound of the present invention modulates the binding of the amyloidogenic protein to a basement membrane component by interacting with a basement membrane glycoprotein or proteoglycan binding site of the amyloidogenic protein. Good. Basement membrane glycoproteins and proteoglycans include laminin, collagen type IV, fibronectin and heparan sulfate proteoglycans (HSPG). In one preferred embodiment, the therapeutic compound inhibits the interaction between amyloidogenic protein and HSPG.

In some embodiments, a therapeutic compound of the invention comprises one cation (ie,
In some embodiments, at least one of R ¹ , R ^2, or R ³ is a cation). When the group of the cation is hydrogen, H ⁺ , the compound is an acid, such as phosphonoformic acid. If the hydrogen is replaced by a metal ion or its equivalent, the compound is a salt of the acid. Pharmaceutically acceptable salts of the therapeutic compounds are within the scope of the invention. For example, at least one of R ¹ , R ² or R ³ is a pharmaceutically acceptable alkali metal (eg, Li, Na, or K), ammonium cation, alkaline earth cation (eg, Ca ²⁺ , Ba ²⁺ , Mg ²⁺ ), a high-valent cation, or a polycationic counterion (eg, a polyammonium cation). (For example,
Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19). Counterion, if present, forming one salt of anionic compound
It will be appreciated that the stoichiometry for will vary depending on the charge of the anionic portion of the compound, if present, and the charge of its counterion. Suitable pharmaceutically acceptable salts include the sodium, potassium or calcium salts, but other salts are contemplated within their pharmaceutically acceptable ranges.

The term “pharmaceutically acceptable esters” refers to the relatively non-toxic, esterified products of the compounds of the present invention. These esters may be prepared in situ during the final separation and purification steps of the compound, or the purified compound may be separately reacted in its free acid form or hydroxyl state with a suitable esterifying agent. And any method is a method known to those skilled in the art.

The carboxylic acids and phosphonic acids can be converted to esters based on methods known to those skilled in the art, for example, treatment with an alcohol in the presence of a catalyst. A preferred ester group (eg, when R ³ is lower alkyl) is an ethyl ester group.

The term “alkyl” refers to a saturated aliphatic group, including a straight-chain alkyl group, a branched-chain alkyl group, a cycloalkyl (alicyclic) group, an alkyl-substituted cycloalkyl group, and a cycloalkyl-substituted alkyl group. Including. In a preferred embodiment, a straight or branched alkyl has up to 30 carbon atoms in its backbone (eg, C ₁ -C ₃₀ for a straight chain, C ₃ -C _{3 for a} branched chain). ₃₀ ), and more preferably 20 or less. Likewise, preferred cycloalkyls have from 4-10 carbon atoms in their ring structure, but more preferably have 4-7 carbon atoms in the ring structure. The term "lower alkyl" refers to an alkyl group having from 1 to 6 carbons in its chain and a cycloalkyl having from 3 to 6 carbons in its ring structure.

Further, as used throughout the specification and claims, the term “alkyl” (including “lower alkyl”) is intended to include both “unsubstituted alkyl” and “substituted alkyl” As intended, the latter refers to an alkyl moiety wherein a hydrogen attached to one or more carbons of the hydrocarbon backbone is replaced by a substituent. Such substituents include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl,
Phosphate, phosphonate, phosphinate, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino , Sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, aralkyl, or aromatic or heteroaromatic components. Those skilled in the art will appreciate that components substituted with a hydrocarbon chain may themselves be optionally substituted. The cycloalkyl may be further substituted, for example, with the substituents described above. An "aralkyl" moiety is an alkyl substituted with an aryl (eg, phenylmethyl (benzyl), etc.).

The term “alkoxy” as used herein refers to a moiety having the structure —O-alkyl, wherein the alkyl moiety is described above.

As used herein, the term “aryl” includes 5- and 6-membered single-ring aromatic radicals, which contain from 0 to 4 heteroatoms, eg, unsubstituted Or substituted benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl groups further include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like. The aromatic ring may be substituted at one or more ring positions, for example, with substituents as described above for alkyl groups. Suitable aryl groups include unsubstituted and substituted phenyl groups.

The term “aryloxy,” as used herein, refers to a group having the structure —O-aryl, wherein the aryl moiety is as defined above.

The term "amino" as used herein, refers to a formula -Nr _a R _b unsubstituted or substituted ingredients, provided that the case R _a and R _b are each independently hydrogen, alkyl, aryl Or heterocyclyl, or R _a and R _b , when taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the ring. Thus, the term "amino" is intended to include cyclic amino moieties, such as, for example, a piperidinyl or pyrrolidinyl group, unless otherwise indicated. "Amino-substituted amino group"
The term “amino group” means that at least one of _Ra and _Rb is further substituted with one amino group.

In one preferred embodiment of the compounds of formulas I-III, R ¹ or R ² (for at least one occurrence) may be a long-chain aliphatic moiety. As used herein, the term "long chain aliphatic component" refers to a straight or branched chain aliphatic component having 10 to 24 carbons in the aliphatic chain (eg, an alkyl or alkenyl component). For example, the long chain aliphatic component is an aliphatic chain of a fatty acid (preferably a naturally occurring fatty acid). Representative long chain aliphatic moieties include aliphatic chains such as stearic acid, oleic acid, linoleic acid, and the like.

The therapeutic compounds of the present invention may be administered in a pharmaceutically acceptable excipient. As used herein, "pharmaceutically acceptable excipient" includes any solvent, excipient, or dispersion medium that is compatible with the activity of the compound and is physiologically acceptable to the subject. , Coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. One example of a pharmaceutically acceptable excipient is normal buffered saline (
0.15 mol of NaCl). The use of such media and agents for pharmaceutically active substances is well known in the art. Unless conventional media or agents are incompatible with the therapeutic compound, their use in compositions suitable for pharmaceutical administration is contemplated. Supplementary active compounds can be added to the present compositions.

In some embodiments, the therapeutic compounds of the present invention have the formula: wherein amyloid deposition is modulated.

Embedded image Wherein R ¹ and R ² are each independently hydrogen, an aliphatic group (preferably 1 to 24 carbon atoms in the chain, more preferably 10 to 2
A branched or straight-chain aliphatic moiety having 4 carbon atoms, or one unsubstituted or substituted cyclic aliphatic having 4 to 7 carbon atoms in the aliphatic ring; Component), one aryl group, one heterocyclic group, or one salt-forming cation; R ³ is hydrogen, lower alkyl, aryl, or one salt-forming cation; ¹ and Y ² are each independently hydrogen, halogen (eg, F, Cl, Br
Or I), lower alkyl, hydroxy, alkoxy, or aryloxy, and n is an integer from 0 to 12. In one preferred embodiment, a therapeutic compound of the invention is one that prevents or inhibits amyloid deposition in a subject that has received the therapeutic compound. Therapeutic compounds suitable for use in the present invention include R ¹ and R ²
Are both cations that form pharmaceutically acceptable salts. In a particularly preferred embodiment, R ¹ , R ² and R ³ are each independently a sodium, potassium or calcium cation and n is 0. In some preferred embodiments of the therapeutic compounds, Y ¹ and Y ² are each hydrogen. Particularly preferred therapeutic compounds are the salts of phosphonoformates. Trisodium phosphonoformate (foscarnet sodium or Foscavir®) is commercially available (eg, from Astra) and its clinical pharmacology is being studied (eg, “Physician's Desk Referenc”).
e ", 51st Ed., pp. 541-545 (1997)).

A further aspect of the present invention includes a pharmaceutical composition for treating amyloidosis. As noted above, the therapeutic compounds in the methods of the invention may be incorporated into pharmaceutical compositions in pharmaceutical excipients in an amount effective to treat amyloidosis.

The present invention further contemplates the use of prodrugs to convert the therapeutic compounds of the invention in vivo (eg, RB Silverman, 1992, "The Organic Che
mistry of Drug Design and Drug Action ", Academic Press, Chp. 8). Such prodrugs can be used (e.g., to allow compounds that normally cannot cross the blood brain barrier to cross the blood brain barrier). ) It can alter biodistribution or alter the pharmacokinetics of the therapeutic compound, for example, esterification of an anionic group such as a phosphonate or carboxylate, such as with an ethyl group or an aliphatic group, resulting in phosphonic acid or When the phosphonic acid or carboxylic ester is administered to a subject, the ester can be enzymatically or non-enzymatically cleaved to expose the anionic group. Such esters can be cyclic, such as cyclic phosphonates, or can be used to link two or more anionic components to linking groups. In one preferred embodiment, the prodrug is a phosphonate or a carboxylate.The cleavage of the anionic group results in an intermediate compound that decomposes to form the active compound. Components produced (eg, acyloxymethyl ester, etc.)
May be esterified. In addition, anionic components (eg, phosphonates or carboxylate) can be esterified to groups that are actively transported in vivo or that are selectively taken up by target organs. . The ester can also be selected to specifically target a particular organ to the therapeutic component, as described below with respect to the components of the carrier. In some embodiments, as described above, the compounds of the present invention have more than one phosphate or carboxylic acid component, such as, for example, one phosphate and one carboxylic acid ester. Or it may have a phosphoric diester. In such embodiments, the parent compound may contain an anionic group and may be active, but cleavage of any or all ester functionality may result in an active compound. In compounds having multiple esterification moieties, the ester group can be selected such that cleavage of one or more ester functionalities occurs selectively to reveal one or more anionic groups. Will be understood. The relative likelihood of cleavage of an ester group is well known, for example, t-butyloxyester generally cleaves more slowly than ethylester under certain conditions. Methods for selecting the appropriate components to effect the desired rate or sequence of ester cleavage are within the ordinary skill in the art. Thus, controlling the number of anionic functionality can provide selective activity of the compounds of the present invention based on the rate or sequence of ester cleavage.

[0045] Carrier or substituent components useful in the present invention may further include components that enable the therapeutic compound to be selectively delivered to one or more target organs. For example, if it is desired to deliver a therapeutic compound to the brain, the carrier molecule may include a component capable of targeting the brain by active or passive transport of the therapeutic compound ("targeting component"). By way of illustration, the carrier molecule may include a redox component, for example, both as described in Bodor U.S. Patent Nos. 4,540,564 and 5,389,623. These patents disclose drugs conjugated to a dihydropyridine component that can enter the brain, where they can be oxidized into charged pyridinium species and trapped in the brain. Becomes Thus, the drug accumulates in the brain. Other carrier components include compounds that can be passively or actively transported in vivo, such as, for example, amino acids or thyroxine. Such carrier components may be removed from the body by metabolism or may be maintained as part of the active compound. Structural mimetics of amino acids (and other actively transported components), including peptidomimetics, are also useful in the present invention. The term "peptide mimetics" as used herein is intended to include peptide analogs that act as suitable substitutes for peptides, for example, by interacting with receptors and enzymes and the like. Peptidomimetics must not only have affinity, but also have potency and substrate function.
That is, the peptidomimetics exhibit the function of a peptide, although the structure is not limited. Peptidomimetics, methods for their preparation and use, are hereby incorporated by reference into Morgan et al., "Approaches to th
e discovery of non-peptide ligands for peptide receptors and peptidases,
"In Annual Reports in Medicinal Chemistry (Virick, FJ, ed.) Pp. 243-2
53, Academic Press, San Diego, CA (1989). Numerous targeting molecules are known, including, for example, asialoglycoproteins (eg, Wu
And other ligands that are transported intracellularly through receptor-mediated endocytosis (see US Pat. No. 5,166,320) for targeting molecules that may be covalently or non-covalently attached to a carrier molecule. See below for other examples). Further, the therapeutic compounds of the present invention may be linked to the amyloidogenic protein in the blood and transported to the site of action.

The targeting and prodrug tactics described above may be combined to produce a compound that can be transported as a prodrug to the desired site of action and then uncovered to become an active compound.

In the methods of the invention, the deposition of amyloid in a subject (eg, the deposition of β-amyloid) is modulated by administering a therapeutic compound of the invention to the subject.
The term "subject" is intended to include organisms that can have amyloidosis. Examples of subjects include humans, monkeys, cows, sheep, goats, dogs, cats,
Includes mice, rats, and their transgenic species. Administration of the compositions of the present invention to the subject to be treated may be performed using known techniques, at dosages and for periods of time effective to modulate amyloid deposition in the subject. The effective amount of the therapeutic compound required to achieve a therapeutic effect will depend on the amount of amyloid already deposited at the subject's clinical site, the age, gender, and weight of the subject, and the amount of the therapeutic compound in the subject. It will vary depending on factors such as the ability to modulate amyloid deposition. Dosage regimes may 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 (eg, phosphonoformic acid, trisodium salt) is 0.5 to 500 mg / kg body weight / day. When in an aqueous composition, a suitable concentration of the active compound (ie, a therapeutic compound capable of modulating amyloid deposition) is from 5 to 500 mM, more preferably from 10 to 10 mM.
0 mM, and even more preferably between 20 and 50 mM.

The therapeutic compounds of the present invention may be effective when administered orally. Thus, one preferred route of administration is oral administration. Depending on the choice, the active compound is administered, for example, subcutaneously,
It may be administered by other suitable routes (eg, by injection), such as intravenous, intramuscular or intraperitoneal. Depending on the route of administration, the active compound may be coated with substances that will protect the compound from the effects of acids and other natural conditions that may inactivate the active compound.

The compounds of the present invention may be prepared 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 can cross the BBB, they may be prepared, for example, in liposomes. Regarding the method for producing liposomes, for example,
See 4,522,811, 5,374,548 and 5,399,331. The liposome may include one or more components that are selectively transported to a particular cell or organ (“targeting components”) to provide targeted drug delivery (eg, VV Ranade (1989) J. Clin. Pharmacol. 29 : 685). Examples of targeting moieties include folate or biotin (see, for example, US Pat. No. 5,416,016 to Low et al.), Mannoside (Umezawa et al., (1988)
) Biochem. Biophys. Res. Commun. 153 : 1038), antibody (PG Bloeman et al.
1995) FEBS Lett. 357 : 140; M. Owais et al. (1995) Antimicrob. Agents Chem
other. 39 : 180), surfactant protein A receptor (Briscoe et al. (1995
) Am. J. Physiol. 1233 : 134), gp120 (Schreier et al. (1994) J. Biol. Che).
m. 269 : 9090), but also K. Keinanen; ML Laukkanen (1994) FEBS Let
t. 346 : 123; JJ Killion; IJ Fidler (1994) Immunomethods 4 : 273. In one preferred embodiment, the therapeutic compound of the invention is prepared in a liposome, but in more preferred embodiments, the liposome may include a targeting moiety.

Delivery and biodistribution can also be influenced by modifying the anionic groups of the compounds according to the invention. For example, esterification of an anionic group, such as a phosphonate or carboxylate, can provide compounds with desired pharmacokinetics, pharmacodynamics, biodistribution, or other properties. Examples of compounds include:
Includes phosphonoformic acid trisodium salt (Foscarir, Foscavir), phosphonoacetate, trisodium salt, and pharmaceutically acceptable salts or esters thereof.

In order to administer the therapeutic compound other than by parenteral administration, it may be necessary to coat the compound with a substance that prevents its inactivation or to administer the compound at the same time. For example, the therapeutic compound may be administered to a subject in a suitable carrier, such as a liposome, or diluent. Pharmaceutically acceptable diluents include saline and aqueous buffers. And water-in-oil-in-water type CGF emulsions in the liposomes, a conventional liposome (Strejan et al, (1984) J. Neuroimmunol 7:. 27.) Are included.

Further, the therapeutic compounds may be administered parenterally (eg, intramuscularly, intravenously, intraperitoneally, intraspinally, or intracerebrally). Dispersants are glycerol, liquid polyethylene glycol,
And mixtures thereof and oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions or sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases, the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and mold. Excipients include, for example, water, ethanol, polyols (eg, glycerol, propylene glycol, and liquid polyethylene glycol, and the like).
, A suitable mixture thereof, and a solvent or dispersion medium containing a vegetable oil. Proper fluidity can be maintained, for example, by using a coating such as lecithin, maintaining the required particle size in the case of dispersion, or using a surfactant. Prevention of the activity of microorganisms, various antibacterial and antifungal agents,
For example, it can be achieved with parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In some cases, it will be preferable to include isotonic agents, such as sugars, sodium chloride, polyhydric alcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition a substance that causes absorption, for example, aluminum monostearate or gelatin.

Sterile injectable solutions are prepared by incorporating the required amount of the therapeutic compound in a suitable solvent, as appropriate, with one or a combination of the above-listed components, followed by filter sterilization. May be. Generally, dispersions are prepared by incorporating the therapeutic compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying and lyophilization, so that the powder of the active ingredient (ie the therapeutic compound) and the further desired ingredients is obtained. , Resulting from those solutions that have been previously sterile filtered.

The therapeutic compound may be administered orally, for example, with an active diluent or an assimilable edible carrier. The therapeutic compound and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet. For oral therapeutic administration, the therapeutic compounds may be incorporated into excipients and used in the form of edible 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.

It is especially advantageous if the parenteral composition is prepared in a unit dosage form for ease of administration and uniformity of dosage. The unit dosage form used here is
Refers to physically discrete units combined as a single dose for the subject to be treated, each unit being calculated to produce the desired therapeutic effect in association with the required pharmaceutical excipient. Will contain a predetermined amount of the therapeutic compound. The details of the unit dosage form of the present invention include (a) the specific properties of the therapeutic compound and the particular therapeutic effect sought to be achieved; and (b) such therapeutic compounds for the purpose of treating amyloid deposition in a subject. It is evident from the limitations inherent in the art of compounding and directly relies on them.

The therapeutic compound may be administered in an aging or depot form so that the therapeutic compound is released over time. Further, the therapeutic compounds of the present invention may be administered transdermally (eg, provided in a patch form with the therapeutic compound together with a suitable carrier).

The active compound is administered in a therapeutically effective amount sufficient to modulate amyloid deposition (or amyloid burden) in the subject. A `` therapeutically effective amount '' is at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, and even more preferably at least about 80%, as compared to an untreated subject. It should be one that regulates amyloid deposition. The ability of a compound to modulate amyloid deposition is demonstrated, for example, by animal model systems known in the art (eg, PCT Publication WO 96 /
28187), model systems believed to predict efficacy in regulating amyloid deposition in human disease, or PCT publication WO 97/07.
It can be assessed by in vitro methods such as the method of Chakrabartty, described in 402, or by the assay described in Example 1 below. Alternatively, depending on the choice, the ability of a compound to modulate amyloid deposition can be used to modulate the interaction between amyloidogenic protein and basement membrane components, for example, using a binding assay as described above. It can also be evaluated by examining the ability of the compound. In addition, the amount or distribution of amyloid deposits in a subject can be determined by non-invasive in vivo, e.g., utilizing a radiolabeled tracer capable of associating with the amyloid deposits and then imaging the amyloid deposits by scintigraphy. (Aprile, C. et al., Eur. J. Nucl. Med. 22 : 1393 (1995); Hawkins, PN,
Baillieres Clin. Rheumatol. 8 : 635 (1994); and the references cited therein). Thus, for example, if a subject's amyloid load is assessed after a period of time following treatment according to the present invention and compared to the subject's amyloid load prior to initiating treatment with a therapeutic compound of the present invention, the subject's amyloid load The effect of the therapeutic compound on amyloid deposition can be determined.

The ability of a compound according to the present invention to modulate amyloid deposition or amyloid load can be measured, in some embodiments, by observing one or more symptoms or signs in vivo associated with amyloid deposition or amyloid load. It will be understood that by doing so, the evaluation can be made. Thus, for example, the ability of a compound to reduce amyloid deposition or amyloid burden is an observable improvement in the clinical manifestations of the underlying amyloid-related disease state or condition, or the progression of the symptoms of that condition. May be accompanied by dulling or delay. Thus, observing the clinical manifestations of the disease may be useful in assessing the amyloid-modulating effects of the compounds of the present invention.

The methods of the present invention are useful for treating amyloidosis associated with any disease in which amyloid deposition occurs. Clinically, amyloidosis may be primary, secondary, familial or isolated. Amyloid has been classified by the type of amyloid-forming protein contained in the amyloid. Non-limiting examples of regulatable amyloid, as identified by amyloidogenic protein, are as follows (
The associated disease is shown in parentheses after the amyloidogenic protein). β-amyloid (Alzheimer's disease, Down syndrome, hereditary intracerebral hemorrhage amyloidosis [Dutch disease], cerebrovascular disease), amyloid A (reactive [secondary] amyloidosis, familial subsurface sea fever, hives and Familial amyloid nephropathy with deafness [Mackle-Wells syndrome]), amyloid κL-chain or amyloid λL-chain (sudden [primary], associated with myeloma or macroglobulinemia), Aβ2M (chronic hemodialysis) , ATTR (familial amyloid polyneuritis [Portugal, Japan, Sweden], familial amyloid cardiomyopathy [Denmark], isolated cardiac amyloid, systemic senile amyloidosis), AI
APP or amylin (adult-onset diabetes, insulinoma), atrial natriuretic factor (isolated atrial amyloid), procalcitonin (medullary thyroid carcinoma),
Gelsolin (familial amyloidosis [Finland]), cystatin C (hereditary cerebral hemorrhage with amyloidosis [Iceland]), AApoA-I (familial amyloidosis polyneuritis [Iowa]), AApoA-II ( Aging in mice), fibrinogen-related amyloid, lysozyme-related amyloid, and AScr or PrP-27 (scrapie, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinka syndrome, bovine spongiform encephalopathy).

The compounds utilized in the methods of the present invention are commercially available and / or may be synthesized by standard techniques known in the art. In general, phosphonates can be prepared from the corresponding phosphonic acid by standard methods. Similarly, carboxylic esters can be prepared from the free carboxylic acids by standard techniques (for references on esterification techniques, see, eg, R. Larock, "Comprehensive."
See Organic Transformations, "VCH Publishers (1989). Carbonate esters can be converted to thionoesters, for example, 2,4-commercially available from Lawesson's reagents (eg, Aldrich Chemical Company, Milwaukee, Wis.). Conversion can be achieved by known reactions, such as treatment with bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide.The compounds of the present invention are further described below. The following examples are further illustrative of the present invention and are in no way intended to be further limiting.

Example 1 Amyloid-forming peptides or proteins that formed amyloid deposits or plaques
Peptides or proteins that have significant amounts of β-sheet secondary structure but are not aggregated are generally known to have less β-sheet structure. It is conceivable that the in vitro ability of a candidate therapeutic compound to be prevented from forming β-sheet secondary structure may be correlated with the ability of the compound to inhibit amyloid formation in vivo. Therefore, the phosphonate compound was converted to circular dichroism (CD
A) Assay system, including the assay, was assayed for its ability to prevent the formation of β-sheet secondary structure.

Aβ is a 40 amino acid protein associated with Alzheimer's disease. Aβ peptide was prepared and purified as described in Fraser, PE et al., Biochemistry 31, 10716 (1992). Briefly, the peptide was synthesized by standard solid phase techniques and purified by HPLC using known techniques.

All CD experiments were performed on commercially available equipment. Cells were maintained at 25 ° C. using a circulating water bath. Computer average averaging of the traces was performed to improve the signal to noise ratio. The solvent signal was subtracted. A CD experiment was performed for each test compound based on the following method.

A stock solution of the purified peptide was prepared by dissolving the peptide in phosphate buffered saline (PBS) to a concentration of 2 mg / ml. Test solutions were made for each potential therapeutic (test compound) as shown below. Aβ stock solution 25 μl Test compound (20 mg / ml) 2.5 μl distilled water 2.5 μl 10 mM Tris-HCl buffer, pH 7 370 μl

The control sample contained no test compound and a total of 5 μl of distilled water was added. Test solutions were incubated for 0 or 24 hours at 37 ° C. before CD measurements. The minimum value of the CD spectrum at 218 nm is considered to be a criterion for the existence of the β-pleated sheet. A comparison comparing this minimum at 218 nm of the candidate compound to the minimum of the control sample is considered to be an indicator of the ability of the candidate compound to inhibit β-pleated sheet formation.

Several candidate compounds were tested using this assay. Phosphonoformate sodium salt (foscarnet sodium) was found to significantly and reproducibly reduce β-sheet formation as measured by this CD assay. Phosphonoacetate was also found to be active in this assay. Thus, phosphonoformate and phosphonoacetate are considered to be inhibitors of amyloid deposition. The ability of 2-carboxyethylphosphonic acid to prevent β-pleated sheet formation was lower in this model system.

The primary results in the different assay formats (the candidate compound and the amyloid peptide were incubated together overnight and then centrifuged to determine the amount of soluble peptide) show that phosphonoformate trisodium salt contains amyloid It turned out to have little effect on the solubility of the peptide. It is possible that the composition of the buffer interfered with the compound's ability to inhibit amyloid deposition.

The neurotoxicity of phosphonoformate trisodium salt was examined in cortical / hippocampal neuronal cultures. No significant toxicity was seen at concentrations from 10 ^-7 M to 10 ^-4 M.

Example 2 The technique described below is further incorporated herein by reference.
n et al., Tet. Lett. 1997, 38: 2791-2794. This technique has the advantage that the reactivity of a nucleophile (eg, a hydroxyl group of a diol that reacts with phosphonic chloride) can be enhanced with a silyl ether (eg, trimethylsilyl ether) to improve selectivity. Have.

To a solution of phenoxycarbonyl) phosphonodichloridate (5 mmol) in 10 ml of dry THF, cooled in a cold water bath under argon, was added vicinal bistrimethylsilyl ether (5 mmol) (eg Wisconsin). A solution of vicinal-diol, prepared from vicinal-diol, such as treatment with trimethylsilyl chloride (TMSCl) or trimethylsilyl triflate (TMSOTf), available from Aldrich Chemical Company of Milwaukee, U.S.A., was added in 10 ml of dry THF. After the addition was complete, the reaction mixture was stirred for 1 hour at room temperature and the solvent was evaporated under reduced pressure. Residue, 90m
g of water in dioxane (5 mmol), neutralize by adding a solution of 5 mmol of aniline in 10 mL of diozane and pouring into 200 mL of 1: 1 diethyl ether: hexane to give the product. Settled. The solid product was filtered and washed with 1: 1 diethyl ether: hexane.

Compounds IVa-Ivg were prepared by the methods described above using the corresponding diols that are readily available to one of ordinary skill in the art using commercially available and / or routine experimentation.

Example 3 Compounds of the formulas IVa, Ivc and Ivd (in the form of salts, for example methylpyridinium and / or anilinium salts) were tested for their ability to inhibit amyloidosis with at least one flash. It was found that these compounds exhibited activity in at least one assay system, both in free or salt form, indicating their ability to be inhibitors of amyloidosis in vivo.

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

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents of the specific procedures set forth herein. Such equivalents are considered to be within the scope of this invention and are intended to cover the following claims.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), AU, BB, BR, CA, CN, HU, ID, IL, JP, MX, NO, NZ, RU, US, YU Angola Place 130 (72) Inventor Thatcher Gregory Earl. J. Canada K7K 4H6 Alfred Street, Kingston, Ontario 371 (72) Inventor Gorin Boris Canada T6I 1C2 Edmonton, Alberta, 3467-109 Street No address F-term (reference) 4C086 AA01 AA02 DA34 GA13 MA02 MA05 MA52 NA41 ZA16ZC AA03 AB20 AB21

Claims (34)

[Claims] 1. A method of modulating amyloid deposition in a subject comprising administering to the subject an effective amount of a therapeutic compound such that modulation of amyloid deposition occurs, wherein the therapeutic compound has the formula: Wherein R ¹ and R ² each independently represent hydrogen, one substituted or unsubstituted aliphatic group, one aryl group, one heterocyclic group, or one salt. R ³ is hydrogen, lower alkyl, aryl, or a cation forming one salt; R ⁴ is hydrogen, lower alkyl, aryl or amino; and X is Are each independently O or S; Y ¹ and Y ² are each independently hydrogen, halogen, alkyl, amino, hydroxy, alkoxy, or aryloxy; Z is XR ² or R ⁴ ; and n is 0. A method that is an integer from to 12. Wherein Z is XR ^2, The method of claim 1. 3. The method of claim ^{2, wherein} R ¹ and R ² are each a cation that forms one pharmaceutically acceptable salt. 4. The method according to claim 3, wherein R ¹ , R ² and R ³ are each individually one sodium, potassium or calcium cation. 5. The method of claim 4, wherein n is 0. 6. The method according to claim 1, wherein at least one of R ¹ and R ² is a long-chain aliphatic component. 7. The method according to claim 6, wherein R ³ is one lower alkyl group. . 8. The method according to claim 1, wherein Y ¹ and Y ² are each hydrogen. 9. The method of claim 1, wherein said therapeutic compound is administered orally. 10. The method of claim 1, further comprising administering the therapeutic compound in a pharmaceutically acceptable excipient. 11. The method of claim 1, wherein administering the therapeutic compound to the subject inhibits amyloid deposition in the subject. 12. The method of claim 1, wherein X is O each time it is present. 13. The compound of the formula: The method of claim 1, wherein 14. The compound of the formula: Wherein _Ra and _Rb are each independently hydrogen, alkyl, aryl, or heterocyclyl, or _Ra and _Rb are taken together with the nitrogen atom to which they are attached, The method of claim 1, wherein a cyclic component having 3 to 8 atoms is formed therein. 15. The method according to claim 14, wherein _Ra and _Rb are each hydrogen. 16. A method of treating a disease state associated with amyloidosis, comprising administering to a subject an effective amount of a therapeutic compound so that the disease state associated with amyloidosis is treated. The therapeutic compound has the formula: Wherein R ¹ and R ² are each independently hydrogen, one aliphatic group, one aryl group, one heterocyclyl group, or one salt-forming cation, and R ³ is Hydrogen, lower alkyl, aryl or a cation forming one salt; Y ¹ and Y ² are each independently hydrogen, halogen, lower alkyl, amino, hydroxy, alkoxy, or aryloxy, and n is 0 to The method is an integer up to 12. 17. The method of claim 16, wherein said disease state is amyloid deposition associated with Alzheimer's disease. 18. The method of claim 16, wherein R ¹ and R ² are each a cation that forms one pharmaceutically acceptable salt. 19. The method of claim 18, wherein R ¹ , R ² and R ³ are each individually one sodium, potassium, or calcium cation. 20. The method according to claim 19, wherein n is 0. 21. The method of claim 16, wherein at least one of R ¹ and R ² is a long chain aliphatic component. 22. The method according to claim 21, wherein R ³ is one lower alkyl group. 23. The method according to claim 16, wherein Y ¹ and Y ² are each hydrogen. 24. The method according to claim 16, wherein said amino group is —NH ₂ . 25. The method of claim 16, wherein said therapeutic compound is administered orally. 26. The method of claim 16, further comprising administering the therapeutic compound in a pharmaceutically acceptable excipient. 27. A method of modulating amyloid deposition in a subject, wherein said amyloid deposition is characterized by an interaction between an amyloidogenic protein and a basement membrane component, wherein said method comprises the steps of: Administering to the subject an effective amount of a therapeutic compound such that modulation of amyloid deposition characterized by an interaction between the components occurs, wherein the therapeutic compound has the formula: Wherein R ¹ and R ² are each independently hydrogen, one aliphatic group, one aryl group, one heterocyclyl group, or one salt-forming cation, and R ³ is Hydrogen, lower alkyl, aryl or a cation forming one salt; Y ¹ and Y ² are each independently hydrogen, halogen, lower alkyl, amino, hydroxy, alkoxy, or aryloxy, and n is 0 to The method is an integer up to 12. 28. The method of claim 27, wherein R ¹ and R ² are each a cation that forms one pharmaceutically acceptable salt. 29. The method according to claim 28, wherein R ¹ , R ² and R ³ are each independently one sodium, potassium or calcium cation. 30. The method of claim 29, wherein n is 0. . 31. The method of claim 27, wherein at least one of R ¹ and R ² is a long chain aliphatic component. 32. R is alkyl or one substituted aryl group, wherein said aryl substituent is H, one electron donating group, or one electron withdrawing group at the meta position. R ′ is alkyl, substituted alkyl or aryl, and R ″ is hydrogen, sodium, potassium, calcium, or a cation forming one pharmaceutically acceptable salt; Wherein the method comprises reacting an ester of carbonylphosphonodiacid halide with a silyl ether of an alcohol under conditions such that the compound is prepared. Including, methods. 33. A compound of the formula (IV) wherein G is one or more electron donating substituents or one electron withdrawing substituent at the meta position and L is one substituted alkyl group. : A compound represented by the formula: 34. R is one alkyl or aryl group, R 'is one substituted alkyl group and the silyl ether of the alcohol is the silyl group of the vicinal diol so that a compound of formula V is formed. 33. The method of claim 32, which is an ether.