Cancer treatment using compounds that selectively target polyploid cancer cells for disruption

Abstract

The disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4 are as described herein. The disclosure also provides methods for identifying a compound that selectively kills polyploid cells, and methods for killing polyploid tumor cells by administering a compound of Formula Ito a patient in need thereof.

1 .- 10 . (canceled) 
     
     
         11 . A method of killing polyploid tumor cells, comprising:
 administering to a patient in need thereof, a compound of Formula I:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is independently selected from hydrogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, alkyloxy, alkyloxyalkyl, alkylamine, dialkylamine, arylamine, heterocyclyl, alkylheterocyclyl, aryl, alkylaryl, and heteroaryl, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, alkyl, cycloalkyl, alkoxy, aryloxy esteryl, and aryl; 
 R 2  is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, alkoxy, and alkyloxyalkyl, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, alkyl, cycloalkyl, alkoxy, aryloxy, esteryl, and aryl; 
 R 3  and R 4  are each independently selected from hydrogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, alkyloxy, alkyloxyalkyl, alkylamine, dialkylamine, arylamine, heterocyclyl, heterocyclyl, alkylheterocyclyl, aryl, alkylaryl, and heteroaryl, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, alkyl, cycloalkyl, alkoxy, aryloxy esteryl, or aryl, or 
 R 3  and R 4  together form a 5 or 6-membered heteroaryl ring or a 6-membered aryl ring, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, alkyl, cycloalkyl, alkoxy, aryloxy esteryl, or aryl. 
 
     
     
         12 . The method of  claim 11 , wherein:
 R 1  is independently selected from hydrogen, hydroxyl, amino, thiol, (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 3 -C 20 )cycloalkyl, (C 5 -C 20 )cycloalkenyl, (C 8 -C 20 )cycloalkynyl, (C 1 -C 20 )alkyl(C 3 -C 20 )cycloalkyl, (C 1 -C 20 )alkyl(C 5 -C 20 )cyclo-alkenyl, (C 1 -C 20 )alkyl(C 8 -C 20 )cycloalkynyl, (C 1 -C 20 )alkyloxy, (C 1 -C 20 )alkyloxy(C 1 -C 20 )alkyl, (C 1 -C 20 )alkylamine, (C 1 -C 20 )dialkylamine, arylamine, heterocyclyl, (C 1 -C 20 )alkylhetero-cyclyl, aryl, (C 1 -C 20 )alkylaryl, and heteroaryl, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, (C 1 -C 6 )alkyl, (C 3 -C 20 )cycloalkyl, (C 1 -C 20 )alkoxy, aryloxy, esteryl, and aryl;   R 2  is independently selected from (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 3 -C 20 )cycloalkyl, (C 1 -C 20 )alkyl(C 3 -C 20 )cycloalkyl, (C 1 -C 20 )alkoxy, and (C 1 -C 20 )alkyloxy(C 1 -C 20 )alkyl, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, (C 1 -C 20 )alkyl, (C 3 -C 20 )cycloalkyl, (C 1 -C 20 )alkoxy, aryloxy, esteryl, and aryl;   R 3  and R 4  are each independently selected from hydrogen, hydroxyl, amino, thiol, (C 1 -C 20 )alkyl, (C 2 -C 20 )alkenyl, (C 2 -C 20 )alkynyl, (C 3 -C 20 )cycloalkyl, (C 5 -C 20 )cycloalkenyl, (C 8 -C 20 )cycloalkynyl, (C 1 -C 20 )alkyl(C 3 -C 20 )cycloalkyl, (C 1 -C 20 )alkyl(C 5 -C 20 )cycloalkenyl, (C 1 -C 20 )alkyl(C 8 -C 20 )cycloalkynyl, (C 1 -C 20 )alkyloxy, (C 1 -C 20 )alkyloxy(C 1 -C 20 )alkyl, (C 1 -C 20 )alkylamine, (C 1 -C 20 )dialkylamine, arylamine, heterocyclyl, alkylheterocyclyl, aryl, alkylaryl, and heteroaryl, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, (C 1 -C 20 )alkyl, (C 3 -C 20 )cycloalkyl, (C 1 -C 20 )alkoxy, aryloxy, esteryl, and aryl, or   R 3  and R 4  together form a 5 or 6 membered heterocyclic or heteroaryl ring or a 6 membered aryl ring, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, (C 1 -C 20 )alkyl, (C 3 -C 20 )cycloalkyl, (C 1 -C 20 )alkoxy, aryloxy, esteryl, and aryl.   
     
     
         13 . The method of  claim 11 , wherein:
 R 3  and R 4  together form a 5-membered heterocyclic ring selected from substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrazolidine, substituted or unsubstituted imidazolidine, substituted or unsubstituted tetrahydrofuran, and substituted or unsubstituted tetrahydrothiophene, or   R 3  and R 4  together form a 5-membered heteroaryl ring selected from substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted indole, substituted or unsubstituted benzofuran, and substituted or unsubstituted benzo[b]thiophene, or   R 3  and R 4  together form a 6-membered heterocyclic ring selected from substituted or unsubstituted piperidine, substituted or unsubstituted piperazine, substituted or unsubstituted thiane, substituted or unsubstituted morpholine, and substituted or unsubstituted thiomorpholine, or   R 3  and R 4  together form a 6-membered heteroaryl ring selected from substituted or unsubstituted pyridine, substituted or unsubstituted pyridazine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrazine, and substituted or unsubstituted morpholine, or   R 3  and R 4  together form a 6-membered aryl ring selected from substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, and substituted or unsubstituted naphthyl.   
     
     
         14 . The method of  claim 11 , wherein:
 R 1  is independently selected from hydroxyl;   R 2  is independently selected from (C 1 -C 20 )alkyl;   R 3  is independently selected from hydroxyl; and   R 4  is independently selected from hydrogen.   
     
     
         15 . A combination of therapeutic agents for use in treating a patient suffering from cancer, comprising:
 a) at least one polyploidy inducing agent for use in inducing polyploidization in one or more cancer cells in the patient; and   b) a compound of Formula I:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is independently selected from hydrogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, alkyloxy, alkyloxyalkyl, alkylamine, dialkylamine, arylamine, heterocyclyl, alkylheterocyclyl, aryl, alkylaryl, and heteroaryl, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, alkyl, cycloalkyl, alkoxy, aryloxy esteryl, and aryl; 
 R 2  is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, alkoxy, and alkyloxyalkyl, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, alkyl, cycloalkyl, alkoxy, aryloxy, esteryl, and aryl; 
 R 3  and R 4  are each independently selected from hydrogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, alkyloxy, alkyloxyalkyl, alkylamine, dialkylamine, arylamine, heterocyclyl, heterocyclyl, alkylheterocyclyl, aryl, alkylaryl, and heteroaryl, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, alkyl, cycloalkyl, alkoxy, aryloxy esteryl, or aryl, or 
 R 3  and R 4  together form a 5 or 6-membered heteroaryl ring or a 6-membered aryl ring, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, alkyl, cycloalkyl, alkoxy, aryloxy esteryl, or aryl. 
 
     
     
         16 . The combination of  claim 15 , wherein the at least one polyploidy inducing agent is an Aurora Kinase inhibitor that is specific to one type of aurora kinases or nonspecific to all three types of aurora kinases. 
     
     
         17 . A method of treating a patient suffering from cancer, comprising:
 a) administering to a patient suffering from cancer a therapeutically effective amount of at least one polyploidy inducing agent, and   b) administering to the patient a therapeutically effective amount of a compound of Formula I:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is independently selected from hydrogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, alkyloxy, alkyloxyalkyl, alkylamine, dialkylamine, arylamine, heterocyclyl, alkylheterocyclyl, aryl, alkylaryl, and heteroaryl, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, alkyl, cycloalkyl, alkoxy, aryloxy esteryl, and aryl; 
 R 2  is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, alkoxy, and alkyloxyalkyl, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, alkyl, cycloalkyl, alkoxy, aryloxy, esteryl, and aryl; 
 R 3  and R 4  are each independently selected from hydrogen, hydroxyl, amino, thiol, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkylcycloalkyl, alkylcycloalkenyl, alkylcycloalkynyl, alkyloxy, alkyloxyalkyl, alkylamine, dialkylamine, arylamine, heterocyclyl, heterocyclyl, alkylheterocyclyl, aryl, alkylaryl, and heteroaryl, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, alkyl, cycloalkyl, alkoxy, aryloxy esteryl, or aryl, or 
 R 3  and R 4  together form a 5 or 6-membered heteroaryl ring or a 6-membered aryl ring, each optionally independently substituted with 1 to 6 substituents selected from hydrogen, halogen, nitro, amino, cyano, isocyano, thiol, hydroxyl, alkyl, cycloalkyl, alkoxy, aryloxy esteryl, or aryl. 
 
     
     
         18 . The method of  claim 17 , wherein the at least one polyploidy inducing agent is an Aurora Kinase inhibitor.