C2-C5-Alkyl-Imidazole-Bisphosphonates

Abstract

C 2 -C 5 -Alkyl-substituted [imidazol-1-yl)-1-hydroxy-1-phosphono-ethyl]-phosphonic acids, as well as methods or processes for their manufacture, their use in the manufacture of pharmaceutical formulations, their use in the treatment of diseases, methods of using them in the treatment of diseases, pharmaceutical formulations encompassing them and/or the compounds for use in the treatment of diseases, are described. The compounds are able to inhibit excessive or inappropriate bone resorption and for the treatment of other diseases which are caused by excessive prenylation of target proteins, such as Hutchinson-Gilford progeria syndrome. The compounds are of the formula I, wherein one of R 1 and R 2 is hydrogen and the other is C 2 -C 5 -alkyl that is branched or unbranched, and can be in free form, in the form of an ester, and/or of a salt.

1 . A compound of the formula I, 
       
         
           
           
               
               
           
         
         wherein one of R 1  and R 2  is hydrogen and the other is C 2 -C 5 -alkyl that can be branched or unbranched, or an ester, and/or a salt thereof. 
       
     
     
         2 . A compound of the formula I according to  claim 1 , wherein
 R 1  is C 2 -C 5 -alkyl, especially propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl or especially ethyl and   R 2  is hydrogen,   or an ester thereof, and/or an (especially pharmaceutically acceptable) salt thereof.   
     
     
         3 . A compound of the formula I according to  claim 1 , wherein
 R 1  is hydrogen and   R 2  is C 2 -C 5 -alkyl, especially propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl or especially ethyl,   or an ester thereof, and/or an (especially pharmaceutically acceptable) salt thereof.   
     
     
         4 . A compound of the formula I according to  claim 1  wherein
 R 1  is hydrogen and 
 R 2  is ethyl, 
 or an ester thereof, and/or an (especially pharmaceutically acceptable) salt thereof. 
 
     
     
         5 . A compound of the formula I according to  claim 1 , wherein
 R 1  is ethyl and   R 2  is hydrogen,   or an ester thereof, and/or an (especially pharmaceutically acceptable) salt thereof.   
     
     
         6 . A compound of the formula I, an ester and/or a pharmaceutically acceptable salt thereof, according to  claim 1  for use in the diagnostic and/or therapeutic treatment of an animal, especially a human. 
     
     
         7 . A compound of the formula I, an ester and/or a pharmaceutically acceptable salt thereof, according to  claim 1  for use in the treatment of excessive or inappropriate bone resorption. 
     
     
         8 . A pharmaceutical composition, comprising a compound of the formula I, an ester and/or a pharmaceutically acceptable salt thereof, according to  claim 1  and at least one pharmaceutically acceptable carrier. 
     
     
         9 . A method of treatment of an animal, especially a human, comprising administering to an animal, especially a human, in need thereof an amount of a compound of the formula I, an ester and/or a pharmaceutically acceptable salt thereof, according to  claim 1 , sufficient for the treatment of excessive or inappropriate bone resorption or a disease caused by excessive prenylation of target proteins. 
     
     
         10 . The use of a compound of the formula I, an ester and/or a pharmaceutically acceptable salt thereof, according to  claim 1  in the treatment of excessive or inappropriate bone resorption or a disease caused by excessive prenylation of target proteins. 
     
     
         11 . The use of a compound of the formula I, an ester and/or a pharmaceutically acceptable salt thereof according to  claim 1  in the treatment of excessive or inappropriate bone resorption or a disease caused by excessive prenylation of target proteins. 
     
     
         12 . A process or method for the manufacture of a compound of the formula I, an ester and/or a salt thereof according to  claim 1 , comprising reacting a carboxylic acid compound of the formula II, 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are as defined for a compound of the formula I in any one of  claims 1  to  5 , with phosphorous oxyhalogenide to give a compound of the formula I, or a salt thereof, 
         and, if desired, converting an obtainable free compound of the formula I into its salt, converting an obtainable salt of a compound of the formula I into the free compound and/or converting an obtainable salt of a compound of the formula I into a different salt thereof.