Combination therapy comprising a diaryl urea compound and a p13, akt kinase or mtor inhibitors (rapamycins) for cancer treatment

Abstract

The present invention relates to pharmaceutical compositions and combinations for treating cancer, comprising a diaryl urea compound e.g. 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-3-fluorophenoxy}-pyridine-2-carboxylic acid methylamide and an PI3K/AKT signaling pathway inhibitor The PI3K/AKI signaling pathway inhibitor comprises PI3 inhibitors {like celecoxilo, viridins, wortmannins}, AKT kinase inhibitors {like perifosine, triciribine} and mTOR inhibitors {like the rapamycins temsirolimus and evorolimus}.

1 . A combination comprising
 a compound of formula I   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, polymorph, solvate, hydrate, metabolite or prodrug form thereof, and at least one second compound which is an PI3K/AKT signalling pathway inhibitor. 
     
     
         2 . The combination of  claim 1 , wherein said second compound is celecoxib, OSU-03012, OSU03013, PX-316, 2′-substituted, 3′-deoxy-phosphatidyl-myo-inositol derivatives, 3-(imidazo[1,2-a]pyridin-3-yl) derivatives, Ly294002, 1C486068, 3-(hetero)aryloxy substituted benzo(b)thiophene derivatives, PX-866, perifosine, triciribine, FKBP12 enhancer, phosphatidylinositol ether lipid analogues, wortmannin or rapamycin or derivatives thereof, or a pharmaceutically-acceptable salt thereof. 
     
     
         3 . The combination of  claim 1 , wherein said second compound is a wortmannin compound of Formula W: 
       
         
           
           
               
               
           
         
       
       a derivative or analog of a wortmannin compound of formula W, a pharmaceutically acceptable salt of the wortmannin compound of formula W, or a pharmaceutically acceptable salt of the derivative or analog of the wortmannin compound of formula W. 
     
     
         4 . The combination of  claim 3 , wherein said derivative or analog of the formula W 
       is selected from
 a) compounds of formula W1 
 
       
         
           
           
               
               
           
         
         where R is H (11-desacetoxywortmannin) or acetoxy and R′ is C 1 -C 6 allcyl, 
         b) Δ9, 11-dehydrodesacetoxywortmannin compounds of formula W2 
       
       
         
           
           
               
               
           
         
         where R′ is C 1 -C 6  alkyl, 
         c) 17(α-dihydro-wortmannin compounds of formula W3 
       
       
         
           
           
               
               
           
         
         where R is H or acetoxy and R′ is C 1 -C 6  alkyl and R″ is H, C 1 -C 6  alkyl, —C(O) OH or —C(O)O— C 1 -C 6  alkyl; 
         d) open A-ring acid or ester of wortmannin compounds of formula W4 
       
       
         
           
           
               
               
           
         
         where R 1  is H, methyl or ethyl and R 2  is H or methyl or 
         e) 11-substituted and 17- substituted derivatives of wortmannin of formula W5 
       
       
         
           
           
               
               
           
         
         where R 4  is =O or —O(CO)R 6 , R 3  is =O, —OH or —O(CO)R 6 , each R 6  is independently phenyl, C 1 -C 6  alkyl or substituted C 1 -C 6  alkyl, where R 4  is =O or —OH, R 3  is not =O. 
       
     
     
         5 . The combination of  claim 1 , wherein said second compound is an Akt-kinase inhibitor. 
     
     
         6 . The combination of  claim 1 , wherein said second compound is Akt-1-1, Akt-1-1,2, API-59CJ-Ome, 1-H-imidazo[4,5-c]pyridinyl derivatives, indole-3-carbinol and derivatives thereof, perifosine, phosphatidylinositol ether lipid analogues, triciribine, or a pharmaceutically-acceptable salt thereof. 
     
     
         7 . The combination of  claim 1 , wherein said second compound is an mTOR inhibitor. 
     
     
         8 . The combination of  claim 1 , wherein said second compound is rapamycin, temsirolimus, everolimus, AP23573, AP23675, AP23464, AP23841, 40-(2-hydroxyethyl)rapamycin, 40-[3- hydroxy(hydroxymethyl) methylpropanoate]-rapamycin, 40-epi-(tetrazolyt)-rapamycin, 32-deoxorapamycin, or 16-pentynyloxy-32(S)-dihydrorapamycin, SAR 943 or a pharmaceutically-acceptable salt thereof. 
     
     
         9 . The combination of  claim 1  comprising a compound of formula (I) and wortmannin. 
     
     
         10 . The combination of  claim 1  comprising a compound of formula (I) and rapamycin. 
     
     
         11 . The combination of  claim 1  wherein the amounts of the active ingredients of the combination are synergistic. 
     
     
         12 . The combination of  claim 1  for treating cancer. 
     
     
         13 . The combination of  claim 12 , wherein said cancer is melanoma, hepatocellular cancer, renal cell carcinoma non small lung cancer, ovarian cancer, prostate cancer, colorectal cancer, breast cancer or pancreatic cancer. 
     
     
         14 . A method for treating cancer in a subject in need thereof comprising administering effective amounts of a compound of formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, polymorph, solvate, hydrate, metabolite or prodrug thereof, and of a second compound which is an PI3K/AKT signalling pathway inhibitor. 
       
     
     
         15 - 16 . (canceled)