Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1999-04-08
2001-12-11
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
Reexamination Certificate
active
06329356
ABSTRACT:
BACKGROUND OF INVENTION
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.
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
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.
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
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 occurrence, O or S; Y
1
and Y
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.
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
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. In a particularly preferred embodiment, R
1
, R
2
and R
3
are each independently a sodium, potassium or calcium cation. In certain embodiments in which at least one of R
1
and R
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
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):
in which R
1
, R
2
, R
3
, Y
1
, Y
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
1
, R
2
, R
3
, Y
1
, Y
2
, and X are as defined above, R
a
and R
b
are each independently hydrogen, alkyl, aryl, or heterocyclyl, or R
a
and R
b
, taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the ring, and n is an integer from 0 to 6. In certain preferred embodiments, R
a
and R
b
are each hydrogen. In certain preferred embodiments, a compound of the invention comprises an &agr;-amino acid (or &agr;-amino acid ester), more preferably a L-&agr;-amino acid or ester.
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.
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 amnyloidosis 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 depositio
Kong Xianqi
Szarek Walter A.
DeConti, Jr. Giulio A.
Hanley Elizabeth A.
Lahive & Cockfield LLP
Neurochem, Inc.
Reamer James H.
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