Thiazoline acid derivatives

Abstract

The present invention relates to novel thiazoline acids and derivatives thereof useful as chelators of trivalent metals in therapeutic applications. For example, the thiazoline acid derivatives are useful in diagnosing and treating pathological conditions associated with an excess of trivalent metals in humans and animals.

I claim:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 Z is CH or N;  
 R is H or acyl;  
 R 1 , R 2 , R 3  and R 5  may be the same or different and represent H, alkyl or hydrocarbyl arylalkyl having up to 14 carbon atoms; and  
 R 4  is H or alkyl having 1-4 carbon atoms;  
 a salt thereof with a pharmaceutically acceptable acid or a pharmaceutically acceptable complex thereof.  
 
     
     
         2 . A compound of  claim 1  wherein Z is CH and R=R 1 =R 2 =R 3 =R 4 =R 5 =H.  
     
     
         3 . A compound of  claim 1  wherein Z is N and R=R 1 =R 2 =R 3 =R 4 =R 5 =H.  
     
     
         4 . A compound of  claim 1  wherein Z is CH, R=R 1 =R 2 =R 3 =R 5 =H, and R 4  is alkyl having 1-4 carbon atoms.  
     
     
         5 . A compound of  claim 4  wherein R 4  is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.  
     
     
         6 . A compound of  claim 1  wherein Z is N, R=R 1 =R 2 =R 3 =R 5 =H, and R 4  is alkyl having 1-4 carbon atoms.  
     
     
         7 . A compound of  claim 6  wherein R 4  is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.  
     
     
         8 . A compound of  claim 1  having the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 Z, R, R 1 , R 2 , R 3 , R 4 , and R 5  have the meanings ascribed thereto in  claim 1;   
 a salt thereof with a pharmaceutically acceptable acid or a pharmaceutically acceptable complex thereof.  
 
     
     
         9 . A compound of  claim 8  wherein Z is CH and R=R 1 =R 2 =R 3 =R 4 =R 5 =H.  
     
     
         10 . A compound of  claim 8  wherein Z is N and R=R 1 =R 2 =R 3 =R 4 =R 5 =H.  
     
     
         11 . A compound of  claim 8  wherein Z is CH, R=R 1 =R 2  =R 3 =R 5 =H, and R 4  is alkyl having 1-4 carbon atoms.  
     
     
         12 . A compound of  claim 11  wherein R 4  is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.  
     
     
         13 . A compound of  claim 8  wherein Z is N, R=R 1 =R 2 =R 3 =R 5 =H, and R 4  is alkyl having 1-4 carbon atoms.  
     
     
         14 . A compound of  claim 13  wherein R 4  is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl.  
     
     
         15 . A compound of  claim 8  wherein Z is CH, R=R 4 =R 1 =R 2 =R 5 =H, and R 3  is alkyl having 1-4 carbon atoms.  
     
     
         16 . A compound of  claim 8  wherein Z is CH, R=R 4 =R 1 =R 3 =R 5 =H, and R 2  is alkyl having 1-4 carbon atoms.  
     
     
         17 . A compound of  claim 8  wherein Z is CH, R=R 4 =R 3 =R 2 R 5 =H, and R 1  is alkyl having 1-4 carbon atoms.  
     
     
         18 . A compound of  claim 8  wherein Z is N, R=R 4 =R 1 =R 2 =R 5 =H, and R 3  is alkyl having 1-4 carbon atoms.  
     
     
         19 . A compound of  claim 8  wherein Z is N, R=R 4 =R 1 =R 3 =R 5 =H, and R 2  is alkyl having 1-4 carbon atoms.  
     
     
         20 . A compound of  claim 8  wherein Z is N, R=R 4 =R 3 =R 2 =R 5 =H, and R 1  is alkyl having 1-4 carbon atoms.  
     
     
         21 . An optically pure compound of  claim 1  or  8 .  
     
     
         22 . An (S)-enantiomer compound of  claim 8  having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         23 . An (S)-enantiomer compound of  claim 8  having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         24 . An (S)-enantiomer compound of  claim 8  having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         25 . An (R)-enantiomer compound of  claim 8  having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         26 . An (R)-enantiomer compound of  claim 8  having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         27 . An (R)-enantiomer compound of  claim 8  having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         28 . A pharmaceutical composition in unit dosage form comprising a therapeutically effective amount of a compound according to  claim 1  or  8  and a pharmaceutically acceptable carrier therefor.  
     
     
         29 . A method of preventing or treating a pathological condition in a human or non-human animal that is associated with an excess of a trivalent metal, ion or compound thereof comprising administering to said animal a therapeutically effective amount of a compound according to  claim 1  or  8 .