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.

What is claimed is:  
     
         1 . A method for modulating amyloid deposition in a subject, comprising administering to a subject an effective amount of a therapeutic compound such that modulation of amyloid deposition occurs, 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;  
 R 4  is hydrogen, lower alkyl, aryl or amino;  
 X is, independently for each occurrence, 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 an integer from 0 to 12.  
 
     
     
         2 . The method of  claim 1 , wherein Z is XR 2 .  
     
     
         3 . The method of  claim 2 , wherein R 1  and R 2  are each a pharmaceutically acceptable salt-forming cation.  
     
     
         4 . The method of  claim 3 , in which R 1 , R 2  and R 3  are each independently a sodium, potassium or calcium cation.  
     
     
         5 . The method of  claim 4 , wherein n is 0.  
     
     
         6 . The method of  claim 1 , wherein at least one of R 1  and R 2  is a long-chain aliphatic moiety.  
     
     
         7 . The method of  claim 6 , wherein R 3  is a lower alkyl group.  
     
     
         8 . The method of  claim 1 , wherein Y 1  and Y 2  are each hydrogen.  
     
     
         9 . The method of  claim 1 , wherein the therapeutic compound is administered orally.  
     
     
         10 . The method of  claim 1 , further comprising administering the therapeutic compound in a pharmaceutically acceptable vehicle.  
     
     
         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, for each occurrence, O.  
     
     
         13 . The method of  claim 1 , wherein the compound is represented by the formula:  
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 1 , wherein the compound is represented by the formula:  
       
         
           
           
               
               
           
         
       
       in which 
 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.  
 
     
     
         15 . The method of  claim 14 , in which R a  and R b  are each hydrogen.  
     
     
         16 . A method for treating a disease state associated with amyloidosis, comprising: 
 administering to a subject an effective amount of a therapeutic compound such that a disease state associated with amyloidosis is treated, wherein the therapeutic compound has the formula                          in which    R 1  and R 2  are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclyl 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, lower alkyl, amino, hydroxy, alkoxy, or aryloxy; and    n is an integer from 0 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 pharmaceutically acceptable salt-forming cation.  
     
     
         19 . The method of  claim 18 , in which R 1 , R 2  and R 3  are each independently a sodium, potassium or calcium cation.  
     
     
         20 . The method of  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 moiety.  
     
     
         22 . The method of  claim 21 , wherein R 3  is a lower alkyl group.  
     
     
         23 . The method of  claim 16 , wherein Y 1  and Y 2  are each hydrogen.  
     
     
         24 . The method of  claim 16 , wherein the amino group is —NH 2 .  
     
     
         25 . The method of  claim 16 , wherein the therapeutic compound is administered orally.  
     
     
         26 . The method of  claim 16 , further comprising administering the therapeutic compound in a pharmaceutically acceptable vehicle.  
     
     
         27 . A method for modulating amyloid deposition in a subject in which said amyloid deposition is characterized by interaction between an amyloidogenic protein and a constituent of a basement membrane, the method comprising administering to the subject an effective amount of a therapeutic compound such that modulation of amyloid deposition characterized by interaction between an amyloidogenic protein and a constituent of a basement membrane occurs, wherein the therapeutic compound has the formula:  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  and R 2  are each independently hydrogen, an aliphatic group, an aryl group, a heterocyclyl 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, lower alkyl, amino, hydroxy, alkoxy, or aryloxy; and  
 n is an integer from 0 to 12.  
 
     
     
         28 . The method of  claim 27 , wherein R 1  and R 2  are each a pharmaceutically acceptable salt-forming cation.  
     
     
         29 . The method of  claim 28 , in which R 1 , R 2  and R 3  are each independently a 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 moiety.  
     
     
         32 . A method for preparing a compound represented by the formula:  
       
         
           
           
               
               
           
         
       
       in which R is alkyl or aryl, and R′ is hydrogen, alkyl, or aryl;  
       the method comprising: 
 reacting an ester of a carbonylphosphono diacid halide with a disiylether of a vicianl diol, under conditions such that the compound of Formula V is prepared.  
 
     
     
         33 . A compound represented by the formula (Formula IV):  
       
         
           
           
               
               
           
         
         wherein G is hydrogen or one of more substituents on the aryl ring and the L is a substituted alkyl group.