Pharmaceutical combinations for treating cancer

Abstract

The present invention relates to pharmaceutical combinations comprising a PPAR agonist and a P38 inhibitor for use in a method for the prevention, delay of progression or treatment of cancer.

1 ) A pharmaceutical combination comprising:
 (a) a PPAR agonist;   (b) a compound of the formula I or II   
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof, wherein
 Z is N or CH; 
 W is NR 2 ; 
 X 1  is O, NR 4  (where R 4  is hydrogen or alkyl), S, or CR 5 R 6  (where R 5  and R 6  are independently hydrogen or alkyl) or C═O; 
 X 2  is O or NR 7 ; 
 Ar 1  is aryl or heteroaryl; 
 R 2  is hydrogen, alkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkylcarbonyl, heteroalkyloxycarbonyl or —R 21 —R 22  where R 21  is alkylene or —C(═O)— and R 22  is alkyl or alkoxy; 
 R 1  is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl, R 12 —SO 2 -heterocycloamino (where R 12  is haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl), —Y 1 —C(O)—Y 2 —R 11  (where Y 1  and Y 2  are independently either absent or an alkylene group and R 11  is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), (heterocyclyl)(cycloalkyl)alkyl or (heterocyclyl)(heteroaryl)alkyl; 
 R 3  is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, alkylene-C(O)—R 31  (where R 31  is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), amino, monoalkylamino, dialkylamino or NR 32 —Y 3 —R 33  (where Y 3  is —C(O), —C(O)O—, —C(O)NR 34 , S(O) 2  or S(O) 2 NR 35 ; R 32 , R 34  and R 35  are independently hydrogen or alkyl; and R 33  is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl or optionally substituted phenyl) or acyl; 
 R 7  is hydrogen or alkyl; and 
 R 8  and R 9  are independently hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, alkylsulfonyl, arylsulfonyl, —C(O)—R 81  (where R 81  is alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, alkoxy, aryloxy, amino, mono- or di-alkylamino, arylamino or aryl(alkyl)amino) or R 8  and R 9  together form ═CR 82 R 83  (where R 82  and R 83  are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl); 
 
         and optionally 
         (c) one or more pharmaceutically acceptable diluents, excipients or carriers. 
       
     
     
         2 ) A pharmaceutical combination according to  claim 1 , comprising
 (a) a PPAR agonist;   (b) a compound of formula I as defined in  claim 1  or a pharmaceutically acceptable salt thereof; and optionally   (c) one or more pharmaceutically acceptable diluents, excipients or carriers.   
     
     
         3 ) A pharmaceutical combination according to  claim 2 , wherein said compound of formula I is 6-(2,4-Difluorophenoxy)-2-[3-hydroxy-1-(2-hydroxyethyl)-propylamino]-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (pamapimod, Formula III) or a pharmaceutically acceptable salt thereof. 
       
         
           
           
               
               
           
         
       
     
     
         4 ) A pharmaceutical combination according to any one of  claims 1  to  3 , wherein said PPAR agonist is pioglitazone or a pharmaceutically acceptable salt thereof. 
     
     
         5 ) A pharmaceutical combination according to any one of  claims 1  to  4 , for use as a medicament. 
     
     
         6 ) A pharmaceutical combination according to any one of  claims 1  to  4  for use in a method for the prevention, delay of progression or treatment of cancer in a subject. 
     
     
         7 ) A pharmaceutical combination for use according to  claim 6 , wherein the cancer is metastatic cancer. 
     
     
         8 ) A pharmaceutical combination for use according to  claim 6 , wherein the cancer is selected from the group consisting of lung cancer, ovarian cancer, prostate cancer, breast cancer, bladder cancer, liver cancer, cancer of the gastrointestinal (GI) tract, hematological cancer and kidney cancer. 
     
     
         9 ) A pharmaceutical combination for use according to  claim 8 , wherein
 (a) said lung cancer is selected from non-small-cell lung carcinoma and small-cell lung carcinoma;   (b) said breast cancer is selected from ductal carcinoma in situ, invasive ductal carcinoma and invasive lobular carcinoma;   (c) said bladder cancer is selected from transitional cell carcinoma, squamous cell carcinoma, small cell carcinoma, adenocarcinoma and sarcoma;   (d) said liver cancer is selected from hepatocellular carcinoma, hepatoblastoma and cholangiocarcinoma;   (e) said cancer of the GI tract is selected from esophageal cancer, gastric cancer, intestinal cancer, colorectal cancer, and anal cancer;   (f) said hematological cancer is selected from acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), lymphoma, myelodysplastic syndrome (MDS) and multiple myeloma;   (g) said kidney cancer is renal cell adenocarcinoma.   
     
     
         10 ) A pharmaceutical combination for use according to  claim 6 , wherein the cancer is cancer of the GI tract, lung cancer or ovarian cancer. 
     
     
         11 ) A pharmaceutical combination for use according to  claim 6 , wherein the cancer is lung cancer or ovarian cancer or wherein the cancer is lung cancer or cancer of the GI tract. 
     
     
         12 ) A pharmaceutical combination comprising:
 (a) a PPAR agonist;   (b) a p38 kinase inhibitor; and optionally   (c) one or more pharmaceutically acceptable diluents, excipients or carriers for use in a method for the prevention, delay of progression or treatment of lung cancer or ovarian cancer or for use in a method for the prevention, delay of progression or treatment of lung cancer or cancer of the GI tract in a subject.   
     
     
         13 ) A pharmaceutical combination for use according to  claim 12 , wherein said P38 kinase inhibitor is inhibiting P38-alpha and/or P38-beta. 
     
     
         14 ) A pharmaceutical combination for use according to  claim 12 , wherein said P38 kinase inhibitor is selected from the group consisting of pamapimod, losmapimod, dilmapimod, AZD7624, ARRY-371797, LY2228820, R9111, PH-797804, BIRB 796, VX-702, VX-745 SB 239063, SB202190, SCIO 469, and BMS 582949 or a pharmaceutically acceptable salt thereof. 
     
     
         15 ) A pharmaceutical combination for use according to  claim 12 , wherein said P38 kinase inhibitor is pamapimod or a pharmaceutically acceptable salt thereof. 
     
     
         16 ) A pharmaceutical combination for use according to  claim 12 , wherein said PPAR agonist is activating PPAR gamma. 
     
     
         17 ) A pharmaceutical combination for use according  claim 12 , wherein said PPAR agonist is pioglitazone or a pharmaceutically acceptable salt thereof.