Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis

Abstract

The present invention relates to a pharmaceutical combination for the treatment of diseases which involves cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis. The invention also relates to a method for the treatment of said diseases, comprising co-administration of effective amounts of specific active compounds and/or co-treatment with radiation therapy, in a ratio which provides an additive and synergistic effect, and to the combined use of these specific compounds and/or radiotherapy for the manufacture of corresponding pharmaceutical combination preparations.

1 . A pharmaceutical combination comprising therapeutically effective amounts of:
 (i) (Z)-3-(1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, or a pharmaceutically acceptable salt thereof; and   (ii) at least a further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent selected from   
       synthetic small molecule VEGF receptor antagonists, small molecule growth factor receptor antagonists, inhibitors of the EGF receptor, excluding 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors which are not classified under the synthetic small-molecules, inhibitors directed to EGF receptor and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors, which are fusion proteins, compounds which interact with nucleic acids and which are classified as alkylating agents or platinum compounds, compounds which interact with nucleic acids and which are classified as anthracyclines, as DNA intercalators or as DNA cross-linking agents, DNA minor-groove binding compounds, anti-metabolites, naturally occurring, semi-synthetic or synthetic bleomycin type antibiotics, inhibitors of DNA transcribing enzymes selected from topoisomerase I and topoisomerase II inhibitors, chromatin modifying agents, mitosis inhibitors, anti-mitotic agents, cell-cycle inhibitors, proteasome inhibitors, enzymes, hormones, hormone antagonists, hormone inhibitors, inhibitors of steroid biosynthesis, steroids, cytokines, hypoxia-selective cytotoxins, inhibitors of cytokines, lymphokines, antibodies directed against cytokines, oral and parenteral tolerance induction agents, supportive agents, chemical radiation sensitizers and protectors, photo-chemically activated drugs, synthetic poly- or oligonucleotides optionally modified or conjugated, non-steroidal anti-inflammatory drugs, cytotoxic antibiotics, antibodies targeting the surface molecules of cancer cells, inhibitors of metalloproteinases, metals, inhibitors of oncogenes, inhibitors of gene transcription or of RNA translation or protein expression, complexes of rare earth elements, and photo-chemotherapeutic agents;
 wherein said pharmaceutical combination is optionally adapted for a co-treatment with radiotherapy or radio-immunotherapy, in the form of a combined preparation for simultaneous, separate or sequential use. 
 
     
     
         2 . The pharmaceutical combination in accordance with  claim 1 , wherein (ii) is selected from vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842, GW-786034, gefitinib, erlotinib, CI-1033 GW-2016, iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272, herceptin, BAY-43-9006, BAY-57-9006, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or a pharmaceutically acceptable salt thereof, atrasentan, rituximab, cetuximab, Avastin™ (bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000, vitaxin, imatinib, VEGFtrap, melphalan, cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil, mechlorethamine, an ethyleneimine compound, an alkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin or a derivative thereof, netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin, olivomycin, propamidine, stilbamidine, an anthramycin, an aziridine, a nitrosourea or a derivative thereof, cytarabine, 5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin, hydroxyurea, folic acid, a phleomycin, a bleomycin or a derivative or salt thereof, CHPP, BZPP, MTPP, BAPP, liblomycin, an acridine or a derivative thereof, a rifamycin, an actinomycin, adramycin, irinotecan (camptosar), topotecan, an amsacrine or analogue thereof, a tricyclic carboxamide, SAHA, MD-275, trichostatin A, CBHA, LAQ824, valproic acid, paclitaxel (taxol), docetaxel, taxotere, navelbine, vinblastin, vincristin, vindesine, vinorelbine, colchicine or a derivative thereof, maytansine, an ansamitocin, rhizoxin, phomopsin, dolastatin, an epipodophyllotoxin, etoposide, teniposide, a steganacin, combretastatin, amphetinile, procarbazine, bortezomib, asparaginase, pegylated asparaginase (pegaspargase),a thymidine-phosphorylase inhibitor, estramustine (T-66), megestrol, flutamide, casodex, anandron, cyproterone acetate, aminogluthetimide, anastrozole, formestan, letrozole leuprorelin, buserelin, goserelin, triptorelin, tamoxifen or its citrate salt, droloxifene, trioxifene, raloxifene, zindoxifene, ICI 164,384, ICI 182,780, aminoglutethimide, formestane, fadrozole, finasteride, ketoconazole, leuprolide, prednisone, prednisolone, methylprednisolone, dexamethasone, budenoside, fluocortolone, triamcinolone, interferon β, IL-10, IL-12, etanercept, thalidomide, its R- and S-enantiomers and its derivatives, revimid (CC-5013), a leukotrien antagonist, mitomycin C, an aziridoquinone, a 2-nitroimidazole, a nitroacridine, a nitroquinoline, a nitropyrazoloacridine, a “dual-function” nitro aromatic, a nitro aromatic deactivated mustard, a N-oxide of a nitrogen mustard, a metal complex of a nitrogen mustard, an anti-CD3 antibody, an anti-CD25 antibody, a tolerance induction agent, minodronic acid or a derivative thereof selected from YM-529, Ono-5920 and YH-529, zoledronic acid monohydrate, ibandronate sodium hydrate, clodronate disodium, metronidazole, misonidazole, benznidazole, nimorazole, RSU-1069, SR-4233, bromodeoxyuridine, iododeoxyuridine, WR-2721, porfimer, photofrin, a benzoporphyrin derivative, a pheophorbide derivative, merocyanin 540 (MC-540), tin etioporpurin, oblimersen, a non-steroidal anti-inflammatory drug selected from acetylsalicyclic acid, mesalazin, ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, indomethacin, sulindac, tolmetin, zomepirac, nabumetone, diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac, acemetacin, fentiazac, clidanac, etodolac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, tenoxicam, lornoxicam, nimesulide, meloxicam, celecoxib and rofecoxib, or a pharmaceutically acceptable salt of a non-steroidal anti-inflammatory drug, a cytotoxic antibiotic, apolizumab, 1D09C3, TIMP-1, TIMP-2, Zinc, P53, Rb, an heterocyclic complex of a lanthanide, PUVA, an inhibitor of the transcription factor complex ESX/DRIP130/Sur-2, geldanamycin or its derivative 17-allylaminogeldanamycin (17-AAG), IM-842, tetrathiomolybdate, squalamine, combrestatin A4, TNP-470, marimastat, neovastat, bicalutamide, abarelix, oregovomab, mitumomab, TLK-286, alemtuzumab, ibritumomab, temozolomide, denileukin diftitox, aldesleukin, dacarbazine, floxuridine, plicamycin, mitotane, pipobroman, plicamycin, tamloxifen and testolactone. 
     
     
         3 . The pharmaceutical combination in accordance with  claim 1 , wherein (ii) is selected from paclitaxel (taxol), docetaxel, taxotere, navelbine, vinblastin, vincristin, vindesine, vinorelbine, melphalan, cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil, mechlorethamine, thalidomide, its R- and S-enantiomers and its derivatives, revimid (CC-5013), an ethyleneimine compound, an alkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin or a derivative thereof, netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin, olivomycin, a phtalanilide such as propamidine or stilbamidine, an anthramycin, an aziridine, a nitrosourea or a derivative thereof, a pyrimidine or purine analogue, cytarabine, 5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin, hydroxyurea, folic acid, an acridine or a derivative thereof, a rifamycin, an actinomycin, adramycin, irinotecan (camptosar), topotecan, an amsacrine or analogue thereof, a tricyclic carboxamide, SAHA, MD-275, trichostatin A, CBHA, LAQ824, valproic acid, bortezomib, vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842, GW-786034, BAY-43-9006, BAY-57-9006, gefitinib, erlotinib, CI-1033, GW-2016, iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272, herceptin, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or a pharmaceutically acceptable salt thereof, an inhibitor of the transcription factor complex ESX/DRIP130/Sur-2, heat shock protein HSP90 modulator geldanamycin and its derivative 17-allylaminogeldanamycin (17-AAG), atrasentan, rituximab, cetuximab, Avastin™ (bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000, vitaxin, imatinib, apolizumab and 1D09C3. 
     
     
         4 . The pharmaceutical combination in accordance with any of  claims 1  to  3 , wherein (i) is the monoethanesulfonate salt of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone. 
     
     
         5 . A pharmaceutical combination preparation kit, comprising a therapeutically effective amount of:
 (i) (Z)-3-(1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, or a pharmaceutically acceptable salt thereof; and   (ii) at least a further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent selected from   
       synthetic small molecule VEGF receptor antagonists, small molecule growth factor receptor antagonists, inhibitors of the EGF receptor, excluding 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors which are not classified under the synthetic small-molecules, inhibitors directed to EGF receptor and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors, which are fusion proteins, compounds which interact with nucleic acids and which are classified as alkylating agents or platinum compounds, compounds which interact with nucleic acids and which are classified as anthracyclines, as DNA intercalators or as DNA cross-linking agents, DNA minor-groove binding compounds, anti-metabolites, naturally occurring, semi-synthetic or synthetic bleomycin type antibiotics, inhibitors of DNA transcribing enzymes selected from topoisomerase I and topoisomerase II inhibitors, chromatin modifying agents, mitosis inhibitors, anti-mitotic agents, cell-cycle inhibitors, proteasome inhibitors, enzymes, hormones, hormone antagonists, hormone inhibitors, inhibitors of steroid biosynthesis, steroids, cytokines, hypoxia-selective cytotoxins, inhibitors of cytokines, lymphokines, antibodies directed against cytokines, oral and parenteral tolerance induction agents, supportive agents, chemical radiation sensitizers and protectors, photo-chemically activated drugs, synthetic poly- or oligonucleotides optionally modified or conjugated, non-steroidal anti-inflammatory drugs, cytotoxic antibiotics, antibodies targeting the surface molecules of cancer cells, inhibitors of metalloproteinases, metals, inhibitors of oncogenes, inhibitors of gene transcription or of RNA translation or protein expression, complexes of rare earth elements, and photo-chemotherapeutic agents;
 and optionally adapted for a co-treatment with radiotherapy or radio-immunotherapy, characterised in that (i) is comprised within a first compartment and (ii) is comprised within a second compartment, such that the administration to a patient in need thereof can be simultaneous, separate or sequential. 
 
     
     
         6 . The pharmaceutical combination preparation kit in accordance with  claim 5 , wherein (i) is the monoethanesulfonate salt of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone. 
     
     
         7 . The pharmaceutical combination preparation kit in accordance with  claim 5 , wherein(ii) is selected from vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842, GW-786034, gefitinib, erlotinib, CI-1033 GW-2016, iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272, herceptin, BAY-43-9006, BAY-57-9006, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or a pharmaceutically acceptable salt thereof, atrasentan, rituximab, cetuximab, Avastin™ (bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000, vitaxin, imatinib, VEGFtrap, melphalan, cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil, mechlorethamine, an ethyleneimine compound, an alkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin or a derivative thereof, netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin, olivomycin, propamidine, stilbamidine, an anthramycin, an aziridine, a nitrosourea or a derivative thereof, cytarabine, 5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin, hydroxyurea, folic acid, a phleomycin, a bleomycin or a derivative or salt thereof, CHPP, BZPP, MTPP, BAPP, liblomycin, an acridine or a derivative thereof, a rifamycin, an actinomycin, adramycin, irinotecan (camptosar), topotecan, an amsacrine or analogue thereof, a tricyclic carboxamide, SAHA, MD-275, trichostatin A, CBHA, LAQ824, valproic acid, paclitaxel (taxol), docetaxel, taxotere, navelbine, vinblastin, vincristin, vindesine, vinorelbine, colchicine or a derivative thereof, maytansine, an ansamitocin, rhizoxin, phomopsin, dolastatin, an epipodophyllotoxin, etoposide, teniposide, a steganacin, combretastatin, amphetinile, procarbazine, bortezomib, asparaginase, pegylated asparaginase (pegaspargase),a thymidine-phosphorylase inhibitor, estramustine (T-66), megestrol, flutamide, casodex, anandron, cyproterone acetate, aminogluthetimide, anastrozole, formestan, letrozole leuprorelin, buserelin, goserelin, triptorelin, tamoxifen or its citrate salt, droloxifene, trioxifene, raloxifene, zindoxifene, ICI 164,384, ICI 182,780, aminoglutethimide, formestane, fadrozole, finasteride, ketoconazole, leuprolide, prednisone, prednisolone, methylprednisolone, dexamethasone, budenoside, fluocortolone, triamcinolone, interferon 13, IL-10, IL-12, etanercept, thalidomide, its R- and S-enantiomers and its derivatives, revimid (CC-5013), a leukotrien antagonist, mitomycin C, an aziridoquinone, a 2-nitroimidazole, a nitroacridine, a nitroquinoline, a nitropyrazoloacridine, a “dual-function” nitro aromatic, a nitro aromatic deactivated mustard, a N-oxide of a nitrogen mustard, a metal complex of a nitrogen mustard, an anti-CD3 antibody, an anti-CD25 antibody, a tolerance induction agent, minodronic acid or a derivative thereof selected from YM-529, Ono-5920 and YH-529, zoledronic acid monohydrate, ibandronate sodium hydrate, clodronate disodium, metronidazole, misonidazole, benznidazole, nimorazole, RSU-1069, SR-4233, bromodeoxyuridine, iododeoxyuridine, WR-2721, porfimer, photofrin, a benzoporphyrin derivative, a pheophorbide derivative, merocyanin 540 (MC-540), tin etioporpurin, oblimersen, a non-steroidal anti-inflammatory drug selected from acetylsalicyclic acid, mesalazin, ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, indomethacin, sulindac, tolmetin, zomepirac, nabumetone, diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac, acemetacin, fentiazac, clidanac, etodolac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, tenoxicam, lornoxicam, nimesulide, meloxicam, celecoxib and rofecoxib, or a pharmaceutically acceptable salt of a non-steroidal anti-inflammatory drug, a cytotoxic antibiotic, apolizumab, 1D09C3, TIMP-1, TIMP-2, Zinc, P53, Rb, an heterocyclic complex of a lanthanide, PUVA, an inhibitor of the transcription factor complex ESX/DRIP130/Sur-2, geldanamycin or its derivative 17-allylaminogeldanamycin (17-AAG), IM-842, tetrathiomolybdate, squalamine, combrestatin A4, TNP-470, marimastat, neovastat, bicalutamide, abarelix, oregovomab, mitumomab, TLK-286, alemtuzumab, ibritumomab, temozolomide, denileukin diftitox, aldesleukin, dacarbazine, floxuridine, plicamycin, mitotane, pipobroman, plicamycin, tamloxifen and testolactone. 
     
     
         8 . The pharmaceutical combination preparation kit in accordance with  claim 5 , wherein(ii) is selected from paclitaxel (taxol), docetaxel, taxotere, navelbine, vinblastin, vincristin, vindesine, vinorelbine, melphalan, cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil, mechlorethamine, thalidomide, its R- and S-enantiomers and its derivatives, revimid (CC-5013), an ethyleneimine compound, an alkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin or a derivative thereof, netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin, olivomycin, a phtalanilide such as propamidine or stilbamidine, an anthramycin, an aziridine, a nitrosourea or a derivative thereof, a pyrimidine or purine analogue, cytarabine, 5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin, hydroxyurea, folic acid, an acridine or a derivative thereof, a rifamycin, an actinomycin, adramycin, irinotecan (camptosar), topotecan, an amsacrine or analogue thereof, a tricyclic carboxamide, SAHA, MD-275, trichostatin A, CBHA, LAQ824, valproic acid, bortezomib, vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842, GW-786034, BAY-43-9006, BAY-57-9006, gefitinib, erlotinib, CI-1033, GW-2016, iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272, herceptin, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or a pharmaceutically acceptable salt thereof, an inhibitor of the transcription factor complex ESX/DRIP130/Sur-2, heat shock protein HSP90 modulator geldanamycin and its derivative 17-allylaminogeldanamycin (17-AAG), atrasentan, rituximab, cetuximab, Avastin™ (bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000, vitaxin, imatinib, apolizumab and 1D09C3. 
     
     
         9 . The pharmaceutical combination preparation kit in accordance with  claim 8 , wherein the formulation of the selected protein tyrosine kinase receptor antagonist is for oral administration. 
     
     
         10 . A method of treating cancer diseases, which method comprises simultaneous, separate or sequential administration of effective amounts of:
 (i) (Z)-3-(1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, or a pharmaceutically acceptable salt thereof; and   (ii) at least a further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent selected from   
       synthetic small molecule VEGF receptor antagonists, small molecule growth factor receptor antagonists, inhibitors of the EGF receptor, excluding 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors which are not classified under the synthetic small-molecules, inhibitors directed to EGF receptor and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors, which are fusion proteins, compounds which interact with nucleic acids and which are classified as alkylating agents or platinum compounds, compounds which interact with nucleic acids and which are classified as anthracyclines, as DNA intercalators or as DNA cross-linking agents, DNA minor-groove binding compounds, anti-metabolites, naturally occurring, semi-synthetic or synthetic bleomycin type antibiotics, inhibitors of DNA transcribing enzymes selected from topoisomerase I and topoisomerase II inhibitors, chromatin modifying agents, mitosis inhibitors, anti-mitotic agents, cell-cycle inhibitors, proteasome inhibitors, enzymes, hormones, hormone antagonists, hormone inhibitors, inhibitors of steroid biosynthesis, steroids, cytokines, hypoxia-selective cytotoxins, inhibitors of cytokines, lymphokines, antibodies directed against cytokines, oral and parenteral tolerance induction agents, supportive agents, chemical radiation sensitizers and protectors, photo-chemically activated drugs, synthetic poly- or oligonucleotides optionally modified or conjugated, non-steroidal anti-inflammatory drugs, cytotoxic antibiotics, antibodies targeting the surface molecules of cancer cells, inhibitors of metalloproteinases, metals, inhibitors of oncogenes, inhibitors of gene transcription or of RNA translation or protein expression, complexes of rare earth elements, and photo-chemotherapeutic agents;
 in the form of a combined preparation optionally adapted for a co-treatment with radiotherapy or radio-immunotherapy. 
 
     
     
         11 . The method in accordance with  claim 10 , wherein(ii) is selected from vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842, GW-786034, gefitinib, erlotinib, CI-1033 GW-2016, iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272, herceptin, BAY-43-9006, BAY-57-9006, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or a pharmaceutically acceptable salt thereof, atrasentan, rituximab, cetuximab, Avastin™ (bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000, vitaxin, imatinib, VEGFtrap, melphalan, cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil, mechlorethamine, an ethyleneimine compound, an alkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin or a derivative thereof, netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin, olivomycin, propamidine, stilbamidine, an anthramycin, an aziridine, a nitrosourea or a derivative thereof, cytarabine, 5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin, hydroxyurea, folic acid, a phleomycin, a bleomycin or a derivative or salt thereof, CHPP, BZPP, MTPP, BAPP, liblomycin, an acridine or a derivative thereof, a rifamycin, an actinomycin, adramycin, irinotecan (camptosar), topotecan, an amsacrine or analogue thereof, a tricyclic carboxamide, SAHA, MD-275, trichostatin A, CBHA, LAQ824, valproic acid, paclitaxel (taxol), docetaxel, taxotere, navelbine, vinblastin, vincristin, vindesine, vinorelbine, colchicine or a derivative thereof, maytansine, an ansamitocin, rhizoxin, phomopsin, dolastatin, an epipodophyllotoxin, etoposide, teniposide, a steganacin, combretastatin, amphetinile, procarbazine, bortezomib, asparaginase, pegylated asparaginase (pegaspargase), a thymidine-phosphorylase inhibitor, estramustine (T-66), megestrol, flutamide, casodex, anandron, cyproterone acetate, aminogluthetimide, anastrozole, formestan, letrozole leuprorelin, buserelin, goserelin, triptorelin, tamoxifen or its citrate salt, droloxifene, trioxifene, raloxifene, zindoxifene, ICI 164,384, ICI 182,780, aminoglutethimide, formestane, fadrozole, finasteride, ketoconazole, leuprolide, prednisone, prednisolone, methylprednisolone, dexamethasone, budenoside, fluocortolone, triamcinolone, interferon β, IL-10, IL-12, etanercept, thalidomide, its R- and S-enantiomers and its derivatives, revimid (CC-5013), a leukotrien antagonist, mitomycin C, an aziridoquinone, a 2-nitroimidazole, a nitroacridine, a nitroquinoline, a nitropyrazoloacridine, a “dual-function” nitro aromatic, a nitro aromatic deactivated mustard, a N-oxide of a nitrogen mustard, a metal complex of a nitrogen mustard, an anti-CD3 antibody, an anti-CD25 antibody, a tolerance induction agent, minodronic acid or a derivative thereof selected from YM-529, Ono-5920 and YH-529, zoledronic acid monohydrate, ibandronate sodium hydrate, clodronate disodium, metronidazole, misonidazole, benznidazole, nimorazole, RSU-1069, SR-4233, bromodeoxyuridine, iododeoxyuridine, WR-2721, porfimer, photofrin, a benzoporphyrin derivative, a pheophorbide derivative, merocyanin 540 (MC-540), tin etioporpurin, oblimersen, a non-steroidal anti-inflammatory drug selected from acetylsalicyclic acid, mesalazin, ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, indomethacin, sulindac, tolmetin, zomepirac, nabumetone, diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac, acemetacin, fentiazac, clidanac, etodolac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, tenoxicam, lornoxicam, nimesulide, meloxicam, celecoxib and rofecoxib, or a pharmaceutically acceptable salt of a non-steroidal anti-inflammatory drug, a cytotoxic antibiotic, apolizumab, 1D09C3, TIMP-1, TIMP-2, Zinc, P53, Rb, an heterocyclic complex of a lanthanide, PUVA, an inhibitor of the transcription factor complex ESX/DRIP130/Sur-2, geldanamycin or its derivative 17-allylaminogeldanamycin (17-AAG), IM-842, tetrathiomolybdate, squalamine, combrestatin A4, TNP-470, marimastat, neovastat, bicalutamide, abarelix, oregovomab, mitumomab, TLK-286, alemtuzumab, ibritumomab, temozolomide, denileukin diftitox, aldesleukin, dacarbazine, floxuridine, plicamycin, mitotane, pipobroman, plicamycin, tamloxifen and testolactone. 
     
     
         12 . The method in accordance with  claim 10 , wherein (ii) is selected from paclitaxel (taxol), docetaxel, taxotere, navelbine, vinblastin, vincristin, vindesine, vinorelbine, melphalan, cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil, mechlorethamine, thalidomide, its R- and S-enantiomers and its derivatives, revimid (CC-5013), an ethyleneimine compound, an alkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin or a derivative thereof, netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin, olivomycin, a phtalanilide such as propamidine or stilbamidine, an anthramycin, an aziridine, a nitrosourea or a derivative thereof, a pyrimidine or purine analogue, cytarabine, 5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin, hydroxyurea, folic acid, an acridine or a derivative thereof, a rifamycin, an actinomycin, adramycin, irinotecan (camptosar), topotecan, an amsacrine or analogue thereof, a tricyclic carboxamide, SAHA, MD-275, trichostatin A, CBHA, LAQ824, valproic acid, bortezomib, vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842, GW-786034, BAY-43-9006, BAY-57-9006, gefitinib, erlotinib, CI-1033, GW-2016, iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272, herceptin, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or a pharmaceutically acceptable salt thereof, an inhibitor of the transcription factor complex ESX/DRIP130/Sur-2, heat shock protein HSP90 modulator geldanamycin and its derivative 17-allylaminogeldanamycin (17-AAG), atrasentan, rituximab, cetuximab, Avastin™ (bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000, vitaxin, imatinib, apolizumab and 1D09C3. 
     
     
         13 . The method in accordance with any one of  claims 10  to  12 , characterised in that (i) is the monoethanesulfonate salt of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone. 
     
     
         14 . The method in accordance with  claim 10 , wherein the formulation of (i) is for oral administration. 
     
     
         15 . The method in accordance with  claim 10 , characterised in that (i) is administered in a daily dosage such that the plasma level of the active substance lies between 10 and 500 ng/ml for at least 12 hours of a 24 hours dosing interval. 
     
     
         16 . The method in accordance with  claim 10 , wherein the cancer disease is selected from prostate cancer, renal cell cancers, bladder cancers, ovarian cancers, cervical cancers, endometrial cancers, lung cancer, colorectal cancers, pancreatic cancer, gastric cancer, oesophageal cancers, hepatocellular cancers, cholangiocellular cancers, head and neck cancer, malignant mesothelioma, breast cancer, malignant melanoma or bone and soft tissue sarcomas, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome and acute lymphoblastic leukemia. 
     
     
         17 . The method in accordance with  claim 16 , wherein the cancer disease is selected from colorectal cancers.