US20150297604A1 - Combination Products with Tyrosine Kinase Inhibitors and their Use - Google Patents

Combination Products with Tyrosine Kinase Inhibitors and their Use Download PDF

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US20150297604A1
US20150297604A1 US14/388,334 US201314388334A US2015297604A1 US 20150297604 A1 US20150297604 A1 US 20150297604A1 US 201314388334 A US201314388334 A US 201314388334A US 2015297604 A1 US2015297604 A1 US 2015297604A1
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alkyl
halo
independently selected
haloalkyl
alkynyl
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Ralph Tiedt
Christian Chatenay-Rivauday
Monko Ito
Mikhail Akimov
Bin Peng
Ying Gong
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Novartis AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to pharmaceutical combinations, e.g. products, comprising a combination of (i) a MET inhibitor and (ii) an EGFR (ErbB-1) inhibitor, or a pharmaceutically acceptable salt thereof, respectively, or a prodrug thereof, which are jointly active in the treatment of proliferative diseases, corresponding pharmaceutical formulations, uses, methods, processes, commercial packages and related invention embodiments.
  • Multigenic diseases such as cancer or other proliferative diseases.
  • multi-target drugs In order to combat such diseases, one approach is to use single multi-target drugs however, here it is required that the targets causally involved into manifestation of a disease are all hit by the drug considered. On the other hand, multi-target drugs may lead to undesired side effects as they may also have impact on targets not involved in the disease manifestation.
  • a different approach is to use a combination of drugs as multi-target drugs. In the best scenario, this may lead to a combined efficiency, e.g. synergy, thus even allowing a reduction of side effects caused by the single drugs when used alone.
  • the components (combination partners) of such drugs may impact separate targets to create a combination effect, and thus may create a combination effect going beyond what is achievable with the single compounds and/or when considering their isolated effects, respectively, either in the same pathway or separate pathways, within an individual cell or in separate cells in separate tissues.
  • one component may alter the ability of another to reach its target, e.g. by inhibiting of efflux pumps or the like.
  • the combination partners may bind to separate sites of the same target.
  • the proto-oncogen cMET encodes the protein Hepatocyte Growth Factor Receptor (HGFR) which has tyrosine kinase activity and is essential for embryonic development and wound healing.
  • HGFR Hepatocyte Growth Factor Receptor
  • HGF Hepatocyte Growth Factor
  • MET Upon Hepatocyte Growth Factor (HGF) stimulation, MET induces several biological responses, leading to invasive growth.
  • Abnormal MET activation triggers tumor growth, formation of new blood vessels (angiogenesis) and metastasis, in various types of malignancies, including cancers of the kidney, liver, stomach, breast and brain.
  • c-MET dysregulated c-Met pathway plays important and sometimes causative (in the case of genetic alterations) roles in tumor formation, growth, maintenance and progression (Birchmeier, C. et al., Nat. Rev. Mol. Cell. Biol. 2003, 4(12):915-925; Boccaccio, C. et al., Nat. Rev. Cancer 2006, 6(8):637-645; Christensen, J. G. et al., Cancer Lett. 2005, 225(1):1-26). HGF and/or c-Met are overexpressed in significant portions of most human cancers, and are often associated with poor clinical outcomes such as more aggressive disease, disease progression, tumor metastasis and shortened patient survival.
  • c-Met receptor can also be activated in cancer patients through genetic mutations (both germline and somatic) and gene amplification. Although gene amplification and mutations are the most common genetic alterations that have been reported in patients, the receptor can also be activated by deletions, truncations, gene rearrangement.
  • carcinomas e.g., bladder, breast, cervical, cholangiocarcinoma, colorectal, esophageal, gastric, head and neck, kidney, liver, lung, nasopharygeal, ovarian, pancreas, prostate, thyroid
  • musculoskeletal sarcomas e.g., osteosarcaoma, synovial sarcoma, rhabdomyosarcoma
  • soft tissue sarcomas e.g., MFH/fibrosarcoma, leiomyosarcoma, Kaposi's sarcoma
  • hematopoietic malignancies e.g., multiple myeloma, lymphomas, adult T cell leukemia, acute myelogenous leukemia, chronic myeloid leukemia
  • other neoplasms e.g., glioblastomas, a
  • MET c-met and activated c-met mutations
  • agents include anti-HGF and antic-Met antibodies, HGF peptide antagonists, decoy c-Met receptor, c-Met peptide antagonists, dominant negative c-Met mutations, c-Met specific antisense oligonucleotides and ribozymes, and selective small molecule c-Met kinase inhibitors (Christensen, J. G. et al., Cancer Lett. 2005, 225(1):1-26).
  • abnormal HGF/MET signaling is also implicated in atherosclerosis, lung fibrosis, renal fibrosis and regeneration, liver diseases, allergic disorders, inflammatory and autoimmune disorders, cerebrovascular diseases, cardiovascular diseases, conditions associated with organ transplantation (Ma, H. et al., Atherosclerosis. 2002, 164(1):79-87; Crestani, B. et al., Lab. Invest. 2002, 82(8):1015-1022; Sequra-Flores, A. A. et al., Rev. Gastroenterol. Mex. 2004, 69(4)243-250; Morishita, R. et al., Curr. Gene Ther. 2004, 4(2)199-206; Morishita, R.
  • the Epidermal Growth Factor Receptor (EGFR, aka ErbB-1; HER1 in humans), is a receptor for ligands of the epidermal growth factor family.
  • EGFR Epidermal Growth Factor Receptor
  • HER1 ErbB-1
  • Several types of cancers are known to be dependent on EGFR over-activity or over-expression, such as lung cancer, anal cancers, glioblastoma multiforme and many other mainly epithelial cancers.
  • RTKs receptor tyrosine kinases
  • MET activation can compensate for loss of EGFR activity (by inhibition) by downstream activation of signal molecules such as HER3, such as MET amplification may compensate, or its ligand hepatocyte growth factor may activate MET (see Engelman, J. A., et al., Science, 316: 1039-1043, 2007; Yano, S., et al., Cancer Res, 68: 9479-9487, 2008; and Turke, A. B., et al., Cancer Cell, 17: 77-88, 2010).
  • MET-dependent cancer cell lines the proliferation of which depends on the activity of MET
  • ligand-induced EGFR activation see Bachleitner-Hofmann, T., et al., Mol Cancer Ther, 7: 3499-3508, 2008.
  • the present invention relates to a pharmaceutical combination (e.g. combination product) comprising (i) a MET inhibitor and (ii) an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, respectively, or a prodrug thereof, respectively, and at least one pharmaceutically acceptable carrier.
  • a pharmaceutical combination e.g. combination product
  • a pharmaceutical combination product comprising (i) a MET inhibitor and (ii) an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, respectively, or a prodrug thereof, respectively, and at least one pharmaceutically acceptable carrier.
  • a further embodiment of this invention provides a combination (e.g. combination product) comprising a quantity which is jointly therapeutically effective against an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer, comprising the combination partners (i) EGFR tyrosine kinase inhibitor and (ii) MET tyrosine kinase inhibitor, or, respectively, a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier material.
  • a combination e.g. combination product
  • a combination comprising a quantity which is jointly therapeutically effective against an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer, comprising the combination partners (i) EGFR tyrosine kinase inhibitor and (ii) MET tyrosine kinase inhibitor, or, respectively, a pharmaceutically acceptable salt thereof
  • a further embodiment relates to the use of the inventive combination (e.g. combination product) for treating an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer.
  • inventive combination e.g. combination product
  • a further embodiment relates to the use of a combination of (i) an EGFR tyrosine kinase inhibitor and (ii) a MET tyrosine kinase inhibitor or, respectively, a pharmaceutically acceptable salt thereof, for the manufacture of a medicament or a pharmaceutical product for treating an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer.
  • a further embodiment relates to a method of treating an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer, with a combination of (i) an EGFR tyrosine kinase inhibitor and (ii) a MET tyrosine kinase inhibitor or, respectively, a pharmaceutically acceptable salt thereof.
  • a further embodiment relates to a method for the treatment of an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer, said method comprising administering an effective amount of a combi-nation of or a combination product comprising (i) an EGFR tyrosine kinase inhibitor and (ii) a MET tyrosine kinase inhibitor to a subject in need thereof, such as a warm-blooded animal, in particular a human.
  • Yet a further embodiment of present invention relates to a pharmaceutical product or a commercial package comprising a combination product according to the invention described herein, in particular together with instructions for simultaneous, separate or sequential use (especially for being jointly active) thereof in the treatment of an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer, in particular for use in the treatment of an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer.
  • a further embodiment of present invention relates to the use of (i) an EGFR tyrosine kinase inhibitor and (ii) a MET tyrosine kinase inhibitor or, respectively, a pharmaceutically acceptable salt thereof, for the preparation of a combination (e.g. a combination product) according to present invention.
  • MET tyrosine kinase inhibitors useful according to the invention, those disclosed in WO 2011/018454 (incorporated herein by reference especially with regard to the classes of compounds and compounds disclosed therein) are a particular embodiment, especially those of the formula (I),
  • Y is C or N
  • X is CH or N
  • B is CH or N
  • A is a ring
  • R 1 is a group selected from i, ii and iii:
  • R 5 is heteroaryl
  • R 6 is hydrogen, deuterium, OH, methyl or halo
  • R 7 is hydrogen, deuterium, halo, or (C 1 -C 3 )alkyl, wherein said (C 1 -C 3 )alkyl is optionally substituted by one or more substituents independently selected from OH and halo;
  • n 0, 1 or 2;
  • R 2 is hydrogen, NH 2 , or (C 1 -C 4 )alkyl, wherein said (C 1 -C 4 )alkyl is optionally substituted by one or more substituents independently selected from OH, NH 2 and halo;
  • R 3 is hydrogen, —CONH 2 , —CONH(C 1 -C 4 )alkyl, —CONHphenyl, wherein the phenyl of said CONHphenyl is optionally substituted by one or more halo, —(C 1 -C 4 )alkyl, —CO(C 1 -C 4 )alkyl, —CO 2 (C 1 -C 4 )alkyl, phenyl, heteroaryl, —COheteroaryl, —CSNH 2 , —CSNH(C 1 -C 4 )alkyl, —CSNHbenzyl, —SO 2 (C 1 -C 4 )alkyl or —COCH 2 heterocyclyl, said heterocyclyl being optionally substituted by (C 1 -C 3 )alkyl;
  • R 4 is hydrogen or (C 1 -C 3 )alkyl
  • R 3 and R 4 together with the nitrogen to which they are attached form a 5 or 6 membered saturated or partially unsaturated monocyclic group comprising 1 ring N atom to which R 3 and R 4 are attached and optionally 1 additional ring heteroatom independently selected from N, O and S, wherein said monocyclic group is substituted by one or two ⁇ O substituents;
  • ring B is a fused aryl or fused heteroaryl ring, each optionally substituted with 1, 2, or 3 —W′—X′—Y′—Z′;
  • the compounds of formula III useful according to the invention have Formula IIIA:
  • the compounds of formula III useful according to the invention have Formula IIIB:
  • A is CH or N, especially N;
  • L 1 is (CR 4 R 5 ) m wherein each of R 4 and R 5 , independently of the other, is H or C 1-6 -alkyl and m is 0, 1 or 2,
  • L 2 is (CR 7 R 8 ) r wherein each of R 7 and R 8 , independently of the other, is H or C 1-6 -alkyl and r is 0, 1 or 2,
  • R 1 is H, halo or C 1-6 -alkyl
  • R 2 is H, halo or C 1-6 -alkyl
  • Cy 2 is aryl, especially phenyl, where said aryl or phenyl is unsubstituted or substituted by one to 3 moieties independently selected from the group consisting of C( ⁇ O)—NR c2 R d2 and halo, wherein R c2 and R d2 are independently selected from H, C 1-10 -alkyl and C 1-6 haloalkyl;
  • Such other MET inhibitors are, for example, selected from the following (including their pharmaceutically acceptable salts, and prodrugs thereof):
  • cabozantinib (Exelixis) (aka XL-184) (a highly preferred compound) which has the formula
  • tivatinib (ArQule, daiichi, Kyowa) (aka ARQ-197) (a highly preferred compound) which has the formula
  • MGCD-265 (MethylGene) (a highly preferred compound) which has the formula
  • AMG-208 (Amgen) (see also WO 2008/008539) which has the formula
  • JNJ-38877605 (Johnson & Johnson) (aka BVT051) (see also WO 2007/075567) which has the formula
  • EMD-1214063 (Merck Serono) (see also WO 2007/019933) which has the formula
  • HM-5016504 Human Medipharma
  • ficlatuzumab (AVEO) monoclonal antibody against HGF (preferred); onartuzumab (Roche) monoclonal antibody against MET (preferred); rilotuzumab (Amgen) monoclonal antibody against HGF (preferred); Tak-701 (Takeda) monoclonal antibody against HGF); LA-480 (Eli Lilly) monoclonal antibody against MET; and/or LY.2875358 (Eli Lilly) monoclonal antibody against MET.
  • EGFR tyrosine kinase inhibitors useful according to the invention those of the quinaolineamine class are to be mentioned, in particular.
  • EGFR tyrosine kinase inhibitors disclosed in WO 96/30347 are to be mentioned here, as a first group, especially 4-(substituted phenylamino)quinazoline derivatives of the formula
  • each R a , R b , R c and R d is independently selected from hydrogen, halo, hydroxy, amino, hydroxyamino, carboxy, C 1-8 alkoxycarbonyl, nitro, guanidino, ureido, carbamoyl,
  • each Ra or Rb is independently selected from cyano-C 1-8 alkyl and R9 wherein R9 is selected from the group consisting of R5, R5O, (R5) 2 N, R7C( ⁇ O), R5ONH, A and R5Y; wherein
  • R5 is C 1-8 alkyl
  • R6 is hydrogen or R5 wherein the R5s if more than one is present are the same or different;
  • R7 is R5, R5O or (R6) 2 N;
  • A is selected from piperidino, morpholino, pyrrolidino and 4-R6-piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, carboxy-C 1-8 alkyl, phenoxy, phenyl, phenylsulfanyl, C 2-8 alkenyl, (R5) 2 N-carbonyl-C 1-8 alkyl; and
  • Y is selected from S, SO, SO 2 ; the alkyl moieties in R5, R5O and (R5) 2 N are optionally substituted with halo or R9 wherein R9 is defined as above, and wherein the resulting groups are optionally substituted with halo or R9 with the proviso that a nitrogen, oxygen or sulfur atom and another heteroatom can not be attached to the same carbon atom, and with the further proviso that Ra and Rb may not comprise more than three R9 units;
  • each Ra or Rb is independently selected from R5-sulfonylamino, phthalimido-C 1-8 alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R10-C 2-4 alkanoylamino wherein R10 is selected from halo, R5O, C 2-4 alkanoyloxy, B7C( ⁇ O) and (R6) 2 N; and wherein said benzamido or benzenesulfonylamino or phenyl or phenoxy or anilino or phenylsulfanyl substituent in Ra or Rb may optionally bear one or two halogens, C 1-8 alkyl, cyano, methansulfonyl or C 1-8 alkoxy substituents;
  • Ra and Rb taken together with the carbons to which they are attached comprise a 5-8 membered ring comprising at least one or two heteroatoms selected from oxygen, sulfur or nitrogen; and wherein the alkyl groups and alkyl portions of the alkoxy or alkylamino groups may be straight chained or if comprised of at least three carbons may be branched or cyclic; each Rc and Rd is independently selected from hydrogen, optionally substituted C 1-8 alkyl, optionally substituted amino, halo, hydroxy, optionally substituted hydroxy; or from azido or R11-ethynyl wherein R11 is selected from hydrogen, optionally substituted C 1-8 alkyl wherein the substituents are selected from hydrogen, amino, hydroxy, R5O, R5NH and (R5) 2 N;
  • X is N
  • Ra is C 1-8 alkyloxy
  • Rb is di-(C 1-8 alkyl)-amino-C 1-8 alkoxy, pyrrolidin-1-yl-C 1-8 alkoxy, piperidino-C 1-8 alkoxy, morpholino-C 1-8 alkoxy, piperazin-1-yl-C 1-8 alkoxy, 4-C 1-8 alkylpiperazin-1-yl-C 1-8 alkoxy, imidazol-1-yl-C 1-8 alkoxy, di-(C 1-8 alkoxy-C 1-8 alkyl)-amino-C 1-8 alkoxy, thiomorpholino-C 1-8 alkoxy, 1-oxothiomorpholino-C 1-8 alkoxy or 1,1-dioxothiomorpholino-C 1-8 alkoxy, and wherein any of the above-mentioned Rb substituents comprising a CH 2 (methylene) group which is not attached to a N or O atom optionally bears on said CH 2 group a hydroxy substitu
  • Rc and Rd are independently of the other halo, trifluoromethyl or C 1-8 alkyl;
  • This compound or its pharmaceutically acceptable salts are especially preferred in the embodiments of the present invention.
  • Ra and Rb is a group CH 3 SO 2 CH 2 CH 2 NHCH 2 —Ar—, wherein Ar is selected from phenyl, furanyl, thiophenyl, pyrrolyl and thiazolyl, each of which may optionally be substituted by one or two substituents selected from the group consisting of one or two halo, C 1-8 alkyl and C 1-8 alkoxy; the other of Ra and Rb is selected from the group consisting of hydrogen, halo, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylamino and di(C 1-8 alkyl)amino;
  • Rc and Rd represents benzyl, halo-, dihalo- or trihalobenzyl, trihalomethylbenzyl, benzoyl, pyridylmethyl, pyridylmethoxy, phenoxy, benzyloxy, halo-, dihalo- or trihalobenzyloxy, trihalomethylbenzyloxy, benzenesulphonyl or hydrogen;
  • Rc and Rd is hydrogen or hydroxy, halo, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, amino, C 1-8 alkylamino, di(C 1-8 alkyl)amino, C 1-8 alkylthio, C 1-8 alkylsulphinyl, C 1-8 alkylsulphonyl, C 1-8 alkylcarbonyl, carboxyl, carbamoyl, C 1-8 alkoxycarbonyl, C 1-8 alkanoylamino, N—(C 1-8 alkyl)carbamoyl, N,N-di(C 1-8 alkyl)carbamoyl, cyano, nitro or trifluoromethyl;
  • EGFR tyrosine kinase inhibitors disclosed in WO97/38983 or especially WO2000031048 are to be mentioned here, as a fourth group, especially 4-(substituted phenylamino)quinazoline derivatives of the formula
  • Ra is D-E-F and Rb is —SR 4* , halo, —OR 4* , —NHR 3* or hydrogen, or
  • Rb is D-E-F and Ra is —SR 4* , halo, —OR 4* , —NHR 3* or hydrogen,
  • D is N(R 2* )—, —O—, —CH(R 2* )—, —N(R 2* )—NH—, —N(R 2* )—O—, —CH(R 2* )—NH—, —CH(R 2* )—O—, —CH(R 2* )—CH 2 —, —NH—CH(R 2* )—, —O—CH(R 2* )—, —S—CH(R 2* )— or absent;
  • E is —C( ⁇ O)—, —S( ⁇ O) 2 —, —P( ⁇ O)(OR 2* )— or —S( ⁇ O)—,
  • F is —C(R 1* ) ⁇ CHR 5* , —C ⁇ C—R 5* , or —C(R 1* ) ⁇ C ⁇ CHR 5* ;
  • E is S( ⁇ O) 2 — or —S( ⁇ O)—
  • D is not —NH—CH(R 2* )— or —O—CH(R 2* )—;
  • R 1* is hydrogen, halogen or C 1-8 alkyl
  • R 2* , R 3* and R 4* are independently hydrogen, C 1-6 alkyl, —(CH 2 ) n* —N-piperidinyl, —(CH 2 ) n* —N— piperazinyl, —(CH 2 ) n* —N 1 -piperazinyl(N 4 —C 1-6 alkyl), —(CH 2 ) n* —N-pyrrolidinyl, —(CH 2 ) n* —N-pyridinyl, —(CH 2 ) n* —N-imidazolyl, —(CH 2 ) n* —N-morpholinyl, —(CH 2 ) n* —N-thiomorpholinyl, —(CH 2 ) n* —N-hexohydroazepinyl or substituted C 1-8 alkyl, wherein the substituents are selected from —OH, —NH 2 , or —N
  • Rc and Rd are independently hydrogen, halo, C 1-8 alkyl, C 3-8 cyloalkyl, C 1-8 alkoxy, C 3-8 cycloalkoxy, nitro, C 1-6 perfluoroalkyl, hydroxy, C 1-6 acyloxy, amino, —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH(C 3-8 cycloalkyl), —NH(C 3-8 cycloalkyl) 2 , hydroxymethyl, C 1-8 acyl, cyano, azido, C 1-8 thioalkyl, C 1-8 sulfinylalkyl, C 1-8 sulfonylalkyl, C 3-8 thiocycloalkyl, C 3-8 sulfinylcycloalkyl, C 3-8 sulfonylcycloalkyl, mercapto, C 1-6 alkoxycarbonyl, C 3-8 cyclo
  • R 5* is hydrogen, halo, C 1-6 perfluoroalkyl, 1,1-difluoro-C 1-6 alkyl, C 1-6 alkyl, —(CH 2 ) n* —N-piperidinyl, —(CH 2 ) n* N-piperazinyl, —(CH 2 ) n* —N 1 -piperazinyl(N 4 —C 1-6 alkyl), —(CH 2 ) n* —N-pyrrolidinyl, —(CH 2 ) n* —N— pyridyl, —(CH 2 ) n* —N-imidazolyl, —(CH 2 ) n* —N-morpholinyl, —(CH 2 ) n* —N-thiomorpholinyl, —CH ⁇ CH 2 , —CH ⁇ CH—C 1-8 alkyl, —(CH 2 ) n* —N-hex
  • R 6* is hydrogen or C 1-8 alkyl
  • n* is 1 to 8, especially 1 to 4; especially the compound of the formula
  • canertinib e.g. used as dihydrochloride
  • canertinib e.g. used as dihydrochloride
  • EGFR tyrosine kinase inhibitors disclosed in WO2005028443 (which is incorporated herein by reference with regard to the generic and specific compounds disclosed therein) are to be mentioned here, as a fifth group, especially 4-(substituted phenylamino)quinazoline derivatives of the formula
  • Ra is C 1-8 alkoxy
  • Rb is amino- or N—[N′-mono- or N′,N′-di(C 1-6 alkyl)]amino ⁇ -C 4-8 alkenoyl)-amino;
  • Rc is halo or R 2 **—(CH 2 ) n** R 3 **—
  • R 2 ** is a pyridyl, thiophenyl, pyrimidinyl, thiazolyl or phenyl, each optionally substituted with up to three substituents selected from C 1-8 alkyl, C 1-8 alkoxy and halogen, R 3 ** is —O— or —S— and n** is 0 to 8, preferably 0 or 1;
  • EGFR inhibitors also antibodies may be mentioned, e.g. Cetuximab (Erbitux®) (ImClone Systems, Bristol-Myers Squibb and Merck KgaA) which is a chimeric (mouse/human) monoclonal antibody, active as an epidermal growth factor receptor (EGFR) inhibitor, which can be administered e.g. intravenously.
  • Cetuximab Erbitux®
  • EGFR epidermal growth factor receptor
  • X is N or C(CN);
  • Ra is selected from the group consisting of C 1-8 alkyloxy or (C 1-8 alkyloxy, 1-piperidin-1-yl, 1-piperazin-1-yl, 4-C 1-8 alkyl-piperazin-1-yl, morpholin-1-yl, thiomorpholino-1-yl, S-oxothiomorpholin-1-yl or S,S-dioxothiomorpholinyl-1-yl)-C 1-8 alkyloxy;
  • Rb is selected from C 3-8 alkenoyl, ⁇ amino- or N—[N′-mono- or N′,N′-di(C 1-8 alkyl)]amino ⁇ -C 4-8 alkenoyl)-amino, [(C 1-8 alkylsulfonyl-C 1-8 alkylamino)-C 1-8 alkyl]-furyl or (C 1-8 alkyloxy, 1-piperidin-1-yl, 1-piperazin-1-yl, 4-C 1-8 alkyl-piperazin-1-yl, morpholin-1-yl, thiomorpholin-1-yl, S-oxothiomorpholin-1-yl or S,S-dioxothiomorpholinyl-1-yl)-C 1-8 alkyloxy;
  • Rc is halo or C 2-8 alkynyl
  • Rd is hydrogen, pyridinyl-C 1-8 alkyloxy or unsubstituted or halogen substituted phenyl-C 1-8 alkyloxy;
  • X is N or C(CN);
  • Ra is methoxy, ethoxy, 3-morpholinopropyloxy or 2-methoxyethoxy
  • Rb is 4-(dimethylamino)-but-2-enoylamino, prop-2-enoylamino, 5-[(2-methylsulfonyl-ethyl)aminomethyl]-furan-2-yl, 2-methoxyethoxy or 3-morpholinopropoxy;
  • Rc is chloro or ethynyl
  • Rd is hydrogen, fluoro, pyridin-2-ylmethoxy or 3-fluorophenyl-methoxy
  • C 1-8 is preferably C 1-6 , more preferably C 1-4 , meaning a linear or branched moiety with 1 to 8, 1 to 6 or 1 to 4 carbon atoms, respectively.
  • C 2-8 is preferably C 2-6 , more preferably C 2-4 , meaning a linear or branched moiety with 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.
  • C 3-8 is preferably C 3-6 , more preferably C 3-4 , meaning moiety with 3 to 8, 3 to 6 or 3 to 4 carbon atoms, respectively.
  • C 4-8 is preferably C 4-6 , more preferably C 4 , meaning a linear or branched moiety with 4 to 8, 4 to 6 or 4 carbon atoms, respectively.
  • Lower refers to a group with up to 8, especially up to 6 carbon atoms, if not defined otherwise.
  • lower alkyl refers to C 1-8 alkyl, e.g. C 1-6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
  • substituents of compounds useful according to the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • C 1-6 alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • stable refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
  • alkyl (also in alkoxy, arylalkyl, heteroarylalkyl, haloalkyl or the like) is meant to refer to a saturated hydrocarbon group which is straight-chained or branched.
  • Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
  • An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • alkylyene refers to a linking alkyl group.
  • alkenyl refers to an alkyl group having one or more double carbon-carbon bonds.
  • Example alkenyl groups include ethenyl, propenyl, and the like.
  • alkenylene refers to a linking alkenyl group.
  • alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds.
  • Example alkynyl groups include ethynyl, propynyl, and the like.
  • alkynylene refers to a linking alkynyl group.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.
  • aryl refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms.
  • arylene refers to a linking aryl group.
  • cycloalkyl refers to non-aromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spirocycles.
  • cycloalkyl groups can have from 3 to about 20 carbon atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3 to 7 carbon atoms. Cycloalkyl groups can further have 0, 1, 2, or 3 double bonds and/or 0, 1, or 2 triple bonds.
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of pentane, pentene, hexane, and the like.
  • a cycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion.
  • One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulfido substituent.
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
  • cycloalkylene refers to a linking cycloalkyl group.
  • heteroaryl refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety.
  • heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like.
  • the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.
  • heteroarylene refers to a linking heteroaryl group.
  • heterocycloalkyl or “heterocyclyl” refers to a non-aromatic heterocycle where one or more of the ring-forming atoms is a heteroatom such as an O, N, or S atom.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spirocycles.
  • heterocycloalkyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like.
  • heterocycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles.
  • a heterocycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion.
  • moieties where one or more ring-forming atoms is substituted by 1 or 2 oxo or sulfido groups.
  • the heterocycloalkyl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.
  • heterocycloalkylene refers to a linking heterocycloalkyl group.
  • biasing refers to an aryl group substituted by another aryl group.
  • heteroaryl refers to a heteroaryl group substituted by another heteroaryl group.
  • halo or “halogen” includes fluoro, chloro, bromo, and iodo.
  • alkoxy refers to an O-alkyl group.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • acyl includes an organic radical corresponding to the residue of, for example, an organic acid from which the hydroxyl group has been removed, i.e., a radical having the formula R A —C(O)—, where R A may in particular be aliphatic or substituted aliphatic, or it may for example be a substituted or unsubstituted mono- or bi-cyclic ring.
  • R may be selected from lower C 1 -C 5 alkyl, C 3 -C 7 cycloalkyl, phenyl, benzyl or phenethyl group.
  • exemplary acyl is alkyl-carbonyl.
  • Examples of acyl groups include, but are not limited to, acetyl, propionyl and butyryl.
  • Lower acyl is for example formyl or lower alkylcarbonyl, in particular acetyl.
  • MET and FGFR inhibitors can be manufactured as described in the patent applications and patents mentioned above, which are also incorporated by reference especially with regard to their manufacturing methods.
  • Compounds useful according to the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, 125 I respectively.
  • Various isotopically labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H, 13 C, and 14 C are incorporated.
  • Such isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or labeled compound may be particularly preferred for PET or SPECT studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a. readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium, for example in the ranges given above.
  • Isotopically-labeled MET and/or EGFR tyrosine kinase inhibitor compounds forming part of a combination product according to the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • the present invention embodiments also include pharmaceutically acceptable salts of the compounds useful according to the invention described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences , 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • prodrugs refer to any covalently bonded carriers which release the active parent drug when administered to a mammalian subject.
  • Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design , ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.
  • a compound included in the inventive combination products e.g. an EGFR tyrosine kinase inhibitor and/or a MET tyrosine kinase inhibitor
  • the present invention relates to a pharmaceutical combination, especially a pharmaceutical combination product, comprising the mentioned combination partners and at least one pharmaceutically acceptable carrier.
  • Combination refers to formulations of the separate partners with or without instructions for combined use or to combination products.
  • the combination partners may thus be entirely separate pharmaceutical dosage forms or pharmaceutical compositions that are also sold independently of each other and where just instructions for their combined use are provided in the package equipment, e.g. leaflet or the like, or in other information e.g. provided to physicians and medical staff (e.g. oral communications, communications in writing or the like), for simultaneous or sequential use for being jointly active, especially as defined below.
  • the terms “coadministration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration and/or at the same time.
  • combination product as used herein thus means a pharmaceutical product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients (which may also be combined).
  • fixed combination means that the active ingredients, e.g. an EGFR tyrosine kinase inhibitor and MET tyrosine kinase inhibitor, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • the active ingredients arepresent in one dosage form, e.g. in one tablet or in one capsule.
  • non-fixed combination means that the active ingredients are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • non-fixed combination thus defines especially a “kit of parts” in the sense that the combination partners (i) EGFR tyrosine kinase inhibitor and (ii) MET tyrosine kinase inhibitor (and if present further one or more co-agents) as defined herein can be dosed independently of each other or by use of different fixed combinations with distinguished amounts of the combination partners, i.e.
  • the combination partners may also be used as entirely separate pharmaceutical dosage forms or pharmaceutical formulations that are also sold independently of each other and just instructions of the possibility of their combined use is or are provided in the package equipment, e.g. leaflet or the like, or in other information e.g. provided to physicians and medical staff.
  • the independent formulations or the parts of the kit of parts can then, e.g. be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the time intervals are chosen such that the effect on the treated disease in the combined use of the parts is larger than the effect which would be obtained by use of only any one of the combination partners (i) and (ii), thus being jointly active.
  • the ratio of the total amounts of the combination partner (i) to the combination partner (ii) to be administered in the combined preparation can be varied, e.g. in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient which different needs can be due to age, sex, body weight, etc. of the patients.
  • the invention also relates to (i) a MET inhibitor and (ii) an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for combined use in a method of treating an EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease, especially a cancer.
  • the MET inhibitor and the EGFR inhibitor for use according to the preceding paragraph are selected as follows:
  • the MET tyrosine kinase inhibitor is selected from the group consisting of (E)-2-(1-(3-((7-fluoroquinolin-6-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethylidene)hydrazinecarboxamide and/or (especially or) 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)imidazo[1,2-b]triazin-2-yl]benzamide, or a pharmaceutically acceptable salt or prodrug thereof, respectively,
  • the EGFR inhibitor is gefinitib and/or (especially or) elotinib, or a pharmaceutically acceptable salt or prodrug thereof.
  • the combination partners (i) and (ii) in any invention embodiment are preferably formulated or used to be jointly (prophylactically or especially therapeutically) active.
  • the term “jointly (therapeutically) active” may mean that the compounds may be given separately or sequentially (in a chronically staggered manner, especially a sequence-specific manner) in such time intervals that they preferably, in the warm-blooded animal, especially human, to be treated, and still show a (preferably synergistic) interaction (joint therapeutic effect).
  • a joint therapeutic effect can, inter alia, be determined by following the blood levels, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals, but this is not to exclude the case where the compounds are jointly active although they are not present in blood simultaneously.
  • the present invention thus pertains to a combination product for simultaneous, separate or sequential use, such as a combined preparation or a pharmaceutical fixed combination, or a combination of such preparation and combination.
  • the compounds useful according to the invention may be manufactured and/or formulated by the same or different manufacturers.
  • the combination partners may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of a physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.
  • any of the above methods involve further administering one or more other (e.g. third) co-agents, especially a chemotherapeutic agent.
  • one or more other (e.g. third) co-agents especially a chemotherapeutic agent.
  • the invention relates in a further embodiment to a combination product, particularly a pharmaceutical composition, comprising a therapeutically effective amount of (i) an EGFR tyrosine kinase inhibitor and (ii) a MET tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, respectively, and at least one third therapeutically active agent (co-agent), e.g. another compound (i) and/or (ii) or a different co-agent.
  • the additional co-agent is preferably selected from the group consisting of an anti-cancer agent; an anti-inflammatory agent.
  • the combination partners forming a corresponding product according to the invention may be mixed to form a fixed pharmaceutical composition or they may be administered separately or pairwise (i.e. before, simultaneously with or after the other drug substance(s)).
  • a combination product according to the invention can besides or in addition be administered especially for cancer therapy in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention, or a combination of these.
  • Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above.
  • Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
  • Possible anti-cancer agents include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity; anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used
  • combination products according to the invention may be used in combination with other tumor treatment approaches, including surgery, ionizing radiation, photodynamic therapy, implants, e.g. with corticosteroids, hormones, or they may be used as radiosensitizers.
  • aromatase inhibitor as used herein relates to a compound which inhibits the estrogen production, i.e. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
  • antiestrogen as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level.
  • the term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride.
  • anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX), which can be formulated, e.g. as disclosed in U.S. Pat. No. 4,636,505.
  • CASODEX bicalutamide
  • gonadorelin agonist as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate.
  • topoisomerase I inhibitor as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in WO99/17804).
  • topoisomerase II inhibitor includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, e.g. CAELYX), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • anthracyclines such as doxorubicin (including liposomal formulation, e.g. CAELYX), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • doxorubicin including liposomal formulation, e.g. CAELYX
  • daunorubicin including liposomal formulation, e
  • microtubule active compound relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, e.g. paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine, discodermolides, cochicine and epothilones and derivatives thereof, e.g. epothilone B or D or derivatives thereof.
  • taxanes e.g. paclitaxel and docetaxel
  • vinca alkaloids e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine
  • discodermolides cochicine and epothilones and derivatives thereof, e.g. epothilone B or D or derivative
  • alkylating compound includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel).
  • histone deacetylase inhibitors or “HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes compounds disclosed in WO 02/22577, especially N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide and pharmaceutically acceptable salts thereof. It further especially includes Suberoylanilide hydroxamic acid (SAHA).
  • SAHA Suberoylanilide hydroxamic acid
  • HDAC histone deacetylase
  • SAHA suberoylanilide hydroxamic acid
  • Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat. No.
  • antimetabolite includes, but is not limited to, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed.
  • platinum compound as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • compounds targeting/decreasing a protein or lipid kinase activity includes, but is not limited to, c-Met tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g.,
  • PDGFR platelet-derived growth factor-receptors
  • compounds which target, decrease or inhibit the activity of PDGFR especially compounds which inhibit the PDGF receptor, e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib, SU101, SU6668 and GFB-111;
  • IGF-IR insulin-like growth factor receptor I
  • compounds which target, decrease or inhibit the activity of IGF-IR especially compounds which inhibit the kinase activity of IGF-I receptor, such as those compounds disclosed in WO 02/092599, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors;
  • Kit/SCFR receptor tyrosine kinase e.g. imatinib
  • UCN-01 safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isochinoline compounds such as those disclosed in WO 00/09495; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor);
  • compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (GLEEVEC) or tyrphostin.
  • a tyrphostin is preferably a low molecular weight (Mr ⁇ 1500) compound, or a pharmaceutically acceptable salt thereof, especially a compound selected from the benzylidenemalonitrile class or the S-arylbenzenemalonirile or bisubstrate quinoline class of compounds, more especially any compound selected from the group consisting of Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4- ⁇ [(2,5-dihydroxyphenyl)methyl]amino ⁇ -benzoic acid adamantyl ester; NSC 680410, adaphostin);
  • k) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 97/02266, e.g. the compound of ex.
  • trastuzumab HerceptinTM cetuximab (ErbituxTM), Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives which are disclosed in WO 03/013541; and
  • l compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF;
  • anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (THALOMID) and TNP-470.
  • TAALOMID thalidomide
  • TNP-470 TNP-470.
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase includes, but is not limited to inhibitors of phosphatase 1, phosphatase 2A, or CDC25, e.g. okadaic acid or a derivative thereof.
  • Compounds which induce cell differentiation processes includes, but is not limited to e.g. retinoic acid, ⁇ - ⁇ - or ⁇ -tocopherol or ⁇ - ⁇ - or ⁇ -tocotrienol.
  • cyclooxygenase inhibitor includes, but is not limited to, e.g. Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, e.g. 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • Cox-2 inhibitors such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, e.g. 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • bisphosphonates as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (CerticanTM), CCI-779 and ABT578.
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulfate degradation.
  • the term includes, but is not limited to, PI-88.
  • biological response modifier refers to a lymphokine or interferons, e.g. interferon ⁇ .
  • inhibitor of Ras oncogenic isoforms e.g. H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras e.g. a “farnesyl transferase inhibitor” e.g. L-744832, DK8G557 or R115777 (Zarnestra).
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase.
  • Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, e.g. telomestatin.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • Compounds which target, decrease or inhibit the activity of methionine aminopeptidase are e.g. bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • Compounds which target, decrease or inhibit the activity of the proteasome include e.g. Bortezomid (VelcadeTM) and MLN 341.
  • matrix metalloproteinase inhibitor or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.
  • MMP matrix metalloproteinase inhibitor
  • FMS-like tyrosine kinase inhibitors e.g. compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors e.g. compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • FMS-like tyrosine kinase receptors are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, e.g. PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90 e.g., 17-allylamino,17-demethoxygeldanamycin (17AAG, 17-DMAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors; IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide, AUY922 from Novartis.
  • antiproliferative antibodies includes, but is not limited to erbitux, bevacizumab, rituximab, PRO64553 (anti-CD40) and 2C4 Antibody.
  • antibodies is meant e.g. intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
  • antigenemic compounds includes, for example, Ara-C, a pyrimidine analog, which is the 2′′-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.
  • Ara-C Ara-C
  • pyrimidine analog which is the 2′′-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine.
  • purine analog of hypoxanthine 6-mercaptopurine (6-MP)
  • 6-MP 6-mercaptopurine
  • fludarabine phosphate fludarabine phosphate.
  • compounds of formula (I) can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
  • compounds of formula (I) can be administered in combination with, e.g., farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • drugs useful for the treatment of AML such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • “Somatostatin receptor antagonists” as used herein refers to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230.
  • Tumor cell damaging approaches refer to approaches such as ionizing radiation.
  • ionizing radiation means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology , Devita et al., Eds., 4 th Edition, Vol. 1, pp. 248-275 (1993).
  • EDG binders refers a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
  • kinesin spindle protein inhibitors is known in the field and includes SB715992 or SB743921 from GlaxoSmithKline, pentamidine/chlorpromazine from CombinatoRx.
  • MEK inhibitors is known in the field and includes ARRY142886 from Array PioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, leucovorin.
  • ribonucleotide reductase inhibitors includes, but is not limited to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
  • ara-C cytosine arabinoside
  • 6-thioguanine 5-fluorouracil
  • cladribine 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
  • Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives, such as PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned in Nandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953-961 (1994).
  • S-adenosylmethionine decarboxylase inhibitors includes, but is not limited to the compounds disclosed in U.S. Pat. No. 5,461,076.
  • VEGF/VEGFR disclosed in WO 98/35958, e.g. 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, e.g. the succinate, or in WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769 947; those as described by Prewett et al, Cancer Res, Vol. 59, pp. 5209-5218 (1999); Yuan et al., Proc Natl Acad Sci USA, Vol. 93, pp.
  • Photodynamic therapy refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers.
  • Examples of photodynamic therapy includes treatment with compounds, such as e.g. VISUDYNE and porfimer sodium.
  • Angiostatic steroids refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone. hydrocortisone, 11- ⁇ -epihydrocotisol, cortexolone, 17 ⁇ -hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • Corticosteroids as used herein includes, but is not limited to compounds, such as e.g. fluocinolone, dexamethasone; in particular in the form of implants.
  • chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • a combination product according to the invention may also be used in combination with or comprise one or more further drug substances selected from the group of anti-inflammatory drug substances; antihistamine drug substances; bronchodilatatory drug substances, NSAID; antagonists of chemokine receptors.
  • Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/035668, WO 03/048181, WO 03/062259, WO 03/064445, WO 03/072592, nonsteroidal glucocorticoid receptor agonists such as those described in WO 00/00531, WO 02/10143, WO 03/082280, WO 03/082787, WO 03/104195, WO 04/005229;
  • steroids in particular glucocorticosteroids such as budesonide,
  • LTB4 antagonists such LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247 and those described in U.S. Pat. No. 5,451,700; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such as cilomilast, Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICIDTM CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kog
  • Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but also those described in WO 01/04118, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP 424021, U.S. Pat. No. 5,171,744, U.S. Pat. No. 3,714,357, WO 03/33495 and WO 04/018422.
  • Suitable chemokine receptors include, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, Takeda antagonists such as N-[[4-[[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-amin-ium chloride (TAK-770), and CCR-5 antagonists described in U.S. Pat. No. 6,166,037 (particularly claims 18 and 19 ), WO 00/66558 (particularly claim 8 ), WO 00/66559 (
  • Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine as well as those disclosed in WO 03/099807, WO 04/026841 and JP 2004107299.
  • pharmaceutically effective preferably relates to an amount that is therapeutically or in a broader sense also prophylactically effective against the progression of a disease or disorder as disclosed herein.
  • a commercial package as used herein defines especially a “kit of parts” in the sense that the components (a) MET tyrosine kinase inhibitor and (b) FGFR tyrosine kinase inhibitor as defined above and below, and optionally further co-agents, can be dosed independently or by use of different fixed combinations with distinguished amounts of the components (a) and (b), i.e., simultaneously or at different time points.
  • these terms comprise a commercial package comprising (especially combining) as active ingredients components (a) and (b), together with instructions for simultaneous, sequential (chronically staggered, in time-specific sequence, preferentially) or (less preferably) separate use thereof in the delay of progression or treatment of a proliferative disease.
  • the parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the time intervals are chosen such that the effect on the treated disease in the combined use of the parts is larger than the effect which would be obtained by use of only any one of the combination partners (a) and (b) (as can be determined according to standard methods.
  • the ratio of the total amounts of the combination partner (a) to the combination partner (b) to be administered in the combined preparation can be varied, e.g., in order to cope with the needs of a patient sub-population to be treated or the needs of the single patient which different needs can be due to the particular disease, age, sex, body weight, etc. of the patients.
  • there is at least one beneficial effect e.g., a mutual enhancing of the effect of the combination partners (a) and (b), in particular a more than additive effect, which hence could be achieved with lower doses of each of the combined drugs, respectively, than tolerable in the case of treatment with the individual drugs only without combi-nation, producing additional advantageous effects, e.g., less side effects or a combined therepeutic effect in a non-effective dosage of one or both of the combination partners (components) (a) and (b), and very preferably a strong synergism of the combination partners (a) and (b).
  • a beneficial effect e.g., a mutual enhancing of the effect of the combination partners (a) and (b)
  • a more than additive effect which hence could be achieved with lower doses of each of the combined drugs, respectively, than tolerable in the case of treatment with the individual drugs only without combi-nation
  • additional advantageous effects e.g., less side effects or a combined therepeutic effect in a non-
  • any combination of simultaneous, sequential and separate use is also possible, meaning that the components (a) and (b) may be administered at one time point simultaneously, followed by administration of only one component with lower host toxicity either chronically, e.g., more than 3-4 weeks of daily dosing, at a later time point and subsequently the other component or the combination of both components at a still later time point (in subsequent drug combination treatment courses for an optimal effect) or the like.
  • the combination products according to the present invention are appropriate for the treatment of various diseases that are mediated by, especially depend on, the activity of EGFR and/or MET tyrosine kinase, respectively. They can thus be used in the treatment of any of the diseases that can be treated by EGFR tyrosine kinase inhibitors and MET tyrosine kinase inhibitors.
  • FGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated disease refers especially to a disease in which activity of one or both kinases leads to abnormal activity of the regulatory pathways including one of both kinases, especially where one or both of the kinases is overactive, e.g. due to overexpression, mutation or relative lack of activity of other regulatory pathways in the cell, e.g. where there is amplification, constitutive activation and/or overactivation of preceding or subsequent regulatory elements.
  • EGFR inhibitors are e.g. useful in the treatment of one or more of the diseases which respond to an inhibition of EGFR activity, especially a neoplastic or tumor disease, especially solid tumor, more especially those cancers in which EGFR kinases are implicated including breast cancer, gastric cancer, lung cancer, cancer of the prostate, bladder cancer and endometrial cancer. Further cancers include cancer of the kidney, liver, adrenal glands, stomach, ovaries, colon, rectum, pancreas, vagina or thyroid, sarcoma, glioblastomas and numerous tumours of the neck and head, as well as leukemias and multiple myeloma. Especially preferred are cancers of breast or ovary; lung cancer, e.g.
  • NSCLC or SCLC head and neck, renal, colorectal, pancreas, bladder, gastric or prostate cancer; or glioma; in particular, glioma or colon, rectum or colorectal cancer or more particularly lung cancer are to be mentioned.
  • diseases dependent on ligands of EGFR such as EGF; TGF- ⁇ ; HB-EGF; amphiregulin; epiregulin; betacellulin, are included.
  • MET inhibitors are e.g. useful in the treatment of MET related diseases, especially cancers that display evidence for simultaneous activation of MET and FGFR, including gene amplification, activating mutations, expression of cognate RTK ligands, phosphorylation of RTKs at residues indicative of activation, e.g.
  • cancer is selected from the group consisting of brain cancer, stomach cancer, genital cancer, urinary cancer, prostate cancer, (urinary) bladder cancer (superficial and muscle invasive), breast cancer, cervical cancer, colon cancer, colorectal cancer, glioma (including glioblastoma, anaplastic astrocytoma, oligoastrocytoma, oligodendroglioma), esophageal cancer, gastric cancer, gastrointestinal cancer, liver cancer, hepatocellular carcinoma (HCC) including childhood HCC, head and neck cancer (including head and neck squamous-cell carcinoma, nasopharyngeal carcinoma), Hurthle cell carcinoma, epithelial cancer, skin cancer, melanoma (including malignant melanoma), mesothelioma, lymphoma, myeloma (including multiple myeloma), leukemias, lung cancer (including non-small cell lung cancer (including all histological subtypes: adeno
  • MET inhibitors are e.g. also useful in the treatment of cancer wherein the cancer is stomach, colon, liver, genital, urinary, melanoma, or prostate.
  • the cancer is liver or esophageal.
  • MET inhibitors are e.g. also useful in the treatment of colon cancer, including metastases, e.g. in the liver, and of non-small-cell lung carcinoma.
  • MET inhibitors are e.g. also may be used in the treatment of hereditary papillary renal carcinoma (Schmidt, L. et al. Nat. Genet. 16, 68-73, 1997) and other proliferative diseases in which c-MET is overexpressed or constitutively activated by mutations (Jeffers and Vande Woude. Oncogene 18, 5120-5125, 1999; and reference cited therein) or chromosomal rearrangements (e.g. TPR-MET; Cooper et al. Nature 311, 29-33, 1984; Park. et al. Cell 45, 895-904, 1986).
  • MET inhibitors are e.g. further useful in the treatment of additional cancers and conditions as provided herein or known in the art.
  • MET inhibitors are e.g. also suitable for the treatment of one or more inflammatory conditions.
  • the inflammatory condition is due to an infection.
  • the method of treatment would be to block pathogen infection.
  • the infection is a bacterial infection, e.g., a Listeria infection. See, e.g., Shen et al. Cell 103: 501-10, (2000) whereby a bacterial surface protein activates c-Met kinase through binding to the extracellular domain of the receptor, thereby mimicking the effect of the cognate ligand HGF/SF.
  • the combination product of the present invention is especially appropriate for treatment of any of the cancers mentioned above amenable to EGFR or Met inhibitor treatment, especially a cancer selected from adenocarcinoma (especially of the breast or more especially of the lung), rhabdomyosarcoma, osteosarcoma, urinary bladder carcinoma, colorectal cancer and glioma.
  • a cancer selected from adenocarcinoma (especially of the breast or more especially of the lung), rhabdomyosarcoma, osteosarcoma, urinary bladder carcinoma, colorectal cancer and glioma.
  • a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by cMet (MET) and/or mediated by EGFR activity, or (ii) characterized by activity (normal or abnormal) of cMet and/or of EGFR; or (2) reducing or inhibiting the activity of cMet and/or of EGFR; or (3) reducing or inhibiting the expression of cMet and/or EGFR.
  • MET mediated by cMet
  • EGFR activity characterized by activity (normal or abnormal) of cMet and/or of EGFR
  • reducing or inhibiting the activity of cMet and/or of EGFR or (3) reducing or inhibiting the expression of cMet and/or EGFR.
  • a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of cMet and/or EGFR; or at least partially reducing or inhibiting the expression of MET and/or EGFR.
  • the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • primates e.g., humans
  • the subject is a primate.
  • the subject is a human.
  • the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • treatment comprises, for example, the prophylactic or especially therapeutic administration of the combination partners to a warm-blooded animal, preferably to a human being, in need of such treatment with the aim to cure the disease or to have an effect on disease regression or on the delay of progression of a disease.
  • a subject is “in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • the combinations according to the invention can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including man, comprising a therapeutically effective amount of at least one pharmacologically active combination partner alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application.
  • enteral such as oral or rectal
  • parenteral administration to mammals (warm-blooded animals), including man
  • one or more of the active ingredients are administered orally.
  • carrier or “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • the pharmaceutical combination product according to the invention (as fixed combination, or as kit, e.g. as combination of a fixed combination and individual formulations for one or both combination partners or as kit of individual formulations of the combination partners) comprises the combination partners (at least one MET tyrosine kinase inhibitor, at least one EGFR tyrosine kinase inhibitor, and optionally one or more further co-agents) of the present invention and one or more pharmaceutically acceptable carrier materials (carriers, excipients).
  • the combination products or the combination partners constituting it can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc.
  • the combination products of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
  • the combination products and/or their combination partners can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers, etc.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more commonly known carriers, e.g. one or more carriers selected from the group consisting of
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • compositions for oral administration especially include an effective amount of one or more or in case of fixed combination formulations each of the combination partners (active ingredients) in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient(s) in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
  • compositions for transdermal application include an effective amount of one or more active ingredients with a suitable carrier.
  • Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like.
  • topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art.
  • Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
  • a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
  • the invention relates also to a kit of parts or a fixed pharmaceutical composition
  • a kit of parts or a fixed pharmaceutical composition comprising an effective amount, especially an amount effective in the treatment of one of the above-mentioned diseases of at least one MET tyrosine kinase inhibitor, at least one EGFR tyrosine kinase inhibitor, or a pharmaceutically acceptable salt thereof, respectively, and optionally of at least one further co-agent, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or parenteral administration and that may be inorganic or organic, solid or liquid.
  • the active ingredient(s) forming part of a combination product according to the present invention can be present each in a relative amount of 0.5 to 95% of weight of the corresponding formulation (regarding the formulation as such, that is without packaging and leaflet), e.g. from 1 to 90, 5 to 95, 10 to 98 or 10 to 60 or 40 to 80% by weight, respectively.
  • the dosage of the active ingredient to be applied to a warm-blooded animal depends upon a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound employed.
  • a physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • each of the combination partners or a pharmaceutically acceptable salt thereof to be administered to warm-blooded animals is preferably from approximately 3 mg to approximately 5 g, more preferably from approximately 10 mg to approximately 1.5 g per person per day, e.g. divided preferably into 1 to 3 single doses, e.g. for use once or twice daily, which may, for example, be of the same size.
  • the pharmaceutical combination product of the present invention can e.g. be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50 mg of for any one or in particular the sum of active ingredients; or (especially for the EGFR inhibitor) 50 to 900, 60 to 850, 75 to 800 or 100 to 600 mg, respectively, for any one or in particular the sum of active ingredients.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or (in animal use) veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • FIG. 1 Graphic representation of the in vitro effect of a combination of the MET inhibitor 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide and the EGFR inhibitor gefitinib which overcomes resistance to single agent gefitinib in HCC827 GR lung cancer cells; round spots: gefitinib; squares: 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide; triangles: gefitinib and 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)imidazo[1,2-b]triazin-2-yl]benzamide combination.
  • FIG. 2 Graphic representation of the in vitro effect of exogenous HGF (hepatocyte growth factor) which renders HCC827 cells resistant to gefitinib.
  • HGF hepatocyte growth factor
  • FIG. 3 Graphic representation of the first combination experiment of the MET inhibitor 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide and the EGFR inhibitor gefitinib in mice (in vivo) given in the Examples.
  • Female athymic mice bearing HCC827GR5 subcutaneous xenografts were treated with 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide, gefitinib, a combination of both agents or vehicle control at the indicated doses and schedules.
  • Right graph Body weights over time.
  • FIG. 4 Graphic representation of the second combination experiment of the MET inhibitor 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide and the EGFR inhibitor gefitinib in mice (in vivo) given in the Examples.
  • Female athymic mice bearing HCC827GR5 subcutaneous xenografts were treated with 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide, gefitinib, a combination of both agents or vehicle control at the indicated doses and schedules.
  • FIG. 5 Graphic representation of the change of tumor volumes over time after treatment discontinuation in mice (in vivo) as described in more detail in the Examples.
  • Female athymic mice bearing HCC827GR5 subcutaneous xenografts were treated with 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide, gefitinib, a combination of both agents or vehicle control at the indicated doses and schedules. Treatments started 11 days post tumor cells implantation and lasted 13 consecutive days.
  • ATCC American Type Culture Collection, Manassas, Va., USA
  • HCC827 GR (gefitinib resistant) were obtained from Dr. Pasi A. Janne (Dana-Farber Cancer Institute, Boston, Mass., USA), see also J. A. Engelman et al., Science 316, 1039 ff (2007). Cell line identity has been confirmed by SNP genotyping. Parental HCC827 cells are commercially available from ATCC (ATCC Number CRL-2868).
  • NSCLC lines were grown in RPMI 1640 medium (Amimed, catalogue number 1-41F01-1) supplemented with 10% heat inactivated FCS, (Amimed, catalogue number 2-01F16-1), 2 mM L-glutamine (Amimed, catalogue number 5-10K00-H), 1 mM sodium pyruvate (Amimed, catalogue number 5-60F00-H) and 10 mM HEPES (Gibco, catalogue number 15630). Cells were incubated at 37° C. in a humidified atmosphere with 5% CO 2 . DNA was extracted with a DNeasy Blood and Tissue Kit (QIAGEN, Inc).
  • the MET inhibitor and gefitinib 10 mM stock solutions were prepared in DMSO and stored at ⁇ 20° C.
  • FIG. 1 shows the results of the experiments.
  • the HCC827 cells were, as expected, highly sensitive to gefinitib with an IC 50 of 3 to 4 nM.
  • 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)imidazo[1,2-b]triazin-2-yl]benzamide did not show any substantial effect on proliferation of the HCC827 cells or any contribution to the effect of the gefitinib/2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide combination.
  • HCC827 GR cells were fully resistant to gefitinib alone, and the effect of 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide monotherapy was modest.
  • the combination of both agents inhibited proliferation as efficiently as gefinitib inhibited parental (not GR) cells, with an IC 50 of around 4 nM gefitinib abd 0.4 nM 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide in a 10:1 mixture.
  • HCC827 cells were treated with a dilution series of gefitinib in the presence or absence of 50 ng/ml recombinant HGF (PeproTech, catalogue number 100-39) Cell viability was measured after 96 hours using an AlamarBlue assay. The initial amount of cells was quantified at the time of compound addition (dashed line), and cell growth on the y axis is expressed as a multiple of this value.
  • HCC827 cells exposed to a serial dilution of gefitinib in the presence or absence of a fixed combination of recombinant hepatocyte growth factor (HGF) was examined.
  • HGF-mediated MET activation could partially revert growth inhibition caused by gefitinib, confirming the concept that MET activity can compensate for loss of EGFR activity in lung cancer models.
  • HCC827GR5 (see also J. A. Engelman et al., Science 316, 1039 ff (2007); gefitinib resistant lung tumor cells) were obtained from Dr. Pasi Janne (Dana-Farber Cancer Institute, Boston, Mass., USA). Cell line identity has been confirmed by SNP genotyping. Cells were grown in RPMI 1640 medium (Amimed #1-41F01-1) supplemented with 10% heat inactivated FCS, (Amimed #2-01F16-I), 2 mM L-glutamine (Amimed #5-10K00-H), 1 mM sodium pyruvate (Amimed #5-60F00-H) and 10 mM HEPES (Gibco #15630). Selective pressure was maintained on the cells by keeping a 0.1 ⁇ M gefitinib concentration in the cell culture medium at all times. Cells were incubated at 37° C. in a humidified atmosphere with 5% CO 2 .
  • HCC827GR5 tumors were established by subcutaneous injection of 5 ⁇ 106 cells in 115 ⁇ l HBSS (Hank's buffered salt solution) containing 50% Matrigel (v/v) (gelatinous protein mixture secreted by Engelbreth-Holm-Swarm (EHS) mouse sarcoma cells, BD Biosciences, Franklin Lakes, N.J., USA) into the right flank of mice. with a 13 gauge trocar needle under Forene® (Isofluran; Abott, Switzerland) anesthesia.
  • EHS Engelbreth-Holm-Swarm
  • mice Engelbreth-Holm-Swarm mice sarcoma cells
  • 2-Fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide was formulated in 0.25% methylcellulose and 0.05% Tween 80 in water, using a water bath sonicator (33 kHz, 1 hour). The application volumes were 10 ml/kg for the single agents and for the vehicle control group or 5 ml/kg when the test compounds were given in combination. All indicated doses refer to free base equivalent of 2-Fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide (dihydrochloride salt).
  • Gefitinib was formulated in N-methyl-2-pyrrolidone:PEG300:Solutol HS15:water (10:30:20:40 v/v).
  • Tumor volumes were measured with calipers and determined according to the formula length x diameter 2 ⁇ /6. In addition to presenting changed of tumor volumes over the course of treatments, antitumor activity is expressed as T/C % ((mean change of tumor volume of treated animals/mean change of tumor volume of control animals) ⁇ 100). Regressions (%) were calculated according to the formula ((mean tumor volume at end of treatment mean tumor volume at start of treatment)/mean tumor volume at start of treatment) ⁇ 100. Body weights and tumor volumes were recorded twice a week.
  • mice Female athymic nude mice were treated orally once a day with 3 mg/kg 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide, alone or in combination with 25 mg/kg gefitinib.
  • Vehicle controls consisted of animals receiving a daily oral administration of 0.25% methylcellulose and 0.05% Tween 80 in water. All administration volumes were 10 ml/kg except in the combination chemotherapy group, where each single agent was administered at 5 ml/kg.
  • both 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide and gefitinib produced a statistically significant antitumor effect (p ⁇ 0.05, ANOVA), with 22.9% regressions and a T/C of 32.5%, respectively.
  • 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide and gefitinib produced statistically significant regressions of 87.3% (p ⁇ 0.05, ANOVA).
  • a post hoc Tukey'a analysis also showed that the antitumor effects produced by gefitinib administered as a single agent was statistically different from both 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide alone and in combination (p ⁇ 0.05, ANOVA).
  • 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide administered as a single agent did not produce a significant effect when compared to the combination (p>0.05, ANOVA, post hoc Tukey's).
  • mice Female athymic nude mice were treated orally once a day with 3 mg/kg 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide, alone or in combination with 25 mg/kg gefitinib.
  • Vehicle controls consisted of animals receiving a daily oral administration of 0.25% methylcellulose and 0.05% Tween 80 in water. All administration volumes were 10 ml/kg except in the combination chemotherapy group, where each single agent was administered at 5 ml/kg.
  • both 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide and gefitinib produced a statistically significant antitumor effect (p ⁇ 0.05, ANOVA), with 21.4% regressions and a T/C of 49.4%, respectively.
  • 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide and gefitinib produced statistically significant regressions of 86.4% (p ⁇ 0.05, ANOVA).
  • the body weight changes in all treatment groups were not significantly different from the vehicle control group (p>0.05, one way ANOVA, post hoc Dunnett's). The body weight increase was statistically significant in all groups excepted the combination group (p ⁇ 0.05, paired t-test). See FIG. 4 .
  • mice bearing HCC827GR5 subcutaneous xenografts were treated with 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide, gefitinib, a combination of both agents or vehicle control at the doses and schedules indicated in FIG. 5 .
  • Treatments started 11 days post tumor cells implantation and lasted 13 consecutive days.
  • the animals in the groups where treatments were extended increased only to a mean of 400+/ ⁇ 80 mm 3 for the 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide-treated animals.
  • c-MET inhibitors are the most active class of compounds in inhibiting the growth of cell lines with c-MET amplification or simultaneous HGF and c-MET expression.
  • cell lines with simultaneous HGF and c-MET expression are also relatively resistant to EGFR inhibitors compared to cell lines with similar c-MET level that lack HGF expression.
  • the trial is a Phase IB/II, open label, multicenter study of 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]benzamide administered orally in combination with gefitinib in adult patients with EGFR mutated, c-MET-amplified non-small cell lung cancer who have progressed after EGFR inhibitor treatment.
  • OS Overall survival
  • Phase Ib To estimate the MTD or RP2D of Compound A or Compound B in combination with gefitinib in NSCLC patients who have c-MET gene amplification 2)
  • Phase II To estimate overall clinical activity of Compound A or Compound B in combination with gefitinib in NSCLC patients with c-MET gene amplification
  • Secondary Objectives 1) To determine safety and tolerability of Compound A or Compound B in combination with gefitinib 2) To estimate time dependent clinical activity of Compound A or Compound B in combination with gefitinib 3)
  • To characterize the PK profile of Compound A or Compound B and gefitinib in NSCLC patient population and to assess potential drug interaction between Compound A or Compound B and gefitinib Study design Open label, single arm, with a Phase Ib Part and a Phase II Part Population Approximately 58 male or female, at least 18 years old patients with EG
  • the Bayesian logistic regression model with overdose control will be used to recommend the dose levels that will be used for dose cohorts that occur after the initial dose cohort.
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