Novel nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic agents

Abstract

The present invention relates to novel nitrophenyl mustard and nitrophenylaziridine alcohols, to their corresponding phosphates, to their use as targeted cytotoxic agents; as bioreductive drugs in hypoxic tumours, and to their use in cell ablation, including gene-directed enzyme-prodrug therapy (GDEPT) and antibody-directed enzyme-prodrug therapy (ADEPT), in conjunction with nitroreductase enzymes.

1 - 7 . (canceled) 
   
   
       8 . A method of anticancer treatment including the step of administering to a subject an amount of a compound of Formula (I) 
     
       
         
         
             
             
         
       
     
   
   
       9 . (canceled) 
   
   
       10 . The method as claimed in  claim 8  including the further step of applying irradiation or one or more chemotherapeutic agents to the subject. 
   
   
       11 . The method as claimed in  claim 8  wherein the subject is a human. 
   
   
       12 . The method as claimed in  claim 8  wherein the amount administered is between about 20% to 100% of the maximum tolerated dose of the subject. 
   
   
       13 - 26 . (canceled) 
   
   
       27  An alcohol compound of Formula (II) 
     
       
         
         
             
             
         
       
       wherein: 
       X represents at any available ring position —CONH—, —SO 2 NH—, —O—, —CH 2 —, —NHCO— or —NHSO 2 —; 
       Y represents at any available ring position —N-aziridinyl, —N(CH 2 CH 2 W) 2 , or —N(CH 2 CHMeW) 2  where each W is independently selected from halogen or —OSO 2 Me; 
       Z represents at any available ring position —NO 2 , -halogen, —CN, —CF 3  or —SO 2 Me; 
       R represents a lower C 1-6  alkyl optionally substituted with one or more groups including hydroxy, amino and N-oxides therefrom or dialkylamino and N-oxides therefrom; and pharmaceutically acceptable salts and derivatives thereof; with the proviso that 
       when Z represents NO 2  and Y represents N(CH 2 CH 2 C1) 2 , X and R together cannot represent —CONHCH 2 (CHOH)CH 2 — and with the further proviso that the following compounds 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       are excluded. 
     
   
   
       28 . The alcohol compound of Formula (II) as claimed in  claim 27  selected from a compound represented by formulae (IIa), (IIb) or (IIc) 
     
       
         
         
             
             
         
       
       wherein Y may represent 
     
     
       
         
         
             
             
         
       
       and wherein 
       n represents 1 to 6 
       Z represents —NO 2 , -halogen, —CN, —CF 3  or —SO 2 Me; and 
       where each W is independently selected from halogen or —OSO 2 Me and pharmaceutically acceptable salts and derivatives thereof with the proviso that 
       when Z represents NO 2  and Y represents N(CH 2 CH 2 Cl) 2 , X and R together cannot represent —CONHCH 2 (CHOH)CH 2 — and with the further proviso that the following compounds 
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       are excluded. 
     
   
   
       29 . The alcohol compound of Formula (II) selected from a compound of Formula (IIb) or (IIc) as defined in  claim 28 . 
   
   
       30 . The alcohol compound of Formula (II) as defined in  claim 28  selected from:
 N-(2-Hydroxyethyl)-5-[bis(2-bromocthyl)amino]-2,4-dinitrobeuzamide;   N-(4-Hydroxybutyl)-5-[bis(2-bromoethyl)amino]l-2,4-dinitrobenzamide;   N-(5-Hydroxypentyl)-5-[bis(2-bromoethyl)amino]-2,4-dinitrobenzamide;   N-(6-Hydroxyhexyl)-5-[bis(2-bromoethyl)amino]-2,4-dinitrobenzamide;   5-[Bis(2-bromoethyl)amino]-N-(2-hydroxyethyl)-4-(methylsulfonyl)-2-nitrobenzamide;   2[(2-Bromoethyl)-5-[[(3-hydroxypropyl)amino]carbonyl]-2,4-dinitroanilino]ethyl methanesulfonate;   5-[Bis(2-iodoethyl)amino]-N-(2-hydxoxyethyl)-2,4-dinitrobenzamide;   2-[Bis(2-Chloroethyl)amino]-N-(2-hydroxyethyl)-3,5-dinitrobenzamide;   2-[Bis(2-bromoethyl)amino]-N-(2-hydroxyethyl)-3,5-dinitrobenzamide;   2-[Bis(2-chloroethyl)amino]-N-(3-hydroxypropyl)-3,5-dinitrobenzamide;   2-[Bis(2-bromoethyl)amino]-N-(3-hydroxypropyl)-3,5-dinitrobenzamide;   2-[Bis(2-chloroethyl)amino]-N-(4-hydroxybutyl)-3,5-dinitrobenzamide,   2-[Bis(2-bromoethyl)amino]-N-(4-hydroxybutyl)-3,5-dinitrobenzamide;   2-[Bis(2-chloroethyl)amino]-N-(5-hydroxypentyl)-3,5-dinitrobenzamide,   2-[Bis(2-bromoethyl)amino]-N-(5-hydroxypentyl)-3,5-dinitrobenzamide;   2-[Bis(2-chloroethyl)amino]-N-(6-hydroxyhexyl)-3,5-dinitrobenzamide;   2-[Bis(2-bromoethyl)amino]-N-(6-hydroxyhexyl)-3,5-dinitrobenzamide;   2-[Bis(2-bromopropyl)amino]-N-(2-hydroxyethyl)-3,5-dinitrobenzamide;   2-((2-Bromoethyl)-2-{[(2-hydroxypropyl)amino]carbonyl}-4,6-dinitroanilino)ethyl methanesulfonate;   2-((2-Bromoethyl)-2-{[(2-hydroxyethyl)amino]carbonyl}-4,6-dinitroanilino)ethyl methanesulfonate;   2-((2-Chloroethyl)-2-{[(2-hydroxyethyl)amino]carbonyl}-4,6-dinitroanilino)ethyl methanosulfonate;   2-[Bis(2-iodoethyl)amino]-N-(2-hydroxyethyl)-3,5-dinitrobenzamide;   2-((2-iodoethyl)-2-{[(2-hydroxyethyl)amino]carbonyl}-4,6-dinilroanilino)ethyl methanesulfonate;   3-[Bis(2-bromoethyl)amino]-N-(2-hydroxyethyl)-2,6-dinitrobenzantide;   2-((2-Bromoethyl)-3-{[(2-hydroxyethyl)amino]carbonyl}-2,4-dinitroanilino)ethyl methanesulfonate;   3-[Bis(2-bromoethyl)amino]-N-(3-hydroxypropyl)-2,6-dinitrobenzamide;   2-((2-bromoethyl)-3-{[(3-hydroxypropyl)amino]carbonyl}-2,4-dinitroanilino)ethyl methanesulfonate;   3-[Bis(2-bromoethyl)amino]-N-(4-hydroxybutyl)-2,6-dinitrobenzamide;   2-((2-Bromoethyl)-3-{[(4-hydroxybutyl)amino)carbonyl}-2,4-dinitroanilino)ethyl methanesulfonate;   2-((2-Chloroethyl)-3-{[(3-hydroxypropyl)amino]carbonyl}-2,4-dinitroanilino)ethyl methanesulfonate; and   2-((2-Iodoethyl)-3-{[(3-hydroxypropyl)amino]carbonyl}-2,4-dinitroanilino)ethyl methanesulfonate.   
   
   
       31 . A method of preparing a compound of formulae (IIa), (IIb) or (IIc) 
     
       
         
         
             
             
         
       
       wherein Y may represent 
     
     
       
         
         
             
             
         
       
       and wherein 
       n represents 1 to 6 
       Z represents —NO 2 , -halogen, —CN, —CF 3  or —SO 2 Me; and 
       where W 1  is halogen and W 2  is —OSO 2 Me 
       and pharmaceutically acceptable salts and derivatives thereof; 
       the method including the step of 
       reacting a compound of formulae (IIa′), (IIb′) or (IIc′) optionally with heating 
     
     
       
         
         
             
             
         
       
       wherein Y may represent 
     
     
       
         
         
             
             
         
       
       wherein W′ 1  and W′ 2  are each halogen; 
       with an effective amount of silver methanesulfonate (AgOMs) in a solvent to give a compound of formulae (IIa), (IIb) or (IIc) defined above in this claim. 
     
   
   
       32 . The method as claimed in  claim 31  wherein the solvent is selected from MeCN or other polar non-protic solvent. 
   
   
       33 . A compound of formula (IIa), (IIb) or (IIc) obtained by the method defined in  claim 31 . 
   
   
       34 . A method of anticancer treatment including the step of administering an amount of a compound of Formula (II) as defined in  claim 27  to a subject. 
   
   
       35 . A method of killing hypoxic cells in a tumour including the step of administering an amount of a compound of Formula (II) as defined in  claim 27  to a subject with the tumour, 
   
   
       36 . The method as claimed in  claim 34  including the further step of applying irradiation or one or more chemotherapeutic agents to the subject. 
   
   
       37 . The method as claimed in  claim 34  wherein the subject is a human. 
   
   
       38 . A method of cell ablation utilising at least one nitroreductase enzyme including the step of using a compound of Formula (II) as defined in  claim 27  in an effective amount to ablate cells which express at least one nitroreductase enzyme. 
   
   
       39 . A method of cell ablation utilising at least one nitroreductase enzyme including the step of administering a compound of Formula (II) as defined in  claim 27  in an effective amount to a subject to ablate cells which express at least one nitroreductase enzyme. 
   
   
       40 . The method as claimed in  claim 39  wherein the at least one nitroreductase enzyme is encoded for by the nfsB gene of either  E. coli  or by orthologous genes in  Clostridia  species. 
   
   
       41 . The method as claimed in  claim 39  wherein the cells that express the at least one nitroreductase enzyme are tumour cells in tissue in the subject. 
   
   
       42 . The method as claimed in  claim 39  wherein the cell ablation is achieved through GDEPT (gene-directed enzyme-prodrug therapy). 
   
   
       43 . The method as claimed in  claim 39  wherein the cell ablation is achieved through ADEPT (antibody-directed enzyme-prodrug therapy). 
   
   
       44 . The method as claimed in  claim 39  wherein the cells are mammalian. 
   
   
       45 . The method as claimed in  claim 39  including the thither step of applying irradiation or one or more chemotherapeutic agents to the subject. 
   
   
       46 . A pharmaceutical composition including a therapeutically effective amount of a compound of Formula (II) as claimed in  claim 27  and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabiliser. 
   
   
       47 - 50 . (canceled) 
   
   
       51 . A method of treating cancer comprising the step of administering an effective amount of the compound 2-[(2-Bromoethyl)-2,4-dinitro-6-[[[2-(phosphonooxy)ethyl]amino]-carbonyl]anilino]ethyl methanesulfonate to a subject.