Phosphono-carboxylate compounds for treating amyloidosis
Therapeutic compounds and methods for modulating amyloid deposition in a subject, whatever its clinical setting, are described. Amyloid deposition is modulated by the administration to a subject of an effective amount of a therapeutic compound comprising a phosphonate group and a carboxylate group, a congener thereof, or a pharmaceutically acceptable salt or ester thereof. In preferred embodiments, an interaction between an amyloidogenic protein and a basement membrane constituent is modulated.
1 . A method for treating or preventing a neurodegenerative disorder in a subject, comprising administering to a subject an effective amount of a therapeutic compound such that the neurodegenerative disorder is treated or prevented, wherein the therapeutic compound has the formula:
in which
R 1 and R 2 are each independently hydrogen, a substituted or unsubstituted aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation;
R 3 is hydrogen, lower alkyl, aryl, -or a salt-forming cation;
Y 1 and Y 2 are each independently hydrogen, halogen, or alkyl, amino, hydroxy, alkoxy, or aryloxy; and
n is an integer from 0 to 12.
2 . The method of claim 1 , wherein R 1 and R 2 are each independently an unsubstituted aliphatic group.
3 . The method of claim 1 , wherein R 1 is an aryl group.
4 . The method of claim 3 , wherein the aryl group is a substituted aryl group.
5 . The method of claim 1 , wherein Y 1 and Y 2 are each hydrogen.
6 . The method of claim 1 , wherein Y 1 is hydrogen and Y 2 is alkyl.
7 . The method of claim 6 , wherein the alkyl is a substituted alkyl.
8 . The method of claim 1 , wherein R 1 and R 2 are each an aliphatic group, R 3 is a hydrogen, n=1, Y 1 is a hydrogen and Y 2 is alkyl.
9 . The method of claim 8 , wherein Y 2 is a substituted alkyl.
10 . The method of claim 1 , wherein R 1 is an aryl group, R 2 is hydrogen, R 3 is an alkyl, n=1, and Y1 and Y2 are each hydrogen.
11 . The method of claim 10 , wherein R 1 is a substituted aryl group.
12 . The method of claim 1 , wherein R 1 and R 2 are each hydrogen.
13 . The method of claim 1 , wherein the neurodegenerative disorder is a β-amyloid disorder.
14 . The method of claim 13 , wherein the β-amyloid disorder is Alzheimer's disease.
15 . A pharmaceutical composition comprising a compound of the following formula:
in which
R 1 and R 2 are each independently hydrogen, a substituted or unsubstituted aliphatic group, an aryl group, a heterocyclic group, or a salt-forming cation;
R 3 is hydrogen, lower alkyl, aryl, -or a salt-forming cation;
Y 1 and Y 2 are each independently hydrogen, halogen, or alkyl, amino, hydroxy, alkoxy, or aryloxy; and
n is an integer from 0 to 12; and a pharmaceutically acceptable vehicle.
16 . The pharmaceutical composition of claim 15 , wherein said pharmaceutical composition is adapted for oral administration.
17 . The pharmaceutical composition of claim 15 , wherein R 1 and R 2 are each an aliphatic group, R 3 is a hydrogen, n=1, Y 1 is a hydrogen and Y 2 is alkyl.
18 . The pharmaceutical composition of claim 17 , wherein Y 2 is a substituted alkyl.
19 . The pharmaceutical composition of claim 15 , wherein R 1 is an aryl group, R 2 is hydrogen, R 3 is an alkyl, n=1, and Y1 and Y2 are each hydrogen.
20 . The pharmaceutical composition of claim 19 , wherein R 1 is a substituted aryl group.
21 . The pharmaceutical composition of claim 15 , wherein R 1 and R 2 are each hydrogen.
22 . A method for administering the pharmaceutical composition of claim 15 to a subject, wherein said pharmaceutical composition is administered at a dosage of between about 0.5 to about 500 mg/kg of the body weight of the subject.