Novel methods for treating cancer

Abstract

The invention provides thiazole-substituted indolin-2-ones as inhibitors of cancer stem cell pathway kinases (CSCPK) and related kinases, and methods of using these compounds, to treat subjects in need thereof.

1 .- 33 . (canceled) 
     
     
         34 . A pharmaceutical composition comprising:
 a compound of the formula:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof in the form of particles which have a median particle size of greater than zero and less than 20 microns, and
 at least one excipient. 
 
     
     
         35 . The pharmaceutical composition according to  claim 34 , wherein the at least one excipient is chosen from polysorbates, lipids, surfactants, glycerides, polyethylene glycols, polyoxyethylene sorbitan alkylates, celluloses, cellulose derivatives, antioxidants, and a mixture thereof. 
     
     
         36 . The pharmaceutical composition according to  claim 34 , wherein the at least one excipient is chosen from polyethylene glycol glyceryl laurates 
     
     
         37 . The pharmaceutical composition according to  claim 34 , wherein the at least one excipient is chosen from polyoxyethylene sorbitan monolaurates. 
     
     
         38 . The pharmaceutical composition according to  claim 34 , wherein the at least one excipient comprises dimyristoylphosphatidylcholine. 
     
     
         39 . The pharmaceutical composition according to  claim 34 , further comprising at least one additional component. 
     
     
         40 . The pharmaceutical composition according to  claim 39 , wherein the at least one additional component is chosen from other active agents, standard vehicles, carriers, liquid carriers, saline, aqueous solutions, diluents, surface active agents, dispersing agents, inert diluents, granulating agents, disintegrating agents, binding agents, lubricating agents, glidants, discharging agents, sweetening agents, flavoring agents, coloring agents, preservatives, physiologically degradable compositions, aqueous vehicles, aqueous solvents, oily vehicles, oily solvents, suspending agents, dispersing agents, wetting agents, suspending agents, emulsifying agents, demulcents, buffers, salts, thickening agents, gelatins, fillers, emulsifying agents, antioxidants, antibiotics, antifungal agents, stabilizing agents, water, glycols, oils, alcohols, crystallization retarding agents, starches, sugars, sucrose, solubilizing agents, pharmaceutically acceptable polymeric materials, and pharmaceutically acceptable hydrophobic materials. 
     
     
         41 . The pharmaceutical composition according to  claim 34 , wherein the pharmaceutical composition is in an oral dosage form chosen from a tablet, a pill, a capsule, a caplet, a powder, a granule, a suspension, a gel, a cachet, a troche, a lozenge, a syrup, an elixir, and an emulsion. 
     
     
         42 . The pharmaceutical composition according to  claim 34 , wherein the compound, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is present in an amount ranging from about 20 mg to about 2000 mg. 
     
     
         43 . The pharmaceutical composition according to  claim 42 , wherein the compound, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is present in an amount of about 300 mg. 
     
     
         44 . A method of treating a cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising:
 a therapeutically effective amount of the compound:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof in the form of particles which have a median particle size of greater than zero and less than 20 microns, and
 at least one excipient. 
 
     
     
         45 . The method according to  claim 44 , wherein the pharmaceutical composition is administered orally and continuously in 28-day cycles. 
     
     
         46 . The method according to  claim 44 , wherein the cancer is a colorectal cancer, a colon cancer, a rectal cancer, a pancreatic cancer, a pancreatic neuroendocrine tumor, a gastroesophageal junction adenocarcinoma, a gastric cancer, a gastroesophageal junction adenocarcinoma/gastric cancer, a head and neck cancer, a hepatocellular carcinoma, a renal cell cancer, an ovarian cancer, a lung cancer, a non-small cell lung cancer, a small cell lung cancer, a breast cancer, a prostate cancer, a castration-resistant prostate cancer, an appendiceal cancer, a melanoma, a sarcoma, a bladder cancer, a gastrointestinal stromal tumor, or a thyroid cancer. 
     
     
         47 . The method according to  claim 44 , wherein the cancer is refractory, recurrent, and/or metastatic. 
     
     
         48 . The method according to  claim 44 , wherein the therapeutically effective amount ranges from about 20 mg to about 2000 mg. 
     
     
         49 . The method according to  claim 48 , wherein the therapeutically effective amount is about 300 mg. 
     
     
         50 . The method according to  claim 44 , wherein the at least one excipient is chosen from polyethylene glycol glyceryl laurates. 
     
     
         51 . The method according to  claim 44 , wherein the at least one excipient is chosen from polyoxyethylene sorbitan monolaurates. 
     
     
         52 . The method according to  claim 44 , wherein the at least one excipient comprises dimyristoylphosphatidylcholine.