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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Cited By (64)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040219643A1 (en) * 2001-06-28 2004-11-04 Greg Winter Dual-specific ligand
US20050271663A1 (en) * 2001-06-28 2005-12-08 Domantis Limited Compositions and methods for treating inflammatory disorders
US20060106203A1 (en) * 2002-06-28 2006-05-18 Domantis Limited Ligand
US20060212008A1 (en) * 2005-02-24 2006-09-21 Peters Donna M Method for treating or preventing steroid-induced glaucoma
US20060252740A1 (en) * 2005-04-29 2006-11-09 Johnson Robert G Jr Method of treating multiple myeloma using 17-AAG or 17-AG or a prodrug of either in combination with a proteasome inhibitor
US20060252739A1 (en) * 2005-04-29 2006-11-09 Johnson Robert G Jr Method of treating multiple myeloma using 17-AAG or 17-AG or a prodrug of either
US20060257406A1 (en) * 2002-12-27 2006-11-16 Domantis Limited Ligand
US20070004720A1 (en) * 2003-10-30 2007-01-04 Birgit Jung Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
US20070027170A1 (en) * 2003-10-17 2007-02-01 Rainer Soyka Process for preparing amino crotonyl compounds
WO2006099396A3 (en) * 2005-03-11 2007-04-12 Univ Colorado Histone deacetylase inhibitors sensitize cancer cells to epidermal growth factor inhibitors
WO2007056244A2 (en) * 2005-11-04 2007-05-18 Merck & Co., Inc. Methods of using saha and erlotinib for treating cancer
US20070142346A1 (en) * 2001-08-06 2007-06-21 Johnson Robert G Jr Method of treating breast cancer using 17-AAG or 17-AG or a prodrug of either in combination with a HER2 inhibitor
WO2007079437A2 (en) * 2006-01-03 2007-07-12 Kereos, Inc. Combination antitumor therapies
US20070197473A1 (en) * 2005-11-04 2007-08-23 Frankel Stanley R Methods of using SAHA and Bortezomib for treating cancer
US20070203110A1 (en) * 2005-11-23 2007-08-30 Licari Peter J 17-Allylamino-17-demethoxygeldanamycin polymorphs and formulations
US20080032719A1 (en) * 2005-10-01 2008-02-07 Outland Research, Llc Centralized establishment-based tracking and messaging service
US20080090233A1 (en) * 2004-05-27 2008-04-17 The Regents Of The University Of Colorado Methods for Prediction of Clinical Outcome to Epidermal Growth Factor Receptor Inhibitors by Cancer Patients
US20080113874A1 (en) * 2004-01-23 2008-05-15 The Regents Of The University Of Colorado Gefitinib sensitivity-related gene expression and products and methods related thereto
US20080182865A1 (en) * 2005-03-11 2008-07-31 Witta Samir E Histone deacetylase inhibitors sensitize cancer cells to epidermal growth factor inhibitors
US20080248001A1 (en) * 2007-04-08 2008-10-09 Immunolight Methods and systems for treating cell proliferation disorders
US20080254040A1 (en) * 2003-04-29 2008-10-16 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis
US20090035281A1 (en) * 2005-03-10 2009-02-05 Universita Degli Studi "Magna Graecia" Di Catanzaro Combination of interleukin-6 antagonists and antiproliferative drugs
US20090068110A1 (en) * 2006-12-22 2009-03-12 Genentech, Inc. Antibodies to insulin-like growth factor receptor
WO2009048947A1 (en) * 2007-10-09 2009-04-16 Board Of Regents, The University Of Texas System Methods of treatment of opioid tolerance, physical dependence, pain, and addiction with inhibitors of certain growth factor receptors
US20090131367A1 (en) * 2007-11-19 2009-05-21 The Regents Of The University Of Colorado Combinations of HDAC Inhibitors and Proteasome Inhibitors
US20090155283A1 (en) * 2005-12-01 2009-06-18 Drew Philip D Noncompetitive Domain Antibody Formats That Bind Interleukin 1 Receptor Type 1
US20090191201A1 (en) * 2005-04-26 2009-07-30 Heiss Markus M Combination of the application of antibodies for immunostimulation together with glucocorticoids
US20090259026A1 (en) * 2002-06-28 2009-10-15 Ian Tomlinson Ligand
US20090306378A1 (en) * 2006-01-26 2009-12-10 Juergen Schroeder Process for preparing aminocrotonylamino-substituted quinazoline derivatives
US20090306101A1 (en) * 2005-11-11 2009-12-10 Flavio Solca Combination treatment of cancer comprising egfr/her2 inhibitors
US20090306044A1 (en) * 2005-11-11 2009-12-10 Flavio Solca Quinazoline derivatives for the treatment of cancer diseases
US20090318480A1 (en) * 2006-09-18 2009-12-24 Boehringer Ingelheim International Gmbh Method for treating cancer harboring egfr mutations
US20100010023A1 (en) * 2000-12-20 2010-01-14 Boehringer Ingelheim Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US20100069414A1 (en) * 1999-06-21 2010-03-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US7696320B2 (en) 2004-08-24 2010-04-13 Domantis Limited Ligands that have binding specificity for VEGF and/or EGFR and methods of use therefor
US20100113392A1 (en) * 2006-11-03 2010-05-06 Badros Ashraf Z Methods of using saha and bortezomib for treating multiple myeloma
US20100144639A1 (en) * 2002-05-11 2010-06-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of inhibitors of the egfr-mediated signal transduction for the treatment of benign prostatic hyperplasia (bph) / prostatic hypertrophy
US20100291103A1 (en) * 2007-06-06 2010-11-18 Domantis Limited Polypeptides, antibody variable domains and antagonists
WO2010130757A1 (en) * 2009-05-14 2010-11-18 Boehringer Ingelheim International Gmbh New combination therapy in treatment of oncological and fibrotic diseases
WO2010146059A2 (en) 2009-06-16 2010-12-23 F. Hoffmann-La Roche Ag Biomarkers for igf-1r inhibitor therapy
WO2011041582A2 (en) 2009-09-30 2011-04-07 President And Fellows Of Harvard College Methods for modulation of autophagy through the modulation of autophagy-inhibiting gene products
US20110142929A1 (en) * 2008-06-06 2011-06-16 Boehringer Ingelheim International Gmbh Solid pharmaceutical formulations comprising bibw 2992
US20110160160A1 (en) * 2007-08-15 2011-06-30 The Research Foundation Of State University Of New York Methods for heat shock protein dependent cancer treatment
US8017321B2 (en) 2004-01-23 2011-09-13 The Regents Of The University Of Colorado, A Body Corporate Gefitinib sensitivity-related gene expression and products and methods related thereto
WO2012027445A1 (en) 2010-08-26 2012-03-01 Boehringer Ingelheim International Gmbh Methods of administering an egfr inhibitor
US8828391B2 (en) 2011-05-17 2014-09-09 Boehringer Ingelheim International Gmbh Method for EGFR directed combination treatment of non-small cell lung cancer
US9139558B2 (en) 2007-10-17 2015-09-22 Wyeth Llc Maleate salts of (E)-N-{4-[3-Chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US9211291B2 (en) 2009-04-06 2015-12-15 Wyeth Llc Treatment regimen utilizing neratinib for breast cancer
US9242965B2 (en) 2013-12-31 2016-01-26 Boehringer Ingelheim International Gmbh Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors
US9265784B2 (en) 2008-08-04 2016-02-23 Wyeth Llc Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine
US9309228B2 (en) 2012-07-19 2016-04-12 Boehringer Ingelheim International Gmbh Fumaric acid salt of 9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one, its use as a medicament and the preparation thereof
US9511063B2 (en) 2008-06-17 2016-12-06 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US9545381B2 (en) 2009-07-06 2017-01-17 Boehringer Ingelheim International Gmbh Process for drying of BIBW2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
CN106393602A (zh) * 2016-08-31 2017-02-15 宁波方正汽车模具有限公司 用于保险杠模具的顶出装置
US20180002399A1 (en) * 2010-12-09 2018-01-04 Five Prime Therapeutics, Inc. Fgfr1 extracellular domain combination therapies
US9907756B2 (en) 2008-06-06 2018-03-06 Boehringer Ingelheim International Gmbh Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative
WO2018183586A1 (en) * 2017-03-29 2018-10-04 Purdue Research Foundation Inhibitors of kinase networks and uses thereof
US10105323B2 (en) 2008-06-06 2018-10-23 Boehringer Ingelheim International Gmbh Pharmaceutical dosage form for immediate release of an indolinone derivative
US20190000920A1 (en) * 2011-11-14 2019-01-03 Five Prime Therapeutics, Inc. Methods of Treating Cancer
CN110573608A (zh) * 2017-02-10 2019-12-13 施明哲 调节纤维母细胞生长因子受体3活化的组合物及方法
US10596162B2 (en) 2005-02-03 2020-03-24 Wyeth Llc Method for treating gefitinib resistant cancer
US10729672B2 (en) 2005-11-04 2020-08-04 Wyeth Llc Antineoplastic combinations with mTOR inhibitor, trastuzumab and/or HKI-272
US11434291B2 (en) 2019-05-14 2022-09-06 Provention Bio, Inc. Methods and compositions for preventing type 1 diabetes
US12006366B2 (en) 2021-01-26 2024-06-11 Provention Bio, Inc. Methods and compositions for preventing type 1 diabetes

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ571508A (en) 2002-05-24 2010-05-28 Schering Corp Neutralizing human anti-IGFR antibody
US7691838B2 (en) 2003-05-30 2010-04-06 Kosan Biosciences Incorporated Method for treating diseases using HSP90-inhibiting agents in combination with antimitotics
JP4338734B2 (ja) * 2003-08-26 2009-10-07 メルク エイチディーエーシー リサーチ エルエルシー Ｈｄａｃ阻害剤による癌処置法
US7399865B2 (en) 2003-09-15 2008-07-15 Wyeth Protein tyrosine kinase enzyme inhibitors
EP1667992B1 (en) 2003-09-19 2007-01-24 Astrazeneca AB Quinazoline derivatives
US7326567B2 (en) 2003-11-12 2008-02-05 Schering Corporation Plasmid system for multigene expression
AR046639A1 (es) 2003-11-21 2005-12-14 Schering Corp Combinaciones terapeuticas de anticuerpo anti- igfr1
GB0406445D0 (en) * 2004-03-23 2004-04-28 Astrazeneca Ab Combination therapy
GB0406446D0 (en) * 2004-03-23 2004-04-28 Astrazeneca Ab Combination therapy
CA2558346A1 (en) * 2004-03-23 2005-10-06 Astrazeneca Ab Combination therapy
WO2005094823A1 (ja) * 2004-03-30 2005-10-13 Kyowa Hakko Kogyo Co., Ltd. Ｆｌｔ－３阻害剤
JP4832426B2 (ja) 2004-04-02 2011-12-07 オーエスアイ・ファーマスーティカルズ・インコーポレーテッド ６，６−二環置換されたヘテロ二環式タンパク質キナーゼ阻害剤
WO2006060419A2 (en) 2004-12-03 2006-06-08 Schering Corporation Biomarkers for pre-selection of patients for anti-igf1r therapy
PE20060777A1 (es) * 2004-12-24 2006-10-06 Boehringer Ingelheim Int Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas
PL1846406T3 (pl) 2005-02-09 2011-04-29 Arqule Inc Pochodne imidowe kwasu maleinowego, kompozycje farmaceutyczne i sposoby leczenia nowotworów
US20070027175A1 (en) * 2005-07-27 2007-02-01 Shaughnessy John Jr Antineoplastic activities of ellipticine and its derivatives
HUE028025T2 (en) 2005-08-03 2016-11-28 Novartis Ag Use of Panobinostat HDAC inhibitor to treat myeloma
EP1792622A1 (en) * 2005-11-11 2007-06-06 GPC Biotech AG Anti-proliferative combination therapy comprising a platinum-based chemotherapeutic agent and EGFR inhibitors or pyrimidine analogues
WO2007057397A1 (en) * 2005-11-15 2007-05-24 Boehringer Ingelheim International Gmbh Treatment of cancer
GB0523810D0 (en) * 2005-11-23 2006-01-04 Astrazeneca Ab Pharmaceutical compositions
US10149889B2 (en) 2005-11-25 2018-12-11 Rutgers, The State University Of New Jersey Compositions for the treatment of cancer, and methods for testing and using the same
US8926990B2 (en) 2009-10-13 2015-01-06 Rutgers, The State University Of New Jersey Treatment and diagnosis of inflammatory disorders and HIV
US8575164B2 (en) * 2005-12-19 2013-11-05 OSI Pharmaceuticals, LLC Combination cancer therapy
BRPI0708446A2 (pt) * 2006-03-01 2011-06-07 Janssen Pharmaceutica Nv tratamento de cáncer combinando agente de linfodepleção com ctls e citocinas
RU2452492C2 (ru) * 2006-04-05 2012-06-10 Новартис Аг КОМБИНАЦИИ, ВКЛЮЧАЮЩИЕ ИНГИБИТОРЫ Bcr-Abl/c-Kit/PDGF-R TK, ДЛЯ ЛЕЧЕНИЯ РАКА
US20070258976A1 (en) * 2006-05-04 2007-11-08 Ward Keith W Combination Therapy for Diseases Involving Angiogenesis
MX2008014912A (es) * 2006-05-26 2008-12-10 Celgene Corp Metodos y composiciones que usan compuestos inmunomoduladores en terapia de combinacion.
WO2007139930A2 (en) 2006-05-26 2007-12-06 Bayer Healthcare Llc Drug combinations with substituted diaryl ureas for the treatment of cancer
EP1870400A1 (en) * 2006-06-08 2007-12-26 Boehringer Ingelheim Pharma GmbH & Co. KG Salts and crystalline salt forms of an 2-indolinone derivative
WO2008008981A1 (en) * 2006-07-13 2008-01-17 Zymogenetics, Inc. Interleukin 21 and tyrosine kinase inhibitor combination therapy
AU2008224929A1 (en) * 2007-03-14 2008-09-18 Mayo Foundation For Medical Education And Research Treating skin cancer
CA2689242C (en) * 2007-05-29 2015-07-07 Kohzoh Imai Agent and method for treatment of cancer
CN101801961B (zh) 2007-06-22 2014-09-24 艾科尔公司 吡咯烷酮、吡咯烷-2,5-二酮、吡咯烷和硫代琥珀酰亚胺衍生物、组合物以及治疗癌症的方法
JP5490688B2 (ja) 2007-06-22 2014-05-14 アークル インコーポレイテッド 癌の治療のためのインドリルピロリジン
BRPI0813355A2 (pt) 2007-06-22 2014-12-30 Arqule Inc Compostos de quinazolinona e métodos de uso dos mesmos
JP2011510018A (ja) * 2008-01-18 2011-03-31 オーエスアイ・フアーマスーテイカルズ・インコーポレーテツド 癌治療のためのイミダゾピラジノール誘導体
WO2009120922A2 (en) 2008-03-27 2009-10-01 Zymogenetics, Inc. Compositions and methods for inhibiting pdgfrbeta and vegf-a
RU2476239C2 (ru) * 2008-04-17 2013-02-27 Де Джонс Хопкинс Юниверсити On01910.na, усиливающий активность химиотерапевтического агента в резистентных к лекарственным средствам опухолях
UA107560C2 (uk) * 2008-06-06 2015-01-26 Фармацевтична лікарська форма для негайного вивільнення похідної індолінону
PT2985025T (pt) 2008-06-06 2018-03-15 Boehringer Ingelheim Int Combinação farmacêutica
EP2138494A1 (en) * 2008-06-26 2009-12-30 Sanofi-Aventis Substituted alkyl pyrimidin-4-one derivatives
ES2711249T3 (es) 2008-06-27 2019-04-30 Celgene Car Llc Compuestos de heteroarilo y usos de los mismos
US8338439B2 (en) 2008-06-27 2012-12-25 Celgene Avilomics Research, Inc. 2,4-disubstituted pyrimidines useful as kinase inhibitors
US11351168B1 (en) 2008-06-27 2022-06-07 Celgene Car Llc 2,4-disubstituted pyrimidines useful as kinase inhibitors
WO2010003057A2 (en) 2008-07-03 2010-01-07 Mayo Foundation For Medical Education And Research Treating cancer
AR072538A1 (es) * 2008-07-29 2010-09-01 Boehringer Ingelheim Int Derivados de indolinonas, composiciones farmacéuticas y usos
US20120157472A1 (en) * 2009-01-14 2012-06-21 Boehringer Ingelheim International Gmbh Method for treating colorectal cancer
US8802384B2 (en) 2009-03-12 2014-08-12 Boehringer Ingelheim International Gmbh Method or system using biomarkers for the monitoring of a treatment
CN101837129B (zh) * 2009-03-19 2012-12-12 鼎泓国际投资（香港）有限公司 含cMet抑制剂、HDAC抑制剂与EGFR酪氨酸激酶抑制剂的药物组合物及其应用
CN102405214A (zh) 2009-04-20 2012-04-04 Osi药物有限责任公司 C-吡嗪-甲胺的制备
JP2012526138A (ja) * 2009-05-07 2012-10-25 オーエスアイ・ファーマシューティカルズ，エルエルシー 副腎皮質癌を治療するためのｏｓｉ−９０６の使用
NZ597695A (en) * 2009-07-17 2014-05-30 Exelixis Inc Crystalline forms of n-[3-fluoro-4-({ 6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]-quinolin-4-yl} oxy)phenyl]-n’-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide
NZ598078A (en) 2009-08-10 2013-07-26 Univ Texas Treatment of brain metastases with macitentan in combination with paclitacel and/or temozolomide and/or radiotherapy
US20120107304A1 (en) * 2010-04-27 2012-05-03 Boehringer Ingelheim International Gmbh Combination therapy in treatment of oncological and fibrotic diseases
KR20130099040A (ko) 2010-08-10 2013-09-05 셀진 아빌로믹스 리서치, 인코포레이티드 Ｂｔｋ 억제제의 베실레이트 염
ES2635713T3 (es) 2010-11-01 2017-10-04 Celgene Car Llc Compuestos de heteroarilo y usos de los mismos
NZ609957A (en) 2010-11-01 2015-08-28 Celgene Avilomics Res Inc Heterocyclic compounds and uses thereof
JP5957003B2 (ja) 2010-11-10 2016-07-27 セルジーン アヴィロミクス リサーチ， インコーポレイテッド 変異体選択的ｅｇｆｒ阻害剤およびその使用
US9352017B2 (en) 2011-03-16 2016-05-31 Rutgers, The State University Of New Jersey Combination therapy with leukotoxin
US9427477B2 (en) 2011-05-09 2016-08-30 Mayo Foundation For Medical Education And Research Cancer treatments
MX2013015357A (es) * 2011-07-01 2014-05-22 Novartis Ag Terapia de combinacion.
CN107028926A (zh) * 2011-08-26 2017-08-11 国立大学法人大阪大学 糖尿病性心血管并发症的预防/治疗剂
JP2014532658A (ja) 2011-10-28 2014-12-08 セルジーン アヴィロミクス リサーチ， インコーポレイテッド ブルトン型チロシンキナーゼ疾患または障害を治療する方法
ES2880109T3 (es) 2012-03-15 2021-11-23 Celgene Car Llc Formas sólidas de un inhibidor de la cinasa del receptor del factor de crecimiento epidérmico
SG10201700799WA (en) 2012-03-15 2017-02-27 Celgene Avilomics Res Inc Salts of an epidermal growth factor receptor kinase inhibitor
KR101386697B1 (ko) * 2012-06-18 2014-04-18 아주대학교산학협력단 이매티닙 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 혈관 투과성 관련 질환의 치료 또는 예방용 조성물
WO2014004543A1 (en) * 2012-06-25 2014-01-03 Mone Zaidi Consulting, Inc. Combination cancer therapy using bisphosphonates and anti-egfr agents
CN103664737A (zh) * 2012-09-25 2014-03-26 杨子娇 一类治疗房角狭窄的化合物及其用途
CA2917407C (en) 2012-10-01 2023-03-14 Mayo Foundation For Medical Education And Research Complexes containing albumin-containing nanoparticles and antibodies to treat cancer
EP2935226A4 (en) 2012-12-21 2016-11-02 Celgene Avilomics Res Inc HETEROARYL COMPOUNDS AND USES THEREOF
KR101911048B1 (ko) 2013-01-29 2018-10-24 삼성전자주식회사 ｐ５３ 활성화제 및 ｃ－Ｍｅｔ 억제제를 포함하는 병용 투여용 약학 조성물
WO2014124230A2 (en) 2013-02-08 2014-08-14 Celgene Avilomics Research, Inc. Erk inhibitors and uses thereof
EP2964260A2 (en) * 2013-03-06 2016-01-13 F. Hoffmann-La Roche AG Methods of treating and preventing cancer drug resistance
WO2014160130A1 (en) 2013-03-13 2014-10-02 Oncoceutics, Inc. Combination therapy with 7-benzyl-10-(2-methylbenzyl)-2,6,7,8,9,10-hexahydroimidazo[1,2-a]pyrido[4,3-d]pyrimidin-5(3h)-one
US9688679B2 (en) 2013-03-13 2017-06-27 Oncoceutics, Inc. 7-benzyl-4-(methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-A]pyrido[3,4-E]pyrimidin-5 (1H)-one, salts thereof and methods of using the same in combination therapy
US9376437B2 (en) 2013-03-13 2016-06-28 Oncoceutics, Inc 7-benzyl-4-(2-methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(1H)-one, salts thereof and methods of using the same in combination therapy
RU2524309C1 (ru) * 2013-04-18 2014-07-27 Государственное бюджетное учреждение здравоохранения Московской области "Московский областной научно-исследовательский клинический институт им. М.Ф. Владимирского" (ГБУЗ МО МОНИКИ им. М.Ф. Владимирского) Способ выбора тактики лечения местно-распространенного рака предстательной железы
US20140350022A1 (en) 2013-05-10 2014-11-27 Boehringer Ingelheim International Gmbh Efficacious treatment of NSCLC and predictive clinical marker of the responsiveness of a tumour to a treatment
US9492471B2 (en) 2013-08-27 2016-11-15 Celgene Avilomics Research, Inc. Methods of treating a disease or disorder associated with Bruton'S Tyrosine Kinase
US9415049B2 (en) 2013-12-20 2016-08-16 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
MX2016016617A (es) 2014-06-16 2017-03-23 Mayo Foundation Tratamiento de mielomas.
EP3160497A4 (en) * 2014-06-27 2018-01-17 H. Lee Moffitt Cancer Center And Research Institute, Inc. Conjugates for immunotherapy
EP3179858B1 (en) 2014-08-13 2019-05-15 Celgene Car Llc Forms and compositions of an erk inhibitor
US9446148B2 (en) 2014-10-06 2016-09-20 Mayo Foundation For Medical Education And Research Carrier-antibody compositions and methods of making and using the same
KR102309882B1 (ko) 2014-11-21 2021-10-06 삼성전자주식회사 c-Met 저해제 및 IGF-1R 저해제를 포함하는 병용 투여용 약학 조성물
CA3209519A1 (en) 2015-01-30 2016-08-04 Oncoceutics, Inc. 7-benzyl-4-(2-methylbenzyl)-2,4,6,7,8,9-hexahydroimidazo [1,2-a]pyrido[3,4-e]pyrimidin-5(1h)-one, analogs thereof, and salts thereof and methods for their use in therapy
EP3056202A1 (en) * 2015-02-16 2016-08-17 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Benzopyrrolidone derivatives possessing antiviral and anticancer properties
TWI700085B (zh) 2015-06-22 2020-08-01 新源生物科技股份有限公司 酪胺酸激酶抑制劑之眼用調配物的用途
TW201707725A (zh) 2015-08-18 2017-03-01 美國馬友醫藥教育研究基金會 載體－抗體組合物及其製造及使用方法
TW201713360A (en) 2015-10-06 2017-04-16 Mayo Foundation Methods of treating cancer using compositions of antibodies and carrier proteins
US10668068B2 (en) * 2015-10-07 2020-06-02 The Research Foundation For The State University Of New York Treating cancer with drug combinations
EP3399861A4 (en) 2016-01-07 2019-08-07 Mayo Foundation for Medical Education and Research INTERFERON CANCER TREATMENT METHODS
WO2017139698A1 (en) 2016-02-12 2017-08-17 Mayo Foundation For Medical Education And Research Hematologic cancer treatments
CA3018340A1 (en) 2016-03-21 2017-09-28 Mayo Foundation For Medical Education And Research Methods for improving the therapeutic index for a chemotherapeutic drug
CA3018341A1 (en) 2016-03-21 2017-09-28 Mayo Foundation For Medical Education And Research Methods for reducing toxicity of a chemotherapeutic drug
US10618969B2 (en) 2016-04-06 2020-04-14 Mayo Foundation For Medical Education And Research Carrier-binding agent compositions and methods of making and using the same
EP3442534A1 (en) 2016-04-13 2019-02-20 Boehringer Ingelheim International GmbH Pharmaceutical combination of nintedanib, trifluridine and tipiracil for treating colorectal cancer
EP3246029A1 (en) 2016-05-19 2017-11-22 Boehringer Ingelheim International Gmbh Pharmaceutical combination of nintedanib and capecitabine for the treatment of colorectal cancer
EP3464240A1 (en) 2016-05-27 2019-04-10 Boehringer Ingelheim International GmbH Use of ecm biomarkers for the determining the treatment onset with nintedanib and pirfenidone
EP3463353A1 (en) 2016-06-01 2019-04-10 Boehringer Ingelheim International GmbH Use of ecm biomarkers for the determining the treatment onset with nintedanib and pirfenidone
ES2937291T3 (es) 2016-09-01 2023-03-27 Mayo Found Medical Education & Res Composiciones de agentes que se unen al transportador PD-L1 y métodos de uso de las mismas para tratar cánceres
KR20190053203A (ko) 2016-09-01 2019-05-17 메이오 파운데이션 포 메디칼 에쥬케이션 앤드 리써치 Ｔ－세포 암을 표적화하는 방법 및 조성물
MX2019002564A (es) 2016-09-06 2019-09-18 Mayo Found Medical Education & Res Composiciones de agente de unión de albúmina-paclitaxel y métodos de uso y elaboración de las mismas.
AU2017324335A1 (en) 2016-09-06 2019-03-28 Mayo Foundation For Medical Education And Research Methods of treating PD-L1 expressing cancer
WO2018048815A1 (en) 2016-09-06 2018-03-15 Nantibodyfc, Llc Methods of treating triple-negative breast cancer using compositions of antibodies and carrier proteins
CN107970246B (zh) * 2016-10-21 2020-08-28 中山大学 非甾体类抗炎药在提高肿瘤细胞对酪氨酸激酶抑制剂的敏感性中的应用
WO2018165528A1 (en) 2017-03-09 2018-09-13 Thomas Jefferson University Methods and compositions for treating cancers using antisense
WO2018177893A1 (en) 2017-03-28 2018-10-04 Boehringer Ingelheim International Gmbh Nintedanib for use in methods for the treatment of muscular dystrophy
CN109316463B (zh) * 2018-08-03 2021-03-19 暨南大学 一种复合纳米粒及其制备方法和应用
CA3118424A1 (en) * 2018-11-02 2020-05-07 Thomas Jefferson University Methods and compositions for treating hepatocellular carcinoma using antisense
EP4125890A1 (en) 2020-04-01 2023-02-08 Boehringer Ingelheim International GmbH Use of biomarkers in the treatment of fibrotic conditions
CN111454346B (zh) * 2020-06-04 2022-04-08 山东农业大学 一种来源于大麦的参与硝态氮调控的转录因子HvNLP2及其用途
WO2024037982A1 (en) 2022-08-16 2024-02-22 Boehringer Ingelheim International Gmbh Pharmaceutical formulations of nintedanib for intraocular use

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US19819A (en) * 1858-03-30 Improvement in lightning-conductors
US108545A (en) * 1870-10-18 Improvement in sled-brakes
US127453A (en) * 1872-06-04 Improvement in cultivators
US176392A (en) * 1876-04-18 Improvement in ironing-tables
US6306874B1 (en) * 1999-10-19 2001-10-23 Merck & Co., Inc. Tyrosine kinase inhibitors
US6762180B1 (en) * 1999-10-13 2004-07-13 Boehringer Ingelheim Pharma Kg Substituted indolines which inhibit receptor tyrosine kinases
US6794393B1 (en) * 1999-10-19 2004-09-21 Merck & Co., Inc. Tyrosine kinase inhibitors

Family Cites Families (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB395546A (en) 1931-10-12 1933-07-20 Robert Pauli Scherer Method of and apparatus for making capsules
US2720463A (en) 1950-11-17 1955-10-11 American Cyanamid Co Gelatin capsule casting composition preparation
US2870062A (en) 1956-04-27 1959-01-20 Scherer Corp R P Gelatin composition for capsules
DE3579384D1 (de) 1984-07-24 1990-10-04 Scherer Gmbh R P Oxytetracyclin-hc1-weichgelatinekapseln und verfahren zu ihrer herstellung.
DE3680924D1 (de) 1985-01-14 1991-09-26 Neorx Corp Metall-radionuklid markiertes protein fuer diagnose und therapie.
US5242679A (en) 1985-01-14 1993-09-07 Neorx Corporation Metal radionuclide labeled proteins for diagnosis and therapy
US4897255A (en) 1985-01-14 1990-01-30 Neorx Corporation Metal radionuclide labeled proteins for diagnosis and therapy
US5082930A (en) 1986-05-29 1992-01-21 Mallinckrodt Medical, Inc. Coupling agents for joining radionuclide metal ions with biologically useful proteins
US4861869A (en) 1986-05-29 1989-08-29 Mallinckrodt, Inc. Coupling agents for joining radionuclide metal ions with biologically useful proteins
ATE106898T1 (de) 1987-03-26 1994-06-15 Neorx Corp Metall-radionuklid-markierte proteine und glykoproteine zur diagnose und therapie.
US4965392A (en) 1987-03-26 1990-10-23 Neorx Corporation Chelating compounds for metal-radionuclide labeled proteins
AU2782292A (en) 1991-09-18 1993-04-27 Sloan-Kettering Institute For Cancer Research Activated stromal fibroblast-specific antibody, f19 and methods of using the same
EP0722342B1 (en) * 1993-09-20 2004-12-29 The Trustees Of The University Of Pennsylvania REGULATION OF bcl-2 GENE EXPRESSION
US20030108545A1 (en) * 1994-02-10 2003-06-12 Patricia Rockwell Combination methods of inhibiting tumor growth with a vascular endothelial growth factor receptor antagonist
US6811779B2 (en) * 1994-02-10 2004-11-02 Imclone Systems Incorporated Methods for reducing tumor growth with VEGF receptor antibody combined with radiation and chemotherapy
SE9504661D0 (sv) 1995-12-22 1995-12-22 Astra Pharma Inc New compounds
WO1997041844A1 (en) * 1996-05-09 1997-11-13 Alcon Laboratories, Inc. Combinations of angiostatic compounds
CO4950519A1 (es) 1997-02-13 2000-09-01 Novartis Ag Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion
AP1444A (en) * 1997-05-28 2005-07-18 Aventis Pharma Inc Quinoline and quinoxaline compounds which inhibit platelet-derived growth factor and/or p56lck tyrosine kinases.
JP2002507598A (ja) 1998-03-26 2002-03-12 スージェン・インコーポレーテッド チロシン蛋白質キナーゼを調節するためのヘテロ環式化合物のファミリー
DE19816624A1 (de) 1998-04-15 1999-10-21 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
SI1115704T1 (en) 1998-09-25 2003-12-31 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel substituted indolinones with an inhibitory effect on various kinases and cyclin/cdk complexes
JP2002533416A (ja) 1998-12-23 2002-10-08 ジー．ディー．サール ＆ カンパニー 新形成の治療における組み合わせ治療としてのシクロオキシゲナーゼ−２インヒビターおよび一つまたはそれ以上の抗腫瘍薬の使用方法
DE19924401A1 (de) 1999-05-27 2000-11-30 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
HUP0201900A3 (en) * 1999-06-21 2003-02-28 Boehringer Ingelheim Pharma Bicyclic heterocycles, pharmaceutical compositions containing them, their use and methods for the production thereof
UA75054C2 (uk) 1999-10-13 2006-03-15 Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг Заміщені в положенні 6 індолінони, їх одержання та їх застосування як лікарського засобу
DE10042696A1 (de) * 2000-08-31 2002-03-14 Boehringer Ingelheim Pharma In 6-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
DE19949209A1 (de) 1999-10-13 2001-04-19 Boehringer Ingelheim Pharma In 5-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
CN100376567C (zh) * 1999-11-05 2008-03-26 阿斯特拉曾尼卡有限公司 作为vegf抑制剂的喹唑啉衍生物
EA005996B1 (ru) 2000-02-15 2005-08-25 Сьюджен, Инк. Пирролзамещенный 2-индолинон, фармацевтическая композиция (варианты), способ модулирования каталитической активности протеинкиназы, способ лечения или профилактики нарушения в организме, связанного с протеинкиназой
WO2001064251A2 (en) * 2000-03-02 2001-09-07 University Of Pittsburgh Of The Commonwealth System Of Higher Education Combination chemotherapy
TWI310684B (en) * 2000-03-27 2009-06-11 Bristol Myers Squibb Co Synergistic pharmaceutical kits for treating cancer
CA2420164A1 (en) * 2000-10-20 2002-05-02 Bristol-Myers Squibb Pharma Company Acylsemicarbazides and their use as cyclin dependent kinase (cdk) inhibitors
DE10054019A1 (de) 2000-11-01 2002-05-23 Boehringer Ingelheim Pharma Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel
US6638965B2 (en) * 2000-11-01 2003-10-28 Boehringer Ingelheim Pharma Kg Substituted indolinones, preparation thereof and their use as pharmaceutical compositions
CA2428160C (en) * 2000-11-06 2009-10-13 Pharma Mar, S.A. Compositions for antitumor treatment containing ecteinascidin 743
CA2430376A1 (en) * 2000-12-08 2002-06-13 David J. Carini Semicarbazides and their uses as cyclin dependent kinase inhibitors
US7019012B2 (en) * 2000-12-20 2006-03-28 Boehringer Ingelheim International Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
DE10063435A1 (de) * 2000-12-20 2002-07-04 Boehringer Ingelheim Pharma Chinazolinderviate,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
JP4477303B2 (ja) * 2001-05-16 2010-06-09 ノバルティス アーゲー Ｎ−｛５−［４−（４−メチル−ピペラジノ−メチル）−ベンゾイルアミド］−２−メチルフェニル｝−４−（３−ピリジル）−２−ピリミジン−アミンおよび化学療法剤を含んでなる併用剤
WO2003011837A1 (en) * 2001-08-01 2003-02-13 Merck & Co., Inc. Tyrosine kinase inhibitors
DE10138538C2 (de) 2001-08-06 2003-12-04 Faustus Forschungs Cie Tumorhemmende Lanthanverbindungen
BR0212435A (pt) * 2001-09-10 2004-08-17 Sugen Inc Derivados de 3-(4,5,6,7-tetraidroindol-2-ilmetilideno)-2-indolinona como inibidores de cinase
CA2461227C (en) * 2001-09-24 2012-05-15 Jessie L.-S Au Methods and compositions to determine the chemosensitizing dose of suramin used in combination therapy
US6998391B2 (en) * 2002-02-07 2006-02-14 Supergen.Inc. Method for treating diseases associated with abnormal kinase activity
DE10221018A1 (de) 2002-05-11 2003-11-27 Boehringer Ingelheim Pharma Verwendung von Hemmern der EGFR-vermittelten Signaltransduktion zur Behandlung von gutartiger Prostatahyperplasie (BPH)/Prostatahypertrophie
US20030225079A1 (en) * 2002-05-11 2003-12-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of inhibitors of the EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH)/prostatic hypertrophy
EP1509226A4 (en) 2002-05-14 2008-04-09 Baylor College Medicine SMALL MOLECULAR INHIBITORS OF THE HER2 EXPRESSION
DE10233500A1 (de) * 2002-07-24 2004-02-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg 3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylen]-6-methoxycarbonyl-2-indolinon-Monoethansulfonat und dessen Verwendung als Arzneimittel
US20050043233A1 (en) 2003-04-29 2005-02-24 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis
DE10349113A1 (de) * 2003-10-17 2005-05-12 Boehringer Ingelheim Pharma Verfahren zur Herstellung von Aminocrotonylverbindungen
US20060058311A1 (en) * 2004-08-14 2006-03-16 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation
CA2833706C (en) * 2005-11-11 2014-10-21 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
EP1948180B1 (en) 2005-11-11 2013-03-13 Boehringer Ingelheim International GmbH Combination treatment of cancer comprising egfr/her2 inhibitors
CA2639936C (en) 2006-01-26 2014-06-17 Boehringer Ingelheim International Gmbh Process for preparing aminocrotonylamino-substituted quinazoline derivatives
AU2007299080B2 (en) 2006-09-18 2013-04-18 Boehringer Ingelheim International Gmbh Method for treating cancer harboring EGFR mutations
PT2985025T (pt) 2008-06-06 2018-03-15 Boehringer Ingelheim Int Combinação farmacêutica
UY31867A (es) * 2008-06-06 2010-01-29 Boehringer Ingelheim Int Nuevas formulaciones farmacéuticas sólidas que comprenden bibw 2992

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US19819A (en) * 1858-03-30 Improvement in lightning-conductors
US108545A (en) * 1870-10-18 Improvement in sled-brakes
US127453A (en) * 1872-06-04 Improvement in cultivators
US176392A (en) * 1876-04-18 Improvement in ironing-tables
US6762180B1 (en) * 1999-10-13 2004-07-13 Boehringer Ingelheim Pharma Kg Substituted indolines which inhibit receptor tyrosine kinases
US6306874B1 (en) * 1999-10-19 2001-10-23 Merck & Co., Inc. Tyrosine kinase inhibitors
US6794393B1 (en) * 1999-10-19 2004-09-21 Merck & Co., Inc. Tyrosine kinase inhibitors

Cited By (122)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8722694B2 (en) 1999-06-21 2014-05-13 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US20100069414A1 (en) * 1999-06-21 2010-03-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
USRE43431E1 (en) 2000-12-20 2012-05-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US20110046168A1 (en) * 2000-12-20 2011-02-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Methods of treating diseases using quinazoline derivatives and pharmaceutical compositions containing them
US20100010023A1 (en) * 2000-12-20 2010-01-14 Boehringer Ingelheim Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US8586608B2 (en) 2000-12-20 2013-11-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
US20070093651A1 (en) * 2001-06-28 2007-04-26 Domantis Limited Ligand
US20050271663A1 (en) * 2001-06-28 2005-12-08 Domantis Limited Compositions and methods for treating inflammatory disorders
US20040219643A1 (en) * 2001-06-28 2004-11-04 Greg Winter Dual-specific ligand
US20070142346A1 (en) * 2001-08-06 2007-06-21 Johnson Robert G Jr Method of treating breast cancer using 17-AAG or 17-AG or a prodrug of either in combination with a HER2 inhibitor
US20090197852A9 (en) * 2001-08-06 2009-08-06 Johnson Robert G Jr Method of treating breast cancer using 17-AAG or 17-AG or a prodrug of either in combination with a HER2 inhibitor
US20100144639A1 (en) * 2002-05-11 2010-06-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of inhibitors of the egfr-mediated signal transduction for the treatment of benign prostatic hyperplasia (bph) / prostatic hypertrophy
US8431585B2 (en) 2002-05-11 2013-04-30 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of inhibitors of the EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH)/prostatic hypertrophy
US20060106203A1 (en) * 2002-06-28 2006-05-18 Domantis Limited Ligand
US20090259026A1 (en) * 2002-06-28 2009-10-15 Ian Tomlinson Ligand
US9321832B2 (en) 2002-06-28 2016-04-26 Domantis Limited Ligand
US20060257406A1 (en) * 2002-12-27 2006-11-16 Domantis Limited Ligand
US20110136826A1 (en) * 2003-04-29 2011-06-09 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis
US20110171289A1 (en) * 2003-04-29 2011-07-14 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis
US7846936B2 (en) 2003-04-29 2010-12-07 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis
US20110039863A1 (en) * 2003-04-29 2011-02-17 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis
US20080254040A1 (en) * 2003-04-29 2008-10-16 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis
US20070027170A1 (en) * 2003-10-17 2007-02-01 Rainer Soyka Process for preparing amino crotonyl compounds
US8426586B2 (en) 2003-10-17 2013-04-23 Boehringer Ingelheim International Gmbh Process for preparing amino crotonyl compounds
US20070004720A1 (en) * 2003-10-30 2007-01-04 Birgit Jung Use of tyrosine kinase inhibitors for the treatment of inflammatory processes
US20080113874A1 (en) * 2004-01-23 2008-05-15 The Regents Of The University Of Colorado Gefitinib sensitivity-related gene expression and products and methods related thereto
US8017321B2 (en) 2004-01-23 2011-09-13 The Regents Of The University Of Colorado, A Body Corporate Gefitinib sensitivity-related gene expression and products and methods related thereto
US9434994B2 (en) 2004-05-27 2016-09-06 The Regents Of The University Of Colorado, A Body Corporate Methods for prediction of clinical outcome to epidermal growth factor receptor inhibitors by non-small cell lung cancer patients
US20080090233A1 (en) * 2004-05-27 2008-04-17 The Regents Of The University Of Colorado Methods for Prediction of Clinical Outcome to Epidermal Growth Factor Receptor Inhibitors by Cancer Patients
US7696320B2 (en) 2004-08-24 2010-04-13 Domantis Limited Ligands that have binding specificity for VEGF and/or EGFR and methods of use therefor
US10596162B2 (en) 2005-02-03 2020-03-24 Wyeth Llc Method for treating gefitinib resistant cancer
US10603314B2 (en) 2005-02-03 2020-03-31 The General Hospital Corporation Method for treating gefitinib resistant cancer
US20060212008A1 (en) * 2005-02-24 2006-09-21 Peters Donna M Method for treating or preventing steroid-induced glaucoma
US8152784B2 (en) * 2005-02-24 2012-04-10 Wisconsin Alumni Research Foundation Method for treating or preventing steroid-induced glaucoma
US20090035281A1 (en) * 2005-03-10 2009-02-05 Universita Degli Studi "Magna Graecia" Di Catanzaro Combination of interleukin-6 antagonists and antiproliferative drugs
US20080182865A1 (en) * 2005-03-11 2008-07-31 Witta Samir E Histone deacetylase inhibitors sensitize cancer cells to epidermal growth factor inhibitors
WO2006099396A3 (en) * 2005-03-11 2007-04-12 Univ Colorado Histone deacetylase inhibitors sensitize cancer cells to epidermal growth factor inhibitors
US20080234265A1 (en) * 2005-03-11 2008-09-25 The Regents Of The University Of Colorado Histone Deacetylase Inhibitors Sensitize Cancer Cells to Epidermal Growth Factor Inhibitors
US20090191201A1 (en) * 2005-04-26 2009-07-30 Heiss Markus M Combination of the application of antibodies for immunostimulation together with glucocorticoids
US8709421B2 (en) * 2005-04-26 2014-04-29 Trion Pharma Gmbh Combination of the application of antibodies for immunostimulation together with glucocorticoids
US10071158B2 (en) 2005-04-26 2018-09-11 Lindis Biotech Gmbh Combination of the application of antibodies for immunostimulation together with glucocorticoids
US10576149B2 (en) 2005-04-26 2020-03-03 Lindis Biotech Gmbh Combination of the application of antibodies for immunostimulation together with glucocorticoids
US7691392B2 (en) 2005-04-29 2010-04-06 Kosan Biosciences Incorporated Method of treating multiple myeloma using 17-AAG or 17-AG or a prodrug of either
US20060252740A1 (en) * 2005-04-29 2006-11-09 Johnson Robert G Jr Method of treating multiple myeloma using 17-AAG or 17-AG or a prodrug of either in combination with a proteasome inhibitor
US20060252739A1 (en) * 2005-04-29 2006-11-09 Johnson Robert G Jr Method of treating multiple myeloma using 17-AAG or 17-AG or a prodrug of either
US20080032719A1 (en) * 2005-10-01 2008-02-07 Outland Research, Llc Centralized establishment-based tracking and messaging service
WO2007053284A3 (en) * 2005-10-28 2009-04-30 Kosan Biosciences Inc Method of treating breast cancer using 17-aag or 17-ag or a prodrug of either in combination with a her2 inhibitor
WO2007056244A2 (en) * 2005-11-04 2007-05-18 Merck & Co., Inc. Methods of using saha and erlotinib for treating cancer
US20070197473A1 (en) * 2005-11-04 2007-08-23 Frankel Stanley R Methods of using SAHA and Bortezomib for treating cancer
US20070197568A1 (en) * 2005-11-04 2007-08-23 Paul Bunn Methods of using SAHA and Erlotinib for treating cancer
US10729672B2 (en) 2005-11-04 2020-08-04 Wyeth Llc Antineoplastic combinations with mTOR inhibitor, trastuzumab and/or HKI-272
US20080221138A1 (en) * 2005-11-04 2008-09-11 Paul Bunn Method of using SAHA and Erlotinib for treating cancer
WO2007056244A3 (en) * 2005-11-04 2007-09-07 Merck & Co Inc Methods of using saha and erlotinib for treating cancer
US20090247549A1 (en) * 2005-11-04 2009-10-01 Frankel Stanley R Methods of using saha and bortezomib for treating cancer
US9539258B2 (en) 2005-11-11 2017-01-10 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
US9089571B2 (en) 2005-11-11 2015-07-28 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
US20090306044A1 (en) * 2005-11-11 2009-12-10 Flavio Solca Quinazoline derivatives for the treatment of cancer diseases
US20090306101A1 (en) * 2005-11-11 2009-12-10 Flavio Solca Combination treatment of cancer comprising egfr/her2 inhibitors
US8404697B2 (en) 2005-11-11 2013-03-26 Boehringer Ingelheim International Gmbh Quinazoline derivatives for the treatment of cancer diseases
US7648976B2 (en) 2005-11-23 2010-01-19 Bristol-Myers Squibb Company 17-allylamino-17-demethoxygeldanamycin polymorphs and formulations
US20070203110A1 (en) * 2005-11-23 2007-08-30 Licari Peter J 17-Allylamino-17-demethoxygeldanamycin polymorphs and formulations
US20090155283A1 (en) * 2005-12-01 2009-06-18 Drew Philip D Noncompetitive Domain Antibody Formats That Bind Interleukin 1 Receptor Type 1
WO2007079437A2 (en) * 2006-01-03 2007-07-12 Kereos, Inc. Combination antitumor therapies
WO2007079437A3 (en) * 2006-01-03 2008-01-10 Kereos Inc Combination antitumor therapies
US8067593B2 (en) 2006-01-26 2011-11-29 Boehringer Ingelheim International Gmbh Process for preparing aminocrotonylamino-substituted quinazoline derivatives
US7960546B2 (en) 2006-01-26 2011-06-14 Boehringer Ingelheim International Gmbh Process for preparing aminocrotonylamino-substituted quinazoline derivatives
US8188274B2 (en) 2006-01-26 2012-05-29 Boehringer Ingelheim International Gmbh Process for preparing aminocrotonylamino-substituted quinazoline derivatives
US20090306378A1 (en) * 2006-01-26 2009-12-10 Juergen Schroeder Process for preparing aminocrotonylamino-substituted quinazoline derivatives
US20110207929A1 (en) * 2006-01-26 2011-08-25 Boehringer Ingelheim International Gmbh Process for preparing aminocrotonylamino-substituted quinazoline derivatives
US20110207932A1 (en) * 2006-01-26 2011-08-25 Boehringer Ingelheim International Gmbh Process for preparing aminocrotonylamino-substituted quinazoline derivatives
US8877764B2 (en) 2006-09-18 2014-11-04 Boehringer Ingelheim International Gmbh Method for treating cancer harboring EGFR mutations
US20090318480A1 (en) * 2006-09-18 2009-12-24 Boehringer Ingelheim International Gmbh Method for treating cancer harboring egfr mutations
US20100113392A1 (en) * 2006-11-03 2010-05-06 Badros Ashraf Z Methods of using saha and bortezomib for treating multiple myeloma
US20090068110A1 (en) * 2006-12-22 2009-03-12 Genentech, Inc. Antibodies to insulin-like growth factor receptor
US11103580B2 (en) 2007-04-08 2021-08-31 Immunolight, Llc Methods and systems for treating cell proliferation disorders
US9358292B2 (en) 2007-04-08 2016-06-07 Immunolight, Llc Methods and systems for treating cell proliferation disorders
US9352040B2 (en) 2007-04-08 2016-05-31 Immunolight, Llc. Methods and systems for treating cell proliferation disorders
WO2008124681A3 (en) * 2007-04-08 2009-02-05 Immunolight Llc Methods and systems for treating cell proliferation disorders
US20080248001A1 (en) * 2007-04-08 2008-10-09 Immunolight Methods and systems for treating cell proliferation disorders
US10398777B2 (en) 2007-04-08 2019-09-03 Immunolight, Llc Methods and systems for treating cell proliferation disorders
CN101711246B (zh) * 2007-04-08 2014-06-25 免疫之光有限责任公司 治疗细胞增殖性疾病的方法和系统
US9682146B2 (en) 2007-04-08 2017-06-20 Immunolight, Llc. Methods and systems for treating cell proliferation related disorders
US20100291103A1 (en) * 2007-06-06 2010-11-18 Domantis Limited Polypeptides, antibody variable domains and antagonists
US8877186B2 (en) 2007-06-06 2014-11-04 Domantis Limited Polypeptides, antibody variable domains and antagonists
US20110160160A1 (en) * 2007-08-15 2011-06-30 The Research Foundation Of State University Of New York Methods for heat shock protein dependent cancer treatment
US8754094B2 (en) 2007-08-15 2014-06-17 The Research Foundation Of State University Of New York Methods for heat shock protein dependent cancer treatment
WO2009048947A1 (en) * 2007-10-09 2009-04-16 Board Of Regents, The University Of Texas System Methods of treatment of opioid tolerance, physical dependence, pain, and addiction with inhibitors of certain growth factor receptors
US8501740B2 (en) 2007-10-09 2013-08-06 Board Of Regents, The University Of Texas System Methods of treatment of opioid tolerance, physical dependence, pain and addiction with inhibitors of certain growth factor receptors
US20100210709A1 (en) * 2007-10-09 2010-08-19 Howard Gutstein B Methods of Treatment of Opioid Tolerance, Physical Dependence, Pain and Addiction With Inhibitors of Certain Growth Factor Receptors
US9630946B2 (en) 2007-10-17 2017-04-25 Wyeth Llc Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US10035788B2 (en) 2007-10-17 2018-07-31 Wyeth Llc Maleate salts of (E)-N-{4[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US9139558B2 (en) 2007-10-17 2015-09-22 Wyeth Llc Maleate salts of (E)-N-{4-[3-Chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US20090131367A1 (en) * 2007-11-19 2009-05-21 The Regents Of The University Of Colorado Combinations of HDAC Inhibitors and Proteasome Inhibitors
US10105323B2 (en) 2008-06-06 2018-10-23 Boehringer Ingelheim International Gmbh Pharmaceutical dosage form for immediate release of an indolinone derivative
US9907756B2 (en) 2008-06-06 2018-03-06 Boehringer Ingelheim International Gmbh Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative
US8545884B2 (en) 2008-06-06 2013-10-01 Boehringer Ingelheim International Gmbh Solid pharmaceutical formulations comprising BIBW 2992
US20110142929A1 (en) * 2008-06-06 2011-06-16 Boehringer Ingelheim International Gmbh Solid pharmaceutical formulations comprising bibw 2992
US9511063B2 (en) 2008-06-17 2016-12-06 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US10111868B2 (en) 2008-06-17 2018-10-30 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US9265784B2 (en) 2008-08-04 2016-02-23 Wyeth Llc Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine
US9211291B2 (en) 2009-04-06 2015-12-15 Wyeth Llc Treatment regimen utilizing neratinib for breast cancer
WO2010130757A1 (en) * 2009-05-14 2010-11-18 Boehringer Ingelheim International Gmbh New combination therapy in treatment of oncological and fibrotic diseases
EP2647375A1 (en) * 2009-05-14 2013-10-09 Boehringer Ingelheim International Gmbh Combination of vargatef and dabigatran for the treatment of oncological and fibrotic diseases
WO2010146059A2 (en) 2009-06-16 2010-12-23 F. Hoffmann-La Roche Ag Biomarkers for igf-1r inhibitor therapy
US10004743B2 (en) 2009-07-06 2018-06-26 Boehringer Ingelheim International Gmbh Process for drying of BIBW2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
US9545381B2 (en) 2009-07-06 2017-01-17 Boehringer Ingelheim International Gmbh Process for drying of BIBW2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
WO2011041582A2 (en) 2009-09-30 2011-04-07 President And Fellows Of Harvard College Methods for modulation of autophagy through the modulation of autophagy-inhibiting gene products
WO2011041584A2 (en) 2009-09-30 2011-04-07 President And Fellows Of Harvard College Methods for modulation of autophagy through the modulation of autophagy-enhancing gene products
WO2012027445A1 (en) 2010-08-26 2012-03-01 Boehringer Ingelheim International Gmbh Methods of administering an egfr inhibitor
US20180002399A1 (en) * 2010-12-09 2018-01-04 Five Prime Therapeutics, Inc. Fgfr1 extracellular domain combination therapies
US8828391B2 (en) 2011-05-17 2014-09-09 Boehringer Ingelheim International Gmbh Method for EGFR directed combination treatment of non-small cell lung cancer
US20190000920A1 (en) * 2011-11-14 2019-01-03 Five Prime Therapeutics, Inc. Methods of Treating Cancer
US10537611B2 (en) * 2011-11-14 2020-01-21 Five Prime Therapeutics, Inc. Methods of treating lung cancer
US9309228B2 (en) 2012-07-19 2016-04-12 Boehringer Ingelheim International Gmbh Fumaric acid salt of 9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one, its use as a medicament and the preparation thereof
US9242965B2 (en) 2013-12-31 2016-01-26 Boehringer Ingelheim International Gmbh Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors
CN106393602A (zh) * 2016-08-31 2017-02-15 宁波方正汽车模具有限公司 用于保险杠模具的顶出装置
CN110573608A (zh) * 2017-02-10 2019-12-13 施明哲 调节纤维母细胞生长因子受体3活化的组合物及方法
US11040973B2 (en) 2017-03-29 2021-06-22 Purdue Research Foundation Inhibitors of kinase networks and uses thereof
WO2018183586A1 (en) * 2017-03-29 2018-10-04 Purdue Research Foundation Inhibitors of kinase networks and uses thereof
US11891391B2 (en) 2017-03-29 2024-02-06 Purdue Research Foundation Inhibitors of kinase networks and uses thereof
US11434291B2 (en) 2019-05-14 2022-09-06 Provention Bio, Inc. Methods and compositions for preventing type 1 diabetes
US12006366B2 (en) 2021-01-26 2024-06-11 Provention Bio, Inc. Methods and compositions for preventing type 1 diabetes

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Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:STEFANIC, MARTIN F.;HILBERG, FRANK;MUNZERT, GERD;AND OTHERS;REEL/FRAME:015500/0192;SIGNING DATES FROM 20040909 TO 20041126

STCB Information on status: application discontinuation

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