US 2011 0171289A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0171289 A1 STEFANC et al. (43) Pub. Date: Jul. 14, 2011

(54) COMBINATIONS FOR THE TREATMENT OF Publication Classification DISEASES INVOLVING CELL (51) Int. Cl. PROLIFERATION, MIGRATION OR A 6LX 9/27 (2006.01) APOPTOSIS OF MYELOMA CELLS, OR A63L/502 (2006.01) ANGIOGENESIS A 6LX 3/5.377 (2006.01) A 6LX 3L/395 (2006.01) Martin Friedrich STEFANIC, A63L/506 (2006.01) (75) Inventors: A63/675 (2006.01) Warthausen-Birkenhard (DE); A633/24 (2006.01) Frank HILBERG, Wien (AT): A63L/7008 (2006.01) Gerd MUNZERT, Ulm (DE): A6II 3/66 (2006.01) Flavio SOLCA, Wien (AT); Anke A63L/704 (2006.01) BAUM, Alland (AT); Jacobus C.A. A63L/7068 (2006.01) van MEEL, Moedling (AT) A 6LX 3L/7076 (2006.01) A638/14 (2006.01) (73) Assignee: BOEHRINGERINGELHEM A638/2 (2006.01) INTERNATIONAL GMBH, A 6LX 3/57 (2006.01) Ingelheim am Rhein (DE) A638/20 (2006.01) A638/16 (2006.01) (21) Appl. No.: 12/912,110 A 6LX 39/395 (2006.01) A6IP35/00 (2006.01) A6IP35/02 (2006.01) (22) Filed: Nov. 9, 2010 (52) U.S. Cl...... 424/450; 514/254.09: 514/248: 514/234.5; 424/133.1: 514/252.18; 514/90; Related U.S. Application Data 424/649; 514/62: 514/110: 514/34: 514/33; (60) Division of application No. 12/140,661, filed on Jun. 514/49; 514/46; 514/20.9: 424/94.6; 424/85.6; 17, 2008, now Pat. No. 7,846,936, which is a continu 514/171; 424/85.2: 514/21.2: 424/130.1 ation of application No. 10/830,147, filed on Apr. 22, (57) ABSTRACT 2004, now abandoned. The present invention relates to a pharmaceutical combina tion for the treatment of diseases which involves cell prolif (60) Provisional application No. 60/542,036, filed on Feb. eration, migration or apoptosis of myeloma cells, or angio 5, 2004. genesis. 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 (30) Foreign Application Priority Data treatment with radiation therapy, in a ratio which provides an additive and Synergistic effect, and to the combined use of Apr. 29, 2003 (EP) ...... O3 O09 587.1 these specific compounds and/or radiotherapy for the manu Jan. 13, 2004 (EP) ...... O4 OOO 508.4 facture of corresponding pharmaceutical combination prepa Jan. 21, 2004 (EP) ...... O4 OO1 1710 rations.

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COMBINATIONS FOR THE TREATMENT OF together with its ligand VEGF and its four sub-types known to DISEASES INVOLVING CELL date (Jung et al., European Journal of Cancer, Vol. 38, pp. PROLIFERATION, MIGRATION OR 1133-1140, 2002). Similar studies reported in previous APOPTOSIS OF MYELOMA CELLS, OR reports show that the overexpression of some of these recep ANGOGENESIS tors is implicated in multiple forms of cancer. For example, studies have provided evidence that the epidermal growth FIELD OF THE INVENTION factor EGF acts as a growth factor in tumours, and that the 0001. This invention relates to a method for the treatment vascular endothelial growth factor VEGF is one of the most of diseases involving cell proliferation, migration or apopto common mediators of tumorangiogenesis, which is essential sis of myeloma cells, or angiogenesis, which method com for the growth and metastasis of solid tumours. Inhibitors of prises co-administration to a person in need of such treatment the receptors have thus been and are still evaluated for cancer and/or co-treatment of a person in need of such treatment with therapy (see for example the article of Cerrington et al. In effective amounts of: Advances in Cancer Research, Academic Press 2000, pp. 0002 (i) a selected protein tyrosine kinase receptor 1-38). antagonist; and 0013 Recent studies have also suggested to combine sev 0003 (ii) at least a further chemotherapeutic or natu eral receptor antagonists together, or in further combination rally occurring, semi-synthetic or synthetic therapeutic with a chemotherapeutic agent or radiation. For example, WO agent; and/or 02/070008 suggests the combination of an antagonist specifi 0004 (iii) radiotherapy or radio-immunotherapy. cally directed against the VEGF receptor with an antagonist 0005. This invention relates also to suitable pharmaceuti specifically directed against the EGF receptor, optionally cal compositions comprising effective amounts of: together with radiation or a chemotherapeutic agent, for the 0006 (i) a selected protein tyrosine kinase receptor inhibition of tumour growth. As example of suitable specific antagonist; and antagonists, WO 02/070008 discloses monoclonal antibodies 0007 (ii) at least a further chemotherapeutic or natu directed against the VEGF receptor and monoclonal antibod rally occurring, semi-synthetic or synthetic therapeutic ies directed against the EGF receptor. agent, 0014 Thus, a large number of protein tyrosine kinase and optionally adapted for a co-treatment with radiotherapy receptor antagonists are currently in clinical development for or radio-immunotherapy, as a combined preparation for the treatment of cancer (see for example the Expert Opinion simultaneous, separate or sequential use in the treatment of Review of Laid & Cherrington in Expert Opin. Invest. Drugs, diseases involving cell proliferation, migration or apoptosis Vol. 12, No. 1, pp. 51-64, 2003). However, proof of efficacy of myeloma cells, orangiogenesis, and especially for inhib for these Substances, used alone or with other cancer thera iting tumour growth, Survival and metastasis. pies, in the treatment of oncological diseases, has so far not 0008. This invention relates also to the combined use of been achieved, either because of a lack of additional benefit effective amounts of: over the standard therapy or because of the discovery of 0009 (i) a selected protein tyrosine kinase receptor unacceptable side-effects. antagonist; and 0015 For example, it has been recently published that an 0010 (ii) at least a further chemotherapeutic or natu angiogenesis inhibitor which has already been clinically rally occurring, semi-synthetic or synthetic therapeutic tested, also in conjunction with chemotherapy, namely the agent, inhibitor with code name SU5416, developed by Pharmacia for the manufacture of a pharmaceutical combined prepara for the treatment of cancer, was associated with disturbing tion for simultaneous, separate or sequential use in the treat side effect, namely thromboembolic events (Ken Garber and ment of diseases involving cell proliferation, migration or Ann Arbor, Nature Biotechnology, Vol. 20, pp. 1067-1068, apoptosis of myeloma cells, or angiogenesis, and especially November 2002). for inhibiting tumour growth, Survival and metastasis, option 0016 For the treatment of diseases of oncological nature, ally in combination with a co-treatment with radiotherapy or a large number of chemotherapeutic agents have already been radio-immunotherapy. Suggested, which can be used as mono-therapy (treatment 0011. This invention relates also to the use of an effective with one agent) or as combination therapy (simultaneous, amount of a selected protein tyrosine kinase receptor antago separate or sequential treatment with more than one agent) nist, for the manufacture of a pharmaceutical composition and/or which may be combined with radiotherapy or radio adapted for a simultaneous, separate or sequential co-treat immunotherapy. In this respect, chemotherapeutic agent ment with radiotherapy or radio-immunotherapy of diseases means a naturally occurring, semi-synthetic or synthetic involving cell proliferation, migration or apoptosis of chemical compound which, alone or via further activation, for myeloma cells, orangiogenesis, and especially for inhibiting example with radiations in the case of radio-immunotherapy, inhibits or kills growing cells, and which can be used or is tumour growth, Survival and metastasis. approved for use in the treatment of diseases of oncological nature, which are commonly also denominated as cancers. In BACKGROUND OF THE INVENTION the literature, these agents are generally classified according 0012. In the last decade, the biological activity of several to their mechanism of action. In this matter, reference can be types and sub-types of the protein tyrosin kinase receptor made, for example, to the classification made in “Cancer family have been characterised Such as, for example, the Chemotherapeutic Agents'. American Chemical Society, epidermal growth factor receptor EGFR and its subtypes 1995, W.O. Foye Ed. ErbB-2 and ErbB-4 (Brignola et al., Journal of Biological 0017 Thus, within the meaning of the present invention, Chemistry, Vol. 277, No. 2, pp. 1576-1585, 2002) or the the following classes of chemotherapeutic agents are espe vascular endothelial growth factor receptors VEGFR 1-3 cially of interest, although not representing a limitation: US 2011/0171289 A1 Jul. 14, 2011

0018 Synthetic small molecule VEGF receptor antago or of non-oncological nature, such as diabetic retinopathy, nists rheumatoid arthritis or psoriasis. 0019 Small molecule growth factor (GF) receptor antagonists SUMMARY OF THE INVENTION (0020 Inhibitors of the EGF receptor and/or VEGF 0042. It has now been found that co-administration to a receptor and/or integrin receptors or any other protein person in need of Such treatment and/or co-treatment of a tyrosine kinase receptors, which are not classified under person in need of such treatment with effective amounts of the synthetic Small-molecules 0.043 (i) a selected protein tyrosine kinase receptor (0021. Inhibitors directed to EGF receptor and/or VEGF antagonist, and receptor and/or integrin receptors or any other protein 0044 (ii) at least a further chemotherapeutic or natu tyrosine kinase receptors, which are fusion proteins rally occurring, semi-synthetic or synthetic therapeutic 0022 Compounds which interact with nucleic acids agent, and/or and which are classified as alkylating agents or platinum 0.045 (iii) radiotherapy or radioimmunotherapy, compounds provides unexpected advantages in the treatment of diseases 0023 Compounds which interact with nucleic acids in which cell proliferation, migration or apoptosis of and which are classified as anthracyclines, as DNA inter myeloma cells, or angiogenesis are involved, to a person in calators or as DNA cross-linking agents need of Such treatment, with high efficacy, in comparison to 0024. Anti-metabolites administration of any of these Substances alone and/or treat 0025 Naturally occurring, semi-synthetic or synthetic ment with radiotherapy or radioimmunotherapy. bleomycin type antibiotics (BLM-group antibiotics) 0046. It has been further found that this co-administration 0026 Inhibitors of DNA transcribing enzymes, espe or co-treatment is especially efficient if the selected protein cially topoisomerase I or topoisomerase II inhibitors tyrosine kinase receptor antagonist is an antagonist of at least 0027 Chromatin modifying agents one receptor selected from VEGFR1 to 3, PDGFRC. and B, 0028 Mitosis inhibitors, anti-mitotic agents, or cell FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit. cycle inhibitors 0047. It has been further found that this co-administration 0029 Proteasome inhibitors or co-treatment is especially efficient if the selected protein 0030 Enzymes tyrosine kinase receptor antagonist is an antagonist of at least 0031 Hormones, hormone antagonists or hormone one receptor selected from VEGFR 1 to 3, PDGFRC. and B, inhibitors, or inhibitors of steroid biosynthesis FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, and 0032 Steroids further an antagonist of a Src tyrosine kinase family member, 0033 Cytokines, hypoxia-selective cytotoxins, inhibi and especially of Src, lck, lyn and fyn, and/or further an tors of cytokines, lymphokines, antibodies directed antagonist of at least one complex of a cyclin dependent against cytokines or oral and parenteral tolerance induc kinase with its specific cyclin or with a viral cyclin, such as tion strategies CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins A, B1, B2, C, D1, D2, 0034 Supportive agents D3, E, F, G1, G2, H, I and K, and/or furtheran inhibitor of the 0035 Chemical radiation sensitizers and protectors paracrine IL-6 secretion. 0036 Photochemically activated drugs 0048. Furtherit has been found that the diseases which can 0037 Synthetic poly- or oligonucleotides be treated by the combination in accordance with the present 0038. Other chemotherapeutic or naturally occurring, invention are all kind of diseases in which cell proliferation, semi-synthetic or synthetic therapeutic agents, such as migration or apoptosis of myeloma cells, orangiogenesis are cytotoxic antibiotics, antibodies targeting Surface mol involved, which can be of oncological nature such as all types ecules of cancer cells, inhibitors of metalloproteinases, of malignant neoplasias or cancers, or of non-oncological inhibitors of oncogenes, inhibitors of gene transcription nature. Such as diabetic retinopathy, rheumatoid arthritis, or or of RNA translation or protein expression, or com psoriasis. plexes of rare earth elements 0049. Further it has been found that the combination treat 0039. Further classes of compounds, so-far not classified ment in accordance with the present invention is especially as chemotherapeutic agents, which are naturally occurring, efficient for inhibiting tumour growth, Survival and metasta semi-synthetic or synthetic therapeutic agents, such as the S1S. non-steroidal anti-inflammatory drugs, especially the 0050. Further it has been found that the combination treat cyclooxygenase (COX) inhibitors and more specifically the ment in accordance with the present invention is especially COX-2 inhibitors, are also of interest for combination thera efficient with selected active Substances, selected dosages and pies. selected dosage forms. 0040. Even if the concept of combining several therapeu 0051. Thus, the present invention provides a method for tic agents or therapies already has been Suggested, and the treatment of diseases involving cell proliferation, migra although various combination therapies are under investiga tion or apoptosis of myeloma cells, or angiogenesis, which tion and in clinical trials, there is still a need for new and method comprises simultaneous, separate or sequential co efficient therapeutic agents for the treatment of diseases in administration of effective amounts of: which cell proliferation, migration or apoptosis of myeloma 0.052 (i) an antagonist of at least one receptor selected cells, or angiogenesis, and there is still a need to develop from VEGFR 1 to 3, PDGFRC. and B, FGFR1, 2 and 3, further combinations which can show increased efficacy and EGFR, HER2, IGF1R, HGFR or c-Kit, which is further reduced side-effects. an antagonist of a Src tyrosine kinase family member, or 0041. These diseases may as well be of oncological nature, a polymorph, metabolite orpharmaceutically acceptable which includes all types of malignant neoplasias or cancers, salt thereof, and US 2011/0171289 A1 Jul. 14, 2011

0053 (ii) at least a further chemotherapeutic or natu inhibitors of cytokines, lymphokines, antibodies directed rally occurring, semi-synthetic or synthetic therapeutic against cytokines or oral and parenteral tolerance induction agent, strategies, Supportive agents, chemical radiation sensitizers in the form of a combined preparation, optionally adapted for and protectors, photochemically activated drugs, synthetic a co-treatment with radiotherapy or radio-immunotherapy, to poly- or oligonucleotides, optionally modified or conjugated, a person in need of Such treatment. non-steroidal anti-inflammatory drugs, cytotoxic antibiotics, 0054 The present invention provides also a method for the antibodies targeting Surface molecules of cancer cells, inhibi treatment of diseases involving cell proliferation, migration tors of metalloproteinases, metals, inhibitors of oncogenes, or apoptosis of myeloma cells, or angiogenesis, which inhibitors of gene transcription or of RNA translation or pro method comprises a simultaneous, separate or sequential co tein expression, complexes of rare earth elements, or photo treatment with an effective amount of an antagonist of at least chemotherapeutic agents. one receptor selected from VEGFR 1 to 3, PDGFRC. and B, 0059. In one preferred embodiment, amongst the chemo FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, therapeutic or naturally occurring, semi-synthetic or syn which is further an antagonist of a Src tyrosine kinase family thetic therapeutic agents, specific compounds are preferred. member, or with a polymorph, metabolite or pharmaceuti 0060. In one embodiment, the disease treated in the cally acceptable salt thereof, and with radiotherapy or radio method in accordance with the present invention is preferably immunotherapy. an oncological disease. In a preferred embodiment, the dis 0055. The protein tyrosine kinase receptorantagonist used ease is selected from Solid tumours. Such as urogenital can in the method in accordance with the present invention is cers (such as prostate cancer, renal cell cancers, bladder can preferably an antagonist of at least one receptor selected from cers), gynecological cancers (such as ovarian cancers, VEGFR 1 to 3, PDGFR C. and B, FGFR1, 2 and 3, EGFR, cervical cancers, endometrial cancers), lung cancer, gas HER2, IGF1R, HGFR, c-Kit, and further an antagonist of a trointestinal cancers (such as colorectal cancers, pancreatic Src-tyrosine kinase family member, and especially of Src, lck, cancer, gastric cancer, oesophageal cancers, hepatocellular lyn or fyn. cancers, cholangiocellular cancers), head and neck cancer, 0056. In a further preferred embodiment, the protein malignant mesothelioma, breast cancer, malignant melanoma tyrosine kinase receptor antagonist may further be an antago or bone and Soft tissue sarcomas, and haematologic neopla nist of at least one complex of a cyclindependent kinase with sias, such as multiple myeloma, acute myelogenous leuke its specific cyclin or with a viral cyclin, such as CDK1, mia, chronic myelogenous leukemia, myelodysplastic Syn CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and drome and acute lymphoblastic leukemia. In a preferred CDK9 with their specific cyclins A, B1, B2, C, D1, D2, D3, E, embodiment, the disease is hormone sensitive or hormone F, G1, G2, H, I and K, and/or further an inhibitor of the refractory prostate cancer, ovarian carcinoma, or Small cell paracrine IL-6 secretion. lung cancer. 0057. In one preferred embodiment, the protein tyrosine 0061. In another embodiment, the disease treated in the kinase receptor antagonist is selected from specific com method in accordance with the present invention is preferably pounds. a non-oncological disease selected from diabetic retinopathy, 0058. The further chemotherapeutic or naturally occur rheumatoid arthritis or psoriasis. ring, semi-synthetic or synthetic therapeutic agent used in the 0062. Thus, the beneficial efficacy of the methods in method in accordance with the present invention can be any accordance with the invention are mainly based on the addi available chemotherapeutic or naturally occurring, semi-syn tive and synergistic effects of the combined treatment, or to an thetic or synthetic therapeutic agent, and more particularly improved tolerability of the treatment by the patient due, for the chemotherapeutic agents which are commonly used for example, to the administration of lower doses of the thera the treatment of cancer. Preferred chemotherapeutic agents peutic agents involved. are selected from the following groups: synthetic Small mol 0063. The unexpected advantages mentioned above may ecule VEGF receptor antagonists, Small molecule growth also be due to a more efficient apoptosis induction by the factor (GF) receptor antagonists, inhibitors of the EGF recep chemotherapeutic agent, once the constitutively active Sur tor and/or VEGF receptor and/or integrin receptors or any vival signal of the protein tyrosin kinase receptor, mediated other protein tyrosine kinase receptors which are not classi by the tumour, is inhibited by the selected protein tyrosine fied under the synthetic small-molecules, inhibitors directed kinase receptor antagonist. to EGF receptor and/or VEGF receptor and/or integrin recep 0064. In the case of the use of an antagonist of protein tors or any other protein tyrosine kinase receptors, which are tyrosine kinase receptors or an inhibitor of other mediators fusion proteins, compounds which interact with nucleic acids involved in angiogenesis, such as for example the vascular and which are classified as alkylating agents or platinum endothelial growth factors (VEGF), the vascular permeability compounds, compounds which interact with nucleic acids factors, the basic fibroblast growth factor (bFGF), interleu and which are classified as anthracyclines, as DNA interca kin-6 (IL-6) or interleukin-8 (IL-8), the epidermal growth lators (including DNA minor-groove binding compounds) or factor (EGF) or the platelet-derived growth factor (PDGF), as DNA cross-linking agents, anti-metabolites, naturally one of the advantages of the method and composition in occurring, semi-synthetic or synthetic bleomycin type anti accordance with the present invention lies in a targeting of the biotics (BLM-group antibiotics), inhibitors of DNA tran treatment to tumour-associated vasculature rather than, or scribing enzymes, and especially the topoisomerase I or together with, the tumour itself, in order to cut the energy topoisomerase II inhibitors, chromatin modifying agents, Supply of cancerous cells. mitosis inhibitors, anti-mitotic agents, cell-cycle inhibitors, 0065. A further advantage is that an induction or reinstate proteasome inhibitors, enzymes, hormones, hormone antago ment of the sensitivity towards the chemotherapeutic agent is nists or hormone inhibitors, or inhibitors of steroid biosyn expected in patients treated with the combination of chemo thesis, steroids, cytokines, hypoxia-selective cytotoxins, therapeutic agents for which the sensitivity gets lost in the US 2011/0171289 A1 Jul. 14, 2011

course of the treatment and of a VEGFR antagonist. This is treatment by radiotherapy or radio-immunotherapy means especially the case of patients Suffering from refractory mul amounts of the agents and/or of the treatment by radiotherapy tiple myeloma and treated with steroids as chemotherapeutic or radio-immunotherapy which are effective to achieve a agent. A combination treatment with steroids and a VEGFR therapeutic effect when used in combination. antagonist is expected to restore the steroid sensitivity of patients Suffering from refractory multiple myeloma. DETAILED DESCRIPTION OF THE INVENTION 0.066 According to the present invention, a synergistic combined preparation is meant to comprise an amount of the 0072. The Diseases selected protein tyrosine kinase receptor antagonist, or of a 0073. As already mentioned hereinbefore, the diseases polymorph, metabolite orpharmaceutically acceptable salt of which can be treated by the combination in accordance with this active compound, and an amount of the further chemo the present invention are all kind of diseases in which cell therapeutic or naturally occurring, semi-synthetic or syn proliferation, migration or apoptosis of myeloma cells, or thetic therapeutic agent, and/or radiotherapy or radio-immu angiogenesis are involved, which can be of oncological notherapy, wherein the amount of the individual therapeutic nature Such as all types of malignant neoplasias or cancers, or agents alone is insufficient to achieve the therapeutic effect of non-oncological nature. Such as diabetic retinopathy, rheu achieved by the administration of the combination of said matoid arthritis, or psoriasis. Among cancers, selected spe therapeutic agents, and wherein the combined effects of the cific target indications are solid tumours, such as urogenital amounts of the therapeutic agents is greater than the Sum of cancers (such as prostate cancer, renal cell cancers, bladder the therapeutic effects achievable with the amounts of the cancers), gynecological cancers (such as ovarian cancers, individual therapeutic agents. cervical cancers, endometrial cancers), lung cancer, gas 0067 Viewed from a different aspect, the present inven trointestinal cancers (such as colorectal cancers, pancreatic tion also relates to a pharmaceutical combination for the cancer, gastric cancer, oesophageal cancers, hepatocellular treatment of diseases in which cell proliferation, migration or cancers, cholangiocellular cancers), head and neck cancer, apoptosis of myeloma cells, or angiogenesis are involved, malignant mesothelioma, breast cancer, malignant melanoma comprising a selected specific protein tyrosine kinase recep or bone and Soft tissue sarcomas, and haematologic neopla tor antagonist and a further chemotherapeutic or naturally sias, such as multiple myeloma, acute myelogenous leuke occurring, semi-synthetic or synthetic therapeutic agent, and/ mia, chronic myelogenous leukemia, myelodysplastic Syn or radiotherapy or radio-immunotherapy, as a combined drome and acute lymphoblastic leukemia. preparation for simultaneous, separate or sequential use in 0074 The combination treatment in accordance with the treatment of said diseases, optionally together with one or present invention is especially efficient for inhibiting tumour more pharmaceutically acceptable diluents and/or carriers. growth, Survival and metastasis. 0068 Viewed from a different aspect, the present inven 0075 Of special interest for the combination treatment is tion also relates to a pharmaceutical combination preparation the treatment of hormone sensitive or hormone refractory kit for the treatment of diseases involving cell proliferation, prostate cancer, ovarian carcinoma, non Small cell lung can migration or apoptosis of myeloma cells, or angiogenesis, cer, Small cell lung cancer, or multiple myeloma. comprising a therapeutically effective amount of a selected (0076. The Selected Protein Tyrosine Kinase Receptor protein tyrosine kinase receptor antagonist, or of a poly Antagonist morph, metabolite or pharmaceutically acceptable salt 0077. As already mentioned hereinbefore, the selected thereof, and a therapeutically effective amount of a further protein tyrosine kinase receptor antagonists that can be used chemotherapeutic or naturally occurring, semi-synthetic or in the context of the present invention include all substances synthetic therapeutic agent, characterised in that the protein that inhibit the stimulation or activation of a protein tyrosine tyrosine kinase receptor antagonist is comprised within a first kinase receptor by a protein tyrosine kinase receptor ligand. compartment and the further chemotherapeutic or naturally In the case of a protein tyrosine kinase receptor belonging to occurring, semi-synthetic or synthetic therapeutic agent is the family of the growth factor receptors, such inhibition of comprised within a second compartment, such that the stimulation or activation inhibits the growth of cells that administration to a patient in need thereof can be simulta express the receptor. neous, separate or sequential, said combination preparation 0078 Some examples of growth factor receptors involved kit being optionally further adapted for a co-treatment with in tumorigenesis are the receptors forepidermal growth factor radiotherapy or radio-immunotherapy. (EGFR), vascular endothelial growth factors (VEGFRs), 0069. In one embodiment in accordance with the present platelet-derived growth factor (PDGFR), insulin-like growth invention, in each compartment of the pharmaceutical com factor (IGFR), nerve growth factor (NGFR), and fibroblast bination preparation kit, each active Substance is formulated growth factor (FGFR). for an oral administration. 0079. By inhibition of stimulation or activation of protein 0070 Viewed from a further aspect, the present invention tyrosine kinase receptor is meant any decrease in the activa thus also provides the use of a selected protein tyrosine kinase tion of the receptor, which need not completely prevent or receptor antagonist in combination with a further chemo stop activation of the receptor. therapeutic or naturally occurring, semi-synthetic or syn 0080 Moreover, inhibition of the receptor stimulation or thetic therapeutic agent, and/or adapted for a co-treatment activation, as defined by the present invention, means inhibi with radiotherapy or radio-immunotherapy, for the manufac tion resulting from interaction of the antagonistand the recep ture of a pharmaceutical combination preparation for the tor or its ligand. By interaction is meant Sufficient physical or treatment of the diseases or indications mentioned hereinbe chemical interaction between the antagonist and the receptor, fore. such that protein tyrosin kinase activity is inhibited. One of 0071. Within the meaning of the present invention, effec skill in the art would appreciate that examples of such chemi tive amounts of therapeutic agents and/or of a therapeutic cal interactions, which include association or bonding, are US 2011/0171289 A1 Jul. 14, 2011

known in the art and include covalent bonding, ionic bonding, I0086. In accordance with the present invention, the hydrogen bonding, etc . . . , between the antagonist and the selected protein tyrosine kinase receptor antagonist is prefer receptor or its ligand. ably an antagonist of at least one receptor selected from 0081. Increased protein tyrosine kinase receptor stimula VEGFR 1 to 3, PDGFR C. and B, FGFR12 and 3, EGFR, HER2, IGF1R, HGFR, c-Kit, and further an antagonist of one tion or activation can result from higher levels of ligand, of the Src-tyrosine kinase family members, and especially Src, receptor gene amplification, increased transcription of the lck, lyn or fyn, or a polymorph, metabolite or pharmaceuti receptor or mutations that cause unregulated receptor signal cally acceptable salt thereof. The selected protein tyrosine ling. Amplification of the gene encoding the receptor results kinase receptor antagonist may further be an antagonist of at in an increased number of ligands binding to the receptor, least one complex of a cyclin dependent kinase with its spe which can further stimulate cell proliferation. The protein cific cyclin or with a viral cyclin, such as CDK1, CDK2, tyrosine kinase receptor may also be over-expressed in the CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with absence of gene amplification, presumably through muta their specific cyclins A, B1, B2, C, D1, D2, D3, E, F, G1, G2, tions that increase its transcription, mRNA translation, or H, I and K, and/or further an inhibitor of the paracrine IL-6 stability of the protein. Protein tyrosine kinase receptor secretion. mutants of the EGFR type have already been identified in 0087. In a further embodiment in accordance with the gliomas, non-small cell lung carcinomas, ovarian carcinomas present invention, the combination of the active Substances is and prostate carcinomas, that have a constitutively active intended for the treatment of oncological diseases involving protein tyrosin kinase, Suggesting a role for high-level EGFR angiogenesis. activity rather than EGFR over-expression in these cancers I0088 Tumour angiogenesis plays an important role in the (see for example Pedersen et al., Ann. Oncol., Vol. 12(6), pp. progression of human malignancies. Inhibition of this pro 745-60, 2001). cess is thought to be an excellent point of therapeutic inter 0082 In one embodiment in accordance with the present vention in the treatment of cancer. Signal transduction invention, the selected protein tyrosine kinase receptor through the vascular endothelial growth factor receptor 2 antagonist inhibits the binding of the protein tyrosine kinase (VEGFR-2) has been shown to play a pivotal role in the receptor to its ligand. proliferation, Survival and migration of endothelial cells in 0083 Binding of a ligand to an external, extracellular tumour angiogenesis. domain of the receptor stimulates receptor dimerization, I0089. In this matter, potent and orally available low autophosphorylation of the receptor, activation of the recep molecular weight antagonists of VEGFR-2 have been devel tor's internal, cytoplasmic protein tyrosin kinase domain, and oped as new compounds which are useful for the treatment of initiation of multiple signal transduction pathways involved diseases involving cell proliferation, migration or apoptosis in regulation of DNA synthesis, cell division, vasculogenesis of myeloma cells, or angiogenesis, and especially as new orangiogenesis. The inhibition produced by the presence of cancer therapeutic agents. These antagonists are thus inhibi the antagonist will consequently reduce this stimulation. tors of the activity of the receptor. Some of these antagonists 0084. In another embodiment in accordance with the are also antagonists of further growth factor receptors, such as present invention, the selected protein tyrosine kinase recep VEGFR-3, PDGFRC. and B, FGFR1, 2 and 3, EGFR, HER2, tor antagonist binds directly to the receptor. The antagonist IGF1R, HGFR, c-Kit, and some also antagonists of the src can bind externally to the extra-cellular portion of the recep tyrosine kinase family members Src, lck, lyn and fyn. tor, which may or may not inhibit binding of the ligand, or (0090. These compounds are disclosed in WO 02/3.6564, internally to the protein tyrosine kinase domain. Examples of WO 99/52869, WO 00/18734, WO 00/73297, WO 01/27080, Such antagonists include, without limitation, biological mol WO 01/27081 and WO O1/32651. The cited documents are ecules. Such as antibodies (and functional equivalents herewith incorporated by reference with respect to any thereof) specific for the receptor, and synthetic kinase inhibi aspects disclosed relating to these specific compounds. tors that act directly on the cytoplasmic domain of the recep 0091. The following compounds are particularly represen tor, such as the so-called “small molecule tyrosine kinase tative and are all combined inhibitors of VEGFR-2 and lok inhibitors'. A non-exhaustive list of small molecule tyrosine which may be used as the selected protein tyrosine kinase kinase inhibitors can be found in the review article of Laid & receptor antagonist within the meaning of the present inven Cherrington, Expert Opinion Invest. Drugs, Vol. 12, No. 1, tion. 2003, the content of which is incorporated herein by refer 0092 (A) (Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N- CCC. methylsulfonyl-amino)-phenylamino)-1-phenyl-methyl 0085 Additional protein tyrosine kinase receptor antago ene)-2-indolinone; nists can easily be determined using well-known methods. 0093 (B) (Z)-3-(1-(4-(N-(3-dimethylaminopropyl)-N- The selected receptor antagonists to be used in the present propionyl-amino)-phenylamino)-1-phenyl-methylene)-2- invention inhibit the protein tyrosin kinase activity of the receptor, which generally involves phosphorylation events. indolinone; Accordingly, phosphorylation assays may for example be 0094 (C) (Z)-3-(1-(4-(dimethylaminomethyl)-pheny useful in determining antagonists useful in the context of the lamino)-1-phenyl-methylene)-5-(butylcarbamoyl)-2-in present invention. In addition, methods specific for detection dolinone; of the receptor expression can be utilized. These include 0.095 (D) (Z)-3-(1-(4-(dimethylaminomethyl)-pheny immunohistochemistry for detection of protein expression, lamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-car fluorescence in situ hybridization for detection of gene ampli bamoyl)-2-indolinone; fication, competitive radioligand binding assays, Solid matrix 0096 (E) (Z)-3-(1-(4-(N-methylsulfonyl-N-(2-dimethy blotting techniques, such as Northern and Southern blots, lamino-ethyl)-amino)-phenylamino)-1-phenyl-meth reverse transcriptase polymerase chain reaction and ELISA. ylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone; US 2011/0171289 A1 Jul. 14, 2011

0097 (F) (Z)-3-(1-(4-(butylaminomethyl)-phenylamino)- azin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1- 1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2- phenyl-methylene-6-methoxycarbonyl-2-indolinone. indolinone; 0.115. When compared to the other above exemplified 0098 (G) (Z)-3-(1-(4-(pyrrolidin-1-yl-methyl)-pheny compounds, this compound is further particularly preferred lamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-car due to its high potency as inhibitor and its better toxicologic bamoyl)-2-indolinone; profile. 0099 (H) (Z)-3-(1-(4-(diethylaminomethyl)-pheny 0116 Particularly preferred is the monoethanesulfonate lamino)-1-phenyl-methylen)-5-(cyclohexylmethyl-car salt of this compound, namely the monoethanesulfonate salt bamoyl)-2-indolinone; of 3-Z-1-(4-(N-(4-methyl-piperazin-1-yl)-methylcarbo 01.00 (I) (Z)-3-(1-(4-(diethylaminomethyl)-pheny nyl)-N-methyl-amino)-anilino)-1-phenyl-methylene-6- lamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-car methoxycarbonyl-2-indolinone, disclosed for example in bamoyl)-2-indolinone; unpublished German patent application DE 102 33 500. 1, 0101 (J) (Z)-3-(1-(4-(diethanolaminomethyl)-pheny unpublished PCT/03/07822 and unpublished U.S. patent lamino)-1-phenyl-methylen)-5-(butylcarbamoyl)-2-in application Ser. No. 10/623,971. dolinone; 0117. In accordance with what is disclosed in DE 10233 0102 (K) (Z)-3-(1-(4-(dimethylaminomethyl)-pheny 500.1, unpublished PCT/03/07822 and unpublished U.S. lamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-car patent application Ser. No. 10/623.971, the monoethane bamoyl)-2-indolinone; sulfonate salt of 3-Z-1-(4-(N-((4-methyl-piperazin-1-yl)- 0103 (L) (Z)-3-(1-(4-(N-acetyl-N-(2-dimethylamino methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-meth ethyl)-amino)-phenylamino)-1-phenyl-methylen)-5-(N- ylene-6-methoxycarbonyl-2-indolinone has the following (3-chlorobenzyl)-carbamoyl)-2-indolinone; chemical structure: 0104 (M) (Z)-3-(1-(4-(butylaminomethyl)-pheny lamino)-1-phenyl-methylen)-5-(N-(3-chlorobenzyl)-car bamoyl)-2-indolinone; 0105 (N) (Z)-3-(1-(4-(dimethylaminomethyl)-pheny lamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-in dolinone; 0106 (O) (Z)-3-(1-(4-(N-(3-dimethylamino-propyl)-N- acetyl-amino)-phenylamino)-1-phenyl-methylene)-6- methoxycarbonyl-2-indolinone; 0107 (P) (Z)-3-(1-(4-(ethylaminomethyl)-phenylamino)- 1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone; 0108 (Q) (Z)-3-(1-(4-(1-methyl-imidazol-2-yl)-pheny lamino)-1-phenyl-methylene)-6-methoxycarbonyl-2-in dolinone; 0109 (R) (Z)-3-(1-(4-(N-(dimethylaminomethylcarbo nyl)-N-methyl-amino)-phenylamino)-1-phenyl-methyl ene)-6-methoxycarbonyl-2-indolinone; 0110 (S) (Z)-3-(1-(4-(methylaminomethyl)-anilino)-1- Compound MES(T) phenyl-methylene)-6-methoxycarbonyl-2-indolinone; 0111 (T) (Z)-3-(1-(4-(N-(4-methyl-piperazin-1-yl)-me Monoethanesulfonate Salt of Compound (T) thylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl methylene-6-methoxycarbonyl-2-indolinone; and 0118. This compound may be selectively obtained by a 0112 (U) 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1- Suitable choice of manufacturing conditions, preferably in its methylpiperidin-4-ylmethoxy)-quinazoline, crystalline hemihydrate form. as well as their polymorphs, metabolites or pharmaceutically 0119 This compound is characterised by a melting point acceptable salts. of T=305+5° C. (determined by DSC=Differential Scanning 0113 Compounds (A) to (B) are described in WO calorimetry, using a Mettler-Toledo DSC82 apparatus; heat 00/18734, compounds (C) to (M) are described in WO ingrate: 10 K/min). 00/73297, compounds (N) to (T) are described in WO 0.120. For the manufacture of the monoethanesulfonate 01/27081, compound (U) is described in WO 01/32651. salt of 3-Z-1-(4-(N-(4-methyl-piperazin-1-yl)-methylcar 0114 Especially representative is the potent and orally bonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene-6- available low molecular weight antagonist of VEGFR 1 to 3, methoxycarbonyl-2-indolinone, a procedure in accordance PDGFRC. and B, FGFR1, 2 and 3, EGFR, HER2, IGF1R, with the following may be used. HGFR and c-Kit, which is further an antagonist of the Src I0121 The starting material used to prepare the monoet tyrosine kinase family members, and especially of Src, lck, hanesulfonate salt of 3-Z-1-(4-(N-(4-methyl-piperazin-1- lyn and fyn, further an antagonist of the complex of cyclin yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl dependent kinases with their specific cyclins or with a viral methylene-6-methoxycarbonyl-2-indolinone may be the cyclin, and further an inhibitor of the paracrine IL-6 secretion, free base 3-Z-1-(4-(N-(4-methyl-piperazin-1-yl)-methyl disclosed, for example, in WOO1/27081, as exemplified com carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene pound number 473, as well as its polymorphs, metabolites or 6-methoxycarbonyl-2-indolinone, which may be obtained in pharmaceutically acceptable salts. This compound, referred accordance with a method known from the prior art and to as (T) in the above list, is 3-Z-1-(4-(N-(4-methyl-piper described, for example, in WO 01/27081. US 2011/0171289 A1 Jul. 14, 2011

0122) Thus, in a first step and in accordance with what is none inhibits the human VEGFR-2 kinase (huVEGFR-2) described in WO 01/27081, 3-Z-1-(4-(N-(4-methyl-piper with an ICs of 21 nM, the murine VEGFR-2 kinase (hu azin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1- VEGFR-2) with an ICs of 13 nM, and the proliferation of phenyl-methylene-6-methoxycarbonyl-2-indolinone is pre VEGF stimulated endothelial cells (HUVEC: IC=9 nM, pared as follows. HSMEC: ICs—12 nM). 0123 10.5 g (30.0 mmol) 1-acetyl-3-(1-ethoxy-1-phenyl 0.139. Furthermore, FGFR-1 and PDGFRO, two members methylene)-6-methoxycarbonyl-2-indolinone (prepared as of the split kinase domain family of receptors important in described in WO 01/27081) and 8.60 g (33.0 mmol) N-(4- angiogenic signaling, are additionally inhibited by this com methyl-piperazin-1-yl)-methylcarbonyl-N-methyl-p-phe pound with ICso's of 69 nM and 59 nM respectively. nylendiamine (prepared as described in WO 01/27081) are 0140. The compound MES(T) is thus highly selective dissolved in 80 ml dimethylformamide and mixed for 1 hour when tested against a panel of numerous different kinases, as at 80°C. After cooling, 6.50 ml piperidine is added and the shown in the following Table I. whole is further mixed for 2 hours at room temperature. Water is added, the liquid over the resulting precipitate is sucked up, and the precipitate is washed again with a low quantity of TABLE I water. The residue is suspended in 200 ml methanol, the Kinase ICsonM liquid is sucked up, and the remaining residue washed with VEGFR-2 21 cold water and diethylether. The resulting product is vacuum muVEGFR-2 13 dried at 110° C. VEGFR-3 13 0.124 Recovered product: 12.4 g (77% of theoretical insR >4OOO GF1R >1000 value) EGFR >SOOOO 0125 IR-spectroscopy: 1610, 1655, 1711 cm HER2 >SOOOO FGFR1 69 (0.126 Ts=253° C. FGFR3 137 I0127. Molecular formula: CHNO PDGFRC 59 0128 Electrospray-mass spectrometry: m/z 540M+H" CDK1 >1OOOO 0129. Element analysis: CDK2 >1OOOO CDK4 >1OOOO Lck 16 Lyn 195 calculated C 68.99 H 6.16 N 12.98 Src. 156 found C 68.32 H 6.29 N 12.85 0141 Noteworthy is also that this specific antagonist 0130. In a second step, and in accordance with what what shows a long lasting inhibition of the receptor VEGFR-2. On is disclosed in DE 10233 500.1, the monoethanesulfonate the molecular and cellular level a short exposure of the com salt of 3-Z-1-(4-(N-(4-methyl-piperazin-1-yl)-methylcar pound MES(T) to cells (e.g. endothelial cells) is enough to bonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene-6- inhibit the activation of the receptor kinase itself and down methoxycarbonyl-2-indolinone will be obtained as follows. stream signalling molecules (e.g. the MAP kinase, MAPK) as 0131 605 g (1.12 mol) 3-Z-1-(4-(N-((4-methyl-piper well as cellular proliferation for at least 32 h. azin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1- 0142. The results of the following experiment evidences phenyl-methylene-6-methoxycarbonyl-2-indolinone are this long-lasting inhibition effect. In order to determine the suspended in 9 litres methanol and heated to 50° C. 183.7g duration of the inhibition induced by MES(T) on the receptor, (1.121 mol) of a 70% aqueous solution of ethanesulfonate is washout experiments were performed. HUVEC and NIH 3T3 added. The resulting solution is cooled to 40° C. and mixed KDR cells were exposed to MES(T) for a limited period of with 4.5 litres terbutylmethylether. Cristallisation occurs time, MES(T) was washed away and cell proliferation (HU after a few minutes. In order to achieve a complete precipita VEC) or VEGFR-2 activation/phosphorylation was analysed tion, the whole is mixed for 16 hours at room temperature. after various periods of time. As shown in FIG. 1, the auto After cooling to a temperature of 10°C., the liquid is sucked phosphorylation of VEGFR-2 is blocked for at least 32 h after up, the precipitate is washed with 2litrester-butylmethylether a 1 hour exposure with 50 nMMES(T). After 8h, 24h, and 32 and vacuum dried at 40° C. h without MES(T), the cells were again stimulated with (0132 Recovered product: 638 g (87.6% of theoretical VEGF and the receptor activation was analysed. Even after 32 value) h no receptor activation could be observed. This strongly (0.133 T. =305+5° C. (DSC 10K/min) suggests that MES(T) exhibits sustained effects on the recep 0134) Purity (measured by HPLC): 99.4% tor kinase even when the MES(T) plasma concentration are 0135 Water content: 1.0 bis 2.0% (KF) very low. 0136. The monoethanesulfonate salt of 3-Z-1-(4-(N-((4- 0143. The results of the following in vivo Xenograft methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)- experiment evidences the effect on tumour cells of compound anilino)-1-phenyl-methylene-6-methoxycarbonyl-2-indoli MES(T). In order to determine this effect, nude mice bearing none can be very easily dissolved in physiologically subcutaneous Falu tumours (Falu tumours are constituted acceptable solubilization agents. of human squamous carcinoma cells) were orally treated with 0.137 Additionally, the compound MES(T) is orally bio the compound MES(T). As shown in FIG. 2, when the mice available in mice. were treated twice weekly with a dose of 100 mg/kg, a reduc 0.138. The monoethanesulfonate salt of 3-Z-1-(4-(N-((4- tion of tumour growth with a T/C (Tumour/Control) value of methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)- 31% can be seen. By increasing the dose to 200 mg/kg orally anilino)-1-phenyl-methylene-6-methoxycarbonyl-2-indoli twice weekly an even better anti-tumour effect is expected. US 2011/0171289 A1 Jul. 14, 2011

0144. This indicates that this antagonist is particularly receptor of type 2, which are as well antagonists of the basic Suitable for a sequential co-administration and/or co-treat fibroblast growth factor (bFGF) and of the platelet derived ment with another chemotherapeutic or naturally occurring, growth factor (PDGF) receptors. Representative compounds semi-synthetic or synthetic therapeutic agent, and/or radio are, for example, indolinone derivatives, such as those therapy or radio-immunotherapy. The scheduled treatment regimen with this antagonist may be, for example, an alter described in WO 02/36564, WO 99/52869, WO 00/18734, nate treatment one day on/one day off one day on/two days WO 00/73297, WO 01/27080, WO 01/27081 and WO off, one week on/one week off, or even two weeks on/two 01/32651. Further representative small molecule VEGF weeks off. receptor antagonists are the compounds described in WO 0145 The monoethanesulfonate salt of 3-Z-1-(4-(N-((4- 01/60814, WO 99/48868, WO 98/35958, and especially the methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)- compounds vatalanib (PTK-787/ZK222584), SU-5416, anilino)-1-phenyl-methylene-6-methoxycarbonyl-2-indoli SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171 none is thus clearly a potent and orally available VEGFR-2 CP-547632, CEP-7055, AG-013736, IM-842 (a dipeptide of kinase inhibitor and anti-tumour agent. L-Glutamyl and L-Tryptophan) or GW-78.6034. 0146 With regard to all aspects of the invention, suitable selected protein tyrosine kinase receptor antagonists are also the active in vivo metabolites of the selected protein tyrosine Small Molecule Growth Factor (GF) Receptor kinase receptor antagonists. For example, an active in vivo Antagonists metabolite of the protein tyrosine kinase receptor antagonist 3-Z-1-(4-(N-(4-methyl-piperazin-1-yl)-methylcarbonyl)- 0150 Small molecule growth factor (GF) receptor antago N-methyl-amino)-anilino)-1-phenyl-methylene-6-meth nists of particular interest are the antagonists of the protein oxycarbonyl-2-indolinone may be the unesterified compound tyrosin kinase (PTK) receptors, especially the antagonists of 3-Z-1-(4-(N-(4-methyl-piperazin-1-yl)-methylcarbonyl)- the epidermal growth factor (EGF) receptor, the dual antago N-methyl-amino)-anilino)-1-phenyl-methylene-6-carbo nists of the epidermal growth factor (EGF) and of the human nyl-2-indolinone. epidermal growth factor of type 2 (HE type 2) receptors or the 0147 Within the meaning of the present invention, all the above-exemplified compounds, and especially the compound antagonists of the mitogen-activated protein kinase (MAPK). (T) and its monoethanesulfonate salt MES(T), may also be Representative compounds which are dual EGFR and HER-2 used as mono-therapy for the treatment of the above-men antagonists are, for example, the quinazoline derivatives dis tioned diseases, namely all kind of diseases in which cell closed in WO 00/78735 and WO 02/50043, gefitinib, erlo proliferation, migration or apoptosis of myeloma cells, or tinib, CI-1033 and GW-2016. Representative compounds angiogenesis are involved, which can be of oncological which are only EGFR antagonists are, for example, iressa nature Such as all types of malignant neoplasias or cancers, or (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272 of non-oncological nature. Such as diabetic retinopathy, rheu and herceptin. Representative compounds which are antago matoid arthritis, or psoriasis. Among cancers, selected spe nists of the mitogen-activated protein kinase (MAPK) are cific target indications for a mono-therapeutic treatment are Solid tumours, such as urogenital cancers (such as prostate BAY-43-9006 (a Raf protein kinase family inhibitor) and cancer, renal cell cancers, bladder cancers), gynecological BAY-57-9006 (a Kdr tyrosine kinase inhibitor). cancers (such as ovarian cancers, cervical cancers, endome 0151. A preferred compound in this class is the quinazo trial cancers), lung cancer, gastrointestinal cancers (such as line derivative disclosed in WO 02/50043 as exemplified colorectal cancers, pancreatic cancer, gastric cancer, oesoph compound of Example 1 (10), namely 4-(3-chloro-4-fluo ageal cancers, hepatocellular cancers, cholangiocellular can rophenyl)amino-6-4-(N,N-dimethylamino)-1-oxo-2- cers), head and neck cancer, malignant mesothelioma, breast buten-1-yl)amino-7-(S)-tetrahydrofuran-3-yloxy)- cancer, malignant melanoma or bone and soft tissue sarco mas, and haematologic neoplasias, Such as multiple quinazoline, or the tautomers, the stereoisomers and the salts myeloma, acute myelogenous leukemia, chronic myelog thereof, particularly the physiologically acceptable salts enous leukemia, myelodysplastic syndrome and acute lym thereof with inorganic or organic acids or bases. Most pre phoblastic leukemia. Of special interest is the treatment of ferred is the di-maleic acid salt of this compound, which can hormone sensitive or hormone refractory prostate cancer, easily be obtained in accordance with the following proce ovarian carcinoma, non Small cell lung cancer, Small cell lung dure. 6.0 kg (12.35 mol) of 4-(3-chloro-4-fluorophenyl) cancer, or multiple myeloma. The above-exemplified com amino-6-4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl) pounds are especially efficient for inhibiting tumour growth, amino-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline are Survival and metastasis. heated up to 70°C. in 84 liter of ethanol. A solution of 2.94 kg The Further Chemotherapeutic or Naturally (25.31 mol) maleic acid in 36 liter ethanol is added. At the Occurring, Semi-Synthetic or Synthetic Therapeutic beginning of crystallisation, the reaction mixture is cooled to Agent 20° C. and stirred for 2 hours. The reaction mixture is cooled to 0° C. and stirred for 3 hours. The precipitate is suction 0148. This compound may preferably be selected from the filtered. The filter cake is washed with 19 liter of ethanol and following classes and examples of compounds, although this vacuum-dried at 40°C. list is not to be considered as limitative. 0152. A further preferred compound in this class is the Synthetic Small Molecule VEGF Receptor 4-(3-chloro-4-fluoro-phenyl)aminol-6-4-(homomorpho Antagonists lin-4-yl)-1-oxo-2-buten-1-yl)amino-7-(S)-(tetrahydrofu 0149 Synthetic small molecule VEGF receptor antago ran-3-yl)oxy-quinazoline, or the salts thereof. The chemical nists of particular interest are the antagonists of the VEGF structural formula of this compound is US 2011/0171289 A1 Jul. 14, 2011

cooled to -3°C. in an ice/acetone cooling bath. The solution of the above-obtained homomorpholin-4-yl-ac F etaldehyde hydrochloride (staring compound II) is then added drop wise within 5 min at a temperature of 0°C. O After the addition has ended the reaction mixture is stirred for another 10 min at 0°C. and for a further hour C NH N-N- /NO at ambient temperature. For working up 100 ml of ethyl NH acetate are added and the aqueous phase is separated off. The organic phase is washed with Saturated Sodium chloride solution, dried over magnesium Sulphate and le evaporated down. The crude product is purified by chro N 9 matography over a silica gel column using ethyl acetate? methanol/conc. methanolic ammonia as eluant. The product obtained is stirred with a little di-isopropyl ether, suction filtered and dried. O (0160 Yield: 2.40 g of (63% of theory) (0161 R, value: 0.09 (silica gel, ethyl acetate/methanol/ 0153. This compound may be obtained in three steps using conc. aqueous ammonia=90:10:1) the following manufacturing conditions. (0162 Mass spectrum (ESI): m/z 542, 544 M+H" Inhibitors of the EGF Receptor and/or VEGF Preparation of the starting compound I: 4-(3-chloro Receptor and/or Integrin Receptors or Any Other 4-fluoro-phenyl)amino-6-(diethoxy-phosphoryl)- Protein Tyrosine Kinase Receptors, which are not acetylamino-7-(S)-(tetrahydrofuran-3-yl)oxy Classified Under the Synthetic Small-Molecules quinazoline (0163. Inhibitors of the EGF receptor and/or VEGF recep 0154) 60.07 g of diethoxyphosphorylacetic acid are tor and/or integrin receptors or any other protein tyrosine placed in 750 ml of N,N-dimethylformamide and at kinase receptors, which are not classified under the synthetic ambient temperature combined with 48.67 g of N,N'- Small-molecules, which are of special interest, are the mono carbonyldiimidazole. After the development of gas has clonal antibodies directed to EGF receptor and/or ceased 90.00 g of 4-(3-chloro-4-fluoro-phenyl)amino 0164 VEGF receptor and/or integrin receptors or any 6-amino-(S)-(tetrahydrofuran-3-yl)oxy-quinazoline other protein tyrosine kinase receptors. Representative com are added and the reaction mixture is stirred for about pounds are, for example, atrasentan (integrin antagonist), rituximab, cetuximab, AvastinTM (bevacizumab), IMC-1C11. 4-5 hours at ambient temperature until the reaction is erbitux (C-225), DC-101, EMD-72000 (humanized EGF complete. The reaction mixture is then heated gently in receptor-specific monoclonal antibody), vitaxin (antibody the water bath and 750 ml of water are added twice. The directed against the C, B integrin), and imatinib (c-Kit inhibi thick Suspension is stirred overnight and the next morn tor). Monoclonal antibodies which can specifically recognize ing another 350 ml of water are added. The suspension is their antigen epitopes on the relevant receptors, are in this cooled in the ice bath, stirred for one hour and suction respect of further special interest. The use of such antibodies, filtered. The filter cake is washed again with 240 ml of which were successful invitro and in animal models, have not N,N-dimethylformamide/water (1:2) and 240 ml of shown satisfying efficacy in patients as mono-drug therapy. diisopropylether and dried at 40°C. in the circulating air Similar results were obtained when other anti-angiogenic or dryer. EGF receptor antagonists than antibodies were used in clini O155 Yield: 117.30 g of (88% of theory) cal trials. It seems that tumours, if some specific sites are I0156 Rf value: 0.37 (silica gel, methylene chloride/ blocked, may use other cell Surface molecules to compensate methanol=9:1) for said original blocking. Thus, tumours do not really shrink O157 Mass spectrum (ESI); m/z =553,555 M+H" during various anti-angiogenic or anti-proliferative therapies. For these reasons, combination therapies were in this case Preparation of the starting compound II: already proposed to circumvent this problem using, for Homomorpholin-4-yl-acetaldehyde-hydrochloride example, monoclonal antibodies together with specific cyto toxic or chemotherapeutic agents or in combination with 0158 Prepared by stirring (2.5 hours) 4-(2,2- radiotherapy or radio-immunotherapy. Indeed, clinical trials dimethoxy-ethyl)-homomorpholine with semi-concen have shown that these combination therapies are more effi trated hydrochloric acid at 80°C. The solution obtained cient than the corresponding mono-administrations. is further reacted directly as below-described. Inhibitors Directed to EGF Receptor and/or VEGF Preparation of the final compound: 4-(3-chloro-4- Receptor and/or Integrin Receptors or Any Other fluoro-phenyl)aminol-6-4-(homomorpholin-4-yl)- Protein Tyrosine Kinase Receptors, which are Fusion 1-oxo-2-buten-1-yl)amino-7-(S)-(tetrahydrofuran Proteins 3-yl)oxy-quinazoline 0.165 A representative compound of this class is, for example, the compound with name VEGFtrap, developed by 0159. A solution of 3.9 g of 4-(3-chloro-4-fluoro-phe the pharmaceutical companies Regeneron and Aventis. nyl)amino-6-2-(diethoxy-phosphoryl)-acetylamino 7-(S)-(tetrahydrofuran-3-yl)oxy-quinazoline (starting Compounds which Interact with Nucleic Acids and compound I) in 20 ml of tetrahydrofuran is added to a which are Classified as Alkylating Agents or solution of 300 mg of lithium chloride in 20 ml of water Platinum Compounds at ambient temperature. Then 2.35 g of potassium 0166 Compounds which interact with nucleic acids and hydroxide flakes are added and the reaction mixture is which are classified as alkylating agents or platinum com US 2011/0171289 A1 Jul. 14, 2011

pounds, have already been described for their use for the nilide hydroxamic acid), MD-275, trichostatin A, CBHA treatment of diseases of oncological nature. Representative (M-carboxycinnamic acid bishydroxamide), LAQ824, or val classes and examples of compounds are melphalan, cyclo proic acid. phosphamide, oxazaphosphorines, cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, Mitosis Inhibitors, Anti-Mitotic Agents, or streptozocin, carmustine (BCNU), lomustine (CCNU), Cell-Cycle Inhibitors buSulfan, ifosfamide, Streptozocin, thiotepa, chlorambucil, nitrogen mustards (such as mechlorethamine), ethyleneimine 0172 Representative classes and examples of compounds compounds and alkylsulphonates. of interest are the anti-cancer drugs from plants, such as the taxanes (paclitaxel or taxol, docetaxel or taxotere), the Vinca alkaloids (navelbine, vinblastin, Vincristin, vindesine or Compounds which Interact with Nucleic Acids and vinorelbine), the tropolone alkaloids (colchicine and deriva which are Classified as Anthracyclines, as DNA tives), the macrollides (maytansine, ansamitocins, rhizoxin), Intercalators or as DNA Cross-Linking Agents the antimitotic peptides (phomopsin, dolastatin), the epi podophyllotoxins or the derivatives of podophyllotoxin (eto 0167 Compounds which interact with nucleic acids and poside, teniposide), the Steganacins and the antimitotic car which are classified as anthracyclines, as DNA intercalators bamate derivatives (combretastatin, amphetinile), or (including DNA minor-groove binding compounds) or as procarbazine. These compounds are codk inhibitors, tubulin DNA cross-linking agents are also of interest for the treat binders or inhibitors of the polo-like kinase. ment of diseases of oncological nature. Representative classes and examples of compounds are daunorubicin, doxo Proteasome Inhibitors rubicin (adriamycin), liposomal doxorubicin (doxil), epiru bicin, idarubicin, mitoxantrone, amsacrine, dactinomycin, 0173 A representative compound of interest belonging to distamycin and derivatives, netropsin, pibenZimol, mitomy this class is, for example, VelcadeTM (bortezomib or PS-341). cin, CC-1065 (Streptomyces Zelensis fermentation product), duocarmycins, mithramycin, chromomycin, olivomycin, Enzymes phtalanilides (propamidine, Stilbamidine), anthramycins, 0.174 Representative compounds and classes of interest aziridines or nitrosoureas and their derivatives. are, for example, asparaginase, pegylated asparaginase (pe gaspargase), and the thymidine-phosphorylase inhibitors. Anti-Metabolites Hormones, Hormone Antagonists or Hormone 0168 Representative classes of anti-metabolites of inter Inhibitors, or Inhibitors of Steroid Biosynthesis est are the pyrimidine and purine analogues or antagonists 0.175 Representative classes and examples of hormones such as fluoropyrimidines and thiopurines, or inhibitors of the of interest are, for example, the gestagens and estrogens. Such nucleoside diphosphate reductase. Representative com as estramustine or T-66, or megestrol. Representative classes pounds are, for example, cytarabine, 5-fluorouracile (5-FU), and examples of hormone antagonists or inhibitors of interest uracil mustard, fludarabine, gemcitabine, capecitabine, mer are, for example, the anti-androgens, such as flutamide, caso captopurine, cladribine, thioguanine, methotrexate, pentosta dex, anandron and cyproterone acetate, the aromatase inhibi tin, hydroxyurea, or folic acid. tors. Such as amonogluthetimide, anastrozole, formestan and letrozole, the GNrHanalogues, such as leuprorelin, buserelin, Naturally Occurring, Semi-Synthetic or Synthetic goserelin and triptorelin, the anti-estrogens, such as tamox Bleomycin Type Antibiotics (BLM-Group ifen and especially its citrate salt, droloxifene, trioxifene, Antibiotics) raloxifene, Zindoxifene, the derivatives of 17 B-estradiol (ICI 164.384 and ICI 182,780), aminoglutethimide, formestane, 0169. Representative classes and compounds of interest fadrozole, finasteride, or ketoconazole, or the LH-RHantago are the phleomycins, bleomycins, bleomycin derivatives and nist leuprolide. Steroid hormone inhibitors are especially salts, CHPP. BZPP, MTPP, BAPP, liblomycin. These agents suitable for the treatment of breast and prostate cancer. are believed to mediate their therapeutic effects via degrada tion of chromosomal DNA or RNA degradation (especially Steroids selective tRNA strand scission). 0176 Representative compounds of interest are, for example, prednisone, prednisolone, methylprednisolone, Inhibitors of DNA Transcribing Enzymes, Especially dexamethasone, budenoside, fluocortolone and triamcino Topoisomerase I or Topoisomerase II Inhibitors lone. The reasons why steroids may be used in the treatment of some cancers and the effects obtained with steroids in the 0170 A representative class and examples of compounds treatment of cancer depends on the type of cancer to be of interest are the acridines and acridine derivatives, rifamy treated. In the treatment of solid tumors, steroids are in first cins, actinomycins, adramycin, camptothecins (irinotecan or line used to control the symptoms. In the case of brain camptosar, topotecan), amsacrines and analogues, and the metastasis, they belong to the standard therapy for reducing tricyclic carboxamides. oedema. They are also used to control the inflammation which surrounds the tumor lesions. In the treatment of hae Chromatin Modifying Agents matologic malignant neoplasias of lymphatic cell lines (ALL, non-Hodgkin lymphoma, myeloma), due to their cytolytic 0171 A representative class of compounds of interest are effect, Steroids are used as a real anti-tumor therapy, alone or the histonedeacetylase inhibitors, such as SAHA (Suberoyla in combination with classical chemotherapeutic agents. The US 2011/0171289 A1 Jul. 14, 2011 naturally occuring steroid tetrahydrocortisol, the synthetic modeoxyuridine, iododeoxyuridine), or the thiophosphates cyclodextrin derivative f3-cyclodextrine tetradecasulfate and (for example WR-2721) as radiation protectors. the tetracycline derivative minocycline, due to their antian giogenic activity, have been Suggested for a combination Photochemically Activated Drugs treatment with cytotoxic standard anticancer therapies. Such 0181 Representative classes and compounds of interest as platinum, melphalan, cyclophosphamide, adriamycin, are, for example, porfimer, photofrin, the benzoporphyrin bleomycin or radiation based therapies (Teicher et al., Cancer derivatives, the pheophorbide derivatives, merocyanin 540 research, Vol. 52, pp. 6702-6704, 1992). The steroid dexam (MC-540), and tin etioporpurin. ethasone has also been tested as primary treatment of multiple myeloma (Dimopoulos et al., Blood, Vol. 80(4), pp. 887-890, Synthetic Poly- or Oligonucleotides 1992). Furthermore, evaluation studies of combination thera pies using dexamethasone and thalidomide, a Substance 0182 Synthetic poly- or oligonucleotides, which may known for its activity as TNF-C. synthesis inhibitor and cytok optionally be modified or conjugated are also of interest. ine antagonist, have been disclosed recently. These studies Representative classes of poly- or oligonucleotides are, for focussed on previously untreated multiple myeloma (Weber example, anti-templates RNAs and DNAs (synthetic or et al., Journal of Clinical Oncology, Vol. 21, No. 1, pp. 16-19. chemically modified oligonucleotides which are inactive per 2003), newly diagnosed myeloma (Rajkumaret al., Journal of Sebut capable of competing with functional template-primers Clinical Oncology, Vol. 20, No. 21, pp. 4319-4323, 2002) and for their specific binding site on an enzyme and thereby multiple myeloma after intensive chemotherapy (Ann. blocking their functions), anti-sense RNAs and DNAs (se Oncol., Vol. 13, No. 7, pp. 1116-1119, 2002). quence-specific inhibitors of protein synthesis which hybrid 0177. With regard to all aspects of the invention, suitable ize with complementary base sequences of a given m-RNA, steroids for the combination treatment are meant to include in Such as oblimersen), especially directed against onco-genes, a non-limiting manner prednisone, prednisolone, methyl growth factor genes or tumor Suppressor genes, antigene prednisolone, dexamethasone, budenoside, fluocortolone and poly- or oligonucleotides (oligonucleotides capable of form triamcinolone. The preferred steroid is dexamethasone. ing triplex DNA structures which selectively inhibit the tran Scription of a target gene), and ribozymes. Cytokines, Hypoxia-Selective Cytotoxins, Inhibitors of Cytokines, Lymphokines, Antibodies Directed Non-Steroidal Anti-Inflammatory Drugs Against Cytokines or Oral and Parenteral Tolerance 0183 Non-steroidal inflammatory drugs (NSAIDs) repre Induction Agents sent also an interesting class of compounds which may be 0.178 Representative classes and examples of compounds used for a combination therapy within the meaning of the of interest are interferons (especially interferon B), interleu present invention. Cyclo-oxygenase (COX) inhibitors are of kins (especially IL-10 and 12), anti-TNFC. antibodies (etan special interest, such as the non-selective COX inhibitors ercept). Immunomodulatory drugs (or IMiDs, especially acetylsalicyclic acid, mesalazin, ibuprofen, naproxen, flurbi inhibitors of the TNF-C. production, such as thalidomide, its profen, fenoprofen, fenbufen, ketoprofen, indoprofen, pir R- and S-enantiomers and its derivatives, or revimid (CC profen, carprofen, oxaprozin, pranoprofen, miroprofen, tioX 5013)), leukotrien antagonists, mitomycin C, aziridoquino aprofen, Suprofen, alminoprofen, tiaprofenic acid, fluprofen, nes (BMY-42355, AZQ, EO-9), 2-nitroimidazoles (mis indomethacin, Sulindac, tolmetin, Zomepirac, nabumetone, onidazole, NLP-1. NLA-1), nitroacridines, nitroquinolines, diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, nitropyrazoloacridines, "dual-function’ nitro aromatics aceclofenac, acemetacin, fentiazac, clidanac, etodolac, Oxpi (RSU-1069, RB-6145), nitro aromatic deactivated mustards nac, mefenamic acid, meclofenamic acid, flufenamic acid, (CB-1954), N-oxides of nitrogen mustards (nitromin), metal nifluminic acid, tolfenamic acid, diflunisal, flufenisal, piroxi complexes of nitrogen mustards, anti-CD3 or anti-CD25 anti cam, tenoxicam, lornoxicam and nimeSulide or the pharma bodies, genetically modified enteric bacteria to achieve tol ceutically acceptable salts thereof, or the selective COX inhibitors meloxicam, celecoxib or rofecoxib. The selective CaCC. COX-2 inhibitor meloxicam is especially preferred. Supportive Agents Other Chemotherapeutic or Naturally Occurring, 0179 A representative class of compounds of interest are, Semi-Synthetic or Synthetic Therapeutic Agents for example, the biphosphonates and their derivatives, such as, for example, minodronic acid (YM-529, Ono-5920, 0.184 Further classes and examples of compounds are of YH-529), Zoledronic acid monohydrate, ibandronate sodium interest for a combination therapy within the meaning of the hydrate, clodronate disodium. These compounds are in clini present invention, Such as, for example, cytotoxic antibiotics, cal development or have been recently approved for the treat antibodies targeting Surface molecules of cancer cells (espe ment of bone metastasis from breast/lung cancer and for the cially HLA-DR antibodies such as, for example, apolizumab treatment of multiple myeloma (Drugs of the Future 2002, and 1D09C3), inhibitors of metalloproteinases (TIMP-1, 27(10), pp. 935-941). TIMP-2), Zinc, inhibitors of oncogenes (especially c-myc, Ras, v-raf or c-Src inhibitors, such as P53 and Rb), inhibitors Chemical Radiation Sensitizers and Protectors of gene transcription (especially the inhibitors of the tran scription factor complex ESX/DRIP130/Sur-2 which con 0180 Representative classes and compounds of interest trols the expression of Her-2, such as those described in WO are, for example, the nitroimidazoles (metronidazole, mis 03/097855) or of RNA translation or protein expression (es onidazole, benZnidazole, nimorazole) and further nitroaryl pecially the inhibitors of HER-2 expression, such as the heat compounds such as RSU-1069, the nitroxyl and N-oxides shock protein HSP90 modulator geldanamycin and its deriva Such as SR-4233, the halogenated pyrimidine analogues (bro tive 17-allylaminogeldanamycin or 17-AAG), complexes of US 2011/0171289 A1 Jul. 14, 2011 rare earth elements such as the heterocyclic complexes of pharmaceutically acceptable salt thereof, a protein kinase lanthanides described for example in German Patent Nr. 101 receptor antagonist which is not classified under the synthetic 38 538, photo-chemotherapeutic agents (PUVA, a combina Small molecules Such as atrasentan, rituximab, cetuximab, tion of psoralen (P) and long-wave ultraviolet radiation AvastinTM (bevacizumab), IMC-1C11, erbitux (C-225), (UVA)), IM-842, tetrathiomolybdate, squalamine, combr DC-101, EMD-72000, vitaxin, imatinib, a protein tyrosine estatin A4, TNP-470, marimastat, neovastat, bicalutamide, kinase inhibitor which is a fusion protein such as VEGFtrap, abarelix, oregovomab, mitumomab, TLK-286, alemtuzumab, an alkylating agent or a platinum compound Such as mel ibritumomab, temozolomide, denileukin diftitox, aldesleu phalan, cyclophosphamide, an oxazaphosphorine, cisplatin, kin, dacarbazine, floxuridine, plicamycin, mitotane, pipobro carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, man, plicamycin, tamloxifen, testolactone. mitomycin, streptozocin, carmustine (BCNU), lomustine 0185. In a preferred embodiment in accordance with the (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, present invention, the further chemotherapeutic or naturally chlorambucil, a nitrogen mustard Such as mechlorethamine, occurring, semi-synthetic or synthetic therapeutic agent is an ethyleneimine compound, an alkylsulphonate, daunorubi selected from synthetic small molecule VEGF receptor cin, doxorubicin (adriamycin), liposomal doxorubicin antagonists, Small molecule growth factor receptor antago (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine, dac nists, inhibitors of the EGF receptor and/or VEGF receptor tinomycin, distamycin or a derivative thereof, metropsin, and/or integrin receptors or any other protein tyrosine kinase pibenZimol, mitomycin, CC-1065, a duocarmycin, mithra receptors which are not classified under the synthetic small mycin, chromomycin, olivomycin, aphtalanilide such as pro molecules, inhibitors directed to EGF receptor and/or VEGF pamidine or stilbamidine, an anthramycin, an aziridine, a receptor and/or integrin receptors or any other protein nitrosourea or a derivative thereof, a pyrimidine or purine tyrosine kinase receptors, which are fusion proteins, com analogue or antagonist or an inhibitor of the nucleoside pounds which interact with nucleic acids and which are clas diphosphate reductase Such as cytarabine, 5-fluorouracile sified as alkylating agents or platinum compounds, com (5-FU), uracil mustard, fludarabine, gemcitabine, capecitab pounds which interact with nucleic acids and which are ine, mercaptopurine, cladribine, thioguanine, methotrexate, classified as anthracyclines, as DNA intercalators or as DNA pentostatin, hydroxyurea, or folic acid, a phleomycin, a bleo cross-linking agents, including DNA minor-groove binding mycin or a derivative or salt thereof, CHPP. BZPP, MTPP, compounds, anti-metabolites, naturally occurring, semi-syn BAPP, liblomycin, an acridine or a derivative thereof, a rifa thetic or synthetic bleomycin type antibiotics, inhibitors of mycin, an actinomycin, adramycin, a camptothecin Such as DNA transcribing enzymes, and especially the topoisomerase irinotecan (camptosar) or topotecan, an amsacrine or ana I or topoisomerase II inhibitors, chromatin modifying agents, logue thereof, a tricyclic carboxamide, an histonedeacetylase mitosis inhibitors, anti-mitotic agents, cell-cycle inhibitors, inhibitor such as SAHA, MD-275, trichostatin A, CBHA, proteasome inhibitors, enzymes, hormones, hormone antago LAQ824, or valproic acid, an anti-cancer drug from plants nists, hormone inhibitors, inhibitors of steroid biosynthesis, Such as paclitaxel (taxol), docetaxel or taxotere, a Vinca alka steroids, cytokines, hypoxia-selective cytotoxins, inhibitors loid such as navelbine, vinblastin, Vincristin, vindesine or of cytokines, lymphokines, antibodies directed against cytok Vinorelbine, a tropolone alkaloid Such as colchicine or a ines, oral and parenteral tolerance induction agents, Support derivative thereof, a macrollide Such as maytansine, an ive agents, chemical radiation sensitizers and protectors, ansamitocin or rhizoxin, an antimitotic peptide Such as pho photo-chemically activated drugs, synthetic poly- or oligo mopsin ordolastatin, an epipodophyllotoxin or a derivative of nucleotides, optionally modified or conjugated, non-steroidal podophyllotoxin Such as etoposide or teniposide, a stegana anti-inflammatory drugs, cytotoxic antibiotics, antibodies cin, an antimitotic carbamate derivative such as combretasta targeting Surface molecules of cancer cells, and especially the tin or amphetinile, procarbazine, a proteasome inhibitor Such HLA-DR antibodies such as, inhibitors of metalloprotein as VelcadeTM (bortezomib or PS-341), an enzyme such as ases, metals, inhibitors of oncogenes, inhibitors of gene tran asparaginase, pegylated asparaginase (pegaspargase) or a Scription or of RNA translation or protein expression, com thymidine-phosphorylase inhibitor, a gestagen oran estrogen plexes of rare earth elements, or photo-chemotherapeutic Such as estramustine (T-66) or megestrol, an anti-androgen agents. Such as flutamide, casodex, anandron or cyproterone acetate, 0186. In a further preferred embodiment in accordance an aromatase inhibitor Such as aminogluthetimide, anastro with the present invention, the further chemotherapeutic or Zole, formestan or letrozole, a GNrH analogue Such as leu naturally occurring, semi-synthetic or synthetic therapeutic prorelin, buserelin, goserelin or triptorelin, an anti-estrogen agent is selected from a small molecule VEGF receptor Such as tamoxifen or its citrate salt, droloxifene, trioxifene, antagonist such as vatalanib (PTK-787/ZK222584), raloxifene or Zindoxifene, a derivative of 17 B-estradiol such SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, as ICI 164.384 or ICI 182,780, aminoglutethimide, formes AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 or tane, fadrozole, finasteride, ketoconazole, a LH-RH antago GW-78.6034, a dual EGFR/HER2 antagonist such as gefi nist Such as leuprolide, a steroid such as prednisone, pred tinib, erlotinib, CI-1033 or GW-2016, an EGFR antagonist nisolone, methylprednisolone, dexamethasone, budenoside, such as iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB fluocortolone or triamcinolone, an interferon Such as inter 569, HKI-272 or herceptin, an antagonist of the mitogen feron B, an interleukin such as IL-10 or IL-12, an anti-TNFC. activated protein kinase such as BAY-43-9006 or BAY-57 antibody such as etanercept, an immunomodulatory drug 9006, a quinazoline derivative such as 4-(3-chloro-4- Such as thalidomide, its R- and S-enantiomers and its deriva fluorophenyl)amino-6-4-(N,N-dimethylamino)-1-oxo-2- tives, or revimid (CC-5013), a leukotrien antagonist, mito buten-1-yl)amino-7-(S)-tetrahydrofuran-3-yloxy)- mycin C, an aziridoquinone such as BMY-42355. AZQ or quinazoline or 4-(3-chloro-4-fluoro-phenyl)amino]-6-4- EO-9, a 2-nitroimidazole such as misonidazole, NLP-1 or (homomorpholin-4-yl)-1-oxo-2-buten-1-yl)amino-7-(S)- NLA-1, a nitroacridine, a nitroquinoline, a nitropyrazoloacri (tetrahydrofuran-3-yl)oxy-quinazoline, O a dine, a "dual-function’ nitro aromatic such as RSU-1069 or US 2011/0171289 A1 Jul. 14, 2011

RB-6145, CB-1954, a N-oxide of nitrogen mustard such as carmycin, mithramycin, chromomycin, olivomycin, a phta nitromin, a metal complex of a nitrogen mustard, an anti-CD3 lanilide Such as propamidine or stilbamidine, an anthramycin, oranti-CD25 antibody, a tolerance induction agent, a biphos an aziridine, a nitrosourea or a derivative thereof, a pyrimi phonate or derivative thereof Such as minodronic acid or its dine or purine analogue or antagonist or an inhibitor of the derivatives (YM-529, Ono-5920, YH-529), Zoledronic acid nucleoside diphosphate reductase such as cytarabine, 5-fluo monohydrate, ibandronate Sodium hydrate or clodronate rouracile (5-FU), uracil mustard, fludarabine, gemcitabine, disodium, a nitroimidazole Such as metronidazole, misonida capecitabine, mercaptopurine, cladribine, thioguanine, meth Zole, benznidazole or nimorazole, a nitroaryl compound Such otrexate, pentostatin, hydroxyurea, or folic acid, an acridine as RSU-1069, a nitroxyl or N-oxide such as SR-4233, an or a derivative thereof, a rifamycin, an actinomycin, adramy halogenated pyrimidine analogue Such as bromodeoxyuri cin, a camptothecin Such as irinotecan (camptosar) or topo dine, iododeoxyuridine, a thiophosphate such as WR-2721, a tecan, an amsacrine or analogue thereof, a tricyclic carboxa photo-chemically activated drug Such as porfimer, photofrin, mide, an histonedeacetylase inhibitor such as SAHA, a benzoporphyrin derivative, a pheophorbide derivative, MD-275, trichostatin A, CBHA, LAQ824, or valproic acid, a merocyanin 540 (MC-540) or tin etioporpurin, an anti-tem proteasome inhibitor such as VelcadeTM (bortezomib or plate or an anti-sense RNA or DNA such as oblimersen, a PS-341), a small molecule VEGF receptor antagonist such as non-steroidal inflammatory drug such as acetylsalicyclic vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, acid, mesalazin, ibuprofen, naproxen, flurbiprofen, fenopro SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, fen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, CEP-7055, AG-013736, IM-842 or GW-786034, an antago oxaprozin, pranoprofen, miroprofen, tioxaprofen, Suprofen, nist of the mitogen-activated protein kinase such as BAY-43 alminoprofen, tiaprofenic acid, fluprofen, indomethacin, 9006 or BAY-57-9006, a dual EGFR/HER2 antagonist such Sulindac, tolmetin, Zomepirac, nabumetone, di-clofenac, fen as gefitinib, erlotinib, CI-1033 or GW-2016, an EGFR clofenac, alclofenac, bromfenac, ibufenac, ace-clofenac, antagonist such as iressa (ZD-1839), tarceva (OSI-774), PKI acemetacin, fentiazac, clidanac, etodolac, oXpinac, mefe 166, EKB-569, HKI-272 or herceptin, a quinazoline deriva namic acid, meclofenamic acid, flufenamic acid, nifluminic tive such as 4-(3-chloro-4-fluorophenyl)amino]-6-4-(N, acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, N-dimethylamino)-1-oxo-2-buten-1-yl)amino-7-((S)- tenoxicam, lornoxicam, nimeSulide, meloxicam, celecoxib, tetrahydrofuran-3-yloxy)-quinazoline or 4-(3-chloro-4- rofecoxib, or a pharmaceutically acceptable salt of a non fluoro-phenyl)amino]-6-4-(homomorpholin-4-yl)-1-oxo steroidal inflammatory drug, a cytotoxic antibiotic, an anti 2-buten-1-yl)amino-7-(S)-(tetrahydrofuran-3-yl)oxy body targeting the surface molecules of cancer cells such as quinazoline, or a pharmaceutically acceptable Salt thereof, an apolizumab or 1D09C3, an inhibitor of metalloproteinases inhibitor of the transcription factor complex ESX/DRIP130/ such as TIMP-1 or TIMP-2, Zinc, an inhibitor of oncogenes Sur-2, an inhibitor of HER-2 expression, such as the heat such as P53 and Rb, a complex of rare earth elements such as shock protein HSP90 modulator geldanamycin and its deriva the heterocyclic complexes of lanthanides, a photo-chemo tive 17-allylaminogeldanamycin or 17-AAG, a protein kinase therapeutic agent such as PUVA, an inhibitor of the transcrip receptor antagonist which is not classified under the synthetic tion factor complex ESX/DRIP130/Sur-2, an inhibitor of Small molecules Such as atrasentan, rituximab, cetuximab, HER-2 expression, such as the heat shock protein HSP90 AvastinTM (bevacizumab), IMC-1C11, erbitux (C-225), modulator geldanamycin and its derivative 17-allylami DC-101, EMD-72000, vitaxin, imatinib, or an antibody tar nogeldanamycin or 17-AAG, or a therapeutic agent selected geting the Surface molecules of cancer cells Such as apoli from IM-842, tetrathiomolybdate, squalamine, combrestatin Zumab or 1D09C3. A4, TNP-470, marimastat, neovastat, bicalutamide, abarelix, 0188 In a further preferred embodiment in accordance oregovomab, mitumomab, TLK-286, alemtuzumab, ibritu with the present invention, the further chemotherapeutic or momab, temozolomide, denileukin diftitox, aldesleukin, dac naturally occurring, semi-synthetic or synthetic therapeutic arbazine, floXuridine, plicamycin, mitotane, pipobroman, pli agent is selected from the above-mentioned quinazoline camycin, tamloxifen or testolactone. derivative disclosed in WO 02/50043 as exemplified com 0187. In a further preferred embodiment in accordance pound of Example 1 (10), namely 4-(3-chloro-4-fluorophe with the present invention, the further chemotherapeutic or nyl)amino-6-4-(N,N-dimethylamino)-1-oxo-2-buten-1- naturally occurring, semi-synthetic or synthetic therapeutic yl)amino-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, or agent is selected from an anti-cancer drug from plants such as the tautomers, the stereoisomers and the salts thereof, par paclitaxel (taxol), docetaxel or taxotere, a Vinca alkaloid Such ticularly the physiologically and pharmaceutically accept as navelbine, vinblastin, Vincristin, vindesine or vinorelbine, able salts thereof with inorganic or organic acids or bases. a Vinca alkaloid such as navelbine, vinblastin, Vincristin, Vin 0189 In a further preferred embodiment in accordance desine or vinorelbine, an alkylating agent or a platinum com with the present invention, the further chemotherapeutic or pound Such as melphalan, cyclophosphamide, an oxazaphos naturally occurring, semi-synthetic or synthetic therapeutic phorine, cisplatin, carboplatin, oxaliplatin, satraplatin, agentis selected from the di-maleic acid salt of the compound tetraplatin, iproplatin, mitomycin, Streptozocin, carmustine 4-(3-chloro-4-fluorophenyl)amino]-6-4-(N,N-dimethy (BCNU), lomustine (CCNU), busulfan, ifosfamide, strepto lamino)-1-oxo-2-buten-1-yl)amino-7-((S)-tetrahydrofuran Zocin, thiotepa, chlorambucil, a nitrogen mustard Such as 3-yloxy)-quinazoline, or the tautomers or stereoisomers mechlorethamine, an immunomodulatory drug such as thali thereof. domide, its R- and S-enantiomers and its derivatives, or 0190. In a further preferred embodiment in accordance revimid (CC-5013)), an ethyleneimine compound, an alkyl with the present invention, the further chemotherapeutic or Sulphonate, daunorubicin, doxorubicin (adriamycin), liposo naturally occurring, semi-synthetic or synthetic therapeutic mal doxorubicin (doxil), epirubicin, idarubicin, mitox agent is selected from 4-(3-chloro-4-fluoro-phenyl)amino antrone, amsacrine, dactinomycin, distamycin or a derivative 6-4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl)amino-7- thereof, netropsin, pibenzimol, mitomycin, CC-1065, a duo (S)-(tetrahydrofuran-3-yl)oxy-quinazoline or the physi US 2011/0171289 A1 Jul. 14, 2011 ologically and pharmaceutically acceptable salts thereof with antibody and the rapidly cleared radionuclide (Drugs of the inorganic or organic acids or bases. future 2003, 28(2), pp. 167-173). Detailed protocols for radiotherapy are readily available to the expert (Cancer Radiation Therapy, Radio-Immunotherapy or Radiotherapy: Methods and Protocols (Methods in Molecular Pre-Targeted Radioimmunotherapy Medicine), Huddart RA Ed., Human Press 2002). The expert knows how to determine an appropriate dosing and applica 0191 Radiation therapy, radio-immunotherapy or pre-tar tion schedule, depending on the nature of the disease and the geted radioimmunotherapy are used for the treatment of dis constitution of the patient. In particular, the expert knows how eases of oncological nature. "Radiotherapy”, or radiation to assess dose-limiting toxicity (DLT) and how to determine therapy, means the treatment of cancer and other diseases with ionizing radiation. Ionizing radiation deposits energy the maximum tolerated dose (MTD) accordingly. that injures or destroys cells in the area being treated (the target tissue) by damaging their genetic material, making it Co-Administration and/or Co-Treatment Therapies impossible for these cells to continue to grow. Radiotherapy 0.192 Co-administration of the selected protein tyrosine may be used to treat localized solid tumors, such as cancers of kinase receptor antagonist and of the further chemotherapeu the skin, tongue, larynx, brain, breast, lung or uterine cervix. tic or naturally occurring, semi-synthetic or synthetic thera It can also be used to treat leukemia and lymphoma, i.e. peutic agent, and/or co-treatment with radiotherapy or radio cancers of the blood-forming cells and lymphatic system, immunotherapy, is meant to include administration and/or respectively. One type of radiation therapy commonly used treatment sequential in time or simultaneous administration involves photons, e.g. X-rays. Depending on the amount of and/or treatment. For sequential administration and/or treat energy they possess, the rays can be used to destroy cancer ment, the selected protein tyrosine kinase receptor antagonist cells on the surface of or deeper in the body. The higher the can be administered before or after administration of the energy of the X-ray beam, the deeper the X-rays can go into the further chemotherapeutic or naturally occurring, semi-syn target tissue. Linear accelerators and betatrons are machines that produce X-rays of increasingly greater energy. The use of thetic or synthetic therapeutic agent, and/or before or after machines to focus radiation (Such as X-rays) on a cancer site treatment with radiotherapy or radio-immunotherapy. is called external beam radiotherapy. Gamma rays are another 0193 The active compounds can be administered orally, form of photons used in radiotherapy. Gamma rays are pro bucally, parenterally, by inhalation spray, rectally or topically, duced spontaneously as certain elements (such as radium, the oral administration being preferred. Parenteral adminis uranium, and cobalt 60) release radiation as they decompose, tration may include Subcutaneous, intravenous, intramuscu or decay. Another technique for delivering radiation to cancer lar and intrasternal injections and infusion techniques. cells is to place radioactive implants directly in a tumor or 0194 The active compounds can be orally administered in body cavity. This is called internal radiotherapy. Brachy a wide variety of different dosage forms, i.e., they may be therapy, interstitial irradiation, and intracavitary irradiation formulated with various pharmaceutically acceptable inert are types of internal radiotherapy. In this treatment, the radia carriers in the form of tablets, capsules, lozenges, troches, tion dose is concentrated in a small area, and the patient stays hard candies, powders, sprays, aqueous Suspensions, elixirs, in the hospital for a few days. Internal radiotherapy is fre syrups, and the like. Such carriers include solid diluents or quently used for cancers of the tongue, uterus, and cervix. A fillers, sterile aqueous media and various non-toxic organic further technique is intra-operative irradiation, in which a Solvents. Moreover, such oral pharmaceutical formulations large dose of external radiation is directed at the tumor and can be suitably sweetened and/or flavoured by means of vari Surrounding tissue during Surgery. Another approach is par ous agents of the type commonly employed for Such pur ticle beam radiation therapy. This type of therapy differs from poses. In general, the compounds of this invention are present photon radiotherapy in that it involves the use of fast-moving in Such oral dosage forms at concentration levels ranging Subatomic particles to treat localized cancers. Some particles from about 0.5% to about 90% by weight of the total compo (neutrons, pions, and heavy ions) deposit more energy along sition, in amounts which are sufficient to provide the desired the path they take through tissue than do X-rays or gamma unit dosages. Other Suitable dosage forms for the compounds rays, thus causing more damage to the cells they hit. This type of this invention include controlled release formulations and of radiation is often referred to as high linear energy transfer devices well known to those who practice in the art. (high LET) radiation. Radio-sensitizers make the tumour 0.195 For purposes of oral administration, tablets contain cells more likely to be damaged, and radio-protectors protect ing various excipients such as sodium citrate, calcium car normal tissues from the effects of radiation. Hyperthermia, bonate and calcium phosphate may be employed along with the use of heat, may also be used for sensitizing tissue to various disintegrants such as Starch and preferably potato or radiation. Another option involves the use of radio-labeled tapioca starch, alginic acid and certain complex silicate, antibodies to deliver doses of radiation directly to the cancer together with binding agents such as polyvinylpyrrolidone, site (radio-immunotherapy). There are numerous methods Sucrose, gelatine and acacia. Additionally, lubricating agents available in the art to link a radioisotope to an antibody. For Such as magnesium Stearate, sodium lauryl Sulfate and talc or example, for the radio-iodination of the antibody, a method as compositions of a similar type may also be employed as fillers disclosed in WO93/05804 may be employed. Another option in soft and hard-filled gelatine capsules; included lactose or is to use a linker molecule between the antibody and the milk Sugar as well as high molecular weight polyethylene radioisotope, e.g. MAG-3 (U.S. Pat. No. 5,082,930, EP 0247 glycols. When aqueous Suspensions and/or elixirs are desired 866), MAG-2 GABA (U.S. Pat. No. 5,681,927, EP 0 284 for oral administration, the essential active ingredient therein 071), and N2S2 (phenthioate, U.S. Pat. No. 4,897.255, U.S. may be combined with various Sweetening or flavouring Pat. No. 5.242,679, EP 0188 256). A further option is pre agents, colouring matter or dyes and, if so desired, emulsify targeted radio-immunotherapy, which may be used to mini ing agents and/or water, ethanol, propylene glycol, glycerine mize the radiation toxicity by separating the long-circulating and various like combinations thereof. US 2011/0171289 A1 Jul. 14, 2011

0196. For purposes of oral administration, an especially or naturally occurring, semi-synthetic or synthetic therapeu suitable pharmaceutical formulation for the selected protein tic agent is a steroid, the steroid may be administered in a kinase receptor antagonist in accordance with the present daily dosage of 5 to 500 mg. invention is softgelatine capsules. Suitable Soft gelatine cap 0202 As already mentioned hereinbefore, detailed proto Sules for the encapsulation of pharmaceutical compounds and cols for radiotherapy are readily available to the expert. The the process for their preparation are described, for example, in expert knows how to determine an appropriate dosing and GB patent No. 395546, U.S. Pat. No. 2,720,463, U.S. Pat. No. application schedule, depending on the nature of the disease 2,870,062, U.S. Pat. No. 4,829,057, and in the following and the constitution of the patient. In particular, the expert publications: ANON (Verpack-Rundsch. Vol. 21, No. 1, knows how to assess dose-limiting toxicity (DLT) and how to determine the maximum tolerated dose (MTD) accordingly. January 1970, pp. 136-138), Lachman et al. (The Theory and In Vitro and In Vivo Combination Studies Showing the Practice of Industrial Pharmacy, Chap. 13, published by Lea Potency to Inhibit the Proliferation and/or to Induce the Apo & Febiger, 1970), Ebert (Soft Gelatine Capsules: A Unique ptosis of Tumour Cells Dosage Form, reprint from Pharmaceutical Technology, 0203. In the following examples of combinations, in vitro October 1977) and R. F. Jimerson (Soft Gelatine Capsule experiments with representative cell lines or in vivo experi Update, Drug Development and Industrial Pharmacy, Vol. 12 ments with nude mice carrying specific tumours, illustrate the (8 & 9), pp. 1133-1144, 1986). potency of the combination of a selected protein tyrosine 0.197 For purposes of parenteral administration, solutions kinase antagonist with a further chemotherapeutic agent and/ of the compounds in Sesame or peanut oil or in aqueous or with radiotherapy to inhibit the proliferation of endothelial propylene glycol may be employed, as well as sterile aqueous ortumour cells and/or to induce the apoptosis of tumourcells. Solutions of the corresponding pharmaceutically acceptable These examples are thus illustrative of the present invention. salts. Such aqueous solutions should be suitably buffered if necessary, and the liquid diluent rendered isotonic with Suf Examples of Combinations ficient saline or glucose. These particular aqueous solutions 0204 1. Combination of an antagonist of at least one are especially Suitable for intravenous, intramuscular and receptor selected from VEGFR 1 to 3, PDGFRC. and B, Subcutaneous injection purposes. In this connection, the ster FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, ile aqueous media employed are readily obtained by standard which is further an antagonist of a Src tyrosine kinase techniques well known to those skilled in the art. For instance, family member, or a polymorph, metabolite or pharma distilled water is ordinarily used as the liquid diluent and the ceutically acceptable salt thereof, and of a steroid, for final preparation is passed through a Suitable bacterial filter the treatment of refractory or relapsed multiple Such as a sintered glass filter or a diatomaceous earth or myeloma unglazed porcelain filter. Preferred filters of this type include 0205. In vitro studies performed with the monoethane the Berkefeld, the Chamberland and the Asbestos Disk-Metal sulfonate salt of 3-Z-1-(4-(N-((4-methyl-piperazin-1-yl)- Seitz filter, wherein the fluid is sucked into a sterile container methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-meth with the aid of a Suction pump. The necessary steps should be ylene-6-methoxycarbonyl-2-indolinone (compound taken throughout the preparation of these inject-able solu MES(T)) have shown that this specific compound has unex tions to insure that the final products are obtained in a sterile pected properties which makes it especially suitable for the condition. treatment of the diseases in accordance with the present 0198 For purposes of transdermal administration, the invention, especially when combined with a steroid, and more dosage form of the particular compound or compounds may specifically with dexamethasone. include, by way of example, Solutions, lotions, ointments, 0206. Amongst these unexpected properties, the follow creams, gels, Suppositories, rate-limiting Sustained release ing are of particular relevance for the target indications: formulations and devices therefore. Such dosage forms com Tyrosine kinase inhibition of VEGFR1 to 3, FGFR1 and 3, prise the particular compound or compounds and may include PDGFRC. Inhibition of src-tyrosine kinase family members ethanol, water, penetration enhancer and inert carriers such as and potential inhibition of the proliferation of myeloma cells; gel-producing materials, mineral oil, emulsifying agents, Inhibition of the neo-angiogenesis induced by VEGF and bFGF: Inhibition of the paracrine IL-6 secretion; Inhibition of benzyl alcohol and the like. the cell contact mediated IL-6 secretion; Inhibition of the 0199. In accordance with one embodiment, the selected autocrine VEGF and bFGF effects; Direct induction of apo protein tyrosine kinase receptor antagonist, or its polymorph ptosis on cell lines with to 4:14). orpharmaceutically acceptable salt, may be administered in a 0207. This specific compound appears to be further espe daily dosage such that the plasma level of the active Substance cially suitable for the treatment of multiple myeloma. The lies between 10 and 500 ng/ml for at least 12 hours of a 24 following recent findings constitute a line of evidence for the hours dosing interval. selection of this specific compound for this indication: 0200. In accordance with a further embodiment, the Neovascularization parallels infiltration of bone marrow in a selected protein tyrosine kinase receptor antagonist, or its murine multiple myeloma model (Yaccoby et al., Blood polymorph or pharmaceutically acceptable salt, may be 1998, Vol. 92(8), pp. 2908-2913) and in multiple myeloma administered in a daily dosage of between 2 mg and 20 mg/kg patients undergoing progression (Vacca et al., Blood 1999, body weight. Vol. 93(9), pp. 3064-3073; Kumar et al., Blood 2002, Blood 0201 The further chemotherapeutic or naturally occur First Edition Paper, Pre-published Online Oct. 17, 2002, DOI ring, semi-synthetic or synthetic therapeutic agent may be 10.1182/blood-2002-08-2441); VEGF has been shown to be administered using Suitable dosage forms, dosage levels and a potent stimulus of angiogenesis (Toi et al., Lancet Oncol. devices well known to those who practice in the art. In accor 2001, Vol.2, pp. 667-673); VEGF is expressed in and secreted dance with one embodiment, if the further chemotherapeutic by multiple myeloma cells (Dankbar et al., Blood 2000, Vol. US 2011/0171289 A1 Jul. 14, 2011 16

95 (8), pp. 2630-2636; Bellamy et al., Cancer Res. 1999, Vol. 0211. In a further experiment, the inhibition effect of the 59(3), pp. 728-33); VEGF induces IL-6 secretion from mar compound MES(T) on the secretion of IL-6 in transwell and row stromal cells, which in turn augments VEGF expression contact co-cultures of myeloma cells (U-266 myeloma cell from clonal plasma cells (Dankbar et al., Blood 2000, Vol. lines) and bone marrow stromal cells (BMSC cells) was 95 (8), pp. 2630-2636); IL-6 is considered a major growth investigated, at different concentrations (0, 50, 125, 250 and factor for multiple myeloma cells in vivo (Klein et al., Blood 500 nM) of MES(T). For comparison, the inhibition effect on 1995, Vol.85(4), pp. 863-872); IL-6 inhibits Dexamethasone BMSC mono-cultures (native) and, as control, the level of induced myeloma cell death (Hardin et al., Blood 1994, Vol. secretion of U266 mono-cultures, were also investigated. The 84(9), pp. 3063-3070); VEGF induces proliferation and trig results of the experiment are shown in the following Table gers migration of multiple myeloma cells (Podar et al., Blood 2001, Vol. 98(2), pp. 428-435); VEGF enhances osteoclastic TABLE III bone resorption, which is a characteristic feature of multiple myeloma (Nakagawa et al., FEBS Lett. 2000, Vol. 473(2), pp. Inhibition of IL-6 secretion 161-164: Nida et al., J. Exp. Med. 1999, Vol. 190(2), pp. MES(T) BMSC Transwell Contact U266 293-298); FGFR3 induces proliferation, inhibits apoptosis COCel- OO- U-266 - BMSC U-266 - BMSC OO and is involved in progression of myeloma cells (Chesi et al., tration cultures co-cultures co-cultures cultures Blood 2001, Vol. 97(3), pp. 729-736: Plowright et al., Blood OnM 153.5 336.1 348.1 2.0 2000, Vol. 95(3), pp. 992-998); FGFR3 is dysregulated and SOM 2134 3S4.5 constitutively activated in a Subset of myeloma patients 125 nM 1921 297.6 259.6 (Chesi et al., Blood 2001, Vol.97(3), pp. 729-736: Chesiet al., 250 nM 69.9 231.1 1994 Nat. Genet. 1997, Vol. 16(3), pp. 260-264); Src family kinases SOOM 38.6 123.9 114.7 are involved in proliferative responses induced in myeloma (Ishikawa et al.; Blood 2002, Vol. 99(6), pp. 2172-2178). 0212. The results of this experiment show that the com 0208. The following results of in vitro experiments evi pound MES(T) is able to decrease to its basal (native) value dence that the properties of the compound MES(T) make it the level of IL-6 secretion of BMSC cultures stimulated by especially suitable for the treatment of multiple myeloma. myeloma cells in transwell and contact co-cultures. Thus, it 0209. In the first experiment, the inhibition effect of the can be concluded that the compound MES(T) interferes with compound MES(T) on the secretion of IL-6 by bone marrow the myeloma-stroma interaction targeting the bone marrow stromal cells (BMSC cells) was investigated, at different con microenvironment by significantly diminishing NFKB-de centrations (0, 10, 50, 125, 250 and 500 nM) of MES(T), in pendent IL-6 production. This further shows the potency of native conditions (native) and in conditions of stimulation of the compound in accordance with the present invention for the cells with the bFGF (+bFGF) or with the VEGF (+VEGF) the treatment of multiple myeloma. growth factors. For comparison, the inhibition effect with 0213. In further experiments, it could be shown that the inhibition of anti-bFGF (+anti-bfGF), anti-VEGF (+anti compound MES(T) provides pro-apoptotic effects int(14:16) VEGF) and a combination of anti-bFGF and anti-VEGF MM1.s myeloma cells (MM1.s myeloma cells carrying the (+anti-VEGF+anti-bFGF) were also investigated. The results translocation tC 14:16)), and that the compound MES(T) of the experiment are shown in the following Table II. enhances the apoptosis induced by dexamethasone.

TABLE II Inhibition of IL-6 secretion by BMSC cells MES(T) +anti-VEGF concentration native +bFGF +VEGF +anti-bFGF +anti-VEGF +anti-bFGF

O nM 1242 216.9 107.4 777 118.9 71.1 10 nM 130.2 1SO.S 122.3 68.9 148.6 68.1 SO M 1704 179.7 130.7 813 155.2 63.4 125 nM 97.5 912 1410 42.4 166.7 86.1 250 nM 76.5 76.9 65.5 33.0 89.4 45.O SOO nM 39.6 43.4 14.8 2O2 16.2 13.5

0210. The results of this experiment show that the com- 0214. Due to these properties, it can be concluded that the pound MES(T) at concentration of 2250 nM inhibits basal compound MES(T)is especially suitable for a combination (native) as well as bFGF/VEGF-stimulated IL-6 secretion of treatment of refractory or relapsed multiple myeloma with a bone marrow stromal cells (BMSC cells), and that the inhi steroid, and especially dexamethasone. bition is more potent than the inhibition obtained with the antibodies. Since the bFGF and VEGF growth factors (re 0215 2. Combination of an antagonist of at least one leased by myeloma cells) have been previously shown to receptor selected from VEGFR 1 to 3, PDGFRC. and B, stimulate BMSC cells and the microvascular endothelium to FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, produce and secrete IL-6, which itself stimulates myeloma which is further an antagonist of a Src tyrosine kinase cells to produce both the bFGF and VEGF growth factors, an family member, or a polymorph, metabolite or pharma inhibition of IL-6 secretion by the compound in accordance ceutically acceptable salt thereof, and of a dual antago with the present invention shows its potency for the treatment nist of the epidermal growth factor (EGF) receptor and of multiple myeloma. of the human epidermal growth factor of type 2 (HE type US 2011/0171289 A1 Jul. 14, 2011

2) receptor, for the treatment of prostate cancer, non b)or IMC-1C11) with EGFR inhibitors (e.g. iressa (ZD Small cell lung cancer or colorectal cancer 1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272 or 0216. The following experiment was performed in order to herceptin) or combined EGFR/HER-2 inhibitors (e.g. the investigate the effect of a combination therapy with subopti quinazoline derivatives disclosed in WO 00/78735 and WO mal doses of an antagonist of at least one receptor selected 02/50043, gefitinib, erlotinib, CI-1033 or GW-2016) will from VEGFR1 to 3, PDGFRC. and B, FGFR1, 2 and 3, EGFR, expectedly have the same or similar effects for anti-tumour HER2, IGF1R, HGFR or c-Kit, which is further an antagonist therapies. of a Src tyrosine kinase family member, namely the di-chlo 0220 3. Combination treatment of an antagonist of at ride salt of (Z)-3-(1-(4-(N-(4-methyl-piperazin-1-yl)-meth least one receptor selected from VEGFR 1 to 3, PDG ylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-me FRC. and B, FGFR1, 2 and 3, EGFR, HER2, IGF1R, thylene-6-methoxycarbonyl-2-indolinone (compound HGFR or c-Kit, which is further an antagonist of a src referred to as C12(T)), which is the di-chloride salt of above tyrosine kinase family member, or a polymorph, exemplified compound (T), and a dual antagonist of the epi metabolite or pharmaceutically acceptable salt thereof dermal growth factor (EGF) receptor and of the human epi (e.g. the compound MES(T)), and of radiation therapy dermal growth factor of type 2 (HE type 2) receptor, namely for the treatment of breast cancer or ovarian cancer the compound 4-(3-chloro-4-fluorophenyl)amino]-6-4- 0221 4. Combination of an antagonist of at least one (N,N-dimethylamino)-1-oxo-2-buten-1-yl)amino-7-((S)- receptor selected from VEGFR 1 to 3, PDGFRC. and B, tetrahydrofuran-3-yloxy)-quinazoline, (compound referred FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, to as EGFR/HER2 inh., and described in WO 02/50.043 as which is further an antagonist of a Src tyrosine kinase exemplified compound of Example 1 (10)), on the reduction family member, or a polymorph, metabolite or pharma of tumour growth, in comparison to the mono-therapies at the ceutically acceptable salt thereof (e.g. the compound same doses. MES(T)), and of a further antagonist of VEGFR 2, 0217 For this purpose, nude mice (NMRI nu/nu) were PDGFR or bFGFR (e.g. vatalanib (PTK-787, ZD-6474, injected subcutaneously with SKOV-3 cells (human ovarian or the monoclonal antibody AvastinTM) or an antagonist carcinoma). Mice carrying established tumours were ran of EGFR (e.g. tarceva (OSI-774)), for the treatment of domised into control and treatment groups (N=10). The mice colorectal cancer, Solid tumours, breast cancer, non in the control group only received the carrier solution (0.5% Small cell lung cancer, Small cell lung cancer or multiple Natrosol), the second group was treated daily per os with 15 myeloma mg/kg EGFR/HER2 inh., the third received once daily 50 0222 5. Combination of an antagonist of at least one mg/kg. C12(T), and the fourth group of mice was treated with receptor selected from VEGFR 1 to 3, PDGFRC. and B, the combination of 15 mg/kg EGFR/HER2 inh. and 50 mg/kg FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, C12(T). FIG. 3 shows the results of the experiment. which is further an antagonist of a Src tyrosine kinase 0218 Daily per os treatment was initially performed for family member, or a polymorph, metabolite or pharma 31 days. At this time point some of the mice from the control ceutically acceptable salt thereof (e.g. the compound group carried tumours bigger than 2000 mm and therefore MES(T)), and of an antimetabolite (e.g. gemcitabine) had to be sacrificed. The calculated treated tumour to control and a platinum compound (e.g. cisplatin), or of an anti tumour (T/C) ratio at this time point was 35% for the group cancer drug from plants (e.g. paclitaxel) and a platinum treated with 15 mg/kg EGFR/HER2 inh., 32% for the group compound (e.g. carboplatin), for the treatment of non treated with 50 mg/kg. C12(T), and 13% for the group treated Small cell lung cancer or ovarian carcinoma with the combination. This result clearly demonstrates the 0223 6. Combination of an antagonist of at least one anti-tumour effect of the combination of a VEGFR-2 and an receptor selected from VEGFR 1 to 3, PDGFRC. and B, EGFR/HER-2 inhibitor in vivo. Furthermore, continuing the FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, treatment until day 64 shows extremely slow tumour growth which is further an antagonist of a Src tyrosine kinase in the combination group in comparison to the single treat family member, or a polymorph, metabolite or pharma ment group where the tumours eventually are growing to ceutically acceptable salt thereof (e.g. the compound comparable sizes as the control treated tumours. MES(T)), and of hormone antagonists (e.g. leuprorelin 0219. From the results of this experiment, it can thus be and flutamide), for a continuous and/or intermittent concluded that the combination of compounds targeting dif treatment of metastatic hormone sensitive prostate can ferent mechanisms involved in and important for tumour C growth such as the VEGFR-2 inhibitor C12(T), inhibiting 0224 7. Combination of an antagonist of at least one tumour angiogenesis, and the combined EGFR/HER-2 receptor selected from VEGFR 1 to 3, PDGFRC. and B, inhibitor EGFR/HER2 inh. inhibiting the proliferative sig FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, nalling through the class I receptor tyrosine kinases, have a which is further an antagonist of a Src tyrosine kinase synergistic anti-tumour efficacy. Thus, all combinations of family member, or a polymorph, metabolite or pharma inhibitors of tumourangiogenesis (e.g. the indolinone deriva ceutically acceptable salt thereof (e.g. the compound tives described in WO 02/36564, WO 99/52869, WO MES(T)), and of a derivative of podophyllotoxin (e.g. 00/18734, WO 00/73297, WO 01/27080, WO 01/27081 or etoposide) and a platinum compound (e.g. carboplatinor WO 01/32651, the small molecule VEGF receptor antago cisplatin), for the treatment of Small cell lung cancer nists described in WO 01/60814, WO 99/48868, WO 0225 8. Combination of an antagonist of at least one 98/35958, and especially the compounds Vatalanib (PTK receptor selected from VEGFR 1 to 3, PDGFRC. and B, 787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, which is further an antagonist of a Src tyrosine kinase IM-842 or GW-78.6034, the monoclonal antibodies directed family member, or a polymorph, metabolite or pharma to the VEGF receptor, and especially AvastinTM (bevacizuma ceutically acceptable salt thereof (e.g. the compound US 2011/0171289 A1 Jul. 14, 2011 18

MES(T)), and of an anticancer drug from plants (e.g. or cis-platin, preferably carboplatin) for the treatment of paclitaxel or taxol), for the treatment of ovarian carci ovarian carcinoma or non-Small cell lung cancer noma, Small cell lung cancer or prostate cancer 0233 16. Combination of an antagonist of at least one 0226 9. Combination of an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFRC. and B, receptor selected from VEGFR 1 to 3, PDGFRC. and B, FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is further an antagonist of a Src tyrosine kinase which is further an antagonist of a Src tyrosine kinase family member, or a polymorph, metabolite or pharma family member, or a polymorph, metabolite or pharma ceutically acceptable salt thereof (e.g. the compound ceutically acceptable salt thereof (e.g. the compound MES(T)), and of a COX-2 inhibitor (e.g. celecoxib, rofe MES(T)), and of an anticancer drug from plants (e.g. coxib or meloxicam), for the treatment of colon or rectal taxotere) for the treatment of prostate cancer CaCC 0227 10. Combination of an antagonist of at least one 0234 17. Combination of an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFRC. and B, receptor selected from VEGFR 1 to 3, PDGFRC. and B, FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is further an antagonist of a Src tyrosine kinase which is further an antagonist of a Src tyrosine kinase family member, or a polymorph, metabolite or pharma family member, or a polymorph, metabolite or pharma ceutically acceptable salt thereof (e.g. the compound ceutically acceptable salt thereof (e.g. the compound MES(T)), and of a platinum compound (e.g. carbopl MES(T)), and of a 5-alpha reductase inhibitor (e.g. fin atin) and an anticancer drug from plants (e.g. paclitaxel), asteride), for the treatment of prostate cancer for the treatment of ovarian carcinoma, especially after 0235. 18. Combination of an antagonist of at least one debulking Surgery receptor selected from VEGFR 1 to 3, PDGFRC. and B, FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, 0228 11. Combination of an antagonist of at least one which is further an antagonist of a Src tyrosine kinase receptor selected from VEGFR 1 to 3, PDGFRC. and B, family member, or a polymorph, metabolite or pharma FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, ceutically acceptable salt thereof (e.g. the compound which is further an antagonist of a Src tyrosine kinase MES(T)), and of a photo-chemotherapeutic agent family member, or a polymorph, metabolite or pharma (PUVA, a combination of psoralen (P) and long-wave ceutically acceptable salt thereof (e.g. the compound ultraviolet radiation (UVA)), for the treatment of psoria MES(T)), and of a topoisomerase I inhibitor (e.g. topo S1S tecan) and an anthracycline (e.g. doxorubicin), for the 0236 Essentially, for the treatment of oncological dis treatment of ovarian cancer eases, the rationale for the combination treatment in accor 0229 12. Combination of an antagonist of at least one dance with the present invention is that there is a therapeutic receptor selected from VEGFR 1 to 3, PDGFRC. and B, advantage for the cancer patient to combine specific and FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, mechanistically acting molecules with more broadly acting which is further an antagonist of a Src tyrosine kinase therapeutic concepts in the following ways: family member, or a polymorph, metabolite or pharma 0237 Through the combination the target cells will ceutically acceptable salt thereof (e.g. the compound have less chance to Survive through possible escape MES(T)), and of a topoisomerase I inhibitor (e.g. topo mechanisms; tecan), for the treatment of Small cell lung cancer or 0238 When compared to the doses used in a mono ovarian carcinoma therapy, due to an additive or synergistic effect of the 0230 13. Combination of an antagonist of at least one combination, the required respective doses of the drugs receptor selected from VEGFR 1 to 3, PDGFRC. and B, can be reduced; FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, 0239 Scheduling of the respective drugs in a combina which is further an antagonist of a Src tyrosine kinase tion reduces the likelihood of the tumour cells to develop family member, or a polymorph, metabolite or pharma resistances against the drugs, leads to a better delivery of ceutically acceptable salt thereof (e.g. the compound certain drugs to the tumour (reduction of intratumoral MES(T)), and of an anticancer drug from plants (e.g. pressure) and may activate further death pathways in the docetaxel) and a steroid hormone (e.g. estramustine), for tumour cells. the treatment of hormone refractory prostate cancer 0240 Thus, by targeting different cellular structures and 0231 14. Combination of an antagonist of at least one compartments, the combination therapies in accordance with receptor selected from VEGFR 1 to 3, PDGFRC. and B, the present invention are expected to provide a clinically FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, relevant benefit in survival or time to tumour progression for which is further an antagonist of a Src tyrosine kinase larger patient population as the corresponding mono-thera family member, or a polymorph, metabolite or pharma pies. As a result of the specific anti-angiogenic therapy with, ceutically acceptable salt thereof (e.g. the compound for example, the compound MES(T), tumours seem to be less MES(T)), and of a Vinca alkaloid (e.g. navelbine) for the capable of recovering from the damage caused by conven treatment of lung cancer tional chemotherapy. Also, by blocking the effects of VEGF 0232 15. Combination of an antagonist of at least one on vascular permeability, a decline of the interstitial pressure receptor selected from VEGFR 1 to 3, PDGFRC. and B, in tumours seems to occur, allowing a greater penetration of FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, the cytotoxic drugs. Maintenance therapy with a specific anti which is further an antagonist of a Src tyrosine kinase angiogenic agent such as, for example, the compound MES family member, or a polymorph, metabolite or pharma (T), after standard cytoreduction, seems also to result in a ceutically acceptable salt thereof (e.g. the compound consolidation of the response obtained with the cytotoxic MES(T)), and of a platinum compound (e.g. carboplatin therapy. This approach is Substantiated by preclinical evi US 2011/0171289 A1 Jul. 14, 2011 dence that combinations of anti-angiogenic compounds with proteasome inhibitors, enzymes, hormones, hormone antago cytotoxic therapies result in Synergistic anti-tumour activity. nists, hormone inhibitors, inhibitors of steroid biosynthesis, 0241 For the treatment of non-oncological diseases, the steroids, cytokines, hypoxia-selective cytotoxins, inhibitors rationale for the combination treatment in accordance with of cytokines, lymphokines, antibodies directed against cytok the present invention is also that there is a therapeutic advan ines, oral and parenteral tolerance induction agents, support tage for the patient to combine specific and mechanistically ive agents, chemical radiation sensitizers and protectors, acting molecules with more broadly acting therapeutic con photo-chemically activated drugs, synthetic poly- or oligo cepts. The expected effect of this combination is to avoid nucleotides optionally modified or conjugated, non-steroidal possible escape mechanisms for the target cells, to reduce the anti-inflammatory drugs, cytotoxic antibiotics, antibodies required respective doses of the drugs in comparison to the targeting the Surface molecules of cancer cells, inhibitors of doses used in a mono-therapy (due to the additive or syner metalloproteinases, metals, inhibitors of oncogenes, inhibi gistic effect of the combination), and to reduce the likelihood tors of gene transcription or of RNA translation or protein of the target cells to develop resistances against the drugs. expression, complexes of rare earth elements, and photo chemotherapeutic agents; LEGEND TO THE FIGURES wherein said pharmaceutical combination is optionally 0242 FIG. 1 adapted for a co-treatment with radiotherapy or radio 0243 Inhibition of VEGFR-2 phosphorylation after vary immunotherapy, in the form of a combined preparation ing exposure of compound MES(T) on NIH3T3 KDR cells. for simultaneous, separate or sequential use. The upper panel shows a Western blot probed with an anti 2. The pharmaceutical combination in accordance with body specific for phosphorylated tyrosine residues (C-PY). claim 1, wherein (ii) is selected from vatalanib (PTK-787/ The lower panel shows a Western blot using an antibody ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, specific for VEGFR-2 (C-KDR). AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, 0244 FIG. 2 IM-842, GW-78.6034, gefitinib, erlotinib, CI-1033 GW-2016, 0245 Evolution of the tumour volume in nude mice bear iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, ing Subcutaneous Falu tumours, untreated (dotted line), HKI-272, herceptin, BAY-43-9006, BAY-57-9006, 4-(3- treated orally twice weekly with a dose of 50 mg/kg of com chloro-4-fluoro-phenyl)aminol-6-4-(homomorpholin-4- pound MES(T) (black line), or treated orally twice weekly yl)-1-oxo-2-buten-1-yl)amino-7-(S)-(tetrahydrofuran-3- with a dose of 100 mg/kg of compound MES(T) (gray line). yl)oxy-quinazoline or a pharmaceutically acceptable salt 0246 FIG.3 thereof, atrasentan, rituximab, cetuximab, AvastinTM (bevaci 0247 Evolution of the tumour volume in nude mice bear Zumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000, ing Subcutaneous ovarian cancer SKOV-3 tumours, untreated vitaxin, imatinib, VEGFtrap, melphalan, cyclophosphamide, (dashes), treated daily per os with 15 mg/kg EGFR/HER2 an oxazaphosphorine, cisplatin, carboplatin, oxaliplatin, inh. (triangles), treated daily with 50 mg/kgCl2(T) (squares), satraplatin, tetraplatin, iproplatin, mitomycin, Streptozocin, or treated with the combination of 15 mg/kg EGFR/HER2 carmustine (BCNU), lomustine (CCNU), busulfan, ifosfa inh. and 50 mg/kg. C12(T) (losanges). mide, Streptozocin, thiotepa, chlorambucil, mechlore 1. A pharmaceutical combination comprising therapeuti thamine, an ethyleneimine compound, an alkylsulphonate, cally effective amounts of: daunorubicin, doxorubicin (adriamycin), liposomal doxoru (i) (Z)-3-(1-(4-(N-(4-methyl-piperazin-1-yl)-methylcar bicin (doxil), epirubicin, idarubicin, mitoxantrone, amsa bonyl)-N-methyl-amino)-anilino)-1-phenyl-methyl crine, dactinomycin, distamycin or a derivative thereof, ene-6-methoxycarbonyl-2-indolinone, or a pharma netropsin, pibenZimol, mitomycin, CC-1065, a duocarmycin, ceutically acceptable salt thereof; and mithramycin, chromomycin, olivomycin, propamidine, stil (ii) at least a further chemotherapeutic or naturally occur bamidine, an anthramycin, an aziridine, a nitrosourea or a ring, semi-synthetic or synthetic therapeutic agent derivative thereof, cytarabine, 5-fluorouracile (5-FU), uracil selected from mustard, fludarabine, gemcitabine, capecitabine, mercap synthetic small molecule VEGF receptor antagonists, small topurine, cladribine, thioguanine, methotrexate, pentostatin, molecule growth factor receptor antagonists, inhibitors of the hydroxyurea, folic acid, a phleomycin, a bleomycin or a EGF receptor, excluding 4-(3-chloro-4-fluorophenyl) derivative or salt thereof, CHPP. BZPP, MTPP, BAPP, liblo amino-6-4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl) mycin, an acridine or a derivative thereof, a rifamycin, an amino-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, and/or actinomycin, adramycin, irinotecan (camptosar), topotecan, VEGF receptor and/or integrin receptors or any other protein an amsacrine or analogue thereof, a tricyclic carboxamide, tyrosine kinase receptors which are not classified under the SAHA, MD-275, trichostatin A, CBHA, LAQ824, valproic synthetic small-molecules, inhibitors directed to EGF recep acid, paclitaxel (taxol), docetaxel, taxotere, navelbine, Vin tor and/or VEGF receptor and/or integrin receptors or any blastin, Vincristin, vindesine, Vinorelbine, colchicine or a other protein tyrosine kinase receptors, which are fusion pro derivative thereof, maytansine, an ansamitocin, rhizoxin, teins, compounds which interact with nucleic acids and which phomopsin, dolastatin, an epipodophyllotoxin, etoposide, are classified as alkylating agents or platinum compounds, teniposide, a steganacin, combretastatin, amphetinile, procar compounds which interact with nucleic acids and which are bazine, bortezomib, asparaginase, pegylated asparaginase classified as anthracyclines, as DNA intercalators or as DNA (pegaspargase),a thymidine-phosphorylase inhibitor, estra cross-linking agents, DNA minor-groove binding com mustine (T-66), megestrol, flutamide, casodex, anandron, pounds, anti-metabolites, naturally occurring, semi-synthetic cyproterone acetate, aminogluthetimide, anastroZole, form or synthetic bleomycin type antibiotics, inhibitors of DNA estan, letrozole leuprorelin, buserelin, goserelin, triptorelin, transcribing enzymes selected from topoisomerase I and tamoxifen or its citrate salt, droloxifene, trioxifene, ralox topoisomerase II inhibitors, chromatin modifying agents, ifene, Zindoxifene, ICI 164.384, ICI 182,780, aminoglute mitosis inhibitors, anti-mitotic agents, cell-cycle inhibitors, thimide, formestane, fadrozole, finasteride, ketoconazole, US 2011/0171289 A1 Jul. 14, 2011 20 leuprolide, prednisone, prednisolone, methylprednisolone, boxamide, SAHA, MD-275, trichostatinA, CBHA, LAQ824, dexamethasone, budenoside, fluocortolone, triamcinolone, valproic acid, bortezomib, vatalanib (PTK-787/ZK222584), interferon B, IL-10, IL-12, etanercept, thalidomide, its R- and SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, S-enantiomers and its derivatives, revimid (CC-5013), a leu AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842, kotrien antagonist, mitomycin C, an aziridoquinone, a 2-ni GW-786034, BAY-43-9006, BAY-57-9006, gefitinib, erlo troimidazole, a nitroacridine, a nitroquinoline, a nitropyra tinib, CI-1033, GW-2016, iressa (ZD-1839), tarceva (OSI Zoloacridine, a "dual-function’ nitro aromatic, a nitro 774), PKI-166, EKB-569, HKI-272, herceptin, 4-(3-chloro aromatic deactivated mustard, a N-oxide of a nitrogen mus 4-fluoro-phenyl)amino]-6-4-(homomorpholin-4-yl)-1- tard, a metal complex of a nitrogen mustard, an anti-CD3 oxo-2-buten-1-yl)amino-7-(S)-(tetrahydrofuran-3-yl) antibody, an anti-CD25 antibody, a tolerance induction agent, oxy-quinazoline or a pharmaceutically acceptable salt minodronic acid or a derivative thereof selected from thereof, an inhibitor of the transcription factor complex ESX/ YM-529, Ono-5920 and YH-529, Zoledronic acid monohy DRIP130/Sur-2, heat shock protein HSP90 modulator drate, ibandronate Sodium hydrate, clodronate disodium, geldanamycin and its derivative 17-allylaminogeldanamycin metronidazole, misonidazole, benznidazole, nimorazole, (17-AAG), atrasentan, rituximab, cetuximab, AvastinTM (be RSU-1069, SR-4233, bromodeoxyuridine, iododeoxyuri vacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD dine, WR-2721, porfimer, photofrin, a benzoporphyrin 72000, vitaxin, imatinib, apolizumab and 1D09C3. derivative, a pheophorbide derivative, merocyanin 540 (MC 4. The pharmaceutical combination inaccordance with any 540), tin etioporpurin, oblimersen, a non-steroidal anti-in of claims 1 to 3, wherein (i) is the monoethanesulfonate salt of flammatory drug selected from acetylsalicyclic acid, 3-Z-1-(4-(N-(4-methyl-piperazin-1-yl)-methylcarbonyl)- mesalazin, ibuprofen, naproxen, flurbiprofen, fenoprofen, N-methyl-amino)-anilino)-1-phenyl-methylene-6-meth fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxycarbonyl-2-indolinone. oxaprozin, pranoprofen, miroprofen, tioxaprofen, Suprofen, 5. A pharmaceutical combination preparation kit, compris alminoprofen, tiaprofenic acid, fluprofen, indomethacin, ing a therapeutically effective amount of Sulindac, tolmetin, Zomepirac, nabumetone, diclofenac, fen (i) (Z)-3-(1-(4-(N-(4-methyl-piperazin-1-yl)-methylcar clofenac, alclofenac, bromfenac, ibufenac, aceclofenac, bonyl)-N-methyl-amino)-anilino)-1-phenyl-methyl acemetacin, fentiazac, clidanac, etodolac, oXpinac, mefe ene-6-methoxycarbonyl-2-indolinone, or a pharma namic acid, meclofenamic acid, flufenamic acid, nifluminic ceutically acceptable salt thereof; and acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, (ii) at least a further chemotherapeutic or naturally occur tenoxicam, lornoxicam, nimeSulide, meloxicam, celecoxib ring, semi-synthetic or synthetic therapeutic agent and rofecoxib, or a pharmaceutically acceptable salt of a selected from non-steroidal anti-inflammatory drug, a cytotoxic antibiotic, synthetic small molecule VEGF receptor antagonists, small apolizumab, 1 D09C3, TIMP-1, TIMP-2, Zinc, P53, Rb, an molecule growth factor receptor antagonists, inhibitors of the heterocyclic complex of a lanthanide, PUVA, an inhibitor of EGF receptor, excluding 4-(3-chloro-4-fluorophenyl) the transcription factor complex ESX/DRIP130/Sur-2, amino-6-4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl) geldanamycin or its derivative 17-allylaminogeldanamycin amino-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, and/or (17-AAG), IM-842, tetrathiomolybdate, squalamine, combr VEGF receptor and/or integrin receptors or any other protein estatin A4, TNP-470, marimastat, neovastat, bicalutamide, tyrosine kinase receptors which are not classified under the abarelix, oregovomab, mitumomab, TLK-286, alemtuzumab, synthetic small-molecules, inhibitors directed to EGF recep ibritumomab, temozolomide, denileukin diftitox, aldesleu tor and/or VEGF receptor and/or integrin receptors or any kin, dacarbazine, floxuridine, plicamycin, mitotane, pipobro other protein tyrosine kinase receptors, which are fusion pro man, plicamycin, tamloxifen and testolactone. teins, compounds which interact with nucleic acids and which 3. The pharmaceutical combination in accordance with are classified as alkylating agents or platinum compounds, claim 1, wherein (ii) is selected from paclitaxel (taxol), doc compounds which interact with nucleic acids and which are etaxel, taxotere, navelbine, vinblastin, Vincristin, vindesine, classified as anthracyclines, as DNA intercalators or as DNA Vinorelbine, melphalan, cyclophosphamide, an oxazaphos cross-linking agents, DNA minor-groove binding com phorine, cisplatin, carboplatin, oxaliplatin, satraplatin, tetra pounds, anti-metabolites, naturally occurring, semi-synthetic platin, iproplatin, mitomycin, streptozocin, carmustine or synthetic bleomycin type antibiotics, inhibitors of DNA (BCNU), lomustine (CCNU), busulfan, ifosfamide, strepto transcribing enzymes selected from topoisomerase I and Zocin, thiotepa, chlorambucil, mechlorethamine, thalido topoisomerase II inhibitors, chromatin modifying agents, mide, its R- and S-enantiomers and its derivatives, revimid mitosis inhibitors, anti-mitotic agents, cell-cycle inhibitors, (CC-5013), an ethyleneimine compound, an alkylsulphonate, proteasome inhibitors, enzymes, hormones, hormone antago daunorubicin, doxorubicin (adriamycin), liposomal doxoru nists, hormone inhibitors, inhibitors of steroid biosynthesis, bicin (doxil), epirubicin, idarubicin, mitoxantrone, amsa steroids, cytokines, hypoxia-selective cytotoxins, inhibitors crine, dactinomycin, distamycin or a derivative thereof, of cytokines, lymphokines, antibodies directed against cytok netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin, ines, oral and parenteral tolerance induction agents, support mithramycin, chromomycin, olivomycin, a phtalanilide Such ive agents, chemical radiation sensitizers and protectors, as propamidine or stilbamidine, an anthramycin, an aziridine, photo-chemically activated drugs, synthetic poly- or oligo a nitrosourea or a derivative thereof, a pyrimidine or purine nucleotides optionally modified or conjugated, non-steroidal analogue, cytarabine, 5-fluorouracile (5-FU), uracil mustard, anti-inflammatory drugs, cytotoxic antibiotics, antibodies fludarabine, gemcitabine, capecitabine, mercaptopurine, targeting the Surface molecules of cancer cells, inhibitors of cladribine, thioguanine, methotrexate, pentostatin, hydrox metalloproteinases, metals, inhibitors of oncogenes, inhibi yurea, folic acid, an acridine or a derivative thereof, a rifamy tors of gene transcription or of RNA translation or protein cin, an actinomycin, adramycin, irinotecan (camptosar), expression, complexes of rare earth elements, and photo topotecan, an amsacrine or analogue thereof, a tricyclic car chemotherapeutic agents; US 2011/0171289 A1 Jul. 14, 2011 21

and optionally adapted for a co-treatment with radio nitro aromatic, a nitro aromatic deactivated mustard, a N-OX therapy or radio-immunotherapy, characterised in that ide of a nitrogen mustard, a metal complex of a nitrogen (i) is comprised within a first compartment and (ii) is mustard, an anti-CD3 antibody, an anti-CD25 antibody, a comprised within a second compartment. Such that the tolerance induction agent, minodronic acid or a derivative administration to a patient in need thereof can be simul thereof selected from YM-529, Ono-5920 and YH-529, taneous, separate or sequential. Zoledronic acid monohydrate, ibandronate sodium hydrate, 6. The pharmaceutical combination preparation kit in clodronate disodium, metronidazole, misonidazole, ben accordance with claim 5, wherein (i) is the monoethane Znidazole, nimorazole, RSU-1069, SR-4233, bromodeox sulfonate salt of 3-Z-1-(4-(N-((4-methyl-piperazin-1-yl)- yuridine, iododeoxyuridine, WR-2721, porfimer, photofrin, a methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-meth benzoporphyrin derivative, a pheophorbide derivative, mero ylene-6-methoxycarbonyl-2-indolinone. cyanin 540 (MC-540), tin etioporpurin, oblimersen, a non 7. The pharmaceutical combination preparation kit in steroidal anti-inflammatory drug selected from acetylsalicy accordance with claim 5, wherein(ii) is selected from vata clic acid, mesalazin, ibuprofen, naproxen, flurbiprofen, lanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, car SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, profen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, AG-013736, IM-842, GW-786034, gefitinib, erlotinib, Suprofen, alminoprofen, tiaprofenic acid, fluprofen, CI-1033 GW-2016, iressa (ZD-1839), tarceva (OSI-774), indomethacin, Sulindac, tolmetin, Zomepirac, nabumetone, PKI-166, EKB-569, HKI-272, herceptin, BAY-43-9006, diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, BAY-57-9006, 4-(3-chloro-4-fluoro-phenyl)amino]-6-4- aceclofenac, acemetacin, fentiazac, clidanac, etodolac, Oxpi (homomorpholin-4-yl)-1-oxo-2-buten-1-yl)amino-7-(S)- nac, mefenamic acid, meclofenamic acid, flufenamic acid, (tetrahydrofuran-3-yl)oxy-quinazoline or a pharmaceuti nifluminic acid, tolfenamic acid, diflunisal, flufenisal, piroxi cally acceptable Salt thereof, atrasentan, rituximab, cam, tenoxicam, lornoxicam, nimeSulide, meloxicam, cele cetuximab, AvastinTM (bevacizumab), IMC-1C11, erbitux coxib and rofecoxib, or a pharmaceutically acceptable salt of (C-225), DC-101, EMD-72000, vitaxin, imatinib, VEGFtrap, a non-steroidal anti-inflammatory drug, a cytotoxic antibi melphalan, cyclophosphamide, an oxazaphosphorine, cispl otic, apolizumab, 1 D09C3, TIMP-1, TIMP-2, Zinc, P53, Rb, atin, carboplatin, oxaliplatin, satraplatin, tetraplatin, ipropl an heterocyclic complex of a lanthanide, PUVA, an inhibitor atin, mitomycin, Streptozocin, carmustine (BCNU), lomus of the transcription factor complex ESX/DRIP130/Sur-2, tine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, geldanamycin or its derivative 17-allylaminogeldanamycin chlorambucil, mechlorethamine, an ethyleneimine com (17-AAG), IM-842, tetrathiomolybdate, squalamine, combr pound, an alkylsulphonate, daunorubicin, doxorubicin estatin A4, TNP-470, marimastat, neovastat, bicalutamide, (adriamycin), liposomal doxorubicin (doxil), epirubicin, ida abarelix, oregovomab, mitumomab, TLK-286, alemtuzumab, rubicin, mitoxantrone, amsacrine, dactinomycin, distamycin ibritumomab, temozolomide, denileukin diftitox, aldesleu or a derivative thereof, netropsin, pibenZimol, mitomycin, kin, dacarbazine, floxuridine, plicamycin, mitotane, pipobro CC-1065, a duocarmycin, mithramycin, chromomycin, man, plicamycin, tamloxifen and testolactone. olivomycin, propamidine, Stilbamidine, an anthramycin, an 8. The pharmaceutical combination preparation kit in aziridine, a nitrosourea or a derivative thereof, cytarabine, accordance with claim 5, wherein(ii) is selected from pacli 5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcit taxel (taxol), docetaxel, taxotere, navelbine, vinblastin, Vin abine, capecitabine, mercaptopurine, cladribine, thiogua cristin, Vindesine, Vinorelbine, melphalan, cyclophospha nine, methotrexate, pentostatin, hydroxyurea, folic acid, a mide, an oxazaphosphorine, cisplatin, carboplatin, phleomycin, a bleomycin or a derivative or salt thereof, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, CHPP. BZPP, MTPP, BAPP, liblomycin, an acridine or a streptozocin, carmustine (BCNU), lomustine (CCNU), derivative thereof, a rifamycin, an actinomycin, adramycin, buSulfan, ifosfamide, Streptozocin, thiotepa, chlorambucil, irinotecan (camptosar), topotecan, an amsacrine or analogue mechlorethamine, thalidomide, its R- and S-enantiomers and thereof, a tricyclic carboxamide, SAHA, MD-275, trichosta its derivatives, revimid (CC-5013), an ethyleneimine com tin A, CBHA, LAQ824, valproic acid, paclitaxel (taxol), doc pound, an alkylsulphonate, daunorubicin, doxorubicin etaxel, taxotere, navelbine, vinblastin, Vincristin, vindesine, (adriamycin), liposomal doxorubicin (doxil), epirubicin, ida Vinorelbine, colchicine or a derivative thereof, maytansine, an rubicin, mitoxantrone, amsacrine, dactinomycin, distamycin ansamitocin, rhizoxin, phomopsin, dolastatin, an epipodo or a derivative thereof, netropsin, pibenZimol, mitomycin, phyllotoxin, etoposide, teniposide, a steganacin, combret CC-1065, a duocarmycin, mithramycin, chromomycin, astatin, amphetinile, procarbazine, bortezomib, asparagi olivomycin, a phtalanilide Such as propamidine or stilbami nase, pegylated asparaginase (pegaspargase),a thymidine dine, an anthramycin, an aziridine, a nitrosourea or a deriva phosphorylase inhibitor, estramustine (T-66), megestrol, tive thereof, a pyrimidine or purine analogue, cytarabine, flutamide, casodex, anandron, cyproterone acetate, amino 5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcit gluthetimide, anastroZole, formestan, letrozole leuprorelin, abine, capecitabine, mercaptopurine, cladribine, thiogua buserelin, goserelin, triptorelin, tamoxifen or its citrate salt, nine, methotrexate, pentostatin, hydroxyurea, folic acid, an droloxifene, trioxifene, raloxifene, Zindoxifene, ICI 164,384, acridine or a derivative thereof, a rifamycin, an actinomycin, ICI 182,780, aminoglutethimide, formestane, fadrozole, fin adramycin, irinotecan (camptosar), topotecan, an amsacrine asteride, ketoconazole, leuprolide, prednisone, prednisolone, or analogue thereof, a tricyclic carboxamide, SAHA, methylprednisolone, dexamethasone, budenoside, fluocor MD-275, trichostatin A, CBHA, LAQ824, valproic acid, tolone, triamcinolone, interferon 13, IL-10, IL-12, etaner bortezomib, vatalanib (PTK-787/ZK222584), SU-5416, cept, thalidomide, its R- and S-enantiomers and its deriva SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171 tives, revimid (CC-5013), a leukotrien antagonist, mitomycin CP-547632, CEP-7055, AG-013736, IM-842, GW-786034, C, an aziridoquinone, a 2-nitroimidazole, a nitroacridine, a BAY-43-9006, BAY-57-9006, gefitinib, erlotinib, CI-1033, nitroquinoline, a nitropyrazoloacridine, a "dual-function' GW-2016, iressa (ZD-1839), tarceva (OSI-774), PKI-166, US 2011/0171289 A1 Jul. 14, 2011 22

EKB-569, HKI-272, herceptin, 4-(3-chloro-4-fluoro-phe CP-547632, CEP-7055, AG-013736, IM-842, GW-786034, nyl)amino]-6-4-(homomorpholin-4-yl)-1-oxo-2-buten-1- gefitinib, erlotinib, CI-1033 GW-2016, iressa (ZD-1839), yl)amino-7-(S)-(tetrahydrofuran-3-yl)oxy-quinazoline or tarceva (OSI-774), PKI-166, EKB-569, HKI-272, herceptin, a pharmaceutically acceptable salt thereof, an inhibitor of the BAY-43-9006, BAY-57-9006, 4-(3-chloro-4-fluoro-phenyl) transcription factor complex ESX/DRIP130/Sur-2, heat aminol-6-4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl) shock protein HSP90 modulator geldanamycin and its deriva amino-7-(S)-(tetrahydrofuran-3-yl)oxy-quinazoline or a tive 17-allylaminogeldanamycin (17-AAG), atrasentan, rit pharmaceutically acceptable salt thereof, atrasentan, rituX uximab, cetuximab, AvastinTM (bevacizumab), IMC-1C11. imab, cetuximab, AvastinTM (bevacizumab), IMC-1C11. erbitux (C-225), DC-101, EMD-72000, vitaxin, imatinib, erbitux (C-225), DC-101, EMD-72000, vitaxin, imatinib, apolizumab and 1D09C3. VEGFtrap, melphalan, cyclophosphamide, an oxazaphos 9. The pharmaceutical combination preparation kit in phorine, cisplatin, carboplatin, oxaliplatin, satraplatin, tetra accordance with claim 8, wherein the formulation of the platin, iproplatin, mitomycin, streptozocin, carmustine selected protein tyrosine kinase receptor antagonist is for oral (BCNU), lomustine (CCNU), busulfan, ifosfamide, strepto administration. Zocin, thiotepa, chlorambucil, mechlorethamine, an ethylene 10. A method of treating cancer diseases, which method imine compound, an alkylsulphonate, daunorubicin, doxoru comprises simultaneous, separate or sequential administra bicin (adriamycin), liposomal doxorubicin (doxil), tion of effective amounts of: epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomy (i) (Z)-3-(1-(4-(N-(4-methyl-piperazin-1-yl)-methylcar cin, distamycin or a derivative thereof, netropsin, pibenZimol, bonyl)-N-methyl-amino)-anilino)-1-phenyl-methyl mitomycin, CC-1065, a duocarmycin, mithramycin, chromo ene-6-methoxycarbonyl-2-indolinone, or a pharma mycin, olivomycin, propamidine, stilbamidine, an anthramy ceutically acceptable salt thereof; and cin, an aziridine, a nitrosourea or a derivative thereof, cytara (ii) at least a further chemotherapeutic or naturally occur bine, 5-fluorouracile (5-FU), uracil mustard, fludarabine, ring, semi-synthetic or synthetic therapeutic agent gemcitabine, capecitabine, mercaptopurine, cladribine, selected from thioguanine, methotrexate, pentostatin, hydroxyurea, folic synthetic small molecule VEGF receptor antagonists, small acid, a phleomycin, a bleomycin or a derivative or salt thereof, molecule growth factor receptor antagonists, inhibitors of the CHPP. BZPP, MTPP, BAPP, liblomycin, an acridine or a EGF receptor, excluding 4-(3-chloro-4-fluorophenyl) derivative thereof, a rifamycin, an actinomycin, adramycin, amino-6-4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl) irinotecan (camptosar), topotecan, an amsacrine or analogue amino-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, and/or thereof, a tricyclic carboxamide, SAHA, MD-275, trichosta VEGF receptor and/or integrin receptors or any other protein tin A, CBHA, LAQ824, valproic acid, paclitaxel (taxol), doc tyrosine kinase receptors which are not classified under the etaxel, taxotere, navelbine, vinblastin, Vincristin, Vindesine, synthetic small-molecules, inhibitors directed to EGF recep Vinorelbine, colchicine or a derivative thereof, maytansine, an tor and/or VEGF receptor and/or integrin receptors or any ansamitocin, rhizoxin, phomopsin, dolastatin, an epipodo other protein tyrosine kinase receptors, which are fusion pro phyllotoxin, etoposide, teniposide, a steganacin, combret teins, compounds which interact with nucleic acids and which astatin, amphetinile, procarbazine, bortezomib, asparagi are classified as alkylating agents or platinum compounds, nase, pegylated asparaginase (pegaspargase), a thymidine compounds which interact with nucleic acids and which are phosphorylase inhibitor, estramustine (T-66), megestrol, classified as anthracyclines, as DNA intercalators or as DNA flutamide, casodex, anandron, cyproterone acetate, amino cross-linking agents, DNA minor-groove binding com gluthetimide, anastroZole, formestan, letrozole leuprorelin, pounds, anti-metabolites, naturally occurring, semi-synthetic buserelin, goserelin, triptorelin, tamoxifen or its citrate salt, or synthetic bleomycin type antibiotics, inhibitors of DNA droloxifene, trioxifene, raloxifene, Zindoxifene, ICI 164,384, transcribing enzymes selected from topoisomerase I and ICI 182,780, aminoglutethimide, formestane, fadrozole, fin topoisomerase II inhibitors, chromatin modifying agents, asteride, ketoconazole, leuprolide, prednisone, prednisolone, mitosis inhibitors, anti-mitotic agents, cell-cycle inhibitors, methylprednisolone, dexamethasone, budenoside, fluocor proteasome inhibitors, enzymes, hormones, hormone antago tolone, triamcinolone, interferon B, IL-10, IL-12, etanercept, nists, hormone inhibitors, inhibitors of steroid biosynthesis, thalidomide, its R- and S-enantiomers and its derivatives, steroids, cytokines, hypoxia-selective cytotoxins, inhibitors revimid (CC-5013), a leukotrien antagonist, mitomycin C, an of cytokines, lymphokines, antibodies directed against cytok aziridoquinone, a 2-nitroimidazole, a nitroacridine, a nitro ines, oral and parenteral tolerance induction agents, Support quinoline, a nitropyrazoloacridine, a "dual-function’ nitro ive agents, chemical radiation sensitizers and protectors, aromatic, a nitro aromatic deactivated mustard, a N-oxide of photo-chemically activated drugs, synthetic poly- or oligo a nitrogen mustard, a metal complex of a nitrogen mustard, an nucleotides optionally modified or conjugated, non-steroidal anti-CD3 antibody, an anti-CD25 antibody, a tolerance induc anti-inflammatory drugs, cytotoxic antibiotics, antibodies tion agent, minodronic acid or a derivative thereof selected targeting the Surface molecules of cancer cells, inhibitors of from YM-529, Ono-5920 and YH-529, Zoledronic acid metalloproteinases, metals, inhibitors of oncogenes, inhibi monohydrate, ibandronate sodium hydrate, clodronate diso tors of gene transcription or of RNA translation or protein dium, metronidazole, misonidazole, benznidazole, nimora expression, complexes of rare earth elements, and photo Zole, RSU-1069, SR-4233, bromodeoxyuridine, iododeox chemotherapeutic agents; yuridine, WR-2721, porfimer, photofrin, a benzoporphyrin in the form of a combined preparation optionally adapted derivative, a pheophorbide derivative, merocyanin 540 (MC for a co-treatment with radiotherapy or radio-immuno 540), tin etioporpurin, oblimersen, a non-steroidal anti-in therapy. flammatory drug selected from acetylsalicyclic acid, 11. The method in accordance with claim 10, wherein (ii) is mesalazin, ibuprofen, naproxen, flurbiprofen, fenoprofen, selected from vatalanib (PTK-787/ZK222584), SU-5416, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171 oxaprozin, pranoprofen, miroprofen, tioxaprofen, Suprofen, US 2011/0171289 A1 Jul. 14, 2011

alminoprofen, tiaprofenic acid, fluprofen, indomethacin, SAHA, MD-275, trichostatin A, CBHA, LAQ824, valproic Sulindac, tolmetin, Zomepirac, nabumetone, diclofenac, fen acid, bortezomib, vatalanib (PTK-787/ZK222584), clofenac, alclofenac, bromfenac, ibufenac, aceclofenac, SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, acemetacin, fentiazac, clidanac, etodolac, oXpinac, mefe AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842, namic acid, meclofenamic acid, flufenamic acid, nifluminic GW-786034, BAY-43-9006, BAY-57-9006, gefitinib, erlo acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, tinib, CI-1033, GW-2016, iressa (ZD-1839), tarceva (OSI tenoxicam, lornoxicam, nimeSulide, meloxicam, celecoxib 774), PKI-166, EKB-569, HKI-272, herceptin, 4-(3-chloro and rofecoxib, or a pharmaceutically acceptable salt of a 4-fluoro-phenyl)amino]-6-4-(homomorpholin-4-yl)-1- non-steroidal anti-inflammatory drug, a cytotoxic antibiotic, oxo-2-buten-1-yl)amino-7-(S)-(tetrahydrofuran-3-yl) apolizumab, 1 D09C3, TIMP-1, TIMP-2, Zinc, P53, Rb, an oxy-quinazoline or a pharmaceutically acceptable salt heterocyclic complex of a lanthanide, PUVA, an inhibitor of thereof, an inhibitor of the transcription factor complex ESX/ the transcription factor complex ESX/DRIP130/Sur-2, DRIP130/Sur-2, heat shock protein HSP90 modulator geldanamycin or its derivative 17-allylaminogeldanamycin geldanamycin and its derivative 17-allylaminogeldanamycin (17-AAG), IM-842, tetrathiomolybdate, squalamine, combr (17-AAG), atrasentan, rituximab, cetuximab, AvastinTM (be estatin A4, TNP-470, marimastat, neovastat, bicalutamide, vacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD abarelix, oregovomab, mitumomab, TLK-286, alemtuzumab, 72000, vitaxin, imatinib, apolizumab and 1D09C3. ibritumomab, temozolomide, denileukin diftitox, aldesleu 13. The method in accordance with any one of claims 10 to kin, dacarbazine, floxuridine, plicamycin, mitotane, pipobro 12, characterised in that (i) is the monoethanesulfonate salt of man, plicamycin, tamloxifen and testolactone. 3-Z-1-(4-(N-(4-methyl-piperazin-1-yl)-methylcarbonyl)- 12. The method in accordance with claim 10, wherein (ii) is N-methyl-amino)-anilino)-1-phenyl-methylene-6-meth selected from paclitaxel (taxol), docetaxel, taxotere, navel oxycarbonyl-2-indolinone. bine, vinblastin, Vincristin, Vindesine, Vinorelbine, mel 14. The method in accordance with claim 10, wherein the phalan, cyclophosphamide, an oxazaphosphorine, cisplatin, formulation of (i) is for oral administration. carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, 15. The method in accordance with claim 10, characterised mitomycin, streptozocin, carmustine (BCNU), lomustine in that (i) is administered in a daily dosage Such that the (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, plasma level of the active substance lies between 10 and 500 chlorambucil, mechlorethamine, thalidomide, its R- and ng/ml for at least 12 hours of a 24 hours dosing interval. S-enantiomers and its derivatives, revimid (CC-5013), an 16. The method in accordance with claim 10, wherein the ethyleneimine compound, an alkylsulphonate, daunorubicin, cancer disease is selected from prostate cancer, renal cell doxorubicin (adriamycin), liposomal doxorubicin (doxil), cancers, bladder cancers, ovarian cancers, cervical cancers, epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomy endometrial cancers, lung cancer, colorectal cancers, pancre cin, distamycin or a derivative thereof, netropsin, pibenZimol, atic cancer, gastric cancer, oesophageal cancers, hepatocellu mitomycin, CC-1065, a duocarmycin, mithramycin, chromo lar cancers, cholangiocellular cancers, head and neck cancer, mycin, olivomycin, a phtalanilide Such as propamidine or malignant mesothelioma, breast cancer, malignant melanoma stilbamidine, an anthramycin, an aziridine, a nitrosourea or a or bone and Soft tissue sarcomas, multiple myeloma, acute derivative thereof, a pyrimidine or purine analogue, cytara myelogenous leukemia, chronic myelogenous leukemia, bine, 5-fluorouracile (5-FU), uracil mustard, fludarabine, myelodysplastic syndrome and acute lymphoblastic leuke gemcitabine, capecitabine, mercaptopurine, cladribine, 18. thioguanine, methotrexate, pentostatin, hydroxyurea, folic 17. The method in accordance with claim 16, wherein the acid, an acridine or a derivative thereof, a rifamycin, an acti cancer disease is selected from colorectal cancers. nomycin, adramycin, irinotecan (camptosar), topotecan, an amsacrine or analogue thereof, a tricyclic carboxamide, c c c c c