Method of Treating Colorectal Cancer

Abstract

The present invention relates to the use of certain platinum compounds including [PtCb(cis-1,4-diaminocyclohexane)], or combinations of these compounds with a variety of other agents for treating and/or preventing the progression of colorectal cancer in mammals. In particular, the invention provides methods of treating and/or preventing oxaliplatin-refractory colorectal cancer in mammals.

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         11 . A method of treating refractory colorectal cancer in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of formula II 
       
         
           
           
               
               
           
         
         wherein R is —(CH 2 ) n — in which n is an integer from one to three; 
         R 1  is hydrogen, carboxyl, an alkyl group of from one to four carbon atoms, an alkyl group of from one to four carbon atoms substituted with an alkoxy group of from one to four carbon atoms, a cycloalkyl group of from three to six carbon atoms, a hydroxyalkyl group of from one to four carbon atoms, an alkoxy group of from one to four carbon atoms or benzyl; and 
         R 2  and R 3  are negatively charged monodentate ligands which may be the same or different and are selected from the group consisting of chloro, bromo, iodo, hydroxo, nitrato, nitrito, acetato and dichloracetato or R 2  and R 3  taken together form a dinegatively charged bidentate ligand selected from the group consisting of sulfato, oxalato, 
       
       
         
           
           
               
               
           
         
         in which R 4  is hydrogen, hydroxyl, or an alkyl group of from one to four carbon atoms, 
       
       
         
           
           
               
               
           
         
         in which o is an integer from one to three and 
       
       
         
           
           
               
               
           
         
       
       and
 R 5  and R 6  are negatively charged monodentate ligands which may be the same or different and are selected from the group consisting of chloro, bromo, iodo, hydroxo, nitrato, nitrito, benzoato, 3,4,5-trihydroxybenzoato, 3,4,5-trimethoxtbenzoato, R 7 (CH 2 ) p —CO 2 — wherein R, is selected from the group consisting of methyl, trifluoromethyl, CH 2 Cl, CH 2 Br, CH 2 F, CHCl 2 , CHBr 2  and CHF 2  and p is zero or an integer of one to five and R 7 (CH 2 ) q —O— wherein R 7  is defined above and q is zero or an integer of one to five. 
 
     
     
         12 . The method of  claim 11  wherein R is —(CH 2 ) n —, in which n is an integer from two to three; R 1  is hydrogen, carboxyl, an alkyl group of from one to four carbon atoms or an alkoxy group of from one to four carbon atoms; and R 2  and R 3  are negatively charged monodentate ligands which may be the same or different and are selected from the group consisting of chloro and bromo or R 2  and R 3  taken together form a dinegatively charged bidentate ligand selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 12  wherein R 1  is hydrogen, carboxyl, methyl, or methoxy. 
     
     
         14 . The method of  claim 11  wherein a compound of formula II is selected from the group consisting of:
 (OC-6-33)-dichloro(cis-1,4-cyclohexanediamine-N,N′)bisdichloroacetateplatinum; 
 [OC-6-22-(cis)]tetrachloro(1,4-cyclohexanediamine-N,N′)platinum; 
 (OC-6-33)-dichloro(cis-1,4-cyclohexanediamine-N,N′)dihydroxyplatinum; 
 (OC-6-33)-[ethanedioato(2)-O,O′](cis-1,4-cyclohexanediamine-N,N′)dihydroxyplatinum; and 
 (OC-6-33)-[ethanedioato(2)-O,O′](cis-1,4-cyclohexanediamine-N,N′)bisdichloroacetateplatinum. 
 
     
     
         15 . The method of  claim 14  wherein a compound of formula II is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 11  wherein the refractory colorectal cancer is oxaliplatin-refractory cancer. 
     
     
         17 . The method of  claim 16  wherein the mammal is a human. 
     
     
         18 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
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         20 . The method of  claim 11  further comprising at least one second therapeutic agent useful in treating colorectal cancer selected from the group consisting of: capecitabine; cetuximab; bevacizumab; a MEK inhibitor; a FOLFOX4 dosing schedule consisting of oxaliplatin, 5-fluorouracil and leucovorin; and a FOLFIRI dosing schedule consisting of irinotecan, 5-fluorouracil and leucovorin.