Combretastatin A-4 phosphate prodrug mono-and di-organic amine salts, mono-and di-amino acid salts, and mono-and di-amino acid ester salts

Abstract

Provided herein are novel and useful combretastatin A-4 prodrug salts that increase the solubility of combretastatin A-4, readily regenerate combretastatin A-4 in vivo under normal physiological conditions, and which produce physiologically tolerable products as a result of the regeneration of combretastatin A-4.

1 . A compound having the structure of formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 one of —OR 1  or —OR 2  is —O − QH + , and the other is hydroxyl or —O − QH + ; and Q is an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH + .  
 
     
     
         2 . The compound of  claim 1 , wherein said amino acid is selected from the group consisting of lysine, tryptophan, arginine, ornithine, proline, glutamine, asparagine, hydroxyproline and steroisomers thereof.  
     
     
         3 . A pharmaceutical composition comprising: 
 (a) a compound having the structure of formula I:                          wherein:    one of —OR 1  or —OR 2  is —O − QH + , and the other is hydroxyl or —OQH + ; and    Q is an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH +  and a pharmaceutically acceptable carrier thereof.    
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein said amino acid is selected from the group consisting of lysine, tryptophan, arginine, ornithine, proline, glutamine, asparagine, hydroxyproline and steroisomers thereof.  
     
     
         5 . A method of modulating tumor growth or metastasis in an animal comprising the administration of an amount effective therefor of a compound having the structure of formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 one of —OR 1  or —OR 2  is —O − QH + , and the other is hydroxyl or —O − QH + ; and Q is an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH + .  
 
     
     
         6 . The method of  claim 5 , wherein said amino acid is selected from the group consisting of lysine, tryptophan, arginine, ornithine, proline, glutamine, asparagine, hydroxyproline, and steroisomers thereof.  
     
     
         7 . A composition formed by mixing compounds comprising: 
 (a) a CA4P free acid having the structure:                          (b) compound Q, wherein Q is an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH + .    
     
     
         8 . The composition of  claim 7  further comprising a pharmaceutically acceptable carrier.  
     
     
         9 . A process for preparing a compound of  claim 1 , comprising the step of contacting, in a solvent, CA4P free acid having the structure:  
       
         
           
           
               
               
           
         
       
       with compound Q, wherein Q is an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH + .  
     
     
         10 . The process of  claim 9 , wherein said compound of  claim 1  is precipitated in crystalline form from said solvent.