US20050043233A1 - Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis - Google Patents

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

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US20050043233A1
US20050043233A1 US10/830,147 US83014704A US2005043233A1 US 20050043233 A1 US20050043233 A1 US 20050043233A1 US 83014704 A US83014704 A US 83014704A US 2005043233 A1 US2005043233 A1 US 2005043233A1
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antagonist
phenyl
amino
indolinone
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Martin Stefanic
Frank Hilberg
Gerd Munzert
Flavio Solca
Anke Baum
Jacobus Van Meel
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Boehringer Ingelheim International GmbH
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Priority claimed from EP03009587A external-priority patent/EP1473043A1/en
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Priority to US10/830,147 priority Critical patent/US20050043233A1/en
Assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH reassignment BOEHRINGER INGELHEIM INTERNATIONAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BAUM, ANKE, VAN MEEL, JACOBUS, MUNZERT, GERD, STEFANIC, MARTIN F., HILBERG, FRANK, SOLCA, FLAVIO
Publication of US20050043233A1 publication Critical patent/US20050043233A1/en
Priority to US12/140,661 priority patent/US7846936B2/en
Priority to US12/912,090 priority patent/US20110039863A1/en
Priority to US12/912,110 priority patent/US20110171289A1/en
Priority to US12/912,098 priority patent/US20110136826A1/en
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Definitions

  • This invention relates to a method for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis, which method comprises co-administration to a person in need of such treatment and/or co-treatment of a person in need of such treatment with effective amounts of:
  • EGF epidermal growth factor
  • VEGF vascular endothelial growth factor
  • Inhibitors of the receptors have thus been and are still evaluated for cancer therapy (see for example the article of Cerrington et al. In Advances in Cancer Research, Academic Press 2000, pp. 1-38).
  • WO 02/070008 suggests the combination of an antagonist specifically directed against the VEGF receptor with an antagonist specifically directed against the EGF receptor, optionally together with radiation or a chemotherapeutic agent, for the inhibition of tumour growth.
  • WO 02/070008 discloses monoclonal antibodies directed against the VEGF receptor and monoclonal antibodies directed against the EGF receptor.
  • angiogenesis inhibitor which has already been clinically tested, also in conjunction with chemotherapy, namely the inhibitor with code name SU5416, developed by Pharmacia for the treatment of cancer, was associated with disturbing side effect, namely thromboembolic events (Ken Garber and Ann Arbor, Nature Biotechnology, Vol. 20, pp. 1067-1068, November 2002).
  • chemotherapeutic agents For the treatment of diseases of oncological nature, a large number of chemotherapeutic agents have already been suggested, which can be used as mono-therapy (treatment with one agent) or as combination therapy (simultaneous, separate or sequential treatment with more than one agent) and/or which may be combined with radiotherapy or radio-immunotherapy.
  • chemotherapeutic agent means a naturally occurring, semi-synthetic or synthetic chemical compound which, alone or via further activation, for example with radiations in the case of radio-immunotherapy, inhibits or kills growing cells, and which can be used or is approved for use in the treatment of diseases of oncological nature, which are commonly also denominated as cancers.
  • these agents are generally classified according to their mechanism of action. In this matter, reference can be made, for example, to the classification made in “Cancer Chemotherapeutic Agents”, American Chemical Society, 1995, W. O. Foye Ed.
  • chemotherapeutic agents are especially of interest, although not representing a limitation:
  • These diseases may as well be of oncological nature, which includes all types of malignant neoplasias or cancers, or of non-oncological nature, such as diabetic retinopathy, rheumatoid arthritis or psoriasis.
  • the selected protein tyrosine kinase receptor antagonist is an antagonist of at least one receptor selected from VEGFR1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit.
  • the selected protein tyrosine kinase receptor antagonist is an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, and further an antagonist of a src tyrosine kinase family member, and especially of src, lck, lyn and fyn, and/or further an antagonist of at least one complex of a cyclin dependent kinase with its specific cyclin or with a viral cyclin, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K, and/or further an inhibitor of the paracrine IL-6 secretion.
  • the diseases which can be treated by the combination in accordance with the present invention are all kind of diseases in which cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis are involved, which can be of oncological nature such as all types of malignant neoplasias or cancers, or of non-oncological nature, such as diabetic retinopathy, rheumatoid arthritis, or psoriasis.
  • the combination treatment in accordance with the present invention is especially efficient for inhibiting tumour growth, survival and metastasis.
  • combination treatment in accordance with the present invention is especially efficient with selected active substances, selected dosages and selected dosage forms.
  • the present invention provides a method for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis, which method comprises simultaneous, separate or sequential co-administration of effective amounts of:
  • the present invention provides also a method for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis, which method comprises a simultaneous, separate or sequential co-treatment with an effective amount of an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is further an antagonist of a src tyrosine kinase family member, or with a polymorph, metabolite or pharmaceutically acceptable salt thereof, and with radiotherapy or radio-immunotherapy.
  • an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is further an antagonist of a src tyrosine kinase family member, or with a polymorph, metabol
  • the protein tyrosine kinase receptor antagonist used in the method in accordance with the present invention is preferably an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR, c-Kit, and further an antagonist of a src-tyrosine kinase family member, and especially of src, lck, lyn or fyn.
  • the protein tyrosine kinase receptor antagonist may further be an antagonist of at least one complex of a cyclin dependent kinase with its specific cyclin or with a viral cyclin, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K, and/or further an inhibitor of the paracrine IL-6 secretion.
  • a cyclin dependent kinase with its specific cyclin or with a viral cyclin, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K, and/or further an inhibitor of the paracrine IL-6 secretion.
  • the protein tyrosine kinase receptor antagonist is selected from specific compounds.
  • Preferred chemotherapeutic agents are selected from the following groups: synthetic small molecule VEGF receptor antagonists, small molecule growth factor (GF) receptor antagonists, inhibitors of the EGF receptor and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors which are not classified under the synthetic small-molecules, inhibitors directed to EGF receptor and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors, which are fusion proteins, compounds which interact with nucleic acids and which are classified as alkylating agents or platinum compounds, compounds which interact with nucleic acids and which are classified as anthracyclines, as DNA intercalators (including DNA minor-groove binding compounds) or as DNA cross-linking agents, anti-metabolites, naturally occurring, semi-synthetic or synthetic bleomycin type antibiotics (BLM-group antibiotics), inhibitors of DNA transcribing enzymes, and especially the topoisomerase I or topo
  • the disease treated in the method in accordance with the present invention is preferably an oncological disease.
  • the disease is selected from solid tumours, such as urogenital cancers (such as prostate cancer, renal cell cancers, bladder cancers), gynecological cancers (such as ovarian cancers, cervical cancers, endometrial cancers), lung cancer, gastrointestinal cancers (such as colorectal cancers, pancreatic cancer, gastric cancer, oesophageal cancers, hepatocellular cancers, cholangiocellular cancers), head and neck cancer, malignant mesothelioma, breast cancer, malignant melanoma or bone and soft tissue sarcomas, and haematologic neoplasias, such as multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome and acute lymphoblastic leukemia.
  • the disease is hormone sensitive
  • the disease treated in the method in accordance with the present invention is preferably a non-oncological disease selected from diabetic retinopathy, rheumatoid arthritis or psoriasis.
  • the beneficial efficacy of the methods in accordance with the invention are mainly based on the additive and synergistic effects of the combined treatment, or to an improved tolerability of the treatment by the patient due, for example, to the administration of lower doses of the therapeutic agents involved.
  • the unexpected advantages mentioned above may also be due to a more efficient apoptosis induction by the chemotherapeutic agent, once the constitutively active survival signal of the protein tyrosin kinase receptor, mediated by the tumour, is inhibited by the selected protein tyrosine kinase receptor antagonist.
  • VEGF vascular endothelial growth factors
  • bFGF basic fibroblast growth factor
  • IL-6 interleukin-6
  • IL-8 interleukin-8
  • EGF epidermal growth factor
  • PDGF platelet-derived growth factor
  • a further advantage is that an induction or reinstatement of the sensitivity towards the chemotherapeutic agent is expected in patients treated with the combination of chemotherapeutic agents for which the sensitivity gets lost in the course of the treatment and of a VEGFR antagonist. This is especially the case of patients suffering from refractory multiple myeloma and treated with steroids as chemotherapeutic agent.
  • a combination treatment with steroids and a VEGFR antagonist is expected to restore the steroid sensitivity of patients suffering from refractory multiple myeloma.
  • a synergistic combined preparation is meant to comprise an amount of the selected protein tyrosine kinase receptor antagonist, or of a polymorph, metabolite or pharmaceutically acceptable salt of this active compound, and an amount of the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent, and/or radiotherapy or radio-immunotherapy, wherein the amount of the individual therapeutic agents alone is insufficient to achieve the therapeutic effect achieved by the administration of the combination of said therapeutic agents, and wherein the combined effects of the amounts of the therapeutic agents is greater than the sum of the therapeutic effects achievable with the amounts of the individual therapeutic agents.
  • the present invention also relates to a pharmaceutical combination for the treatment of diseases in which cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis are involved, comprising a selected specific protein tyrosine kinase receptor antagonist and a further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent, and/or radiotherapy or radio-immunotherapy, as a combined preparation for simultaneous, separate or sequential use in treatment of said diseases, optionally together with one or more pharmaceutically acceptable diluents and/or carriers.
  • the present invention also relates to a pharmaceutical combination preparation kit for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis, comprising a therapeutically effective amount of a selected protein tyrosine kinase receptor antagonist, or of a polymorph, metabolite or pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent, characterised in that the protein tyrosine kinase receptor antagonist is comprised within a first compartment and the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent is comprised within a second compartment, such that the administration to a patient in need thereof can be simultaneous, separate or sequential, said combination preparation kit being optionally further adapted for a co-treatment with radiotherapy or radio-immunotherapy.
  • each active substance in each compartment of the pharmaceutical combination preparation kit, is formulated for an oral administration.
  • effective amounts of therapeutic agents and/or of a therapeutic treatment by radiotherapy or radio-immunotherapy means amounts of the agents and/or of the treatment by radiotherapy or radio-immunotherapy which are effective to achieve a therapeutic effect when used in combination.
  • the diseases which can be treated by the combination in accordance with the present invention are all kind of diseases in which cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis are involved, which can be of oncological nature such as all types of malignant neoplasias or cancers, or of non-oncological nature, such as diabetic retinopathy, rheumatoid arthritis, or psoriasis.
  • selected specific target indications are solid tumours, such as urogenital cancers (such as prostate cancer, renal cell cancers, bladder cancers), gynecological cancers (such as ovarian cancers, cervical cancers, endometrial cancers), lung cancer, gastrointestinal cancers (such as colorectal cancers, pancreatic cancer, gastric cancer, oesophageal cancers, hepatocellular cancers, cholangiocellular cancers), head and neck cancer, malignant mesothelioma, breast cancer, malignant melanoma or bone and soft tissue sarcomas, and haematologic neoplasias, such as multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome and acute lymphoblastic leukemia.
  • urogenital cancers such as prostate cancer, renal cell cancers, bladder cancers
  • gynecological cancers such as ovarian cancers, cervical
  • the combination treatment in accordance with the present invention is especially efficient for inhibiting tumour growth, survival and metastasis.
  • the selected protein tyrosine kinase receptor antagonists that can be used in the context of the present invention include all substances that inhibit the stimulation or activation of a protein tyrosine kinase receptor by a protein tyrosine kinase receptor ligand.
  • a protein tyrosine kinase receptor belonging to the family of the growth factor receptors such inhibition of stimulation or activation inhibits the growth of cells that express the receptor.
  • growth factor receptors involved in tumorigenesis are the receptors for epidermal growth factor (EGFR), vascular endothelial growth factors (VEGFRs), platelet-derived growth factor (PDGFR), insulin-like growth factor (IGFR), nerve growth factor (NGFR), and fibroblast growth factor (FGFR).
  • EGFR epidermal growth factor
  • VEGFRs vascular endothelial growth factors
  • PDGFR platelet-derived growth factor
  • IGFR insulin-like growth factor
  • NGFR nerve growth factor
  • FGFR fibroblast growth factor
  • inhibition of stimulation or activation of protein tyrosine kinase receptor is meant any decrease in the activation of the receptor, which need not completely prevent or stop activation of the receptor.
  • Increased protein tyrosine kinase receptor stimulation or activation can result from higher levels of ligand, receptor gene amplification, increased transcription of the receptor or mutations that cause unregulated receptor signalling. Amplification of the gene encoding the receptor results in an increased number of ligands binding to the receptor, which can further stimulate cell proliferation.
  • the protein tyrosine kinase receptor may also be over-expressed in the absence of gene amplification, presumably through mutations that increase its transcription, mRNA translation, or stability of the protein.
  • Protein tyrosine kinase receptor mutants of the EGFR type have already been identified in gliomas, non-small cell lung carcinomas, ovarian carcinomas and prostate carcinomas, that have a constitutively active protein tyrosin kinase, suggesting a role for high-level EGFR activity rather than EGFR over-expression in these cancers (see for example Pedersen et al., Ann. Oncol., Vol. 12(6), pp. 745-60, 2001).
  • the selected protein tyrosine kinase receptor antagonist inhibits the binding of the protein tyrosine kinase receptor to its ligand.
  • Binding of a ligand to an external, extracellular domain of the receptor stimulates receptor dimerization, autophosphorylation of the receptor, activation of the receptor's internal, cytoplasmic protein tyrosin kinase domain, and initiation of multiple signal transduction pathways involved in regulation of DNA synthesis, cell division, vasculogenesis or angiogenesis.
  • the inhibition produced by the presence of the antagonist will consequently reduce this stimulation.
  • the selected protein tyrosine kinase receptor antagonist binds directly to the receptor.
  • the antagonist can bind externally to the extra-cellular portion of the receptor, which may or may not inhibit binding of the ligand, or internally to the protein tyrosine kinase domain.
  • Examples of such antagonists include, without limitation, biological molecules, such as antibodies (and functional equivalents thereof) specific for the receptor, and synthetic kinase inhibitors that act directly on the cytoplasmic domain of the receptor, such as the so-called “small molecule tyrosine kinase inhibitors”.
  • Additional protein tyrosine kinase receptor antagonists can easily be determined using well-known methods.
  • the selected receptor antagonists to be used in the present invention inhibit the protein tyrosin kinase activity of the receptor, which generally involves phosphorylation events. Accordingly, phosphorylation assays may for example be useful in determining antagonists useful in the context of the present invention.
  • methods specific for detection of the receptor expression can be utilized. These include immunohistochemistry for detection of protein expression, fluorescence in situ hybridization for detection of gene amplification, competitive radioligand binding assays, solid matrix blotting techniques, such as Northern and Southern blots, reverse transcriptase polymerase chain reaction and ELISA.
  • the selected protein tyrosine kinase receptor antagonist is preferably an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1,2 and 3, EGFR, HER2, IGF1R, HGFR, c-Kit, and further an antagonist of one of the src-tyrosine kinase family members, and especially src, lck, lyn or fyn, or a polymorph, metabolite or pharmaceutically acceptable salt thereof.
  • the selected protein tyrosine kinase receptor antagonist may further be an antagonist of at least one complex of a cyclin dependent kinase with its specific cyclin or with a viral cyclin, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K, and/or further an inhibitor of the paracrine IL-6 secretion.
  • a cyclin dependent kinase with its specific cyclin or with a viral cyclin, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K, and/or further an inhibitor of the paracrine IL-6 secretion.
  • the combination of the active substances is intended for the treatment of oncological diseases involving angiogenesis.
  • Tumour angiogenesis plays an important role in the progression of human malignancies. Inhibition of this process is thought to be an excellent point of therapeutic intervention in the treatment of cancer. Signal transduction through the vascular endothelial growth factor receptor 2 (VEGFR-2) has been shown to play a pivotal role in the proliferation, survival and migration of endothelial cells in tumour angiogenesis.
  • VEGFR-2 vascular endothelial growth factor receptor 2
  • VEGFR-2 potent and orally available low molecular weight antagonists of VEGFR-2 have been developed as new compounds which are useful for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis, and especially as new cancer therapeutic agents. These antagonists are thus inhibitors of the activity of the receptor. Some of these antagonists are also antagonists of further growth factor receptors, such as VEGFR-3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR, c-Kit, and some also antagonists of the src-tyrosine kinase family members src, lck, lyn and fyn.
  • the following compounds are particularly representative and are all combined inhibitors of VEGFR-2 and lck which may be used as the selected protein tyrosine kinase receptor antagonist within the meaning of the present invention.
  • VEGFR 1 to 3 PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR and c-Kit
  • src tyrosine kinase family members and especially of src, lck, lyn and fyn
  • further an antagonist of the complex of cyclin dependent kinases with their specific cyclins or with a viral cyclin and further an inhibitor of the paracrine IL-6 secretion, disclosed, for example, in WO 01/27081, as exemplified compound number 473, as well as its polymorphs, metabolites or pharmaceutically acceptable salts.
  • This compound referred to as (T) in the above list, is 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone.
  • this compound is further particularly preferred due to its high potency as inhibitor and its better toxicologic profile.
  • the monoethanesulfonate salt of this compound namely the monoethanesulfonate salt of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, disclosed for example in unpublished German patent application DE 102 33 500.1, unpublished PCT/03/07822 and unpublished U.S. patent application Ser. No. 10/623,971.
  • the monoethanesulfonate salt of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone has the following chemical structure:
  • This compound may be selectively obtained by a suitable choice of manufacturing conditions, preferably in its crystalline hemihydrate form.
  • the starting material used to prepare the monoethanesulfonate salt of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone may be the free base.
  • 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone is prepared as follows.
  • the monoethanesulfonate salt of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone can be very easily dissolved in physiologically acceptable solubilization agents.
  • the compound MES(T) is orally bioavailable in mice.
  • FGFR-1 and PDGFR ⁇ two members of the split kinase domain family of receptors important in angiogenic signaling, are additionally inhibited by this compound with IC 50 's of 69 nM and 59 nM respectively.
  • the compound MES(T) is thus highly selective when tested against a panel of numerous different kinases, as shown in the following Table I.
  • this antagonist is particularly suitable for a sequential co-administration and/or co-treatment with another chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent, and/or radiotherapy or radio-immunotherapy.
  • the scheduled treatment regimen with this antagonist may be, for example, an alternate treatment one day on/one day off, one day on/two days off, one week on/one week off, or even two weeks on/two weeks off.
  • the monoethanesulfonate salt of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone is thus clearly a potent and orally available VEGFR-2 kinase inhibitor and anti-tumour agent.
  • all the above-exemplified compounds, and especially the compound (T) and its monoethanesulfonate salt MES(T), may also be used as mono-therapy for the treatment of the above-mentioned diseases, namely all kind of diseases in which cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis are involved, which can be of oncological nature such as all types of malignant neoplasias or cancers, or of non-oncological nature, such as diabetic retinopathy, rheumatoid arthritis, or psoriasis.
  • diseases namely all kind of diseases in which cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis are involved, which can be of oncological nature such as all types of malignant neoplasias or cancers, or of non-oncological nature, such as diabetic retinopathy, rheumatoid arthritis, or psorias
  • selected specific target indications for a mono-therapeutic treatment are solid tumours, such as urogenital cancers (such as prostate cancer, renal cell cancers, bladder cancers), gynecological cancers (such as ovarian cancers, cervical cancers, endometrial cancers), lung cancer, gastrointestinal cancers (such as colorectal cancers, pancreatic cancer, gastric cancer, oesophageal cancers, hepatocellular cancers, cholangiocellular cancers), head and neck cancer, malignant mesothelioma, breast cancer, malignant melanoma or bone and soft tissue sarcomas, and haematologic neoplasias, such as multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome and acute lymphoblastic leukemia.
  • urogenital cancers such as prostate cancer, renal cell cancers, bladder cancers
  • gynecological cancers such
  • This compound may preferably be selected from the following classes and examples of compounds, although this list is not to be considered as limitative.
  • Synthetic small molecule VEGF receptor antagonists of particular interest are the antagonists of the VEGF receptor of type 2, which are as well antagonists of the basic fibroblast growth factor (bFGF) and of the platelet derived growth factor (PDGF) receptors.
  • Representative compounds are, for example, indolinone derivatives, such as those described in WO 02/36564, WO 99/52869, WO 00/18734, WO 00/73297, WO 01/27080, WO 01/27081 and WO 01/32651.
  • VEGF receptor antagonists are the compounds described in WO 01/60814, WO 99/48868, WO 98/35958, and especially the compounds vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 (a dipeptide of L-Glutamyl and L-Tryptophan) or GW-786034.
  • Representative compounds which are only EGFR antagonists are, for example, iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272 and herceptin.
  • Representative compounds which are antagonists of the mitogen-activated protein kinase (MAPK) are BAY-43-9006 (a Raf protein kinase family inhibitor) and BAY-57-9006 (a Kdr tyrosine kinase inhibitor).
  • a preferred compound in this class is the quinazoline derivative disclosed in WO 02/50043 as exemplified compound of Example 1(10), namely 4-[(3-chloro-4-fluorophenyl)amino]-6- ⁇ [4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino ⁇ -7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, or the tautomers, the stereoisomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases.
  • the di-maleic acid salt of this compound which can easily be obtained in accordance with the following procedure.
  • a further preferred compound in this class is the 4-[(3-chloro-4-fluoro-phenyl)amino]-6- ⁇ [4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino ⁇ -7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, or the salts thereof.
  • the chemical structural formula of this compound is
  • This compound may be obtained in three steps using the following manufacturing conditions.
  • the suspension is cooled in the ice bath, stirred for one hour and suction filtered.
  • the filter cake is washed again with 240 ml of N,N-dimethylformamide/water (1:2) and 240 ml of diisopropylether and dried at 40° C. in the circulating air dryer.
  • the solution of the above-obtained homomorpholin-4-yl-acetaldehyde hydrochloride (staring compound II) is then added drop wise within 5 min at a temperature of 0° C. After the addition has ended the reaction mixture is stirred for another 10 min at 0° C. and for a further hour at ambient temperature. For working up 100 ml of ethyl 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 evaporated down. The crude product is purified by chromatography 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.
  • Inhibitors of the EGF receptor and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors which are not classified under the synthetic small-molecules, which are of special interest, are the monoclonal antibodies directed to EGF receptor and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors.
  • Representative compounds are, for example, atrasentan (integrin antagonist), rituximab, cetuximab, AvastinTM (bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000 (humanized EGF receptor-specific monoclonal antibody), vitaxin (antibody directed against the ⁇ , ⁇ 3 integrin), and imatinib (c-Kit inhibitor).
  • Monoclonal antibodies which can specifically recognize their antigen epitopes on the relevant receptors, are in this respect of further special interest. The use of such antibodies, which were successful in vitro and in animal models, have not shown satisfying efficacy in patients as mono-drug therapy.
  • tumours if some specific sites are blocked, may use other cell surface molecules to compensate for said original blocking. Thus, tumours do not really shrink during various anti-angiogenic or anti-proliferative therapies.
  • combination therapies were in this case already proposed to circumvent this problem using, for example, monoclonal antibodies together with specific cytotoxic or chemotherapeutic agents or in combination with radiotherapy or radio-immunotherapy. Indeed, clinical trials have shown that these combination therapies are more efficient than the corresponding mono-administrations.
  • a representative compound of this class is, for example, the compound with name VEGFtrap, developed by the pharmaceutical companies Regeneron and Aventis.
  • Compounds which interact with nucleic acids and which are classified as anthracyclines, as DNA intercalators (including DNA minor-groove binding compounds) or as DNA cross-linking agents are also of interest for the treatment of diseases of oncological nature.
  • Representative classes and examples of compounds are daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin and derivatives, netropsin, pibenzimol, mitomycin, CC-1065 ( Streptomyces zelensis fermentation product), duocarmycins, mithramycin, chromomycin, olivomycin, phtalanilides (propamidine, stilbamidine), anthramycins, aziridines or nitrosoureas and their derivatives.
  • Representative classes of anti-metabolites of interest are the pyrimidine and purine analogues or antagonists such as fluoropyrimidines and thiopurines, or inhibitors of the nucleoside diphosphate reductase.
  • Representative compounds are, for example, cytarabine, 5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin, hydroxyurea, or folic acid.
  • Representative classes and compounds of interest are the phleomycins, bleomycins, bleomycin derivatives and salts, CHPP, BZPP, MTPP, BAPP, liblomycin. These agents are believed to mediate their therapeutic effects via degradation of chromosomal DNA or RNA degradation (especially selective tRNA strand scission).
  • a representative class and examples of compounds of interest are the acridines and acridine derivatives, rifamycins, actinomycins, adramycin, camptothecins (irinotecan or camptosar, topotecan), amsacrines and analogues, and the tricyclic carboxamides.
  • a representative class of compounds of interest are the histonedeacetylase inhibitors, such as SAHA (suberoylanilide hydroxamic acid), MD-275, trichostatin A, CBHA (M-carboxycinnamic acid bishydroxamide), LAQ824, or valproic acid.
  • SAHA suberoylanilide hydroxamic acid
  • MD-275 trichostatin A
  • CBHA M-carboxycinnamic acid bishydroxamide
  • LAQ824 valproic acid
  • Mitosis Inhibitors Anti-Mitotic Agents, or Cell-Cycle Inhibitors
  • Representative classes and examples of compounds 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 vinorelbine), the tropolone alkaloids (colchicine and derivatives), the macrolides (maytansine, ansamitocins, rhizoxin), the antimitotic peptides (phomopsin, dolastatin), the epipodophyllotoxins or the derivatives of podophyllotoxin (etoposide, teniposide), the steganacins and the antimitotic carbamate derivatives (combretastatin, amphetinile), or procarbazine.
  • These compounds are cdk inhibitors, tubulin binders or inhibitors of the polo-like kinase.
  • a representative compound of interest belonging to this class is, for example, VelcadeTM (bortezomib or PS-341).
  • Representative compounds and classes of interest are, for example, asparaginase, pegylated asparaginase (pegaspargase), and the thymidine-phosphorylase inhibitors.
  • Hormones Hormones, Hormone Antagonists or Hormone Inhibitors, or Inhibitors of Steroid Biosynthesis
  • hormones of interest are, for example, the gestagens and estrogens, such as estramustine or T-66, or megestrol.
  • hormone antagonists or inhibitors of interest are, for example, the anti-androgens, such as flutamide, casodex, anandron and cyproterone acetate, the aromatase inhibitors, such as amonogluthetimide, anastrozole, formestan and letrozole, the GNrH analogues, such as leuprorelin, buserelin, goserelin and triptorelin, the anti-estrogens, such as tamoxifen and especially its citrate salt, droloxifene, trioxifene, raloxifene, zindoxifene, the derivatives of 17 ⁇ -estradiol (ICI 164,384 and ICI 182,780), aminoglutethimide, formestane, fadrozole, fina
  • Representative compounds of interest are, for example, prednisone, prednisolone, methylprednisolone, dexamethasone, budenoside, fluocortolone and triamcinolone.
  • steroids are in first line used to control the symptoms.
  • brain metastasis they belong to the standard therapy for reducing oedema. They are also used to control the inflammation which surrounds the tumor lesions.
  • ALL haematologic malignant neoplasias of lymphatic cell lines
  • steroids are used as a real anti-tumor therapy, alone or in combination with classical chemotherapeutic agents.
  • suitable steroids for the combination treatment are meant to include in a non-limiting manner prednisone, prednisolone, methylprednisolone, dexamethasone, budenoside, fluocortolone and triamcinolone.
  • the preferred steroid is dexamethasone.
  • Cytokines Hypoxia-Selective Cytotoxins, Inhibitors Of Cytokines, Lymphokines, Antibodies Directed against Cytokines or Oral and Parenteral Tolerance Induction Agents
  • Interferons especially interferon ⁇
  • interleukins especially IL-10 and 12
  • anti-TNF ⁇ antibodies etanercept
  • Immunomodulatory drugs or IMiDs, especially inhibitors of the TNF- ⁇ production, such as thalidomide, its R- and S-enantiomers and its derivatives, or revimid (CC-5013)
  • leukotrien antagonists mitomycin C, aziridoquinones (BMY-42355, AZQ, EO-9), 2-nitroimidazoles (misonidazole, NLP-1, NLA-1), nitroacridines, nitroquinolines, nitropyrazoloacridines, “dual-function” nitro aromatics (RSU-1069, RB-6145), nitro aromatic deactivated mustards (CB-1954), N-oxides of nitrogen mustards (nitromin), metal complexes of nitrogen mustards, anti-CD3 or anti-CD25 antibodies, genetically modified enteric bacteria to
  • a representative class of compounds of interest are, for example, the biphosphonates and their derivatives, such as, for example, minodronic acid (YM-529, Ono-5920, YH-529), zoledronic acid monohydrate, ibandronate sodium hydrate, clodronate disodium. These compounds are in clinical development or have been recently approved for the treatment of bone metastasis from breast/lung cancer and for the treatment of multiple myeloma (Drugs of the Future 2002, 27(10), pp. 935-941).
  • nitroimidazoles metalazole, misonidazole, benznidazole, nimorazole
  • nitroaryl compounds such as RSU-1069
  • the nitroxyl and N-oxides such as SR-4233
  • the halogenated pyrimidine analogues bromodeoxyuridine, iododeoxyuridine
  • the thiophosphates for example WR-2721
  • Representative classes and compounds of interest are, for example, porfimer, photofrin, the benzoporphyrin derivatives, the pheophorbide derivatives, merocyanin 540 (MC-540), and tin etioporpurin.
  • Synthetic poly- or oligonucleotides which may optionally be modified or conjugated are also of interest.
  • Representative classes of poly- or oligonucleotides are, for example, anti-templates RNAs and DNAs (synthetic or chemically modified oligonucleotides which are inactive per se but capable of competing with functional template-primers for their specific binding site on an enzyme and thereby blocking their functions), anti-sense RNAs and DNAs (sequence-specific inhibitors of protein synthesis which hybridize with complementary base sequences of a given m-RNA, such as oblimersen), especially directed against onco-genes, growth factor genes or tumor suppressor genes, antigene poly- or oligonucleotides (oligonucleotides capable of forming triplex DNA structures which selectively inhibit the transcription of a target gene), and ribozymes.
  • Non-steroidal inflammatory drugs represent also an interesting class of compounds which may be used for a combination therapy within the meaning of the present invention.
  • Cyclo-oxygenase (COX) inhibitors are of special interest, such as the non-selective COX inhibitors acetylsalicyclic acid, mesalazin, ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, indomethacin, sulindac, tolmetin, zomepirac, nabumetone, diclofenac, fenclofenac, alclofenac, bromfenac
  • cytotoxic antibiotics antibodies targeting surface molecules of cancer cells (especially HLA-DR antibodies such as, for example, apolizumab and 1D09C3), inhibitors of metalloproteinases (TIMP-1, TIMP-2), Zinc, inhibitors of oncogenes (especially c-myc, Ras, v-raf or c-src inhibitors, such as P53 and Rb), inhibitors of gene transcription (especially the inhibitors of the transcription factor complex ESX/DRIP130/Sur-2 which controls the expression of Her-2, such as those described in WO 03/097855) or of RNA translation or protein expression (especially the inhibitors of HER-2 expression, such as the heat shock protein HSP90 modulator geldanamycin and its derivative 17-allylaminogeldanamycin or 17-AAG), complexes of rare earth elements such as the heterocyclic complexes of lanthanides described for example
  • photo-chemotherapeutic agents PUVA, a combination of psoralen (P) and long-wave ultraviolet radiation (UVA)
  • IM-842 tetrathiomolybdate
  • squalamine combrestatin A4
  • TNP-470 marimastat
  • neovastat bicalutamide
  • abarelix oregovomab
  • mitumomab TLK-286
  • alemtuzumab alemtuzumab
  • ibritumomab temozolomide
  • denileukin diftitox aldesleukin
  • dacarbazine floxuridine
  • plicamycin mitotane
  • pipobroman plicamycin
  • tamloxifen testolactone
  • the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent is selected from synthetic small molecule VEGF receptor antagonists, small molecule growth factor receptor antagonists, inhibitors of the EGF receptor and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors which are not classified under the synthetic small-molecules, inhibitors directed to EGF receptor and/or VEGF receptor and/or integrin receptors or any other protein tyrosine kinase receptors, which are fusion proteins, compounds which interact with nucleic acids and which are classified as alkylating agents or platinum compounds, compounds which interact with nucleic acids and which are classified as anthracyclines, as DNA intercalators or as DNA cross-linking agents, including DNA minor-groove binding compounds, anti-metabolites, naturally occurring, semi-synthetic or synthetic bleomycin type antibiotics, inhibitors of DNA transcribing enzymes, and especially
  • the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent is selected from a small molecule VEGF receptor antagonist such as vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 or GW-786034, a dual EGFR/HER2 antagonist such as gefitinib, erlotinib, CI-1033 or GW-2016, an EGFR antagonist such as iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272 or herceptin, an antagonist of the mitogen-activated protein kinase such as BAY-43-9006 or BAY-57-9006, a quinazoline derivative such as 4-
  • a small VEGF receptor antagonist such as va
  • the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent is selected from an anti-cancer drug from plants such as paclitaxel (taxol), docetaxel or taxotere, a vinca alkaloid such as navelbine, vinblastin, vincristin, vindesine or vinorelbine, a vinca alkaloid such as navelbine, vinblastin, vincristin, vindesine or vinorelbine, an alkylating agent or a platinum compound such as melphalan, cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambuci
  • an anti-cancer drug from plants such as
  • the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent is selected from the above-mentioned quinazoline derivative disclosed in WO 02/50043 as exemplified compound of Example 1(10), namely 4-[(3-chloro-4-fluorophenyl)amino]-6- ⁇ [4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino ⁇ -7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, or the tautomers, the stereoisomers and the salts thereof, particularly the physiologically and pharmaceutically acceptable salts thereof with inorganic or organic acids or bases.
  • the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent is selected from the di-maleic acid salt of the compound 4-[(3-chloro-4-fluorophenyl)amino]-6- ⁇ [4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino ⁇ -7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, or the tautomers or stereoisomers thereof.
  • the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent is selected from 4-[(3-chloro-4-fluoro-phenyl)amino]-6- ⁇ [4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino ⁇ -7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or the physiologically and pharmaceutically acceptable salts thereof with inorganic or organic acids or bases.
  • Radiotherapy means the treatment of cancer and other diseases with ionizing radiation. Ionizing radiation deposits energy that injures or destroys cells in the area being treated (the target tissue) by damaging their genetic material, making it impossible for these cells to continue to grow.
  • Radiotherapy may be used to treat localized solid tumors, such as cancers of the skin, tongue, larynx, brain, breast, lung or uterine cervix. It can also be used to treat leukemia and lymphoma, i.e. cancers of the blood-forming cells and lymphatic system, respectively.
  • One type of radiation therapy commonly used involves photons, e.g. X-rays.
  • the rays can be used to destroy cancer cells on the surface of or deeper in the body. The higher the energy of the x-ray beam, the deeper the x-rays can go into the target tissue.
  • Linear accelerators and betatrons are machines that produce x-rays of increasingly greater energy. The use of machines to focus radiation (such as x-rays) on a cancer site is called external beam radiotherapy.
  • Gamma rays are another form of photons used in radiotherapy. Gamma rays are produced spontaneously as certain elements (such as radium, uranium, and cobalt 60) release radiation as they decompose, or decay.
  • Another technique for delivering radiation to cancer cells is to place radioactive implants directly in a tumor or body cavity.
  • This is called internal radiotherapy.
  • Brachytherapy, interstitial irradiation, and intracavitary irradiation are types of internal radiotherapy. In this treatment, the radiation dose is concentrated in a small area, and the patient stays in the hospital for a few days. Internal radiotherapy is frequently used for cancers of the tongue, uterus, and cervix.
  • intra-operative irradiation in which a large dose of external radiation is directed at the tumor and surrounding tissue during surgery.
  • Another approach is particle beam radiation therapy. This type of therapy differs from photon radiotherapy in that it involves the use of fast-moving subatomic particles to treat localized cancers.
  • Radio-sensitizers make the tumour cells more likely to be damaged, and radio-protectors protect normal tissues from the effects of radiation. Hyperthermia, the use of heat, may also be used for sensitizing tissue to radiation.
  • radio-labeled antibodies to deliver doses of radiation directly to the cancer site (radio-immunotherapy). There are numerous methods available in the art to link a radioisotope to an antibody.
  • a method as disclosed in WO 93/05804 may be employed.
  • Another option is to use a linker molecule between the antibody and the radioisotope, e.g. MAG-3 (U.S. Pat. No. 5,082,930, EP 0 247 866), MAG-2 GABA (U.S. Pat. No. 5,681,927, EP 0 284 071), and N2S2 (phenthioate, U.S. Pat. No. 4,897,255, U.S. Pat. No. 5,242,679, EP 0 188 256).
  • MAG-3 U.S. Pat. No. 5,082,930, EP 0 247 866
  • MAG-2 GABA U.S. Pat. No. 5,681,927, EP 0 284 071
  • N2S2 phenthioate, U.S. Pat. No. 4,897,255, U.S. Pat. No. 5,242,679, EP 0 188 256.
  • Co-administration of the selected protein tyrosine kinase receptor antagonist and of the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent, and/or co-treatment with radiotherapy or radio-immunotherapy is meant to include administration and/or treatment sequential in time or simultaneous administration and/or treatment.
  • the selected protein tyrosine kinase receptor antagonist can be administered before or after administration of the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent, and/or before or after treatment with radiotherapy or radio-immunotherapy.
  • the active compounds can be administered orally, bucally, parenterally, by inhalation spray, rectally or topically, the oral administration being preferred.
  • Parenteral administration may include subcutaneous, intravenous, intramuscular and intrasternal injections and infusion techniques.
  • the active compounds can be orally administered in a wide variety of different dosage forms, i.e., they may be formulated with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspensions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents.
  • such oral pharmaceutical formulations can be suitably sweetened and/or flavoured by means of various agents of the type commonly employed for such purposes.
  • the compounds of this invention are present in such oral dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, in amounts which are sufficient to provide the desired unit dosages.
  • Other suitable dosage forms for the compounds of this invention include controlled release formulations and devices well known to those who practice in the art.
  • the essential active ingredient therein may be combined with various sweetening or flavouring agents, colouring matter or dyes and, if so desired, emulsifying agents and/or water, ethanol, propylene glycol, glycerine and various like combinations thereof.
  • an especially suitable pharmaceutical formulation for the selected protein kinase receptor antagonist in accordance with the present invention is soft gelatine capsules.
  • Suitable soft gelatine capsules for the encapsulation of pharmaceutical compounds and the process for their preparation are described, for example, in GB patent No. 395546, U.S. Pat. No. 2,720,463, U.S. Pat. No. 2,870,062, U.S. Pat. No. 4,829,057, and in the following publications: ANON (Verpack-Rundsch., Vol. 21, No. 1, January 1970, pp. 136-138), Lachman et al. (The Theory and Practice of Industrial Pharmacy, Chap.
  • solutions of the compounds in sesame or peanut oil or in aqueous propylene glycol may be employed, as well as sterile aqueous solutions of the corresponding pharmaceutically acceptable salts.
  • aqueous solutions should be suitably buffered if necessary, and the liquid diluent rendered isotonic with sufficient saline or glucose.
  • these particular aqueous solutions are especially suitable for intravenous, intramuscular and subcutaneous injection purposes.
  • the sterile aqueous media employed are readily obtained by standard techniques well known to those skilled in the art.
  • distilled water is ordinarily used as the liquid diluent and the final preparation is passed through a suitable bacterial filter such as a sintered glass filter or a diatomaceous earth or unglazed porcelain filter.
  • suitable bacterial filter such as a sintered glass filter or a diatomaceous earth or unglazed porcelain filter.
  • Preferred filters of this type include the Berkefeld, the Chamberland and the Asbestos Disk-Metal Seitz filter, wherein the fluid is sucked into a sterile container with the aid of a suction pump. The necessary steps should be taken throughout the preparation of these inject-able solutions to insure that the final products are obtained in a sterile condition.
  • the dosage form of the particular compound or compounds may include, by way of example, solutions, lotions, ointments, creams, gels, suppositories, rate-limiting sustained release formulations and devices therefore.
  • dosage forms comprise the particular compound or compounds and may include ethanol, water, penetration enhancer and inert carriers such as gel-producing materials, mineral oil, emulsifying agents, benzyl alcohol and the like.
  • the selected protein tyrosine kinase receptor antagonist, or its polymorph or pharmaceutically acceptable salt may be administered in a daily dosage such that the plasma level of the active substance lies between 10 and 500 ng/ml for at least 12 hours of a 24 hours dosing interval.
  • the selected protein tyrosine kinase receptor antagonist, or its polymorph or pharmaceutically acceptable salt may be administered in a daily dosage of between 2 mg and 20 mg/kg body weight.
  • the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent may be administered using suitable dosage forms, dosage levels and devices well known to those who practice in the art.
  • the further chemotherapeutic or naturally occurring, semi-synthetic or synthetic therapeutic agent is a steroid
  • the steroid may be administered in a daily dosage of 5 to 500 mg.
  • the expert knows how to determine an appropriate dosing and application schedule, depending on the nature of the disease and the constitution of the patient. In particular, the expert knows how to assess dose-limiting toxicity (DLT) and how to determine the maximum tolerated dose (MTD) accordingly.
  • DLT dose-limiting toxicity
  • MTD maximum tolerated dose
  • Neovascularization parallels infiltration of bone marrow in a murine multiple myeloma model (Yaccoby et al., Blood 1998, Vol. 92(8), pp. 2908-2913) and in multiple myeloma patients undergoing progression (Vacca et al., Blood 1999, Vol. 93(9), pp.
  • VEGF has been shown to be a potent stimulus of angiogenesis (Toi et al., Lancet Oncol. 2001, Vol. 2, pp. 667-673); VEGF is expressed in and secreted by multiple myeloma cells (Dankbar et al., Blood 2000, Vol. 95(8), pp. 2630 -2636; Bellamy et al., Cancer Res. 1999, Vol. 59(3), pp.
  • VEGF induces IL-6 secretion from marrow stromal cells, which in turn augments VEGF expression from clonal plasma cells
  • IL-6 is considered a major growth factor for multiple myeloma cells in vivo (Klein et al., Blood 1995, Vol. 85(4), pp. 863-872); IL-6 inhibits Dexamethasone-induced myeloma cell death (Hardin et al., Blood 1994, Vol. 84(9), pp.
  • VEGF induces proliferation and triggers migration of multiple myeloma cells (Podar et al., Blood 2001, Vol. 98(2), pp. 428-435); VEGF enhances osteoclastic bone resorption, which is a characteristic feature of multiple myeloma (Nakagawa et al., FEBS Lett. 2000, Vol. 473(2), pp. 161-164; Niida et al., J. Exp. Med. 1999, Vol. 190(2), pp. 293-298); FGFR3 induces proliferation, inhibits apoptosis and is involved in progression of myeloma cells (Chesi et al., Blood 2001, Vol.
  • FGFR3 is dysregulated and constitutively activated in a subset of myeloma patients (Chesi et al., Blood 2001, Vol. 97(3), pp. 729-736; Chesi et al., Nat. Genet. 1997, Vol. 16(3), pp. 260-264); Src family kinases are involved in proliferative responses induced in myeloma (Ishikawa et al.; Blood 2002, Vol. 99(6), pp. 2172-2178).
  • the inhibition effect of the compound MES(T) on the secretion of IL-6 by bone marrow stromal cells (BMSC cells) was investigated, at different concentrations (0, 10, 50, 125, 250 and 500 nM) of MES(T), in native conditions (native) and in conditions of stimulation of the cells with the bFGF (+bFGF) or with the VEGF (+VEGF) growth factors.
  • BMSC cells bone marrow stromal cells
  • the results of this experiment show that the compound MES(T) at concentration of ⁇ 250 nM inhibits basal (native) as well as bFGF/VEGF-stimulated IL-6 secretion of bone marrow stromal cells (BMSC cells), and that the inhibition is more potent than the inhibition obtained with the antibodies.
  • an inhibition of IL-6 secretion by the compound in accordance with the present invention shows its potency for the treatment of multiple myeloma.
  • the compound MES(T) provides pro-apoptotic effects in t(14;16) MM1.s myeloma cells (MM1.s myeloma cells carrying the translocation t(14;16)), and that the compound MES(T) enhances the apoptosis induced by dexamethasone.
  • the compound MES(T) is especially suitable for a combination treatment of refractory or relapsed multiple myeloma with a steroid, and especially dexamethasone.
  • an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof, and of a dual antagonist of the epidermal growth factor (EGF) receptor and of the human epidermal growth factor of type 2 (HE type 2) receptor, for the treatment of prostate cancer, non-small cell lung cancer or colorectal cancer
  • FIG. 3 shows the results of the experiment.
  • VEGF receptor antagonists described in WO 01/60814, WO 99/48868, WO 98/35958, and especially the compounds vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 or GW-786034, the monoclonal antibodies directed to the VEGF receptor, and especially AvastinTM (bevacizumab)or IMC-1C11) with EGFR inhibitors (e.g.
  • an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof (e.g. the compound MES(T)), and of a further antagonist of VEGFR 2, PDGFR or bFGFR (e.g. vatalanib (PTK-787, ZD-6474, or the monoclonal antibody AvastinTM) or an antagonist of EGFR (e.g. tarceva (OSI-774)), for the treatment of colorectal cancer, solid tumours, breast cancer, non-small cell lung cancer, small cell lung cancer or multiple myeloma
  • an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof (e.g. the compound MES(T)), and of an antimetabolite (e.g. gemcitabine) and a platinum compound (e.g. cisplatin), or of an anticancer drug from plants (e.g. paclitaxel) and a platinum compound (e.g. carboplatin), for the treatment of non-small cell lung cancer or ovarian carcinoma
  • a src tyrosine kinase family member or a polymorph, metabolite or pharmaceutically acceptable salt thereof (e.g. the compound MES(T))
  • an antimetabolite e.g. gemcitabine
  • an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof (e.g. the compound MES(T)), and of a derivative of podophyllotoxin (e.g. etoposide) and a platinum compound (e.g. carboplatin or cisplatin), for the treatment of small cell lung cancer
  • an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof (e.g. the compound MES(T)), and of an anticancer drug from plants (e.g. paclitaxel or taxol), for the treatment of ovarian carcinoma, small cell lung cancer or prostate cancer
  • an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof (e.g. the compound MES(T)), and of a platinum compound (e.g. carboplatin) and an anticancer drug from plants (e.g. paclitaxel), for the treatment of ovarian carcinoma, especially after debulking surgery
  • an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof (e.g. the compound MES(T)), and of a topoisomerase I inhibitor (e.g. topotecan) and an anthracycline (e.g. doxorubicin), for the treatment of ovarian cancer
  • a src tyrosine kinase family member or a polymorph, metabolite or pharmaceutically acceptable salt thereof (e.g. the compound MES(T)
  • a topoisomerase I inhibitor e.g. topotecan
  • an anthracycline e.g. doxorubicin
  • an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof (e.g. the compound MES(T)), and of a topoisomerase I inhibitor (e.g. topotecan), for the treatment of small cell lung cancer or ovarian carcinoma
  • an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof (e.g. the compound MES(T)), and of a vinca alkaloid (e.g. navelbine) for the treatment of lung cancer
  • an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof (e.g. the compound MES(T)), and of a platinum compound (e.g. carboplatin or cis-platin, preferably carboplatin) for the treatment of ovarian carcinoma or non-small cell lung cancer
  • a platinum compound e.g. carboplatin or cis-platin, preferably carboplatin
  • an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof (e.g. the compound MES(T)), and of a 5-alpha reductase inhibitor (e.g. finasteride), for the treatment of prostate cancer
  • an antagonist of at least one receptor selected from VEGFR 1 to 3, PDGFR ⁇ and ⁇ , FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit which is further an antagonist of a src tyrosine kinase family member, or a polymorph, metabolite or pharmaceutically acceptable salt thereof (e.g. the compound MES(T)), and of a photo-chemotherapeutic agent (PUVA, a combination of psoralen (P) and long-wave ultraviolet radiation (UVA)), for the treatment of psoriasis
  • the rationale for the combination treatment in accordance with the present invention is that there is a therapeutic advantage for the cancer patient to combine specific and mechanistically acting molecules with more broadly acting therapeutic concepts in the following ways:
  • the combination therapies in accordance with the present invention are expected to provide a clinically relevant benefit in survival or time to tumour progression for larger patient population as the corresponding mono-therapies.
  • the specific anti-angiogenic therapy with, for example, the compound MES(T)
  • tumours seem to be less capable of recovering from the damage caused by conventional chemotherapy.
  • VEGF vascular endothelial growth factor
  • a decline of the interstitial pressure in tumours seems to occur, allowing a greater penetration of the cytotoxic drugs.
  • Maintenance therapy with a specific anti-angiogenic agent such as, for example, the compound MES(T), after standard cytoreduction, seems also to result in a consolidation of the response obtained with the cytotoxic therapy. This approach is substantiated by preclinical evidence that combinations of anti-angiogenic compounds with cytotoxic therapies result in synergistic anti-tumour activity.
  • the rationale for the combination treatment in accordance with the present invention is also that there is a therapeutic advantage for the patient to combine specific and mechanistically acting molecules with more broadly acting therapeutic concepts.
  • the expected effect of this combination is to avoid possible escape mechanisms for the target cells, to reduce the required respective doses of the drugs in comparison to the doses used in a mono-therapy (due to the additive or synergistic effect of the combination), and to reduce the likelihood of the target cells to develop resistances against the drugs.
  • FIG. 1 A first figure.
  • VEGFR-2 phosphorylation after varying exposure of compound MES(T) on NIH3T3 KDR cells.
  • the upper panel shows a Western blot probed with an antibody specific for phosphorylated tyrosine residues ( ⁇ -PY).
  • the lower panel shows a Western blot using an antibody specific for VEGFR-2 ( ⁇ -KDR).

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