Compositions including triciribine and one or more platinum compounds and methods of use thereof

Abstract

This application encompasses combination therapies including triciribine and related compounds and one or more platinum compounds and compositions with reduced toxicity for the treatment and prevention of tumors, cancer, and other disorders associated with abnormal cell proliferation.

1 . A composition comprising:
 (i) a compound of the formula I-IV:   
       
         
           
           
               
               
           
         
         
           wherein each R 2 ′, R 3 ′ and R 5 ′ are independently hydrogen, optionally substituted phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower alkyl); amide, sulfonate ester including alkyl or arylalkyl; sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as for example as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group that, in vivo, provides a compound wherein R2′, R3′ or R5′ is independently H or mono-, di- or tri-phosphate; 
           wherein R x  and R y  are independently hydrogen, optionally substituted phosphate; acyl (including lower acyl); amide, alkyl (including lower alkyl); aromatic, polyoxyalkylene such as polyethyleneglycol, optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group. In one embodiment, the compound is administered as a 5′-phosphoether lipid or a 5′-ether lipid. 
           R 1  and R 2  each are independently H, optionally substituted straight chained, branched or cyclic alkyl (including lower alkyl), alkenyl, or alkynyl, CO-alkyl, CO-alkenyl, CO-alkynyl, CO-aryl or heteroaryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl; 
         
         (ii) one or more platinum compounds as in formula V, 
       
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3  and R 4  are each independently hydrogen, optionally substituted amine, aromatic amine, heteroaromatic amine, optionally substituted straight chained, branched or cyclic alkyl, aromatic, heteroaromatic or cyclic ring formed among R 1 , R 2 , R 3  and R 4 ; 
 R 5  and R 6  are each independently halogen, optionally substituted alkoxy, optionally substituted ester, optionally substituted alkyl amine, aromatic amine, heteroaromatic amine: 
 (iii) a pharmaceutically acceptable carrier. 
 
     
     
         2 . The composition of  claim 1 , wherein the compound of formula I is triciribine. 
     
     
         3 . The composition of  claim 1 , wherein the compound of formula I is triciribine phosphate. 
     
     
         4 . The composition of  claim 1 , wherein the compound of formula I is triciribine phosphate monohydrate. 
     
     
         5 . The composition of  claim 1 , wherein the platinum compounds of formula V is 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 , R 2 , R 3  and R 4  are each independently hydrogen, optionally substituted amine, aromatic amine, heteroaromatic amine, optionally substituted straight chained, branched or cyclic alkyl, aromatic, heteroaromatic or cyclic ring formed among R 1 , R 2 , R 3  and R 4    
 R 5  and R 6  are each independently halogen. 
 
     
     
         6 . The composition of  claim 1 , wherein the one or more platinum compounds are selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The composition of  claim 1 , wherein the compound of formula I is present in a dose amount of at least 10 mg/m 2 . 
     
     
         8 . The composition of  claim 1 , wherein the compound of formula V is present in an amount of at least 1 mg/kg. 
     
     
         9 . The composition of  claim 1 , suitable for parenteral administration. 
     
     
         10 . The composition of  claim 9 , wherein the parenteral administration is intravenous administration. 
     
     
         11 . The composition of  claim 1 , suitable for oral administration. 
     
     
         12 . The composition of  claim 1 , suitable for topical administration. 
     
     
         13 . A method of treating a tumor or cancer in a mammal comprising administering to the mammal an effective amount of a composition comprising:
 a compound of formula I-IV:   
       
         
           
           
               
               
           
         
         
           wherein each R2′, R3′ and R5′ are independently hydrogen, optionally substituted phosphate or phosphonate (including mono-, di-, or triphosphate or a stabilized phosphate prodrug); acyl (including lower acyl); alkyl (including lower iky amide, sulfonate ester including alkyl or arylalkyl; sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as for example as described in the definition of an aryl given herein; optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving group that, in vivo, provides a compound wherein R2′, R3′ or R5′ is independently H or mono-, di- or tri-phosphate; 
           wherein R x  and R y  are independently hydrogen, optionally substituted phosphate; acyl (including lower acyl); amide, alkyl (including lower alkyl); aromatic, polyoxyalkylene such as polyethyleneglycol, optionally substituted arylsulfonyl; a lipid, including a phospholipid; an amino acid; a carbohydrate; a peptide; or cholesterol; or other pharmaceutically acceptable leaving roup. In one embodiment, the compound is administered as a 5′-phosphoether lipid or a 5′-ether lipid. 
           R 1  and R 2  each are independently H, optionally substituted straight chained, branched or cyclic alkyl (including lower alkyl), alkenyl, or alkynyl, CO-alkyl, CO-alkenyl, CO-alkynyl, CO-aryl or heteroaryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl; and 
         
         (ii) one or more platinum compounds of formula V, 
       
       
         
           
           
               
               
           
         
         wherein
 R 1 , R 2 , R 3  and R 4  are each independently hydrogen, optionally substituted amine, aromatic amine, heteroaromatic amine, optionally substituted straight chained, branched or cyclic alkyl, aromatic, heteroaromatic or cyclic ring formed among R 1 , R 2 , R 3  and R 4 ; 
 R 5  and R 6  are each independently halogen, optionally substituted alkoxy, optionally substituted ester, optionally substituted alkyl amine, aromatic amine, heteroaromatic amine. 
 
       
     
     
         14 . The method of  claim 13 , wherein a compound of formula I-IV and a compound of formula V are administered simultaneously. 
     
     
         15 . The method of  claim 13 , wherein a compound of formula I-IV is administered followed by the administration of a compound of formula V. 
     
     
         16 . The method of  claim 13 , wherein a compound of formula V is administered followed by the administration of a compound of formula I-IV. 
     
     
         17 . The method of  claim 13 , wherein the compound of formula I-IV is administered one time per week for three weeks followed by a one week period wherein the compound is not administered. 
     
     
         18 . The method of  claim 13 , wherein the compound of formula V is administered one time per week for three weeks followed by a one week period wherein the compound of formula I-IV is not administered. 
     
     
         19 . The method of  claim 18 , wherein the dosing schedule is repeated at least twice. 
     
     
         20 . The method of  claim 18 , wherein the dosing schedule is repeated at least 4 times. 
     
     
         21 . The method of  claim 13 , wherein the tumor treated is breast, pancreatic, ovarian and colorectal tumors. 
     
     
         22 . The method of  claim 13 , wherein at least 10 g/m 2  of the compound of formula I-IV is administered. 
     
     
         23 . The method of  claim 13 , wherein 100 mg/m 2  or less of the compound of formula I-IV is administered. 
     
     
         24 . The method of  claim 13 , wherein at least 1 mg/kg of the compound of formula V is administered. 
     
     
         25 . The method of  claim 13 , wherein 10 mg/kg or less of the compound of formula V is administered.