N-oxides and derivatives of melphalan for treating diseased states associated with hypoxia inducible factor

Abstract

This invention relates to compounds which are N-oxides and derivatives thereof, as well as their use to treat HIF related diseases. These compounds have the general formula set out below and are used to treat a variety of diseases associated with HIF: wherein R is an alkyl, aryl, arakyl or derivatives thereof such as CH 3 OCH 2 CH 2 —, CH 3 CH 2 OCH 2 CH 2 —, C 6 H 5 OCH 2 CH 2 —, C 6 H 5 CH 2 —, CH 3 (CH 2 ) 3 OCH 2 CH 2 Cl; or any one of the following:

What is claimed:  
     
         1 . A therapeutic compound or a salt thereof useful for treating cells under either normoxic or hypoxic conditions having the formula:  
       
         
           
           
               
               
           
         
       
       wherein R is an alkyl, aryl or derivative thereof, or any of the following:  
       
         
           
           
               
               
           
         
       
     
     
         2 . The theraputic compound set out in  claim 1  having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         2 . A pharmaceutical formulation comprising a compound or a salt of said compound as set out in  claim 1  or  claim 2 , together with a pharmaceutically acceptable carrier or diluent.  
     
     
         3 . A pharmaceutical formulation comprising a compound as set out in  claim 3  together with another pharmaceutical.  
     
     
         4 . The therapeutic compound as set out in  claim 2  having the name (S-2-amino-3-[4′-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride)  
     
     
         5 . The salt of the compounds set out in  claim 1  or  claim 2 .  
     
     
         6 . The salt as set out in  claim 6  wherein the salt is HCl, acetate, tosylate or picrate.  
     
     
         7 . A pharmaceutical formulation comprising a compound as set out in  claim 1 , or a salt of said compound, together with a pharmaceutically acceptable carrier or diluent.  
     
     
         8 . A therapeutic compound or salt thereof useful for treating cells under normoxic or hypoxic conditions having the formula:  
       
         
           
           
               
               
           
         
       
       wherein R is an alkyl, aryl or derivative thereof, or any of the following:  
       
         
           
           
               
               
           
         
       
     
     
         9 . A pharmaceutical formulation comprising a compound as set out in  claim 9  or a salt of said compound, together with a pharmaceutically acceptable carrier or diluent.  
     
     
         10 . A pharmaceutical formulation comprising a compound as set out in  claim 9  together with another pharmaceutical.  
     
     
         11 . A method of inhibiting angiogenic growth in a patient in need thereof comprised of administering a compound of  claim 10 .  
     
     
         12 . A method of inhibiting HIF-1-α in a patient in need thereof comprised of administering a compound of  claim 10 .  
     
     
         13 . A method of inhibiting VEGF formation in a patient in need thereof comprised of administering a compound in accordance with  claim 10 .  
     
     
         14 . A method of inhibiting tumor formation in a patient in need thereof comprised of administering a compound of  claim 10.