Hydroxylation activated drug release

Abstract

The present invention concerns prodrugs whose aromatic oxidation, particularly their enzymatic aromatic hydroxylation, results in their activation by the release of a drug moiety. It particularly concerns anti-tumour prodrugs and those which are specifically activated by the hydroxylation activity of the P-450 enzyme CYP1B1.

1 . A prodrug comprising a drug moiety bound to a carrier framework, the prodrug being activated by aromatic oxidation of the carrier framework to release the drug moiety.  
     
     
         2 . A prodrug according to  claim 1 , being activated by aromatic hydroxylation.  
     
     
         3 . A prodrug according to  claim 2 , being activated by enzymatic aromatic hydroxylation.  
     
     
         4 . A prodrug according to  claim 1 , and having the formula (Z):  
       
         
           
           
               
               
           
         
       
       wherein: 
 X=H, OH, OMe or N(CH 3 ) 2 ; and  
 n=0-6;  
 and:  
 R 1 =H, C 1-4  lower alkyl, or together with R 2  forms part of a cycloalkyl group which may be further substituted to form part of a polycyclic cycloalkyl group, or with R 2  forms part of a steroidal carbon framework;  
 R 2 =H, C 1-4  lower alkyl, or together with R 1  and/or R 3  forms part of a cycloalkyl, polycyclic cycloalkyl or steroidal carbon framework, or forms part of a polycyclic aromatic group by linkage to R 4 ;  
 R 3 =H, C 1-4  lower alkyl or together wit R 2  forms part of a cycloalkyl, polycyclic cycloalkyl or steroidal carbon framework; and  
 R 4 =H or is fused directly to the aromatic position designated by R 2  and either: 
 the drug moiety is derived from a drug having a free amino, hydroxyl or thiol group and which links it to the rest of the prodrug, such tat A represents NH, NR (R=C 1-4  lower alkyl), O or S; or  
 the drug moiety is derived from a drug having a carboxylate group, an ester linkage joining it to the rest of the prodrug and A being absent  
 
 
     
     
         5 . A prodrug according to  claim 1 , being an anti-tumour prodrug.  
     
     
         6 . A prodrug according to  claim 1 , the drug moiety being a cytotoxic or cytostatic agent.  
     
     
         7 . A prodrug according to  claim 6 , a cytotoxic drug moiety being selected from the group of colchicine, esperimycin, taxol, daunomycin, staurosporin, and nitrogen mustard.  
     
     
         8 . A prodrug according to  claim 1 , being activated by hydroxylation by CYP1B1.  
     
     
         9 . A prodrug according to  claim 1 , the drug moiety being an antimitotic agent, an alkylating agent, an antifolate, a DNA damaging agent or an enzyme inhibitor.  
     
     
         10 . A prodrug according to  claim 4 , the olefin linkage  
       
         
           
           
               
               
           
         
       
       having a cis- or trans-geometry.  
     
     
         11 . A prodrug according to  claim 4 , the olefin linkage  
       
         
           
           
               
               
           
         
       
       being acyclic or cyclic.  
     
     
         12 . A prodrug according to  claim 4 , the olefin linkage  
       
         
           
           
               
               
           
         
       
       forming part of an aromatic or polycyclic aromatic system.  
     
     
         13 . A prodrug according to  claim 1 , the linkage to the drug moiety from the carrier framework being from a hydroxyalkyl group in the prodrug via a carbamate, carbonate or thiocarbonate linker to an amino, hydroxy or thiol group in the drug moiety.  
     
     
         14 . A prodrug according to  claim 1 , having a steroid carbon carrier framework.  
     
     
         15 . A prodrug according to  claim 1 , being derived from estradiol.  
     
     
         16 . A prodrug according to  claim 4 , having the formula of any one of formulae (I)-(IX):  
       
         
           
           
               
               
           
         
       
       wherein —OR=—OMe or —OH.  
     
     
         17 . A prodrug according to  claim 4  having the formula of any one of Formulae (X)-(XV):  
       
         
           
           
               
               
           
         
       
     
     
         18 . A prodrug according to any one of the preceding claims, its aromatic oxidation being by hydroxylation and causing the release of the drug moiety and carbon dioxide.  
     
     
         19 . A prodrug according to  claim 1  for use in a method of treatment or diagnosis of the human or animal body.  
     
     
         20 . The use of a prodrug according to  claim 1  in the manufacture of a medicament.  
     
     
         21 . A method of manufacture of a medicament, comprising the use of a prodrug according to  claim 1 .  
     
     
         22 . A method of treatment of a patient, comprising administering to the patient a prodrug according to  claim 1.