Pyrroloquinolinyl-pyrrolidine-2,5-dione formulations and methods for preparing and using same

Abstract

The present invention provides pyrroloquinolinyl-pyrrole-2,5-dione formulations and methods of treating a cell proliferative disorder, such as a cancer, by administering to a subject in need thereof a therapeutically effective amount of the formulations containing pyrroloquinolinyl-pyrrole-2,5-dione compounds.

What is claimed is: 
     
         1 . A composition comprising a compound having solubility of 0 to 10 pg/mL in water at 37° C., wherein the compound is in the form of crystalline particles and wherein 99% of the particles have a diameter of 27 nm or lower, wherein the compound is a compound of formula III, 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—(C3-C9) 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 )—, —(NR8)—, S, and O; 
         R8 is 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, —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; and 
         m is 1 or 2, 
       
       wherein the aryl, heteroaryl, —O—aryl, —S—aryl, —O—heteroaryl, and —S—heteroaryl groups 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—(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. 
     
     
         2 . The composition of  claim 1 , wherein 90% of the particles have a diameter of 17 μm or lower. 
     
     
         3 . The composition of  claim 1 , wherein 90% of the particles have a diameter of about 4 μm to about 10 μm. 
     
     
         4 . The composition of  claim 1 , wherein 50% of the particles have a diameter of 7 μm or lower. 
     
     
         5 . The composition of  claim 1 , wherein 50% of the particles have a diameter of about 1 μm to about 4 μm. 
     
     
         6 . The composition of  claim 1 , wherein the composition is substantially free of surfactant. 
     
     
         7 . The composition of  claim 1 , wherein the composition comprises less than 1% surfactant. 
     
     
         8 . The composition of  claim 1 , wherein the composition comprises less than 0.5% surfactant. 
     
     
         9 . The composition of  claim 1 , wherein the composition comprises less than 0.1% surfactant. 
     
     
         10 . The composition of  claim 1 , wherein the compound has a solubility of 0 to 3.5 pg/mL in water at 37° C. 
     
     
         11 . The composition of  claim 1 , wherein the compound is (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1 -ij]quinolin-1-yl)-4-(1H-indo1-3-yl)pyrrolidine-2,5-dione or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The composition of  claim 1 , further comprising an additive. 
     
     
         13 . The composition of  claim 12 , wherein the additive is a diluent, disintegrant, binder, lubricant, stabilizer, or corrective. 
     
     
         14 . The composition of  claim 13 , wherein the diluent is a sugar derivative, a starch derivative or a cellulose derivative. 
     
     
         15 . The composition of  claim 14 , wherein the diluent is lactose. 
     
     
         16 . The composition of  claim 1 , further comprising a coating agent. 
     
     
         17 . The composition of  claim 16 , wherein the coating agent is a sugar coating base agent, water-soluble film coating base agent, enteric film coating base agent, or sustained-release film coating base agent. 
     
     
         18 . The composition of  claim 16 , wherein the coating agent can further comprise a plasticizer, diluent, lubricant, masking agent, colorant, gloss agent, or antiseptic. 
     
     
         19 . The composition of  claim 1 , wherein the composition is a powder, fine granule, granule, capsule, or tablet. 
     
     
         20 . The composition of  claim 1 , comprising about 10% to about 60% of the compound by weight.