Compositions and methods for treatment of cancer

Abstract

The present invention relates to pyrroloquinolinyl-pyrrolidine-2,5-dione compounds in combination with chemotherapeutic agents. The present invention provides methods of treating a cell proliferative disorder, such as a cancer, by administering to a subject in need thereof a therapeutically effective amount of a pyrroloquinolinyl-pyrrole-2,5-dione compound or pyrroloquinolinyl-pyrrolidine-2,5-dione compound of the present invention and also administering a effective amount of a chemotherapeutic agent.

What is claimed is: 
     
         1 . A pyrroloquinolinyl-pyrrolidine-2,5-dione compound of formula IVa, IVb, Va, or Vb, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R1, R2 and R3 are independently selected from the group consisting of hydrogen, F, Cl, Br, I, —NR5R6, —(C 1 -C 6 ) alkyl, —(C 1 -C 6 ) substituted alkyl, —(C 3 -C 9 ) cycloalkyl, —(C 3 -C 9 ) substituted cycloalkyl, —O—(C 1 -C 6 ) alkyl, —O—(C 1 -C 6 ) substituted alkyl, —O—(C 3 -C 9 ) cycloalkyl, —O—(C 3 -C 9 ) substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl; 
 R4 is selected from the group consisting of hydrogen, —(C 1 -C 6 ) alkyl, and —CH 2 R7; 
 R5 and R6 are independently selected from the group consisting of hydrogen and —(C 1 -C 6 ) alkyl; 
 R7 is selected from the group consisting of —O—P(═O)(OH) 2 , —O—P(═O)(—OH)(—O—(C 1 -C 6 ) alkyl), —O—P(═O)(—O—(C 1 -C 6 ) alkyl) 2 , —O—P(═O)(—OH)(—O—(CH 2 )-phenyl), —O—P(═O)(—O—(CH 2 )-phenyl) 2 , a carboxylic acid group, an amino carboxylic acid group, and a peptide; 
 Q is selected from the group consisting of aryl, heteroaryl, —O-aryl, —S-aryl, —O— heteroaryl, and —S-heteroaryl; 
 X is selected from the group consisting of —(CH 2 )—, S, —(NR8)-, and O; 
 R8 is independently selected from the group consisting of hydrogen, —(C 1 -C 6 ) alkyl, —(C 1 -C 6 ) substituted alkyl, —(C 3 -C 9 ) cycloalkyl, —(C 3 -C 9 ) substituted cycloalkyl, and —O—(C 1 -C 6 ) alkyl, —C(═O)—O—(C 1 -C 6 ) alkyl and —C(═O)—O—(C 1 -C 6 ) substituted alkyl; 
 Y is selected from the group consisting of —(CH 2 )— and a bond; 
 wherein said aryl, heteroaryl, —O-aryl, —S-aryl, —O-heteroaryl, and —S-heteroaryl may be substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, —NR5R6, —(C 1 -C 6 ) alkyl, —(C 1 -C 6 ) substituted alkyl, —(C 3 -C 9 ) cycloalkyl, —(C 3 -C 9 ) substituted cycloalkyl, —O—(C 1 -C 6 ) alkyl, —O—(C 1 -C 6 ) substituted alkyl, —O—(C 3 -C 9 ) cycloalkyl, —O—(C 3 -C 9 ) substituted cycloalkyl, -aryl, -aryl-(C 1 -C 6 ) alkyl, -aryl-O—(C 1 -C 6 ) alkyl, —O-aryl, —O—(C 1 -C 4 ) alkyl-aryl, heteroaryl, heterocyclyl, —O—(C 1 -C 4 ) alkyl-heterocycle, and —(S(═O) 2 )—(C 1 -C 6 ) alkyl; and 
 m is 1 or 2. 
 
     
     
         2 . The compound of  claim 1 , wherein Q is an indolyl group or an indolyl group substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, —(C 1 -C 6 ) alkyl, —(C 1 -C 6 ) fluoro-substituted alkyl, —(C 3 -C 9 ) cycloalkyl, —(C 3 -C 9 ) fluoro-substituted cycloalkyl, —O—(C 1 -C 6 ) alkyl, —O—(C 1 -C 6 ) fluoro-substituted alkyl, —O—(C 3 -C 9 ) cycloalkyl, —O—(C 3 -C 9 ) fluoro-substituted cycloalkyl, -aryl, —O-aryl, —O—(C 1 -C 4 ) alkyl-aryl, —O—(C 1 -C 4 ) alkyl-heterocycle, and —S(═O) 2 —(C 1 -C 6 ) alkyl. 
     
     
         3 . The compound of  claim 1 , wherein R4 is —CH 2 R7, and R7 is —O—P(═O)(OH) 2 , —O—P(═O)(—OH)(—O—(C 1 -C 6 ) alkyl), —O—P(═O)(—O—(C 1 -C 6 ) alkyl) 2 , a carboxylic acid group, an amino carboxylic acid group, or a peptide. 
     
     
         4 . The compound of  claim 3 , wherein R7 is —O—P(═O)(OH) 2 , —O—P(═O)(—OH)(—O—(C 1 -C 6 ) alkyl), or —O—P(═O)(—O—C 1 -C 6 )alkyl) 2 . 
     
     
         5 . The compound of  claim 3 , wherein R7 is a carboxylic acid group, an amino carboxylic acid group, or a peptide. 
     
     
         6 . The compound of  claim 5 , wherein R7 is alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine. 
     
     
         7 . The compound of  claim 6 , wherein R7 is L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamine, L-glutamic acid, L-glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, or L-valine. 
     
     
         8 . The compound of  claim 5 , wherein R7 is a peptide. 
     
     
         9 . The compound of  claim 8 , wherein said peptide is comprised of two or more imino or amino acids selected from the group consisting of: L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamine, L-glutamic acid, L-glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine. 
     
     
         10 . The compound of  claim 1 , wherein R1, R2 and R3 are each hydrogen. 
     
     
         11 . The compound of  claim 1 , wherein R4 is hydrogen. 
     
     
         12 . A method of treating a cell proliferative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein the cell proliferative disorder is selected from lung cancer, colon cancer, breast cancer, pancreatic cancer, prostate cancer, chronic myelogenous leukemia, melanoma, and ovarian cancer. 
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or excipients.