Acid-Labile Lipophilic Prodrugs of Cancer Chemotherapeutic Agents

Abstract

The present application discloses an acid labile lipophilic molecular conjugate of cancer chemotherapeutic agents and methods for reducing or substantially eliminating the side effects of chemotherapy associated with the administration of a cancer chemotherapeutic agent to a patient in need thereof.

What is claimed is: 
     
         1 - 17 . (canceled) 
     
     
         18 . A pharmaceutical composition comprising an acid labile lipophilic molecular conjugate (ALLMC) of the formula  1 : 
       
         
           
           
               
               
           
         
         wherein:
 R is a 2′ hydroxyl residue of a paclitaxel, a docetaxel or an abeo-taxane compound; 
 R 1  is hydrogen; 
 R 2  is a C 5 -C 22  alkyl; 
 Y is selected from O, NR′ or S wherein R′ is hydrogen or C 1 -C 6  alkyl; 
 Z is O or S; 
 Q is O; and T is O; 
 
         or an enantiomer, diastereoisomer or mixtures thereof; and 
         a pharmaceutically acceptable salt thereof; 
         wherein the acid labile lipophilic molecular conjugate (ALLMC) is dissolved in the lipid core of a pseudo-LDL particle; and the pharmaceutical composition is formulated as a liquid formulation or solution for parenteral administration. 
       
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the liquid formulation is a lipid emulsion (INTRALIPID®) for intravenous injection. 
     
     
         20 . The pharmaceutical composition of  claim 18 , wherein the liquid formulation is a buffered, isotonic, aqueous solution. 
     
     
         21 . The composition of  claim 18 , wherein the liquid formulation further comprise suitable diluents selected from the group consisting of normal isotonic saline solution, 5% dextrose in water or buffered sodium or ammonium acetate solution. 
     
     
         22 . The pharmaceutical composition of  claim 18 , wherein the acid labile lipophilic molecular conjugate is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The pharmaceutical composition of  claim 18 , wherein the acid labile lipophilic molecular conjugate of  claim 18 , where the conjugate is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The pharmaceutical composition of  claim 18 , wherein the acid labile lipophilic molecular conjugate of  claim 18 , where the conjugate is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The pharmaceutical composition of  claim 18 , wherein the acid labile lipophilic molecular conjugate of  claim 18 , where the conjugate is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The pharmaceutical composition of  claim 18 , wherein the acid labile lipophilic molecular conjugate of  claim 18 , where the conjugate is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The pharmaceutical composition of  claim 18 , wherein the acid labile lipophilic molecular conjugate of  claim 18 , where the conjugate is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The pharmaceutical composition of  claim 18 , wherein the acid labile lipophilic molecular conjugate of  claim 18 , where the conjugate is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         29 . The pharmaceutical composition of  claim 18 , wherein the acid labile lipophilic molecular conjugate of  claim 18 , where the abeo-taxane conjugate is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         30 . The pharmaceutical composition of  claim 18 , wherein the acid labile lipophilic molecular conjugate of  claim 18 , where the abeo-taxane conjugate is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         31 . The pharmaceutical composition of  claim 18 , wherein the acid labile lipophilic molecular conjugate of  claim 18 , where the abeo-taxane conjugate is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         32 . A method for the treatment of cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound or composition of  claim 18 , to a patient in need of such treatment. 
     
     
         33 . The method of  claim 32 , wherein the cancer is selected from the group consisting of leukemia, neuroblastoma, glioblastoma, cervical, colorectal, pancreatic, renal and melanoma. 
     
     
         34 . The method of  claim 32 , wherein the cancer is selected from the group consisting of lung, breast, prostate, ovarian and head and neck. 
     
     
         35 . A method for reducing or substantially eliminating the side effects of chemotherapy associated with the administration of a cancer chemotherapeutic agent to a patient, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising an acid labile lipophilic molecular conjugate of the formula 1: 
       
         
           
           
               
               
           
         
         wherein:
 R is a 2′ hydroxyl residue of a paclitaxel, a docetaxel or an abeo-taxane compound; 
 R 1  is hydrogen; 
 R 2  is a C 5 -C 22  alkyl; 
 Y is selected from O, NR′ or S wherein R′ is hydrogen or C 1 -C 6  alkyl; 
 Z is O or S; 
 Q is O; and T is O; 
 
         or an enantiomer, diastereoisomer or mixtures thereof; 
         or a pharmaceutically acceptable salt thereof; 
         wherein the acid labile lipophilic molecular conjugate (ALLMC) is dissolved in the lipid core of a pseudo-LDL particle; and the pharmaceutical composition is formulated as a liquid formulation or solution for parenteral administration. 
       
     
     
         36 . The method of  claim 35 , wherein the method provides a higher concentration of the cancer chemotherapeutic agent in a cancer cell of the patient.