Imidazoquinolines as lipid kinase inhibitors

Abstract

The invention relates to a combination comprising compounds of formula (I) and one or more other antiproliferative compounds, hormones or radiation, pharmaceutical preparations comprising the combination thereof, and the application thereof in a process for the treatment of tumors.

1 . A combination comprising (a) a compound according to Formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is naphthyl or phenyl wherein said phenyl is substituted by one or two substituents independently selected from the group consisting of 
         Halogen; 
         lower alkyl unsubstituted or substituted by halogen, cyano, imidazolyl or triazolyl; 
         cycloalkyl; 
         amino substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkyl sulfonyl, lower alkoxy and lower alkoxy lower alkylamino; 
         piperazinyl unsubstituted or substituted by one or two substituents independently selected from the group consisting of lower alkyl and lower alkyl sulfonyl; 
         2-oxo-pyrrolidinyl; 
         lower alkoxy lower alkyl; 
         imidazolyl; 
         pyrazolyl; 
         and triazolyl; 
         R 2  is O or S; 
         R 3  is lower alkyl; 
         R 4  is pyridyl unsubstituted or substituted by halogen, cyano, lower alkyl, lower alkoxy or piperazinyl unsubstituted or substituted by lower alkyl; 
         pyrimidinyl unsubstituted or substituted by lower alkoxy; 
         quinolinyl unsubstituted or substituted by halogen; 
         or quinoxalinyl; 
         R 5  is hydrogen or halogen; 
         n is 0 or 1; 
         R 6  is oxido; 
         with the proviso that if n=1, the N-atom bearing the radical R 6  has a positive charge; 
         R 7  is hydrogen or amino; 
         or a tautomer or a pharmaceutically acceptable salt thereof, and (b) one or more other antiproliferative compounds, hormones or radiation for separate, simultaneous, or sequential use. 
       
     
     
         2 . A combination according to  claim 1 , wherein the compound of formula I is
 2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile or a tautomer thereof or a pharmaceutically acceptable salt thereof.   
     
     
         3 . A combination according to  claim 1 , wherein the compound of formula I is
 8-(6-Methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one or a tautomer thereof or a pharmaceutically acceptable salt thereof.   
     
     
         4 . A combination according to  claim 1 , wherein the one or more antiproliferative compound is selected from the group consisting of aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active compounds, alkylating compounds, histone deacetylase inhibitors, compounds which induce cell differentiation processes, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platin compounds, compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds, compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase, gonadorelin agonists, anti-androgens, methionine aminopeptidase inhibitors, bisphosphonates, biological response modifiers, antiproliferative antibodies, heparanase inhibitors, inhibitors of Ras oncogenic isoforms, telomerase inhibitors, proteasome inhibitors, compounds used in the treatment of hematologic malignancies, compounds which target, decrease or inhibit the activity of Flt-3, Hsp90 inhibitors, kinesin spindle protein inhibitors and MEK inhibitors, or a combination thereof. 
     
     
         5 . A combination according to  claim 1 , wherein the one or more antiproliferative compound is selected from the group consisting of exemestane, ketokonazole, anastrozole, letrozole, tamoxifen, fulvestrant, gimatecan, irinotecan, doxorubicin, paclitaxel, docetaxel, vincristine, epothilones and derivatives thereof, N-hydroxy-3-[4-[[2-hydroxyethyl)[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4][[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, 5-fluorouracil, capecitabine, gemcitabine, pemetrexed, carboplatin, cis-platin, cisplatinum, oxaliplatin, ARRY142886, AZ6244, imatinib, nilotinib, trastuzumab, cetuximab, Iressa, Tarceva, rapamycin, everolimus, Bortezomid, PKC412, bevacizumab, rituximab, PKC412, octreotide, SOM230, and FTY720, or a combination thereof. 
     
     
         6 . A combination according to  claim 1 , wherein the compound of formula I is administered in combination with hormones or radiation. 
     
     
         7 . A combination according to  claim 1  for use in the treatment of one or more tumors. 
     
     
         8 . A pharmaceutical preparation comprising the combination according to  claim 1  and, optionally, a pharmaceutically acceptable carrier. 
     
     
         9 . A method for the treatment of a tumor comprising the administration to a subject in need thereof a therapeutically effective amount of a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is naphthyl or phenyl wherein said phenyl is substituted by one or two substituents independently selected from the group consisting of 
         Halogen; 
         lower alkyl unsubstituted or substituted by halogen, cyano, imidazolyl or triazolyl; 
         cycloalkyl; 
         amino substituted by one or two substituents independently selected from the group consisting of lower alkyl, lower alkyl sulfonyl, lower alkoxy and lower alkoxy lower alkylamino; 
         piperazinyl unsubstituted or substituted by one or two substituents independently selected from the group consisting of lower alkyl and lower alkyl sulfonyl; 
         2-oxo-pyrrolidinyl; 
         lower alkoxy lower alkyl; 
         imidazolyl; 
         pyrazolyl; 
         and triazolyl; 
         R 2  is O or S; 
         R 3  is lower alkyl; 
         R 4  is pyridyl unsubstituted or substituted by halogen, cyano, lower alkyl, lower alkoxy or piperazinyl unsubstituted or substituted by lower alkyl; 
         pyrimidinyl unsubstituted or substituted by lower alkoxy; 
         quinolinyl unsubstituted or substituted by halogen; 
         or quinoxalinyl; 
         R 5  is hydrogen or halogen; 
         n is 0 or 1; 
         R 6  is oxido; 
         with the proviso that if n=1, the N-atom bearing the radical R 6  has a positive charge; 
         R 7  is hydrogen or amino; 
         or a tautomer or a pharmaceutically acceptable salt thereof, and (b) one or more other antiproliferative compounds, hormones or radiation. 
       
     
     
         10 . A combination comprising (a) 2-Methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile or a tautomer thereof or a pharmaceutically acceptable salt thereof and (b) one or more antiproliferative compounds selected from the group consisting of exemestane, letrozole, fulvestrant, irinotecan, doxorubicin, paclitaxel, docetaxel, capecitabine, carboplatin, cis-platin, cisplatinum, imatinib, nilotinib, trastuzumab, cetuximab, everolimus, bevacizumab, and SOM230, or a combination thereof. 
     
     
         11 . A combination according to  claim 10  for use in the treatment of one or more tumors.