Novel Prodrugs And Methods Of Use Thereof

Abstract

The invention relates to compounds of use as targeted cytotoxic agents and methods of use thereof. In particular, the invention relates to prodrugs that are substantially resistant to human AKR1C3 enzyme metabolism, methods of cell ablation using said compounds and methods of treatment of cancer and other hyperproliferative disorders using said compounds.

1 - 20 . (canceled) 
     
     
         21 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein W represents Cl, Br, I, or OSO 2 R, 
         X represents Cl, Br, I, or OSO 2 R, 
         Y represents H, CN, or SO 2 R, 
         each R independently represents a lower C 1-6  alkyl group, and 
         Z is selected from the group consisting of radicals of Formula (Ic): 
       
       
         
           
           
               
               
           
         
         where 
         R 1  represents H, or a lower C1-6 alkyl group; 
         R 2  and R 3  may independently represent H, or a lower C 1-6  alkyl group, 
         n represents an integer from 2 to 6; and 
         * represents a point of attachment to Formula I; 
         or a pharmaceutically acceptable salt of said compound. 
       
     
     
         22 . A compound of formula I as claimed in  claim 21 , wherein W is bromine or iodine. 
     
     
         23 . A compound of formula I as claimed in  claim 21 , wherein X is bromine or OSO 2 Me. 
     
     
         24 . A compound of formula I as claimed in  claim 21 , wherein R 1  is hydrogen, methyl or ethyl. 
     
     
         25 . A compound of formula I as claimed in  claim 21 , wherein n represents 2 or 3. 
     
     
         26 . The compound of  claim 21 , wherein the pharmaceutically acceptable salt of the compound is a methanesulfonate salt. 
     
     
         27 . A compound of formula I as claimed in  claim 21  represented by the formula (Ib): 
       
         
           
           
               
               
           
         
       
     
     
         28 . A compound of formula I as claimed in  claim 27  represented by the formula (Ib) wherein Y represents SO 2 Me. 
     
     
         29 . A compound of formula (Ib) as claimed in  claim 27 , wherein Z is 
       
         
           
           
               
               
           
         
         wherein n represents 2 to 6, R 1  represents H, methyl or ethyl, and R 2  and R 3  may independently represent H, or a lower C1-6 alkyl group. 
       
     
     
         30 . A compound of formula (Ib) as claimed in  claim 29  selected from:
 5-(bis(2-bromoethyl)amino)-N-(2-(dimethylamino)ethyl)-4-(methylsulfonyl)-2-nitrobenzamide (compound 36), 
 5-(bis(2-bromoethyl)amino)-N-(2-(dimethylamino)ethyl)-N-methyl-4-(methylsulfonyl)-2-nitrobenzamide (compound 37), 
 5-(bis(2-bromoethyl)amino)-N-(3-(dimethylamino)propyl)-4-(methylsulfonyl)-2-nitrobenzamide (compound 38), 
 5-(bis(2-bromoethyl)amino)-N-(3-(dimethylamino)propyl)-N-methyl-4-(methylsulfonyl)-2-nitrobenzamide (compound 39), 
 5-(bis(2-bromoethyl)amino)-N-(2-(dimethylamino)ethyl)-4-(ethylsulfonyl)-2-nitrobenzamide (compound 48), 
 5-(bis(2-bromoethyl)amino)-N-(2-(dimethylamino)ethyl)-4-(ethylsulfonyl)-N-methyl-2-nitrobenzamide (compound 49), 
 5-(bis(2-bromoethyl)amino)-N-(3-(dimethylamino)propyl)-4-(ethylsulfonyl)-2-nitrobenzamide (compound 50), and 
 5-(bis(2-bromoethyl)amino)-N-(3-(dimethylamino)propyl)-4-(ethylsulfonyl)-N-methyl-2-nitrobenzamide (compound 51). 
 
     
     
         31 . A compound of formula I as claimed in  claim 21  wherein X is OSO 2 Me. 
     
     
         32 . A compound of formula I as claimed in  claim 31  selected from:
 2-((2-bromoethyl)(5-((2-(dimethylamino)ethyl)carbamoyl)-2-(methylsulfonyl)-4-nitrophenyl)amino)ethyl methanesulfonate (compound 324), 
 2-((2-bromoethyl)(5-((2-(dimethylamino)ethyl)(methyl)carbamoyl)-2-(methylsulfonyl)-4-nitrophenyl)amino)ethyl methanesulfonate (compound 325), 
 2-((2-bromoethyl)(5-((3-(dimethylamino)propyl)carbamoyl)-2-(methylsulfonyl)-4-nitrophenyl)amino)ethyl methanesulfonate (compound 326), and 
 2-((2-bromoethyl)(5-((3-(dimethylamino)propyl)(methyl)carbamoyl)-2-(methylsulfonyl)-4-nitrophenyl)amino)ethyl methanesulfonate (compound 327). 
 
     
     
         33 . A compound of formula I as claimed in  claim 31  selected from:
 2-((2-bromoethyl)(5-((2-(dimethylamino)ethyl)carbamoyl)-2-(ethylsulfonyl)-4-nitrophenyl)amino)ethyl methanesulfonate (compound 336), 
 2-((2-bromoethyl)(5-((2-(dimethylamino)ethyl)(methyl)carbamoyl)-2-(ethylsulfonyl)-4-nitrophenyl)amino)ethyl methanesulfonate (compound 337), 
 2-((2-bromoethyl)(5-((3-(dimethylamino)propyl)carbamoyl)-2-(ethylsulfonyl)-4-nitrophenyl)amino)ethyl methanesulfonate (compound 338), and 
 2-((2-bromoethyl)(5-((3-(dimethylamino)propyl)(methyl)carbamoyl)-2-(ethylsulfonyl)-4-nitrophenyl)amino)ethyl methanesulfonate (compound 339). 
 
     
     
         34 . A compound of formula I as claimed in  claim 31  selected from:
 3-(5-((2-bromoethyl) (2-((methylsulfonyl)oxy)ethyl)amino)-4-(methylsulfonyl)-2-nitrobenzamido)propanoic acid (compound 340), 
 4-(5-((2-bromoethyl) (2-((methylsulfonyl)oxy)ethyl)amino)-4-(methylsulfonyl)-2-nitrobenzamido)butanoic acid (compound 341), 
 3-(5-((2-bromoethyl)(2-((methylsulfonyl)oxy)ethyl)amino)-N-methyl-4-(methylsulfonyl)-2-nitrobenzamido)propanoic acid (compound 342), 
 4-(5-((2-bromoethyl)(2-((methylsulfonyl)oxy)ethyl)amino)-N-methyl-4-(methylsulfonyl)-2-nitrobenzamido)butanoic acid (compound 343), 3-(5-((2-bromoethyl)(2-((methylsulfonyl)oxy)ethyl)amino)-4-(ethylsulfonyl)-2-nitrobenzamido)propanoic acid (compound 344), 
 4-(5-((2-bromoethyl)(2-((methylsulfonyl)oxy)ethyl)amino)-4-(ethylsulfonyl)-2-nitrobenzamido)butanoic acid (compound 345), 
 3-(5-((2-bromoethyl)(2-((methylsulfonyl)oxy)ethyl)amino)-4-(ethylsulfonyl)-N-methyl-2-nitrobenzamido) propanoic acid (compound 346), and 
 4-(5-((2-bromoethyl)(2-((methylsulfonyl)oxy)ethyl)amino)-4-(ethylsulfonyl)-N-methyl-2-nitrobenzamido)butanoic acid (compound 347). 
 
     
     
         35 . A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in  claim 21 , or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabiliser. 
     
     
         36 . A method for treating cancer, the method comprising administering a compound of formula (I) of  claim 21 , or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount to a tumor cell, or therapeutically proximate to said tumor cell, in a solid and/or hypoxic tumor in a subject. 
     
     
         37 . The method as claimed in  claim 36 , wherein said therapeutically effective amount is comprised in a pharmaceutical composition further comprising at least one a pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabilizer. 
     
     
         38 . The method as claimed in  claim 36  wherein the cancer is selected from colon cancer, cervical cancer, or lung cancer. 
     
     
         39 . The method as claimed in  claim 36 , further including the steps of:
 a. irradiating the tumor cells; or   b. administering one or more chemotherapeutic agents and/or therapies in the subject;   before, during or after the administration of the compounds of formula (I) or pharmaceutically acceptable salt thereof.   
     
     
         40 . The method as claimed in  claim 36 , wherein said therapeutically effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof is formulated for parenteral administration.