Compounds, compositions, and methods for the treatment of cancers

Abstract

The present teachings relate to compounds and compositions for treatment of cancers. In some embodiments, the composition comprises a platinum (IV) complex having at least one polar moiety as a ligand.

1 - 24 . (canceled) 
     
     
         25 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof, 
       wherein:
 two of R 1 , R 2 , R 3 , and R 4  are each independently a halide or a carboxylate; 
 the remaining two of R 1 , R 2 , R 3 , and R 4  are each independently ammonia; 
 (i) X is NR 5  and Y is absent, C(R 6 ) 2 , or NR 6 ; or 
 (ii) X is absent, C(R 5 ) 2 , or NR 5  and Y is NR 6 ; and 
 R 5  and R 6  are each independently hydrogen, alkyl, alkenyl, alkynyl, ether, amine, or carboxylate, wherein each of the alkyl, alkenyl, alkynyl, ether, and amine is unsubstituted or substituted with one or more halogen, hydroxyl, ether, alkoxy, or amine; wherein each of the ether, alkoxy, or amine is unsubstituted or substituted; 
 provided that when X and Y are each NH, 
 each R 5  and R 6  are independently hydrogen, linear alkyl, alkenyl, alkynyl, ether, amine, or carboxylate, wherein each of the linear alkyl, alkenyl, alkynyl, ether, and amine is unsubstituted or substituted with one or more halogen, hydroxyl, ether, alkoxy, or amine; wherein each of the ether, alkoxy, or amine is unsubstituted or substituted. 
 
     
     
         26 . The compound of  claim 25 , wherein the compound has Formula Ia: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The compound of  claim 25 , wherein:
 when X is NR 5 , Y is absent or C(R 6 ) 2 , and   when Y is NR 6 , X is absent or C(R 5 ) 2 .   
     
     
         28 . The compound of  claim 25 , wherein X and Y are different. 
     
     
         29 . The compound of  claim 25 , wherein each of R 1  and R 2  is ammonia. 
     
     
         30 . The compound of  claim 25 , wherein each of R 3  and R 4  is Cl. 
     
     
         31 . The compound of  claim 25 , wherein R 3  and R 4  are joined together to form oxalate. 
     
     
         32 . The compound of  claim 25 , wherein one of R 5  and R 6  is methyl. 
     
     
         33 . The compound of  claim 25 , wherein X or Y is absent. 
     
     
         34 . The compound of  claim 25 , wherein X or Y is NH. 
     
     
         35 . The compound of  claim 25 , wherein one of R 5  and R 6  is an alkyl that is unsubstituted or substituted with an amine, wherein the amine is unsubstituted or substituted. 
     
     
         36 . The compound of  claim 25 , wherein the compound has a log P of less than about 2.0,
 wherein the log P is determined by   (i) measuring a retention time of the compound on a reverse phase HPLC column by applying a mobile phase, wherein the mobile phase comprises:
 (A) 95/5 mixture of water/acetonitrile with 0.1% trifluoroacetic acid; and 
 (B) 95/5 mixture of acetonitrile/water with 0.1% trifluoroacetic acid; 
 at a gradient of 90% (A) :10% (B) to 0% (A) :100% (B) over 8 minutes, at a flow rate of 1.5 ml/min; and 
   (ii) comparing the retention time of the compound to a reference sample.   
     
     
         37 . The compound of  claim 36 , wherein the compound has a log P of less than about 1.7. 
     
     
         38 . The compound of  claim 36 , wherein the compound has a log P of less than about 1.3. 
     
     
         39 . The compound of  claim 36 , wherein the compound has a log P of less than about 1.1. 
     
     
         40 . The compound of  claim 25 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         41 . A pharmaceutical composition comprising in unit dosage form a compound having the formula I, and a pharmaceutically acceptable carrier 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof, 
       wherein:
 two of R 1 , R 2 , R 3 , and R 4  are each independently a halide or a carboxylate; 
 the remaining two of R 1 , R 2 , R 3 , and R 4  are each independently ammonia; 
 (i) X is NR 5  and Y is absent, C(R 6 ) 2 , or NR 6 ; or 
 (ii) X is absent, C(R 5 ) 2 , or NR 5  and Y is NR 6 ; and 
 R 5  and R 6  are each independently hydrogen, alkyl, alkenyl, alkynyl, ether, amine, or carboxylate, wherein each of the alkyl, alkenyl, alkynyl, ether, and amine is unsubstituted or substituted with one or more halogen, hydroxyl, ether, alkoxy, or amine; wherein each of the ether, alkoxy, or amine is unsubstituted or substituted; 
 provided that when X and Y are each NH, 
 each R 5  and R 6  are independently hydrogen, linear alkyl, alkenyl, alkynyl, ether, amine, or carboxylate, wherein each of the linear alkyl, alkenyl, alkynyl, ether, and amine is unsubstituted or substituted with one or more halogen, hydroxyl, ether, alkoxy, or amine; wherein each of the ether, alkoxy, or amine is unsubstituted or substitute. 
 
     
     
         42 . The pharmaceutical composition of  claim 41 , in a form suitable for intravenous administration. 
     
     
         43 . The pharmaceutical composition of  claim 41 , wherein the pharmaceutical composition comprises a buffering agent. 
     
     
         44 . The pharmaceutical composition of  claim 41 , wherein the pharmaceutical composition comprises a sugar. 
     
     
         45 . A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutical composition comprising a compound of formula I 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof, 
       wherein:
 two of R 1 , R 2 , R 3 , and R 4  are each independently a halide or a carboxylate; 
 the remaining two of R 1 , R 2 , R 3 , and R 4  are each independently ammonia; 
 (i) X is NR 5  and Y is absent, C(R 6 ) 2 , or NR 6 ; or 
 (ii) X is absent, C(R 5 ) 2 , or NR 5  and Y is NR 6 ; and 
 R 5  and R 6  are each independently hydrogen, alkyl, alkenyl, alkynyl, ether, amine, or carboxylate, wherein each of the alkyl, alkenyl, alkynyl, ether, and amine is unsubstituted or substituted with one or more halogen, hydroxyl, ether, alkoxy, or amine; wherein each of the ether, alkoxy, or amine is unsubstituted or substituted; 
 provided that when X and Y are each NH, 
 each R 5  and R 6  are independently hydrogen, linear alkyl, alkenyl, alkynyl, ether, amine, or carboxylate, wherein each of the linear alkyl, alkenyl, alkynyl, ether, and amine is unsubstituted or substituted with one or more halogen, hydroxyl, ether, alkoxy, or amine; wherein each of the ether, alkoxy, or amine is unsubstituted or substitute. 
 
     
     
         46 . The method of  claim 45 , wherein the cancer is lung cancer. 
     
     
         47 . The method of  claim 45 , wherein the cancer is ovarian cancer. 
     
     
         48 . The method of  claim 45 , wherein the cancer is breast cancer. 
     
     
         49 . The method of  claim 45 , wherein the cancer is prostate cancer