Phosphono-carboxylate compounds for treating amyloidosis

Abstract

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.