Compositions including triciribine and bortezomib and derivatives thereof and methods of use thereof

Abstract

This application relates to combination therapies including triciribine and related compounds and bortezomib and derivatives thereof analogs 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 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 alkyl); amide, sulfonate ester including alkyl or arylalkyl; sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with 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 viva, 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) a compound of formula V: 
       
       
         
           
           
               
               
           
         
       
       wherein
 R 1 , R 2 , R 3 , R 4 , and R 5  each are independently H, optionally halogenated, substituted straight chained, branched or cyclic alkyl (including lower alkyl), alkoxyl, alkenyl, or alkynyl, aryl, CO-alkyl, CO-alkenyl, CO-alkynyl, CO-aryl or heteroaryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl; and 
 (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 phosphonate monohydrate. 
     
     
         5 . The composition of  claim 1 , wherein the bortezomib and derivatives thereof are of the formula: 
       
         
           
           
               
               
           
         
       
       wherein at least one of R 1 -R 5  is —H. 
     
     
         6 . The composition of  claim 1 , wherein the bortezomib and derivatives thereof are of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         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 II is present in an amount of at least 10 mg/m 2 . 
     
     
         9 . The composition of  claim 1 , suitable for parenteral administration. 
     
     
         10 . The composition of  claim 1 , 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:
 (i) 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 alkyl); amide, sulfonate ester including alkyl or arylalkyl; sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with 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) a compound of formula V: 
       
       
         
           
           
               
               
           
         
       
       wherein
 R 1 , R 2 , R 3 , R 4 , and R 5  each are independently H, optionally halogenated, substituted straight chained, branched or cyclic alkyl (including lower alkyl), alkoxyl, alkenyl, or alkynyl, aryl, CO-alkyl, CO-alkenyl, CO-alkynyl, CO-aryl or heteroaryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, sulfonyl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl. 
 
     
     
         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 is not administered. 
     
     
         19 . The method of  claim 14 , wherein the dosing schedule is repeated at least twice. 
     
     
         20 . The method of  claim 14 , 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 mg/m 2  of the compound of formula I-IV is administered. 
     
     
         23 . The method of  claim 13 , wherein 10 mg/m 2  or less of the compound of formula I-IV is administered. 
     
     
         24 . The method of  claim 13 , wherein at least 10 mg/m 2  of the compound of formula V is administered. 
     
     
         25 . The method of  claim 13 , wherein 10 mg/m 2  or less of the compound of formula V is administered. 
     
     
         26 . The method of  claim 13 , wherein 10 mg/m 2  or less of the compound of formula V is administered as a 3 to 5 second bolus intravenous injection twice weekly for 2 weeks.