WO2019105835A1 - Combinations of copanlisib and anetumab ravtansine - Google Patents

Combinations of copanlisib and anetumab ravtansine Download PDF

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Publication number
WO2019105835A1
WO2019105835A1 PCT/EP2018/082194 EP2018082194W WO2019105835A1 WO 2019105835 A1 WO2019105835 A1 WO 2019105835A1 EP 2018082194 W EP2018082194 W EP 2018082194W WO 2019105835 A1 WO2019105835 A1 WO 2019105835A1
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amino
alkyl
cancer
alkoxy
dihydroimidazo
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PCT/EP2018/082194
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French (fr)
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Christoph SCHATZ
Sabine ZITZMANN- KOLBE
Oliver Politz
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Bayer Consumer Care Ag
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Publication of WO2019105835A1 publication Critical patent/WO2019105835A1/en

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    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6859—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from liver or pancreas cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6869—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of the reproductive system: ovaria, uterus, testes, prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to combinations of : component A : anetumab ravtansine ;
  • component B which is selected from :
  • component B1 one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) or (B2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ;
  • ⁇ component B2 bevacizumab (also referred to hereinafter as its tradename Avastin) ;
  • component B3 doxorubicin (also referred to hereinafter as its tradename Doxil or Caelyx) ;
  • component C one or more further pharmaceutical agents ;
  • components A and B in any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • Another aspect of the present invention relates to the use of such combinations as described supra for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly cancers with altered activation of PI3K pathway and/or particular PI3K isoform(s) induced modulation of immune response, which not only provide survival signaling to tumor cells but also cause impaired anti-tumor immunity and/or the resistance to the cancer immune therapies.
  • the applicable cancer indications are, but not limited to, ovarian cancer, colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia.
  • the present invention relates to a kit comprising a combination of component A : anetumab ravtansine ;
  • component B which is selected from : • component B1 : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) or (B2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ;
  • component B2 bevacizumab (also referred to hereinafter as its tradename Avastin) ;
  • compounent B3 doxorubicin (also referred to hereinafter as its tradename Doxil or Caelyx) ;
  • components A) and B) in any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • Cancer is the second most prevalent cause of death in the United States, causing 450,000 deaths per year. While substantial progress has been made in identifying some of the likely environmental and hereditary causes of cancer, there is a need for additional therapeutic modalities that target cancer and related diseases. In particular there is a need for therapeutic methods for treating diseases associated with dysregulated growth / proliferation.
  • Cancer is a complex disease arising after a selection process for cells with acquired functional capabilities like enhanced survival / resistance towards apoptosis and a limitless proliferative potential. Thus, it is preferred to develop drugs for cancer therapy addressing distinct features of established tumors.
  • the PI3K signaling pathway is one of the prominent pathways that promote tumor cell survival.
  • PI3K is activated by many cancer related receptor tyrosine kinases (e.g. VEGFR, PDGFR, EGFR, HER2/3, or IGF-1R), cell adhesion molecules, GPCR, and oncogenic proteins (such as Ras).
  • cancer related receptor tyrosine kinases e.g. VEGFR, PDGFR, EGFR, HER2/3, or IGF-1R
  • cell adhesion molecules e.g. VEGFR, PDGFR, EGFR, HER2/3, or IGF-1R
  • GPCR cell adhesion molecules
  • oncogenic proteins such as Ras.
  • the PI3K pathway activation by genetic alteration of PI3K (activation mutation and/or amplification) and/or I oss-of-f unction of the tumour suppressor PTEN are frequently found in many tumors.
  • activation of PI3K is one of the major
  • PI3K Once PI3K is activated, it catalyzes the generation of PIP3 from PIP2.
  • the biological active PIP3 binds to the pleckstrin homology (PH) domains of PDK-1, AKT, and other PH-domain containing proteins, such as Rho and PLC. As the consequence of binding to PIP3, these proteins are translocated to the cell membrane and are subsequently activated to induce tumor cell proliferation, survival, invation and migration.
  • PH pleckstrin homology
  • PI3K In addition to the roles in tumor cells, PI3K also regulate the activity of the tumor stroma cells (cells that form part of the tumor mass but are not malignantly transformed).
  • the stroma cells include (a) the vasculature, (b) infiltrating immune cells, (c) fibroblasts and (d) other connective tissue.
  • Recent data indicate that the four class I PI3K isoforms have both redoundant and distinct roles in regulating the PI3K signalling in each of these stromal elements.
  • the complexity and/or difficulty in predicting the final outcomes of PI3K inhibitors have been realized, particularly with regard to different isoform profiles and/or other technical properties of PI3K inhibitors.
  • PI3Ks Phosphatidylinositol 3-kinase pathway
  • ovarian cancer gastric cancer, ovarian cancer, lung cancer, endometrial cancer and breast cancer
  • PI3Ks Phosphatidylinositol 3-kinase pathway
  • PI3Ks pathway comprises a family of intracellular signal transducer enzymes with three key regulatory nodes: PI3K, AKT, and mammalian target of rapamycin (mTOR) [see: Lux MP, Fasching PA, Schrauder MG, Hein A, Jud SM, Rauh C, Beckmann MW.
  • mTOR mammalian target of rapamycin
  • Activation of the PI3K pathway including the downstream factor AKT provides a survival signaling to tumor cells and has been shown to be associated with resistance to chemotherapy, [see: Steelman LS, Navolanic P, Chappell WH, Abrams SL, Wong EW, Martel li AM, Cocco L, Stivala F, Libra M, Nicoletti F, Drobot LB, Franklin RA, McCubrey JA. Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells. Cell Cycle. 2011; 10:3003-15. htps://doi.org/10.4161/cc.10.17.171191.
  • Phosphatidylinositol 3-kinase (PI3Ka)/AKT axis blockade with taselisib or ipatasertib enhances the efficacy of anti-microtubule drugs in human breast cancer cells
  • 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride (a highly selective pan-Class I PI3K inhibitor with predominant activity against PI3Ka and PI3K6) and anetumab ravtansine as defined herein, were investigated as combination in inhibiting cancers with mesothellin expression.
  • the applicable cancer indications are, but not limited to, mesothelioma, ovarian cancer, lung cancer, pancreatic cancer, breast cancer, gastric cancer, thymic cancer, colorectal cancer, cholangiocarcinoma, head and neck cancer, endometrial cancer and lymphoma.
  • component A anetumab ravtansine, as described and defined herein ;
  • component B which is selected from :
  • component B1 one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) or (B2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein ;
  • component B2 bevacizumab (also referred to hereinafter as its tradename Avastin), as described and defined herein ; and
  • component B3 doxorubicin (also referred to hereinafter as its tradename Doxil or Caelyx), as described and defined herein ;
  • component B which is selected from :
  • component B1 one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) or (B2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein ;
  • component B2 bevacizumab (also referred to hereinafter as its tradename Avastin), as described and defined herein ;
  • component B3 doxorubicin (also referred to hereinafter as its tradename Doxil or Caelyx), as described and defined herein ; in which optionally either or both of said components A and B of any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially, would be effective in the treatment or prophylaxis of cancer, particularly ovarian cancer, colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia.
  • doxorubicin also referred to hereinafter as its tradename Doxil or Caelyx
  • the combinations of the present invention as described and defined herein show a beneficial effect in the treatment of cancer, particularly ovarian cancer, colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia.
  • cancer particularly ovarian cancer, colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia.
  • the present invention relates to combinations of : component A : anetumab ravtansine, as described and defined herein ; and
  • component B which is selected from :
  • component B1 one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) or (B2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein ;
  • component B2 bevacizumab (also referred to hereinafter as its tradename Avastin), as described and defined herein ;
  • component B3 doxorubicin (also referred to hereinafter as its tradename Doxil or Caelyx), as described and defined herein ; in which optionally either or both of said components A and Bl) of any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • a cancer particularly ovarian cancer, colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia.
  • the present invention relates to a kit comprising a combination of : component A : anetumab ravtansine, as described and defined herein ;
  • component B which is selected from :
  • component Bl one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) or (B2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein ;
  • component B2 bevacizumab (also referred to hereinafter as its tradename Avastin), as described and defined herein ;
  • component B3 doxorubicin (also referred to hereinafter as its tradename Doxil or Caelyx), as described and defined herein ; in which optionally either or both of components A and B in any of the above-mentioned combinations are in the form of a pharmaceutical formu lation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independ nently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • Component A which is anetumab ranvastine.
  • Anetumab ravtansine (MF-T-SPDB-DM4) is an antibody drug conjugate (ADC) comprising the monoclonal antibody MF-T (also known as anetumab) d irected against the mesothelin antigen, and the maytansinoid tubulin polymerization inhibitor N 2' -deacetyl-N 2' (4-methyl-4-mercapto-l- oxopentyl)-maytansine (termed DM4, CAS Reg. No. 796073-69-3) which are linked via an SPDB- (N-succin imidyl-4-(2-pyridyld ithio) butanoate) linker.
  • ADC antibody drug conjugate
  • MF-T is an antibody comprising a variable region of the heavy chain (VH) of SEQ ID NO: 1 (VH: QVELVQSGAE VKKPGESLKI SCKGSGYSFT SYWIGWVRQA PGKGLEWMGI IDPGDSRTRY SPSFQGQVTI SADKSISTAY LQWSSLKASD TAMYYCARGQ LYGGTYMDGW GQGTLVTVSS) and a variable region of the light chain of SEQ ID NO: 2 (VL: DIALTQPASV SGSPGQSITI SCTGTSSDIG GYNSVSWYQQ HPGKAPKLMI YGVNNRPSGV SNRFSGSKSG NTASLTISGL QAEDEADYYC SSYDIESATP VFGGGTKLTV LGQ).
  • VH variable region of the heavy chain of SEQ ID NO: 1
  • VH QVELVQSGAE VKKPGESLKI SCKGSGYSFT SYWIGWVRQA PGKGLEWMGI IDPGDSRTRY SP
  • MF-T is an antibody comprising a region of the heavy chain of SEQ ID NO: 3 (HC: QVELVQSGAE VKKPGESLKI SCKGSGYSFT SYWIGWVRQA PGKGLEWMGI IDPGDSRTRY SPSFQGQVTI SADKSISTAY LQWSSLKASD TAMYYCARGQ LYGGTYMDGW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTL
  • anetumab ravtansine antibody drug conjugates comprise 1 to 6 DM4 drug moieties (antibody drug ratio).
  • a pharmaceutical composition preferentially comprises a mixture of antibody drug conjugates resulting in an average antibody drug ration of 3 to 4, and even more preferred 3.3 to 3.6.
  • anetumab ravtansine is an antibody drug conjugate of the formu la
  • MF-T is the antibody MF-T where the antibody is attached via a lysine residue, and n is 1 to 6.
  • Methods for preparation of anetumab ravtansine are disclosed e.g. in WO 2009/068204 (Al) and WO 2010/124797 (Al).
  • Methods for the production of maytansinoids and conjugates thereof are disclosed e.g. in WO 2005/020883 (A2), WO 2004/103272 (A2), and WO 2007/024536 (A2).
  • a preferred formulation for anetumab ravtansine is a lyophilisate resulting in anetumab ravtansine in 130 mM glycine, 10 mM L-histidine, 5% (w/v) sucrose, 0.01% (w/v) polysorabte 80, preferentially pH 5.5 after reconstitution using water for injection and the resulting aqueous solution itself.
  • the aqueous solution of anetumab ravtansine for intravenous injection, sterile and free from bacterial endotoxins is used.
  • a preferred dosage regimen for anetumab ravtansine injection is 5 to 7 and even more preferred 6.5 mg per kg body weight given at 3 week intervals.
  • an immunoglobulin molecule preferably comprises a molecule having four polypeptide chains, two heavy chains (H chains, HC) and two light chains (L chains, LC) which are typically linked by disulphide bridges.
  • Each heavy chain comprises a variable domain of the heavy chain (abbreviated VH) and a constant domain of the heavy chain.
  • the constant domain of the heavy chain may, for example, comprise three domains CHI, CH2 and CH3.
  • Each light chain comprises a variable domain (abbreviated VL) and a constant domain.
  • the constant domain of the light chain comprises a domain (abbreviated CL).
  • CL constant domain
  • the VH and VL domains may be subdivided further into regions having hypervariability, also referred to as complementarity determining regions (abbreviated CDR) and regions having low sequence variability (framework region, abbreviated FR).
  • CDR complementarity determining regions
  • FR frame region
  • each VH and VL region is composed of three CDRs and up to four FRs.
  • FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 For example from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • An antibody may be obtained from any suitable species, e.g. rabbit, llama, camel, mouse or rat. In one embodiment, the antibody is of human or murine origin.
  • An antibody may, for example, be human, humanized or chimeric.
  • component B1 which is one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) :
  • X represents CR 5 R 6 or NH
  • Y 1 represents CR 3 or N
  • Chemical bond between y 2 — y 3 represents a single bond or double bond, with the proviso that when theY 2 — Y 3 represents a double bond,
  • Y 2 and Y 3 independently represent CR 4 or N, and when Y 2 — Y 3 represents a single bond, Y 2 and Y 3 independently represent CR 3 R 4 or NR 4 ; Z 1 , Z 2 , Z 3 and Z 4 independently represent CH , CR 2 or N;
  • R 1 represents aryl optionally having 1 to 3 substituents selected from R , C 3 -s cycloalkyl optionally having 1 to 3 substituents selected from R ,
  • Ci- 6 alkyl optionally substituted by
  • Ci- 6 alkoxy optionally substituted by
  • R represents
  • halogen nitro, hydroxy, cyano, carboxy, amino, N-(Ci- 6 alkyl)amino, N-(hydroxyCi- 6 alkyl)amino, N,N-di(Ci- 6 alkyl)amino, N-(Ci- 6 acyl)amino, N-(formyl)-N-(Ci- 6 alkyl)amino, N- (Ci- 6 alkanesulfonyl) amino, N-(carboxyCi- 6 alkyl)-N-(Ci- 6 alkyl)amino, N-(Ci- 6 alkoxycabonyl)amino, N-[N,N-di(Ci- 6 alkyl)amino methylene]amino, N-[N,N-di(Ci- 6 alkyl)amino (Ci- 6 alkyl)methylene]amino, N-[N,N-di(Ci- 6
  • N-arylamino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R 101 , N-(aryl Ci- 6 alkyl)amino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R 101 , aryl Ci- 6 alkoxycarbonyl wherein said aryl moiety is optionally having 1 to 3 substituents selected from R 101 ,
  • Ci- 6 al kyl optionally substituted by
  • Ci- 6 alkoxy optionally substituted by
  • R 101 represents
  • halogen carboxy, amino, N-(C I-6 alkyl)amino, N,N-di(Ci- 6 alkyl)amino, aminocarbonyl, N- (Ci- 6 alkyl)aminocarbonyl, N,N-di(Ci- 6 alkyl)aminocarbonyl, pyridyl,
  • Ci- 6 alkyl optionally substituted by cyano or mono- di- or tri- halogen
  • Ci-galkoxy optionally substituted by cyano, carboxy, amino, N-(C I-6 alkyl)amino, N,N- di(Ci- 6 alkyl)amino, aminocarbonyl, N-(Ci- 6 alkyl)aminocarbonyl, N,N-di(Ci-
  • R 2 represents hydroxy, halogen, nitro, cyano, amino, N-(Ci- 6 alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(hydroxyCi- 6 alkyl)amino, N-(hydroxyCi- 6 alkyl)-N-(Ci- 6 alkyl)amino, Ci- 6 acyloxy, aminoCi- 6 acyloxy, C 2-6 alkenyl, aryl,
  • Ci- 6 alkyl Ci- 6 alkoxy, oxo, amino, amino Ci_ 6 al kyl, N-(Ci- 6 alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(C I-6 acyl)amino, N-(Ci- 6 alkyl)carbonylamino, phenyl, phenyl Ci- 6 alkyl, carboxy, Ci- 6 alkoxycarbonyl, aminocarbonyl, N-(Ci- 6 alkyl)aminocarbonyl, or N,N-di(Ci- 6alkyl)amino,
  • R 20 represents Ci- 6 alkyl, Ci- 6 alkoxy, amino, N-(Ci- 6 alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(C I-6 acyl)amino, or a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by
  • Ci- 6 alkyl Ci- 6 alkoxy, oxo, amino, N-(Ci- 6 alkyl)amino, N,N-di(Ci- 6 alkyl)amino, N- (Ci- 6 acyl)amino, phenyl, or benzyl,
  • Ci- 6 alkyl optionally substituted by R 21
  • R 21 represents cyano, mono-, di or tri- halogen, hydroxy, amino, N-(Ci- 6 alkyl)amino, N,N-di(Ci- 6 alkyl)amino, N- (hydroxyCi-s alkyl) amino, N- (halophenylCi-s alkyl) amino, amino C 2.6 alkylenyl, Ci- 6 alkoxy, hydroxyCi-s alkoxy, -C(O)- R 201 , NHC(O)- R 201 , C - cycloalkyl, isoindolino, phthalimidyl, 2-oxo-l,3-oxazolidinyl, aryl or a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N optionally substituted by
  • Ci- 6 alkyl Ci- 6 alkoxy, Ci- 6 alkoxycarbonyl, hydroxyCi-s alkoxy, oxo, amino, aminoCi- 6 alkyl, N-(Ci- 6 alkyl)amino, N,N-di(Ci- 6 alkyl)amino, N-(C I-6 acyl)amino, or benzyl, wherein
  • R 201 represents hydroxy, amino, N-(Ci- 6 alkyl)amino, N,N-di(Ci- 6 alkyl)amino, N- (halophenylCi- 6 alkyl) amino, Ci_ 6 al kyl, aminoCi-g alkyl, aminoC 2-6 alkylenyl, Ci- 6 alkoxy, a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N optionally substituted by
  • Ci- 6 alkyl Ci- 6 alkoxy, Ci- 6 alkoxycarbonyl, hydroxyCi- 6 alkoxy, oxo, amino, N-(Ci- 6 alkyl)amino, N,N-di(Ci- 6 alkyl)amino, N-(C I-6 acyl)amino or benzyl;
  • R 3 represents hydrogen, halogen, aminocarbonyl, or Ci- 6 alkyl optionally substituted by aryl Ci- 6 alkoxy or mono-, di- or tri- halogen;
  • R 4 represents hydrogen or Ci- 6 alkyl
  • R 5 represents hydrogen or Ci- 6 alkyl
  • R 6 represents halogen, hydrogen or Ci- 6 alkyl ; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; said compounds are published as compounds of general formulae I, l-a, and l-b in International patent application PCT/EP2003/010377, published as WO 04/029055 A1 on April 08, 2004, which is incorporated herein by reference in its entirety.
  • said compounds of general formula I, l-a and l-b are described on pp. 6 et seq., they may be synthesized according to the methods given therein on pp. 26 et seq., and are exemplified as specific compound Examples 1-1 to 1-210 on pp.
  • Said component B1 may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • said combinations are of: component B1 : which is one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl), supra, which is selected from the list consisting of specific compound Examples 1-1 to 1-210 on pp. 47 to 106, specific compound Examples 2-1 to 2-368 on pp. 107 to 204, specific compound Examples 3-1 to 3-2 on pp. 205 to 207, and specific compound Examples 4-1 to 4-2 on pp.
  • component B1 is one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl), supra, which is selected from the list consisting of specific compound Examples 1-1 to 1-210 on pp. 47 to 106, specific compound Examples 2-1 to 2-368 on pp. 107 to 204, specific compound Examples 3-1 to 3-2 on pp. 205 to 207, and specific compound Examples 4-1 to 4-2 on pp.
  • Such a component Bl may be : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimid-azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride, (which is hereinafter referred to as "compound Bl” or "cpd.
  • Said component B1 may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • compound Bl 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimid- azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride, (which is hereinafter referred to as "compound Bl” or "cpd. Bl”) may be synthesized as described in Examples 1 and 2 of international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 11, 2012, (which is incorporated herein by reference in its entirety).
  • component Bl which is one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (B2) :
  • X represents CR 5 R 6 or NH; represents CR 3 or N; the chemical bond between y 2 — y 3 represents a single bond or double bond, with the proviso that when theY 2 — Y 3 represents a double bond, Y 2 and Y 3 independently represent CR 4 or N, and
  • Y 2 and Y 3 independently represent CR 3 R 4 or NR 4 ;
  • Z 1 , Z 2 , Z 3 and Z 4 independently represent CH , CR 2 or N;
  • R 1 represents aryl optionally having 1 to 3 substituents selected from R , C 3 -s cycloalkyl optionally having 1 to 3 substituents selected from R ,
  • Ci- 6 alkyl optionally substituted by aryl, heteroaryl, Ci- 6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,
  • Ci- 6 alkoxy optionally substituted by carboxy, aryl, heteroaryl, Ci- 6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,
  • R represents halogen, nitro, hydroxy, cyano, carboxy, amino, N- (Ci- 6 alkyl)amino, N-(hydroxyCi- 6 alkyl)amino, N,N-di(Ci- 6 alkyl)amino, N-(Ci- 6acyl)amino, N-(formyl)-N-(Ci- 6 alkyl)amino, N-(Ci- 6 alkanesulfonyl) amino, N- (carboxyCi- 6 alkyl)-N-(Ci- 6 alkyl)amino, N-(Ci- 6 alkoxycabonyl)amino, N-[N,N-di(Ci- 6alkyl)amino methylene]amino, N-[N,N-di(Ci- 6 alkyl)amino (Ci- 6alkyl)methylene]amino, N-[N,N-di(Ci
  • Ci- 6 alkoxy optionally substituted by mono-, di- or tri- halogen, N- (Ci- 6 alkyl)sulfonamide, or N-(aryl)sulfonamide,
  • R 101 represents halogen, carboxy, amino, N-(C I-6 alkyl)amino, N,N-di(Ci- 6alkyl)amino, aminocarbonyl, N-(Ci- 6 alkyl)aminocarbonyl, N,N-di(Ci- 6alkyl)aminocarbonyl, pyridyl,
  • Ci- 6 alkyl optionally substituted by cyano or mono- di- or tri- halogen
  • Ci- 6 alkoxy optionally substituted by cyano, carboxy, amino, N-(C I-6 alkyl)amino, N,N-di(Ci- 6 alkyl)amino, aminocarbonyl, N-(Ci- 6alkyl)aminocarbonyl, N,N-di(Ci- 6 alkyl)aminocarbonyl or mono-, di- or tri- halogen;
  • R 2 represents hydroxy, halogen, nitro, cyano, amino, N-(Ci- 6 alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(hydroxyCi- 6 alkyl)amino, N-(hydroxyCi- 6 alkyl)-N-(Ci- 6 alkyl)amino, Ci-g acyloxy, aminoCi-g acyloxy, C - 6 alkenyl, aryl, a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, Ci- 6 alkyl, Ci- 6 alkoxy, oxo, amino, amino Ci- 6 al kyl, N-(Ci- 6 alkyl)amino, N,N-di(Ci- 6 alkyl)amino, N-(C I-6 acyl)amino, N-(
  • R 20 represents Ci- 6 alkyl, Ci- 6 alkoxy, amino, N-(Ci- 6 alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(C I-6 acyl)amino, or a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by Ci- 6 alkyl, Ci- 6 alkoxy, oxo, amino, N-(Ci- 6 alkyl)amino, N,N-di(Ci- 6 alkyl)amino, N-(Ci- 6 acyl)amino, phenyl, or benzyl,
  • Ci- 6 alkyl optionally substituted by R 21 ,
  • Ci- 6 alkoxy optionally substituted by R 21 ,
  • R 21 represents cyano, mono-, di or tri- halogen, hydroxy, amino, N- (Ci- 6 alkyl)amino, N,N-di(Ci- 6 alkyl)amino, N- (hydroxyCi- 6 alkyl) amino, N- (halophenylCi- 6 alkyl) amino, amino C 2.6 alkylenyl, Ci- 6 alkoxy, hydroxyCi- 6 alkoxy, -C(O)- R 201 , -NHC(O)- R 201 , C 3 - scycloalkyl, isoindolino, phthalimidyl, 2-oxo-l,3-oxazolidinyl, aryl or a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N , and optionally substituted by hydroxy, Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 al
  • R 201 represents hydroxy, amino, N-(Ci- 6 alkyl)amino, N,N-di(Ci- 6alkyl)amino, N- (halophenylCi-s alkyl) amino, Ci-ealkyl, aminoCi- 6 alkyl, aminoC 2-6 alkylenyl, Ci- 6 alkoxy, a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, Ci- 6 alkyl, Ci- 6 alkoxy, Ci- 6 alkoxycarbonyl, hydroxyCi- 6 alkoxy, oxo, amino, N-(Ci- 6 alkyl)amino, N,N- di(Ci- 6 alkyl)amino, N-(C I-6 acyl)amino or benzyl;
  • R 3 represents hydrogen, halogen, aminocarbonyl, or Ci- 6 alkyl optionally substituted by aryl Ci- 6 alkoxy or mono-, di- or tri- halogen;
  • R 4 represents hydrogen or Ci- 6 alkyl
  • R 5 represents hydrogen or Ci- 6 alkyl
  • R 6 represents halogen, hydrogen or Ci- 6 alkyl ; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; said compounds are published as compounds of general formulae I, la, lb, lc, Id and le in International patent application PCT/US2007/024985, published as WO 2008/070150 A1 on June 12, 2008, which is incorporated herein by reference in its entirety.
  • said compounds of general formula I, la, lb, lc, Id and le are described on pp. 9 et seq., they may be synthesized according to the methods given therein on pp. 42, et seq., and are exemplified as specific compound Examples 1 to 103 therein on pp. 65 to 101. Biological test data for certain of said compounds are given therein on pp. 101 to 107.
  • dinydrochloride it may be synthesized according to the methods given in said Examples 1 and
  • alkyl' refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, such as illustratively, methyl, ethyl, n-propyl 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched or branched chain having about 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, 1- butenyl, 2-and butenyl.
  • alkynyl refers to a straight or branched chain hydrocarbonyl radicals having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 10 carbon atoms presently being preferred) e.g., ethynyl.
  • alkoxy denotes an alkyl group as defined herein attached via oxygen linkage to the rest of the molecule. Representative examples of those groups are methoxy and ethoxy.
  • alkoxyakyl denotes an alkoxy group as defined herein attached via oxygen linkage to an alkyl group which is then attached to the main structure at any carbon from alkyl group that results in the creation of a stable structure the rest of the molecule.
  • Representative examples of those groups are -CH2OCH3 and --CH2OC2H 5 .
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and examples of multicyclic cycloalkyl groups include perhydronapththyl, adamantyl and norbornyl groups bridged cyclic group or sprirobicyclic groups e.g sprio (4,4) non-2-yl.
  • cycloalkylalkyl refers to cyclic ring-containing radicals containing in the range of about about 3 up to 8 carbon atoms directly attached to alkyl group which is then also attached to the main structure at any carbon from the alkyl group that results in the creation of a stable structure such as cyclopropylmethyl, cyclobuyylethyl, cyclopentylethyl.
  • aryl refers to aromatic radicals having in the range of 6 up to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, biphenyl.
  • arylalkyl refers to an aryl group as defined herein directly bonded to an alkyl group as defined herein which is then attached to the main structure at any carbon from alkyl group that results in the creation of a stable structure the rest of the molecule, e.g., --CH C 6 H 5 , -- CzHsCsHs .
  • heterocyclic ring refers to a stable 3- to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heteroaromatic or heteroaryl aromatic).
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl cinnolinyl dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazil, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl tetrahydroisouinolyl, piperidinyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-
  • the heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroarylalkyl refers to heteroaryl ring radical as defined herein directly bonded to alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom from alkyl group that results in the creation of a stable structure.
  • heterocyclyl refers to a heterocylic ring radical as defined herein.
  • the heterocylyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heterocyclylalkyl refers to a heterocylic ring radical as defined herein directly bonded to alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at carbon atom in the alkyl group that results in the creation of a stable structure.
  • carbonyl refers to an oxygen atom bound to a carbon atom of the molecule by a double bond.
  • halogen refers to radicals of fluorine, chlorine, bromine and iodine.
  • Said component B1 may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • component B1 which is one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (A2), supra, which is selected from the list consisting of :
  • Example 4 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]-l,3-thiazole-5-carboxamide.
  • Example 13 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2- c]quinazolin-5-yl]pyrimidine-5-carboxamide.
  • Example 14 N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2- c]quinazolin-5-yl]-6-(2-pyrrolidin-l-ylethyl)nicotinamide.
  • component B1 may be 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimid-azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride, (which is hereinafter referred to as "compound Bl” or "cpd.
  • Said component Bl may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • said combinations are of component B2 : bevacizumab (also referred to hereinafter as its tradename Avastin ), as described and defined herein.
  • compound B2: bevacizumab (CAS number: 216974-75-3, DrugBank entry DB00112, also referred to hereinafter as its tradename Avastin) is an antibody well known in the art.
  • Bevacizumab comprises a region of the heavy chain of SEQ ID NO: 5 (HC:
  • a preferred dosage regimen for bevacizumab is 5 to 15 mg per kg body weight given at 2 or 3 week intervals dependent on tumor type.
  • said combinations are of component B3 : doxorubicin (also referred to hereinafter as its tradename Doxil or Caelyx), as described and defined herein.
  • compound B3 doxorubicin [(7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy- 6,9,ll-trihydroxy-9-(2-hyd roxyacetyl)-4-methoxy-8,10-dihydro-7FI-tetracene-5,12-dione] sold under the trade names Adriamycin among others, is a chemotherapy medication used to treat cancer.
  • doxorubicin sold as Doxil (also referred to hereinafter as its tradename Doxil). Further a non- pegylated liposomal doxorubicin is available (called Myocet).
  • Doxorubicin as used herein includes if not further specified all variants (pegylated and non- pegylated) and versions (liposomal and non-liposomal) of doxorubicin.
  • a preferred form of doxorubicin is pegylated (polyethylene glycol coated) liposome-encapsu lated form of doxorubicin (also referred to hereinafter as its tradename Doxil)
  • the most commonly used dosage of doxorubicin is 40 to 60 mg/m 2 IV every 21 to 28 days. Alternatively, 60 to 75 mg/m 2 IV once every 21 days.
  • said combinations are of : component A : anetumab ravtansine.
  • Said component A may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • said combinations are of: component A : anetumab ravtansine ;
  • component B1 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2- c]quinazolin-5-yl]pyrimidine-5-carboxamide or 2-amino-N-[7-methoxy-8-(3-morpholin-4- ylpropoxy)-2,3-dihydroimid-azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide
  • Said component Bl may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • the present invention relates to a combination of any component A mentioned herein with any component Bl mentioned herein.
  • the present invention relates to a combination of a component A with a component Bl, as mentioned in the Examples section herein.
  • components A and Bl of any of the combinations of the present invention may be in a useful form, such as pharmaceutically acceptable salts, co precipitates, metabolites, hydrates, solvates and prodrugs of all the compounds of examples.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts/' J. Pharm. Sci. 1977, 66, 1-19.
  • Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid.
  • Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts.
  • acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
  • acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-na
  • Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, or butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl sulfate, or diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, or butyl chlorides,
  • a solvate for the purpose of this invention is a complex of a solvent and a compound of the invention in the solid state.
  • Exemplary solvates would include, but are not limited to, complexes of a compound of the invention with ethanol or methanol. Hydrates are a specific form of solvate wherein the solvent is water.
  • the components A or B1 may, independently from one another, be in the form of a pharmaceutical composition or formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • compositions can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes combinations in which components A and B, independently of one another, are pharmaceutical formulations compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a said component.
  • a pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of component, and/or combination.
  • a pharmaceutically effective amount of a combination is preferably that amount which produces a result or exerts an influence on the particular condition being treated.
  • the combinations of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like. It is possible for the compounds according to the invention to have systemic and/or local activity.
  • they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • the compounds according to the invention for oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
  • Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step for example intravenous, intraarterial, intracardial, intraspinal or intralumbal
  • absorption for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
  • Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops nasal solutions, nasal sprays
  • tablets/films/wafers/capsules for lingual, sublingual or buccal
  • the compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients.
  • Pharmaceutically suitable excipients include, inter alia,
  • fillers and carriers for example cellulose, microcrystalline cellulose (such as, for example, Avicel”), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos * )
  • ointment bases for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols
  • bases for suppositories for example polyethylene glycols, cacao butter, hard fat
  • solvents for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins
  • surfactants for example sodium dodecyl sulfate
  • lecithin phospholipids
  • fatty alcohols such as, for example, Lanette *
  • sorbitan fatty acid esters such as, for example, Span
  • polyoxyethylene sorbitan fatty acid esters such as, for example, Tween *
  • polyoxyethylene fatty acid glycerides such as, for example, Cremophor *
  • polyoxethylene fatty acid esters polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic * )
  • buffers for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • acids and bases for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • isotonicity agents for example glucose, sodium chloride
  • adsorbents for example highly-disperse silicas
  • viscosity-increasing agents for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl- cellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol * ); alginates, gelatine),
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab * ), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSof )
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab * ), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSof )
  • flow regulators for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil * )
  • lubricants for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil * )
  • mould release agents for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil * )
  • coating materials for example sugar, shellac
  • film formers for films or diffusion membranes which dissolve rapidly or in a modified manner for example polyvinylpyrrolidones (such as, for example, Kollidon * ), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropyl- methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit * )),
  • capsule materials for example gelatine, hydroxypropylmethylcellulose
  • polymers for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit * ), polyvinylpyrrolidones (such as, for example, Kollidon * ), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
  • synthetic polymers for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit * ), polyvinylpyrrolidones (such as, for example, Kollidon * ), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
  • plasticizers for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate
  • stabilisers for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gal late
  • antioxidants for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gal late
  • preservatives for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate
  • colourants for example inorganic pigments such as, for example, iron oxides, titanium dioxide
  • flavourings • flavourings, sweeteners, flavour- and/or odour-masking agents.
  • the present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
  • cancer includes, but is not limited to, cancers of the breast, lung, brain, reproductive organs, digestive tract, urinary tract, liver, eye, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include multiple myeloma, lymphomas, sarcomas, and leukemias.
  • breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to lung cancer, particularly small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
  • Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
  • Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, melanoma, particularly malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • the present invention relates to a method for using the combinations of the present invention, in the treatment or prophylaxis of a cancer, particularly (but not limited to) colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia, etc..
  • a cancer particularly (but not limited to) colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia, etc.
  • Combinations can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis, in the treatment or prophylaxis of cancer, in particular (but not limited to) colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia, etc..
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a combination of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc.
  • treating or “treatment” as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
  • the effective dosage of the combinations of this invention can readily be determined for treatment of the indication.
  • the amount of the active ingredient to be administered in the treatment of the condition can vary widely according to such considerations as the particular combination and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • "drug holidays" in which a patient is not dosed with a drug for a certain period of time may be beneficial to the overall balance between pharmacological effect and tolerability.
  • a unit dosage may contain from about 0.5 mg to about 1,500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
  • the average daily dosage for administration by injection will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific combination employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a combination of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • the combinations of component A and component B1 of this invention can be administered as the sole pharmaceutical agent or in combination with one or more further pharmaceutical agents where the resulting combination of components A, B1 and C causes no unacceptable adverse effects.
  • the combinations of components A and B1 of this invention can be combined with component C, i.e. one or more further pharmaceutical agents, such as known anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agents, and the like, as well as with admixtures and combinations thereof.
  • Component C can be one or more pharmaceutical agents such as 1311-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basilixima
  • component C in combination with a combination of components A and B1 of the present invention will serve to:
  • Compound A means anetumab ravtansine (MF-T-SPDB-DM4), which is an antibody drug conjugate (ADC) comprising the monoclonal antibody MF-T (also known as anetumab) directed against the mesothelin antigen, and the maytansinoid tubulin polymerization inhibitor N 2' -deacetyl-N 2' (4-methyl-4-mercapto-l-oxopentyl)-maytansine (termed DM4, CAS Reg. No. 796073-69-3) which are linked via an SPDB- (N-succinimidyl-4-(2- pyridyldithio) butanoate) linker.
  • ADC antibody drug conjugate
  • Methods for preparation of anetumab ravtansine are disclosed e.g. in WO 2009/068204 (Al) and WO 2010/124797 (Al).
  • Methods for the production of maytansinoids and conjugates thereof are disclosed e.g. in WO 2005/020883 (A2), WO 2004/103272 (A2), and WO 2007/024536 (A2).
  • a preferred formulation for anetumab ravtansine is a lyophilisate resulting in anetumab ravtansine in 130 mM glycine, 10 mM L-histidine, 5% (w/v) sucrose, 0.01% (w/v) polysorabte 80, preferentially pH 5.5 after reconstitution using water for injection and the resulting aqueous solution itself.
  • the aqueous solution of anetumab ravtansine for intravenous injection, sterile and free from bacterial endotoxins is used.
  • a preferred dosage regimen for anetumab ravtansine injection is 5 to 7 and even more preferred 6.5 mg per kg body weight given at 3 week intervals.
  • Compound Bl (or “cpd. Bl”) means 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimid-azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride: it is published in international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 11, 2012, (which is incorporated herein by reference in its entirety), as the compound of Examples 1 and 2 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride: it may be synthesized according to the methods given in said Examples 1 and 2.
  • 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2-c]quinazolin-5- yl] pyrimidine-5-carboxamide dihydrochloride is a compound of structure :
  • Compound B2 (or “cpd. B2") means bevacizumab. It is obtained as Avastin from Roche Pharma AG batch B7226H03.
  • Compound B3 (or “cpd. B3”) means doxorubicin. It is obtained as Caelyx from Janssen-Cilag GmbH PZN: 07683692 Batch: GDZSZOO.
  • Ovarian cancer cell line OVCAR-3 was maintained in vitro in cell cultural medium supplemented with serum at 37 ⁇ C in an atmosphere of 5% C02 in air. The cells in an exponential growth phase were harvested and counted for tumor inoculation.
  • female NOD-Scid mice weres inoculated subcutaneously at the right lower flank region with tumor cells (8xl0 6 cells per mouse) in 0.1 ml of PBS with matrigel for tumor development. Before commencement of treatment, all animals were weighed and the tumor sizes were measured using a caliper every 2-3 days. Since the tumor size can affect the effectiveness of any given treatment, tumor size was used as numeric parameter to randomize selected animals into specified groups to minimize the systematic error. The randomization was performed using matched distribution method. The treatments were started when the mean tumor size reached 30-40mm 2 . The test article administration and the animal numbers in each study group were shown in the experimental design Table 1. The date of tumor cell inoculation was denoted as day 0.
  • Compound A was formulated in lOmM histidine, 130mM glycine, 5% sucrose pH 5.5.
  • Compound B1 was formulated with 0.9% NaCI.
  • the animals were checked daily for morbidity and mortality. At the time of routine monitoring, the animals were checked for any effects of tumor growth and treatments on normal behavior such as mobility, visual estimation of food and water consumption, body weight gain/loss (body weights were measured thrice weekly), eye/hair matting and any other abnormal effect. Death and observed clinical signs were recorded.
  • Figure 1A and 1C show antitumor activity of compound A alone with T/C of 0.3 but no tumor shrinkage.
  • Figure 1A shows tumor growth inhibition in the ovarian cancer model OVCAR-3 : y-axis shows the tumor size in mm 2 measured by caliper. X-axis shows the days after start of treatment.
  • Figure IB shows tumor response in the ovarian cancer OVCAR-3 model : the y-axis shows the percent change of tumor size on the day before start of therapy and the tumor size on day 72 at the end of the experiment for each mouse.
  • the color code identifies mice from different treatment groups.
  • Figure 1C shows the responses in the OVCAR-3 ovarian cancer model treated with Cpd A and/or Cpd Bl.
  • PR partial response ( >30% tumor shrinkage);
  • CR complete response;
  • the anti-tumor activity of Compound A and Compound B2 was assessed in the ovarian cancer model OVCAR-3. Experiment was performed as described above. Tumor growth curves (Figure 2B), tumor response (Figure 2B) and treatement over control (Figure 2C) were used as anti tumor activity endpoints. The tolerability was assessed by maximal body weight change Figure 2C).
  • Figure 2A and 2C show antitumor activity of compound A alone with T/C of 0.3 and 0.77 but no tumor shrinkage.
  • the best tumor response with compound A monotherapy was stable disease ( Figure 2B and 2C).
  • Figure 2A shows tumor growth inhibition in the ovarian cancer model OVCAR-3 : the y-axis shows the tumor size in mm 2 measured by caliper. The X-axis shows the days after start of treatment.
  • Figure 2B shows tumor response in the ovarian cancer OVCAR-3 model : the y-axis shows the percent change of tumor size on the day before start of therapy and the tumor size on day 72 at the end of the experiment for each mouse.
  • the color code identifies mice from different treatment groups.
  • Figure 2C shows responses in the OVCAR-3 ovarian cancer model treated with Cpd A and/or Cpd B2 : PR: partial response ( >30% tumor shrinkage); CR: complete response;
  • SD stable disease (less than 30% tumor shrinkage and less than 20% tumor growth); PD: progressive disease (>20% tumor growth), Response rate: %CR+%PR
  • Ovarian cancer cell line OVCAR-8 was maintained in vitro in cell cultural medium supplemented with serum at 37?C in an atmosphere of 5% C02 in air. The cells in an exponential growth phase were harvested and counted for tumor inoculation.
  • female nude/nude mice were inoculated subcutaneously at the right lower flank region with tumor cells (2xl0 6 cells per mouse) in 0.1 ml of PBS with 50% matrigel for tumor development. Before commencement of treatment, all animals were weighed and the tumor sizes were measured using a caliper every 2-3 days. Since the tumor size can affect the effectiveness of any given treatment, tumor size was used as numeric parameter to randomize selected animals into specified groups to minimize the systematic error. The randomization was performed using matched distribution method. The treatments were started when the mean tumor size reached 30-40mm2. The test article administration and the animal numbers in each study group were shown in the experimental design Table 3. The date of tumor cell inoculation was denoted as day 0.
  • the anti-tumor activity of Compound A and Compound B3 was assessed in the ovarian cancer model OVCAR-8. Experimenet was performed as described above. Tumor growth curves (Figure 3A), tumor response (Figure 3B) and treatement over control (Figure 3B) were used as anti tumor activity endpoints. The tolerability was assessed by maximal body weight change Figure 3B).
  • Figure 3A shows tumor growth inhibition in the ovarian cancer model OVCAR-8 : the y-axis shows the tumor size in mm 2 measured by caliper. The X-axis shows the days after start of treatment.
  • Figure 3B shows responses in the OVCAR-3 ovarian cancer model treated with Cpd A and/or Cpd B3 : PR: partial response ( >30% tumor shrinkage); CR: complete response;

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Abstract

The present invention relates to : •* combinations of : • component A : anetumab ravtansine; • component B : which is selected from : • component B1 : one or more 2,3-dihydroimidazo[1,2- c]quinazoline compounds of general formula (Bl) or (B2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; in which optionally some or all of the components are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. dependently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route; •* such combinations for use in the treatment or prophylaxis of a cancer; and •* a kit comprising such a combination.

Description

COMBINATIONS OF COPANLISIB AND ANETUMAB RAVTANSINE
The present invention relates to combinations of : component A : anetumab ravtansine ;
component B : which is selected from :
• component B1 : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) or (B2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ;
· component B2 : bevacizumab (also referred to hereinafter as its tradename Avastin) ;
• component B3 : doxorubicin (also referred to hereinafter as its tradename Doxil or Caelyx) ;
and, optionally,
component C : one or more further pharmaceutical agents ;
in which optionally either or both of components A and B in any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
Another aspect of the present invention relates to the use of such combinations as described supra for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly cancers with altered activation of PI3K pathway and/or particular PI3K isoform(s) induced modulation of immune response, which not only provide survival signaling to tumor cells but also cause impaired anti-tumor immunity and/or the resistance to the cancer immune therapies. The applicable cancer indications are, but not limited to, ovarian cancer, colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia. In a further aspect, the present invention relates to a kit comprising a combination of component A : anetumab ravtansine ;
component B : which is selected from : • component B1 : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) or (B2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ;
• component B2 : bevacizumab (also referred to hereinafter as its tradename Avastin) ;
• compounent B3 : doxorubicin (also referred to hereinafter as its tradename Doxil or Caelyx) ;
in which optionally either or both of said components A) and B) in any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
BACKGROUND OF THE INVENTION
Combinations of anetumab ravtansine and PI3K Inhibitors:
Cancer is the second most prevalent cause of death in the United States, causing 450,000 deaths per year. While substantial progress has been made in identifying some of the likely environmental and hereditary causes of cancer, there is a need for additional therapeutic modalities that target cancer and related diseases. In particular there is a need for therapeutic methods for treating diseases associated with dysregulated growth / proliferation.
Cancer is a complex disease arising after a selection process for cells with acquired functional capabilities like enhanced survival / resistance towards apoptosis and a limitless proliferative potential. Thus, it is preferred to develop drugs for cancer therapy addressing distinct features of established tumors.
The PI3K signaling pathway is one of the prominent pathways that promote tumor cell survival. PI3K is activated by many cancer related receptor tyrosine kinases (e.g. VEGFR, PDGFR, EGFR, HER2/3, or IGF-1R), cell adhesion molecules, GPCR, and oncogenic proteins (such as Ras). The PI3K pathway activation by genetic alteration of PI3K (activation mutation and/or amplification) and/or I oss-of-f unction of the tumour suppressor PTEN are frequently found in many tumors. Furthermore, activation of PI3K is one of the major mechanisms causing the resistance of tumors to radio-, chemo- and targeted therapeutics.
Once PI3K is activated, it catalyzes the generation of PIP3 from PIP2. The biological active PIP3 binds to the pleckstrin homology (PH) domains of PDK-1, AKT, and other PH-domain containing proteins, such as Rho and PLC. As the consequence of binding to PIP3, these proteins are translocated to the cell membrane and are subsequently activated to induce tumor cell proliferation, survival, invation and migration.
In addition to the roles in tumor cells, PI3K also regulate the activity of the tumor stroma cells (cells that form part of the tumor mass but are not malignantly transformed). The stroma cells include (a) the vasculature, (b) infiltrating immune cells, (c) fibroblasts and (d) other connective tissue. Recent data indicate that the four class I PI3K isoforms have both redoundant and distinct roles in regulating the PI3K signalling in each of these stromal elements. The complexity and/or difficulty in predicting the final outcomes of PI3K inhibitors have been realized, particularly with regard to different isoform profiles and/or other technical properties of PI3K inhibitors.
The Phosphatidylinositol 3-kinase (PI3Ks) pathway is commonly altereted in several human cancer indications including ovarian cancer, gastric cancer, ovarian cancer, lung cancer, endometrial cancer and breast cancer, [see: Bader, A. G., Kang, S., and Vogt, P. K. (2006), Cancer-Specific Mutations in PI3KCA are Oncogenic In Vivo, Proc. Nat. Acad. Sci. 103, 1475- 1479.]. PI3Ks pathway comprises a family of intracellular signal transducer enzymes with three key regulatory nodes: PI3K, AKT, and mammalian target of rapamycin (mTOR) [see: Lux MP, Fasching PA, Schrauder MG, Hein A, Jud SM, Rauh C, Beckmann MW. The PI3K Pathway: Background and Treatment Approaches. Breast Care. 2016; 11:398-404. https://doi.Org/10.1159/000453133.1 Activation of the PI3K pathway including the downstream factor AKT provides a survival signaling to tumor cells and has been shown to be associated with resistance to chemotherapy, [see: Steelman LS, Navolanic P, Chappell WH, Abrams SL, Wong EW, Martel li AM, Cocco L, Stivala F, Libra M, Nicoletti F, Drobot LB, Franklin RA, McCubrey JA. Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells. Cell Cycle. 2011; 10:3003-15. htps://doi.org/10.4161/cc.10.17.171191. More recently inhibition of PI3K has been shown to enhance the activity of anti-microtubile drgs in human cancer cell lines, [see: F. Morgillo, C. Della Corte, A. Diana, C. di Mauro, V. Ciaramella, G. Barra, V. Belli, E. Franzese, R. Bianco, E. Maiello, F. De Vita, F. Ciardiello and M. Orditura (2017). "Phosphatidylinositol 3-kinase (PI3Ka)/AKT axis blockade with taselisib or ipatasertib enhances the efficacy of anti-microtubule drugs in human breast cancer cells" Oncotarget 2017 Aug 22;8(44):76479-76491. doi: 10.18632/oncotarget.20385],
In this invention we found enhanced anti-tumor activity when combining inhibition of the PI3K pathway with an antibody drug conjugate targeting mesothelin expressing tumor cells, providing for a treatment option for patients with mesothelin expressing tumors.
As described in the present invention, 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride, (a highly selective pan-Class I PI3K inhibitor with predominant activity against PI3Ka and PI3K6) and anetumab ravtansine as defined herein, were investigated as combination in inhibiting cancers with mesothellin expression. The applicable cancer indications are, but not limited to, mesothelioma, ovarian cancer, lung cancer, pancreatic cancer, breast cancer, gastric cancer, thymic cancer, colorectal cancer, cholangiocarcinoma, head and neck cancer, endometrial cancer and lymphoma.
Unexpectedly, and this represents a basis of the present invention, when combinations of: component A : anetumab ravtansine, as described and defined herein ;
and
component B : which is selected from :
• component B1 : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) or (B2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein ;
• component B2 : bevacizumab (also referred to hereinafter as its tradename Avastin), as described and defined herein ; and
• component B3 : doxorubicin (also referred to hereinafter as its tradename Doxil or Caelyx), as described and defined herein ;
were evaluated for the treatment of ovarian cancer, synergistically increased anti-tumor activities were demonstrated with these combinations compared to each monotherapy, providing a fundamental rationale for the clinical combination therapy using such PI3K inhibitors-containing combinations.
To the Applicant's knowledge, no generic or specific disclosure or suggestion in the prior art is known that either combinations of: component A : anetumab ravtansine, as described and defined herein ;
and
component B : which is selected from :
• component B1 : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) or (B2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein ;
• component B2 : bevacizumab (also referred to hereinafter as its tradename Avastin), as described and defined herein ;
• component B3 : doxorubicin (also referred to hereinafter as its tradename Doxil or Caelyx), as described and defined herein ; in which optionally either or both of said components A and B of any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially, would be effective in the treatment or prophylaxis of cancer, particularly ovarian cancer, colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia.
Based on the action of the testing compounds described in this invention, the combinations of the present invention as described and defined herein, show a beneficial effect in the treatment of cancer, particularly ovarian cancer, colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia.
Accordingly, in accordance with a first aspect, the present invention relates to combinations of : component A : anetumab ravtansine, as described and defined herein ; and
component B : which is selected from :
• component B1 : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) or (B2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein ;
• component B2 : bevacizumab (also referred to hereinafter as its tradename Avastin), as described and defined herein ;
• component B3 : doxorubicin (also referred to hereinafter as its tradename Doxil or Caelyx), as described and defined herein ; in which optionally either or both of said components A and Bl) of any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
In accordance with a second aspect, of the present invention relates to the use of any of such combinations as described supra for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly ovarian cancer, colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia.
Further, in accordance with a third aspect, the present invention relates to a kit comprising a combination of : component A : anetumab ravtansine, as described and defined herein ;
and
component B : which is selected from :
• component Bl : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) or (B2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein ;
• component B2 : bevacizumab (also referred to hereinafter as its tradename Avastin), as described and defined herein ; • component B3 : doxorubicin (also referred to hereinafter as its tradename Doxil or Caelyx), as described and defined herein ; in which optionally either or both of components A and B in any of the above-mentioned combinations are in the form of a pharmaceutical formu lation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independ nently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
Detailed description of the Invention
In accordance with the above-mentioned aspects of the present invention, said combinations are of:
Component A : which is anetumab ranvastine.
Anetumab ravtansine (MF-T-SPDB-DM4) is an antibody drug conjugate (ADC) comprising the monoclonal antibody MF-T (also known as anetumab) d irected against the mesothelin antigen, and the maytansinoid tubulin polymerization inhibitor N2'-deacetyl-N2' (4-methyl-4-mercapto-l- oxopentyl)-maytansine (termed DM4, CAS Reg. No. 796073-69-3) which are linked via an SPDB- (N-succin imidyl-4-(2-pyridyld ithio) butanoate) linker.
MF-T is an antibody comprising a variable region of the heavy chain (VH) of SEQ ID NO: 1 (VH: QVELVQSGAE VKKPGESLKI SCKGSGYSFT SYWIGWVRQA PGKGLEWMGI IDPGDSRTRY SPSFQGQVTI SADKSISTAY LQWSSLKASD TAMYYCARGQ LYGGTYMDGW GQGTLVTVSS) and a variable region of the light chain of SEQ ID NO: 2 (VL: DIALTQPASV SGSPGQSITI SCTGTSSDIG GYNSVSWYQQ HPGKAPKLMI YGVNNRPSGV SNRFSGSKSG NTASLTISGL QAEDEADYYC SSYDIESATP VFGGGTKLTV LGQ).
Preferentially, MF-T is an antibody comprising a region of the heavy chain of SEQ ID NO: 3 (HC: QVELVQSGAE VKKPGESLKI SCKGSGYSFT SYWIGWVRQA PGKGLEWMGI IDPGDSRTRY SPSFQGQVTI SADKSISTAY LQWSSLKASD TAMYYCARGQ LYGGTYMDGW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK) and a region of the light chain of SEQ ID NO: 4 (LC: DIALTQPASV SGSPGQSITI SCTGTSSDIG GYNSVSWYQQ HPGKAPKLMI YGVNNRPSGV SNRFSGSKSG NTASLTISGL QAEDEADYYC SSYDIESATP VFGGGTKLTV LGQPKAAPSV TLFPPSSEEL QANKATLVCL ISDFYPGAVT VAWKGDSSPV KAGVETTTPS KQSNNKYAAS SYLSLTPEQW KSHRSYSCQV THEGSTVEKT VAPTECS). Preferentially, anetumab ravtansine antibody drug conjugates comprise 1 to 6 DM4 drug moieties (antibody drug ratio). A pharmaceutical composition preferentially comprises a mixture of antibody drug conjugates resulting in an average antibody drug ration of 3 to 4, and even more preferred 3.3 to 3.6. Preferentially, anetumab ravtansine is an antibody drug conjugate of the formu la
Figure imgf000009_0001
in which
MF-T is the antibody MF-T where the antibody is attached via a lysine residue, and n is 1 to 6.
Methods for preparation of anetumab ravtansine are disclosed e.g. in WO 2009/068204 (Al) and WO 2010/124797 (Al). Methods for the production of maytansinoids and conjugates thereof (including DM4) are disclosed e.g. in WO 2005/020883 (A2), WO 2004/103272 (A2), and WO 2007/024536 (A2). A preferred formulation for anetumab ravtansine is a lyophilisate resulting in anetumab ravtansine in 130 mM glycine, 10 mM L-histidine, 5% (w/v) sucrose, 0.01% (w/v) polysorabte 80, preferentially pH 5.5 after reconstitution using water for injection and the resulting aqueous solution itself.
Preferably, the aqueous solution of anetumab ravtansine for intravenous injection, sterile and free from bacterial endotoxins is used.
A preferred dosage regimen for anetumab ravtansine injection is 5 to 7 and even more preferred 6.5 mg per kg body weight given at 3 week intervals.
In accordance with the present invention, the term "antibody" is to be understood in its broadest meaning and comprises immunoglobulin molecules, for example intact or modified monoclonal antibodies, polyclonal antibodies or multispecific antibodies (e.g. bispecific antibodies). An immunoglobulin molecule preferably comprises a molecule having four polypeptide chains, two heavy chains (H chains, HC) and two light chains (L chains, LC) which are typically linked by disulphide bridges. Each heavy chain comprises a variable domain of the heavy chain (abbreviated VH) and a constant domain of the heavy chain. The constant domain of the heavy chain may, for example, comprise three domains CHI, CH2 and CH3. Each light chain comprises a variable domain (abbreviated VL) and a constant domain. The constant domain of the light chain comprises a domain (abbreviated CL). The VH and VL domains may be subdivided further into regions having hypervariability, also referred to as complementarity determining regions (abbreviated CDR) and regions having low sequence variability (framework region, abbreviated FR). Typically, each VH and VL region is composed of three CDRs and up to four FRs. For example from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. An antibody may be obtained from any suitable species, e.g. rabbit, llama, camel, mouse or rat. In one embodiment, the antibody is of human or murine origin. An antibody may, for example, be human, humanized or chimeric.
In accordance with the above-mentioned aspects of the present invention, said combinations are of: component B1 : which is one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) :
Figure imgf000011_0001
wherein
X represents CR5R6or NH; Y1 represents CR3 or N;
Chemical bond between y2— y3 represents a single bond or double bond, with the proviso that when theY2— Y3 represents a double bond,
Y2 and Y3 independently represent CR4 or N, and when Y2— Y3 represents a single bond, Y2 and Y3 independently represent CR3R4 or NR4; Z1, Z2, Z3 and Z4 independently represent CH , CR2 or N;
R1 represents aryl optionally having 1 to 3 substituents selected from R , C3-s cycloalkyl optionally having 1 to 3 substituents selected from R ,
Ci-6 alkyl optionally substituted by
aryl, heteroaryl, Ci-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,
Ci-6 alkoxy optionally substituted by
carboxy, aryl, heteroaryl, Ci-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen, or a 3 to 15 membered mono- or bi-cyclic heterocyclic ring that is saturated or unsaturated, and contains 1 to 3 heteroatoms selected from the group consisting of N, O and S, and optionally having 1 to 3 substituents selected from R
wherein
R represents
halogen, nitro, hydroxy, cyano, carboxy, amino, N-(Ci-6alkyl)amino, N-(hydroxyCi- 6alkyl)amino, N,N-di(Ci-6alkyl)amino, N-(Ci-6acyl)amino, N-(formyl)-N-(Ci-6alkyl)amino, N- (Ci-6alkanesulfonyl) amino, N-(carboxyCi-6alkyl)-N-(Ci-6alkyl)amino, N-(Ci- 6alkoxycabonyl)amino, N-[N,N-di(Ci-6alkyl)amino methylene]amino, N-[N,N-di(Ci- 6alkyl)amino (Ci-6 alkyl)methylene]amino, N-[N,N-di(Ci-6alkyl)amino C2-6alkenyl]amino, aminocarbonyl, N-(Ci-6alkyl)aminocarbonyl, N,N-di(Ci-6alkyl)aminocarbonyl, C3- scycloalkyl, Ci-6 alkylthio, Ci-6alkanesulfonyl, sulfamoyl, Ci-6alkoxycarbonyl,
N-arylamino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101, N-(aryl Ci-6alkyl)amino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101, aryl Ci-6alkoxycarbonyl wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101,
Ci-6al kyl optionally substituted by
mono-, di- or tri- halogen, amino, N-(Ci-6alkyl)amino or N,N-di(Ci-6alkyl)amino,
Ci-6alkoxy optionally substituted by
mono-, di- or tri- halogen, N-(Ci-6alkyl)sulfonamide, or N-(aryl)sulfonamide, or
a 5 to 7 membered saturated or unsaturated ring having 1 to 3 heteroatoms selected from the group consisting of O, S and N, and optionally having 1 to 3 substituents selected from R101
wherein
R101 represents
halogen, carboxy, amino, N-(CI-6 alkyl)amino, N,N-di(Ci-6alkyl)amino, aminocarbonyl, N- (Ci-6alkyl)aminocarbonyl, N,N-di(Ci-6alkyl)aminocarbonyl, pyridyl,
Ci-6 alkyl optionally substituted by cyano or mono- di- or tri- halogen,
or
Ci-galkoxy optionally substituted by cyano, carboxy, amino, N-(CI-6 alkyl)amino, N,N- di(Ci-6alkyl)amino, aminocarbonyl, N-(Ci-6alkyl)aminocarbonyl, N,N-di(Ci-
6alkyl)aminocarbonyl or mono-, di- or tri- halogen; R2 represents hydroxy, halogen, nitro, cyano, amino, N-(Ci-6alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(hydroxyCi-6alkyl)amino, N-(hydroxyCi-6alkyl)-N-(Ci-6alkyl)amino, Ci- 6 acyloxy, aminoCi-6 acyloxy, C2-6alkenyl, aryl,
a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, Ci-6 alkyl, Ci-6 alkoxy, oxo, amino, amino Ci_6al kyl, N-(Ci-6alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(CI-6 acyl)amino, N-(Ci-6alkyl)carbonylamino, phenyl, phenyl Ci-6 alkyl, carboxy, Ci-6alkoxycarbonyl, aminocarbonyl, N-(Ci-6alkyl)aminocarbonyl, or N,N-di(Ci- 6alkyl)amino,
-C(O)- R20
wherein
R20 represents Ci-6 alkyl, Ci-6 alkoxy, amino, N-(Ci-6alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(CI-6 acyl)amino, or a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by
Ci-6 alkyl, Ci-6 alkoxy, oxo, amino, N-(Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N- (Ci-6 acyl)amino, phenyl, or benzyl,
Ci-6 alkyl optionally substituted by R21
or
Ci-6 alkoxy optionally substituted by R21
wherein
R21 represents cyano, mono-, di or tri- halogen, hydroxy, amino, N-(Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N- (hydroxyCi-s alkyl) amino, N- (halophenylCi-s alkyl) amino, amino C2.6 alkylenyl, Ci-6 alkoxy, hydroxyCi-s alkoxy, -C(O)- R201, NHC(O)- R201, C - cycloalkyl, isoindolino, phthalimidyl, 2-oxo-l,3-oxazolidinyl, aryl or a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N optionally substituted by
hydroxy, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxycarbonyl, hydroxyCi-s alkoxy, oxo, amino, aminoCi-6alkyl, N-(Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N-(CI-6 acyl)amino, or benzyl, wherein
R201 represents hydroxy, amino, N-(Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N- (halophenylCi-6 alkyl) amino, Ci_6al kyl, aminoCi-g alkyl, aminoC2-6 alkylenyl, Ci-6 alkoxy, a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N optionally substituted by
hydroxy, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxycarbonyl, hydroxyCi-6 alkoxy, oxo, amino, N-(Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N-(CI-6 acyl)amino or benzyl;
R3 represents hydrogen, halogen, aminocarbonyl, or Ci-6 alkyl optionally substituted by aryl Ci-6 alkoxy or mono-, di- or tri- halogen;
R4 represents hydrogen or Ci-6 alkyl;
R5 represents hydrogen or Ci-6 alkyl; and
R6 represents halogen, hydrogen or Ci-6 alkyl ; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; said compounds are published as compounds of general formulae I, l-a, and l-b in International patent application PCT/EP2003/010377, published as WO 04/029055 A1 on April 08, 2004, which is incorporated herein by reference in its entirety. In WO 04/029055, said compounds of general formula I, l-a and l-b are described on pp. 6 et seq., they may be synthesized according to the methods given therein on pp. 26 et seq., and are exemplified as specific compound Examples 1-1 to 1-210 on pp. 47 to 106, specific compound Examples 2-1 to 2-368 on pp. 107 to 204, specific compound Examples 3-1 to 3-2 on pp. 205 to 207, and as specific compound Examples 4-1 to 4-2 on pp. 208 to 210, therein.
Such a compound, 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimid- azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride, (which is hereinafter referred to as "compound Bl" or "cpd. Bl") is published in international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 11, 2012, (which is incorporated herein by reference in its entirety), as the compound of Examples 1 and 2 : 2- amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2-c]quinazolin-5- yl] pyrimidine-5-carboxamide dinydrochloride: it may be synthesized according to the methods given in said Examples 1 and 2.
Said component B1 may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
In accordance with another embodiment of the above-mentioned aspects of the present invention, said combinations are of: component B1 : which is one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl), supra, which is selected from the list consisting of specific compound Examples 1-1 to 1-210 on pp. 47 to 106, specific compound Examples 2-1 to 2-368 on pp. 107 to 204, specific compound Examples 3-1 to 3-2 on pp. 205 to 207, and specific compound Examples 4-1 to 4-2 on pp. 208 to 210, of in International patent application PCT/EP2003/010377, published as WO 04/029055 A1 on April 08, 2004, which is incorporated herein by reference in its entirety; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof.
Such a component Bl may be : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimid-azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride, (which is hereinafter referred to as "compound Bl" or "cpd. Bl") is published in international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 11, 2012, (which is incorporated herein by reference in its entirety), as the compound of Examples 1 and 2 : 2- amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2-c]quinazolin-5- yl] pyrimidine-5-carboxamide dihydrochloride: it may be synthesized according to the methods given in said Examples 1 and 2. Said component B1 may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
As mentioned supra, said specific compound Examples may be synthesized according to the methods given in WO 04/029055 A1 on pp. 26 et seq..
As mentioned supra, 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimid- azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride, (which is hereinafter referred to as "compound Bl" or "cpd. Bl") may be synthesized as described in Examples 1 and 2 of international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 11, 2012, (which is incorporated herein by reference in its entirety). In accordance with another embodiment of the above-mentioned aspects of the present invention, said combinations are of : component Bl : which is one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (B2) :
Figure imgf000016_0001
in which :
X represents CR5R6or NH; represents CR3 or N; the chemical bond between y2— y3 represents a single bond or double bond, with the proviso that when theY2— Y3 represents a double bond, Y2 and Y3 independently represent CR4 or N, and
when y2— y3 represents a single bond, Y2 and Y3 independently represent CR3R4 or NR4;
Z1, Z2, Z3 and Z4 independently represent CH , CR2 or N;
R1 represents aryl optionally having 1 to 3 substituents selected from R , C3-s cycloalkyl optionally having 1 to 3 substituents selected from R ,
Ci-6 alkyl optionally substituted by aryl, heteroaryl, Ci-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,
Ci-6 alkoxy optionally substituted by carboxy, aryl, heteroaryl, Ci-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,
or
a 3 to 15 membered mono- or bi-cyclic heterocyclic ring that is saturated or unsaturated, optionally having 1 to 3 substituents selected from R , and contains 1 to 3 heteroatoms selected from the group consisting of N, O and S, wherein
R represents halogen, nitro, hydroxy, cyano, carboxy, amino, N- (Ci-6alkyl)amino, N-(hydroxyCi-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N-(Ci- 6acyl)amino, N-(formyl)-N-(Ci-6alkyl)amino, N-(Ci-6alkanesulfonyl) amino, N- (carboxyCi-6alkyl)-N-(Ci-6alkyl)amino, N-(Ci-6alkoxycabonyl)amino, N-[N,N-di(Ci- 6alkyl)amino methylene]amino, N-[N,N-di(Ci-6alkyl)amino (Ci- 6alkyl)methylene]amino, N-[N,N-di(Ci-6alkyl)amino C -6alkenyl]amino, aminocarbonyl, N-(Ci-6alkyl)aminocarbonyl, N,N-di(Ci-6alkyl)aminocarbonyl, C3-8cycloalkyl, Ci-6 alkylthio, Ci-6alkanesulfonyl, sulfamoyl, Ci-6alkoxycarbonyl, N-arylamino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101, N-(aryl Ci-6alkyl)amino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101, aryl Ci-6alkoxycarbonyl wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101, Ci_6al kyl optionally substituted by mono-, di- or tri- halogen, amino, N-(Ci- 6alkyl)amino or N,N-di(Ci-6alkyl)amino,
Ci-6alkoxy optionally substituted by mono-, di- or tri- halogen, N- (Ci-6alkyl)sulfonamide, or N-(aryl)sulfonamide,
or
a 5 to 7 membered saturated or unsaturated ring having 1 to 3 heteroatoms selected from the group consisting of O, S and N, and optionally having 1 to 3 substituents selected from R101 wherein
R101 represents halogen, carboxy, amino, N-(CI-6 alkyl)amino, N,N-di(Ci- 6alkyl)amino, aminocarbonyl, N-(Ci-6alkyl)aminocarbonyl, N,N-di(Ci- 6alkyl)aminocarbonyl, pyridyl,
Ci-6 alkyl optionally substituted by cyano or mono- di- or tri- halogen, and
Ci-6alkoxy optionally substituted by cyano, carboxy, amino, N-(CI-6 alkyl)amino, N,N-di(Ci-6alkyl)amino, aminocarbonyl, N-(Ci- 6alkyl)aminocarbonyl, N,N-di(Ci-6alkyl)aminocarbonyl or mono-, di- or tri- halogen;
R2 represents hydroxy, halogen, nitro, cyano, amino, N-(Ci-6alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(hydroxyCi-6alkyl)amino, N-(hydroxyCi-6alkyl)-N-(Ci-6alkyl)amino, Ci-g acyloxy, aminoCi-g acyloxy, C -6alkenyl, aryl, a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, Ci-6 alkyl, Ci-6 alkoxy, oxo, amino, amino Ci-6al kyl, N-(Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N-(CI-6 acyl)amino, N-(Ci-6alkyl)carbonylamino, phenyl, phenyl Ci-6 alkyl, carboxy, Ci-6alkoxycarbonyl, aminocarbonyl, N-(Ci-
6alkyl)aminocarbonyl, or N,N-di(Ci-6alkyl)amino, -C(O)- R20
wherein
R20 represents Ci-6 alkyl, Ci-6 alkoxy, amino, N-(Ci-6alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(CI-6 acyl)amino, or a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by Ci-6 alkyl, Ci-6 alkoxy, oxo, amino, N-(Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N-(Ci- 6 acyl)amino, phenyl, or benzyl,
Ci-6 alkyl optionally substituted by R21,
or
Ci-6 alkoxy optionally substituted by R21,
wherein
R21 represents cyano, mono-, di or tri- halogen, hydroxy, amino, N- (Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N- (hydroxyCi-6 alkyl) amino, N- (halophenylCi-6 alkyl) amino, amino C2.6 alkylenyl, Ci-6 alkoxy, hydroxyCi-6 alkoxy, -C(O)- R201, -NHC(O)- R201, C3- scycloalkyl, isoindolino, phthalimidyl, 2-oxo-l,3-oxazolidinyl, aryl or a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N , and optionally substituted by hydroxy, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxycarbonyl, hydroxyCi-6 alkoxy, oxo, amino, aminoCi-galkyl, N-(Ci-6alkyl)amino, N,N- di(Ci-6alkyl)amino, N-(CI-6 acyl)amino, or benzyl, wherein
R201 represents hydroxy, amino, N-(Ci-6alkyl)amino, N,N-di(Ci- 6alkyl)amino, N- (halophenylCi-s alkyl) amino, Ci-ealkyl, aminoCi-6 alkyl, aminoC2-6 alkylenyl, Ci-6 alkoxy, a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxycarbonyl, hydroxyCi-6 alkoxy, oxo, amino, N-(Ci-6alkyl)amino, N,N- di(Ci-6alkyl)amino, N-(CI-6 acyl)amino or benzyl;
R3 represents hydrogen, halogen, aminocarbonyl, or Ci-6 alkyl optionally substituted by aryl Ci-6 alkoxy or mono-, di- or tri- halogen;
R4 represents hydrogen or Ci-6 alkyl;
R5 represents hydrogen or Ci-6 alkyl; and
R6 represents halogen, hydrogen or Ci-6 alkyl ; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; said compounds are published as compounds of general formulae I, la, lb, lc, Id and le in International patent application PCT/US2007/024985, published as WO 2008/070150 A1 on June 12, 2008, which is incorporated herein by reference in its entirety. In WO 2008/070150, said compounds of general formula I, la, lb, lc, Id and le are described on pp. 9 et seq., they may be synthesized according to the methods given therein on pp. 42, et seq., and are exemplified as specific compound Examples 1 to 103 therein on pp. 65 to 101. Biological test data for certain of said compounds are given therein on pp. 101 to 107.
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimid-azo[l,2-c]quinazolin-5- yl] pyrimidine-5-carboxamide dihydrochloride, (which is hereinafter referred to as "compound Bl" or "cpd. Bl") is published in international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 11, 2012, (which is incorporated herein by reference in its entirety), as the compound of Examples 1 and 2 : 2-amino-N-[7-methoxy-8-(3-morpholin- 4-ylpropoxy)-2,3-dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide
dinydrochloride: it may be synthesized according to the methods given in said Examples 1 and
2. The definitions used in relation to the structure (B2) in this text are as follows :
The term 'alkyl' refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, such as illustratively, methyl, ethyl, n-propyl 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).
The term "alkenyl " refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched or branched chain having about 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l-propenyl, 1- butenyl, 2-and butenyl.
The term "alkynyl" refers to a straight or branched chain hydrocarbonyl radicals having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 10 carbon atoms presently being preferred) e.g., ethynyl.
The term "alkoxy" denotes an alkyl group as defined herein attached via oxygen linkage to the rest of the molecule. Representative examples of those groups are methoxy and ethoxy.
The term "alkoxyakyl" denotes an alkoxy group as defined herein attached via oxygen linkage to an alkyl group which is then attached to the main structure at any carbon from alkyl group that results in the creation of a stable structure the rest of the molecule. Representative examples of those groups are -CH2OCH3 and --CH2OC2H5 .
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and examples of multicyclic cycloalkyl groups include perhydronapththyl, adamantyl and norbornyl groups bridged cyclic group or sprirobicyclic groups e.g sprio (4,4) non-2-yl. The term "cycloalkylalkyl" refers to cyclic ring-containing radicals containing in the range of about about 3 up to 8 carbon atoms directly attached to alkyl group which is then also attached to the main structure at any carbon from the alkyl group that results in the creation of a stable structure such as cyclopropylmethyl, cyclobuyylethyl, cyclopentylethyl.
The term "aryl" refers to aromatic radicals having in the range of 6 up to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, biphenyl.
The term "arylalkyl" refers to an aryl group as defined herein directly bonded to an alkyl group as defined herein which is then attached to the main structure at any carbon from alkyl group that results in the creation of a stable structure the rest of the molecule, e.g., --CH C6H5, -- CzHsCsHs .
The term "heterocyclic ring" refers to a stable 3- to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heteroaromatic or heteroaryl aromatic). Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl cinnolinyl dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazil, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl tetrahydroisouinolyl, piperidinyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4- piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl pyridazinyl, oxazolyl oxazolinyl oxasolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, isochromanyl . The term "heteroaryl" refers to heterocyclic ring radical as defined herein which are aromatic. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "heteroarylalkyl" refers to heteroaryl ring radical as defined herein directly bonded to alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom from alkyl group that results in the creation of a stable structure.
The term "heterocyclyl" refers to a heterocylic ring radical as defined herein. The heterocylyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "heterocyclylalkyl" refers to a heterocylic ring radical as defined herein directly bonded to alkyl group. The heterocyclylalkyl radical may be attached to the main structure at carbon atom in the alkyl group that results in the creation of a stable structure.
The term "carbonyl" refers to an oxygen atom bound to a carbon atom of the molecule by a double bond.
The term "halogen" refers to radicals of fluorine, chlorine, bromine and iodine.
Said component B1 may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
In accordance with another embodiment of the above-mentioned aspects of the present invention, said combinations are of : component B1 : which is one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (A2), supra, which is selected from the list consisting of :
Example 1 N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2- c]quinazolin-5-yl]pyrimidine-5-carboxamide
Example 2 : N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-
2.3-dihydroimidazo[l,2-c]quinazolin-5-yl)nicotinamide
Example 3 : N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-
2.3-dihydroimidazo[l,2-c]quinazolin-5-yl)-2,4-dimethyl-l,3-thiazole-5-carboxamide
Example 4 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]-l,3-thiazole-5-carboxamide.
Example 5 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl] isonicotinamide
Example 6 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]-4-methyl-l,3-thiazole-5-carboxamide
Example 7 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2- c]quinazolin-5-yl]-4-propylpyrimidine-5-carboxamide
Example 8 : N-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl}nicotinamide
Example 9 : N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydroimidazo[l,2- c]quinazolin-5-yl}pyrimidine-5-carboxamide
Example 10 : N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-
2.3-dihydroimidazo[l,2-c]quinazolin-5-yl)nicotinamide
Example 11 : N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-
2.3-dihydroimidazo[l,2-c]quinazolin-5-yl)nicotinamide
Example 12 : N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[l,2-c]quinazolin- 5-yl}nicotinamide 1-oxide
Example 13 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2- c]quinazolin-5-yl]pyrimidine-5-carboxamide.
Example 14 N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2- c]quinazolin-5-yl]-6-(2-pyrrolidin-l-ylethyl)nicotinamide.
Example 15 : 6-(cyclopentylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-
2.3-dihydroimidazo[l,2-c]quinazolin-5-yl]nicotinamide
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, Said compounds are published as specific compound Examples 1 to 103 in International patent application PCT/US2007/024985, published as WO 2008/070150 A1 on June 12, 2008, which is incorporated herein by reference in its entirety. I n WO 2008/070150, said specific compound Examples may be synthesized according to the Examples. Biological test data for certain of said compounds are given therein on pp. 101 to 107.
Specifically, component B1 may be 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimid-azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride, (which is hereinafter referred to as "compound Bl" or "cpd. Bl") is published in international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 11, 2012, (which is incorporated herein by reference in its entirety), as the compound of Examples 1 and 2 : 2- amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2-c]quinazolin-5- yl] pyrimidine-5-carboxamide dihydrochloride: it may be synthesized accord ing to the methods given in said Examples 1 and 2.
Said component Bl may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
In accordance with another embodiment of the above-mentioned aspects of the present invention, said combinations are of component B2 : bevacizumab (also referred to hereinafter as its tradename Avastin ), as described and defined herein. compound B2: bevacizumab (CAS number: 216974-75-3, DrugBank entry DB00112, also referred to hereinafter as its tradename Avastin) is an antibody well known in the art.
Bevacizumab comprises a region of the heavy chain of SEQ ID NO: 5 (HC:
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWI NTYTGEPTYAADFKRRFTF
SLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTS
GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNT
KVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV
EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK) and a region of the light chain of SEQ ID NO: 6 (LC:
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDFTLTI SSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQW KVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC).
A preferred dosage regimen for bevacizumab is 5 to 15 mg per kg body weight given at 2 or 3 week intervals dependent on tumor type.
In accordance with another embodiment of the above-mentioned aspects of the present invention, said combinations are of component B3 : doxorubicin (also referred to hereinafter as its tradename Doxil or Caelyx), as described and defined herein. compound B3: doxorubicin [(7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy- 6,9,ll-trihydroxy-9-(2-hyd roxyacetyl)-4-methoxy-8,10-dihydro-7FI-tetracene-5,12-dione] sold under the trade names Adriamycin among others, is a chemotherapy medication used to treat cancer. There is a pegylated (polyethylene glycol coated) liposome-encapsulated form of doxorubicin, sold as Doxil (also referred to hereinafter as its tradename Doxil). Further a non- pegylated liposomal doxorubicin is available (called Myocet).
Doxorubicin as used herein includes if not further specified all variants (pegylated and non- pegylated) and versions (liposomal and non-liposomal) of doxorubicin. A preferred form of doxorubicin is pegylated (polyethylene glycol coated) liposome-encapsu lated form of doxorubicin (also referred to hereinafter as its tradename Doxil)
When used in combination with other chemotherapy drugs, the most commonly used dosage of doxorubicin is 40 to 60 mg/m2 IV every 21 to 28 days. Alternatively, 60 to 75 mg/m2 IV once every 21 days.
In accordance with an embodiment of the above-mentioned aspects of the present invention, said combinations are of : component A : anetumab ravtansine. Said component A may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
In accordance with an embodiment of the above-mentioned aspects of the present invention, said combinations are of: component A : anetumab ravtansine ;
and
component B1 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2- c]quinazolin-5-yl]pyrimidine-5-carboxamide or 2-amino-N-[7-methoxy-8-(3-morpholin-4- ylpropoxy)-2,3-dihydroimid-azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide
dihydrochloride, (which is hereinafter referred to as "compound Bl" or "cpd. Bl").
Said component Bl may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
In accordance with an embodiment, the present invention relates to a combination of any component A mentioned herein with any component Bl mentioned herein.
In a particular embodiment, the present invention relates to a combination of a component A with a component Bl, as mentioned in the Examples section herein.
Useful forms of components A and Bl of the combinations of the present invention
As mentioned supra, either or both of components A and Bl of any of the combinations of the present invention may be in a useful form, such as pharmaceutically acceptable salts, co precipitates, metabolites, hydrates, solvates and prodrugs of all the compounds of examples. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts/' J. Pharm. Sci. 1977, 66, 1-19. Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts. Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
Representative salts of the compounds of this invention include the conventional non-toxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate.
Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, or butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl sulfate, or diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. A solvate for the purpose of this invention is a complex of a solvent and a compound of the invention in the solid state. Exemplary solvates would include, but are not limited to, complexes of a compound of the invention with ethanol or methanol. Hydrates are a specific form of solvate wherein the solvent is water.
Pharmaceutical formulations of
Figure imgf000044_0001
A and B1 of the combinations of the present invention
As mentioned supra, the components A or B1 may, independently from one another, be in the form of a pharmaceutical composition or formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
Said compositions can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes combinations in which components A and B, independently of one another, are pharmaceutical formulations compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a said component. A pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of component, and/or combination. A pharmaceutically effective amount of a combination is preferably that amount which produces a result or exerts an influence on the particular condition being treated. The combinations of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like. It is possible for the compounds according to the invention to have systemic and/or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms.
For oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia,
• fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel”), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos*)), • ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols),
• bases for suppositories (for example polyethylene glycols, cacao butter, hard fat),
• solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins),
• surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette*), sorbitan fatty acid esters (such as, for example, Span”), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween*), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor*), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic*),
• buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),
• isotonicity agents (for example glucose, sodium chloride),
• adsorbents (for example highly-disperse silicas),
• viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl- cellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol*); alginates, gelatine),
• disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab*), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSof )),
• flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil*)),
• coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon*), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropyl- methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit*)),
• capsule materials (for example gelatine, hydroxypropylmethylcellulose),
• synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit*), polyvinylpyrrolidones (such as, for example, Kollidon*), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
• plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),
• penetration enhancers,
• stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gal late),
• preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),
• colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),
• flavourings, sweeteners, flavour- and/or odour-masking agents.
The present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
Method of treating cancer
Within the context of the present invention, the term "cancer" includes, but is not limited to, cancers of the breast, lung, brain, reproductive organs, digestive tract, urinary tract, liver, eye, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include multiple myeloma, lymphomas, sarcomas, and leukemias.
Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
Examples of cancers of the respiratory tract include, but are not limited to lung cancer, particularly small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, melanoma, particularly malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer. Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
The present invention relates to a method for using the combinations of the present invention, in the treatment or prophylaxis of a cancer, particularly (but not limited to) colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia, etc.. Combinations can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis, in the treatment or prophylaxis of cancer, in particular (but not limited to) colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia, etc.. This method comprises administering to a mammal in need thereof, including a human, an amount of a combination of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc. which is effective for the treatment or prophylaxis of cancer, in particular (but not limited to) colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia, etc.. The term "treating" or "treatment" as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
Dose and administration
Based upon standard laboratory techniques known to evaluate compounds useful for the treatment or prophylaxis of cancer, in particular (but not limited to) colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia, etc., by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the combinations of this invention can readily be determined for treatment of the indication. The amount of the active ingredient to be administered in the treatment of the condition can vary widely according to such considerations as the particular combination and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1,500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific combination employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a combination of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
Therapies using combinations of component A as described supra, component B1 as described supra, and component C: one or more further pharmaceutical agents.
The combinations of component A and component B1 of this invention can be administered as the sole pharmaceutical agent or in combination with one or more further pharmaceutical agents where the resulting combination of components A, B1 and C causes no unacceptable adverse effects. For example, the combinations of components A and B1 of this invention can be combined with component C, i.e. one or more further pharmaceutical agents, such as known anti-angiogenesis, anti-hyper-proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agents, and the like, as well as with admixtures and combinations thereof.
Component C, can be one or more pharmaceutical agents such as 1311-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium- 103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium- 186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib , rucaparib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc- HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.
Generally, the use of component C in combination with a combination of components A and B1 of the present invention will serve to:
(1) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone,
(2) provide for the administration of lesser amounts of the administered chemotherapeutic agents, (3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies, (4) provide for treating a broader spectrum of different cancer types in mammals, especially humans,
(5) provide for a higher response rate among treated patients, (6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments,
(7) provide a longer time for tumor progression, and/or (8) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
The following Examples describe the feasability of the present invention, but not restricting the invention to these Examples only.
EXAMPLES
The following abbreviations are used in the Examples:
"Compound A" (or "cpd. A") means anetumab ravtansine (MF-T-SPDB-DM4), which is an antibody drug conjugate (ADC) comprising the monoclonal antibody MF-T (also known as anetumab) directed against the mesothelin antigen, and the maytansinoid tubulin polymerization inhibitor N2'-deacetyl-N2' (4-methyl-4-mercapto-l-oxopentyl)-maytansine (termed DM4, CAS Reg. No. 796073-69-3) which are linked via an SPDB- (N-succinimidyl-4-(2- pyridyldithio) butanoate) linker.
Methods for preparation of anetumab ravtansine are disclosed e.g. in WO 2009/068204 (Al) and WO 2010/124797 (Al). Methods for the production of maytansinoids and conjugates thereof (including DM4) are disclosed e.g. in WO 2005/020883 (A2), WO 2004/103272 (A2), and WO 2007/024536 (A2).
A preferred formulation for anetumab ravtansine is a lyophilisate resulting in anetumab ravtansine in 130 mM glycine, 10 mM L-histidine, 5% (w/v) sucrose, 0.01% (w/v) polysorabte 80, preferentially pH 5.5 after reconstitution using water for injection and the resulting aqueous solution itself.
Preferably, the aqueous solution of anetumab ravtansine for intravenous injection, sterile and free from bacterial endotoxins is used.
A preferred dosage regimen for anetumab ravtansine injection is 5 to 7 and even more preferred 6.5 mg per kg body weight given at 3 week intervals.
"Compound Bl" (or "cpd. Bl") means 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimid-azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride: it is published in international patent application PCT/EP2012/055600, published as WO 2012/136553 on October 11, 2012, (which is incorporated herein by reference in its entirety), as the compound of Examples 1 and 2 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride: it may be synthesized according to the methods given in said Examples 1 and 2.
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2-c]quinazolin-5- yl] pyrimidine-5-carboxamide dihydrochloride is a compound of structure :
Figure imgf000056_0001
. 2 HCI and is an example of component B1 as described and defined herein.
"Compound B2" (or "cpd. B2") means bevacizumab. It is obtained as Avastin from Roche Pharma AG batch B7226H03.
"Compound B3" (or "cpd. B3") means doxorubicin. It is obtained as Caelyx from Janssen-Cilag GmbH PZN: 07683692 Batch: GDZSZOO.
Experimental Methods
Ovarian cancer cell line OVCAR-3 was maintained in vitro in cell cultural medium supplemented with serum at 37^C in an atmosphere of 5% C02 in air. The cells in an exponential growth phase were harvested and counted for tumor inoculation. To investigate anti-tumor efficacy and mechanisms of action in vivo, female NOD-Scid mice weres inoculated subcutaneously at the right lower flank region with tumor cells (8xl06 cells per mouse) in 0.1 ml of PBS with matrigel for tumor development. Before commencement of treatment, all animals were weighed and the tumor sizes were measured using a caliper every 2-3 days. Since the tumor size can affect the effectiveness of any given treatment, tumor size was used as numeric parameter to randomize selected animals into specified groups to minimize the systematic error. The randomization was performed using matched distribution method. The treatments were started when the mean tumor size reached 30-40mm2. The test article administration and the animal numbers in each study group were shown in the experimental design Table 1. The date of tumor cell inoculation was denoted as day 0.
Table 1. Experimental design
Figure imgf000057_0001
Compound A was formulated in lOmM histidine, 130mM glycine, 5% sucrose pH 5.5. Compound B1 was formulated with 0.9% NaCI.
After inoculation of tumor cells, the animals were checked daily for morbidity and mortality. At the time of routine monitoring, the animals were checked for any effects of tumor growth and treatments on normal behavior such as mobility, visual estimation of food and water consumption, body weight gain/loss (body weights were measured thrice weekly), eye/hair matting and any other abnormal effect. Death and observed clinical signs were recorded.
Tumor volumes were measured every 2-3 days in two dimensions using a caliper, and the size was expressed in mm2 using the formula: tumor area = long diameter of the tumor x short diameter of the tumor. The entire procedures of dosing as well as tumor and body weight measurement were conducted in a Laminar Flow Cabinet. Statistical Analysis: Summary statistics, including mean and the standard error of the mean (SEM), are provided for the tumor volume of each group at each time point. Statistical analysis of difference in tumor volume between the comparing groups was conducted using independent-samples T test. P-values were rounded to three decimal places, with the exception that raw P-values less than 0.001 were stated as P<0.001. All tests were two-sided. P<0.05 was considered to be statistically significant.
EXAMPLE 1: SYNERGISTIC COMBINATIONS OF COMPONENT A AND COMPONENT Bl OF THE
PRESENT INVENTION IN THE OVCAR-3 OVARIAN CANCER MOUSE MODEL
The anti-tumor activity of Compound A and Compound B1 was assessed in the ovarian cancer model OVCAR-3. Experiment was performed as described above. Tumor growth curves (Figure
IB), tumor response (Figure IB) and treatment over control (Figure 1C) were used as anti tumor activity endpoints. The tolerability was assessed by maximal body weight change Figure
IC).
Figure 1A and 1C show antitumor activity of compound A alone with T/C of 0.3 but no tumor shrinkage.
Figure 1A shows tumor growth inhibition in the ovarian cancer model OVCAR-3 : y-axis shows the tumor size in mm2 measured by caliper. X-axis shows the days after start of treatment.
Figure IB shows tumor response in the ovarian cancer OVCAR-3 model : the y-axis shows the percent change of tumor size on the day before start of therapy and the tumor size on day 72 at the end of the experiment for each mouse. The color code identifies mice from different treatment groups.
Figure 1C shows the responses in the OVCAR-3 ovarian cancer model treated with Cpd A and/or Cpd Bl. PR: partial response ( >30% tumor shrinkage); CR: complete response;
SD: stable disease (less than 30% tumor shrinkage and less than 20% tumor growth); PD: progressive disease (>20% tumor growth), Response rate: %CR+%PR The best tumor response with compound A monotherapy was stable disease (Figure IB and 1C). Compound B1 showed very little anti-tumor activity as monotherapy with T/C of 0.64 and 0.7 depending on the start of therapy and only progressive disease (Figure 1C). Surprisingly combined treatment of compound A and compound B1 showed improved tumor activity resulting in partial response (PR) shown in Figure IB and 1C. Partial response was only seen in combination treatment not in any of the mice treated with monotherapies. PR response is a clinicaly well established endpoint for clinical trials suggesting a benefit for ovarian cancer patients treated with a combination of compound A and Bl. The improved tumor response was seen when compound Bl treatment started on d2 but also when start of compound Bl treatment was delayed until d9. All treatments were well tolerated as indicated by less than 10% maximal body weight loss in all treatment groups.
EXAMPLE 2: SYNERGISTIC COMBINATIONS OF COMPONENT A AND COMPONENT B2 OF THE PRESENT INVENTION IN THE OVCAR-3 OVARIAN CANCER MOUSE MODEL
The anti-tumor activity of Compound A and Compound B2 was assessed in the ovarian cancer model OVCAR-3. Experiment was performed as described above. Tumor growth curves (Figure 2B), tumor response (Figure 2B) and treatement over control (Figure 2C) were used as anti tumor activity endpoints. The tolerability was assessed by maximal body weight change Figure 2C).
Table 2. Experimental design
Figure imgf000059_0001
Figure imgf000060_0001
Figure 2A and 2C show antitumor activity of compound A alone with T/C of 0.3 and 0.77 but no tumor shrinkage. The best tumor response with compound A monotherapy was stable disease (Figure 2B and 2C).
Figure 2A shows tumor growth inhibition in the ovarian cancer model OVCAR-3 : the y-axis shows the tumor size in mm2 measured by caliper. The X-axis shows the days after start of treatment.
Figure 2B shows tumor response in the ovarian cancer OVCAR-3 model : the y-axis shows the percent change of tumor size on the day before start of therapy and the tumor size on day 72 at the end of the experiment for each mouse. The color code identifies mice from different treatment groups.
Figure 2C shows responses in the OVCAR-3 ovarian cancer model treated with Cpd A and/or Cpd B2 : PR: partial response ( >30% tumor shrinkage); CR: complete response;
SD: stable disease (less than 30% tumor shrinkage and less than 20% tumor growth); PD: progressive disease (>20% tumor growth), Response rate: %CR+%PR
Compound B2 showed anti-tumor activity as monotherapy with T/C of 0.39 but only stable disease as best response (Figure 2C). Surprisingly combined treatment of compound A and compound B2 showed improved tumor activity resulting in partial response (PR) shown in Figure 2B and 2C. Partial response was only seen in combination treatment not in any of the mice treated with monotherapies. PR response is a clinicaly well established endpoint for clinical trials suggesting a benefit for ovarian cancer patients treated with a combination of compound A and B2. The improved tumor response was seen when compound A treatment was dosed on dl, d4 d46, d49 and also when compound A was given on dl and d46 only. EXAMPLE 3: SYNERGISTIC COMBINATIONS OF COMPONENT A AND COMPONENT B3 OF THE
PRESENT INVENTION IN THE OVCAR-8 OVARIAN CANCER MOUSE MODEL
Ovarian cancer cell line OVCAR-8 was maintained in vitro in cell cultural medium supplemented with serum at 37?C in an atmosphere of 5% C02 in air. The cells in an exponential growth phase were harvested and counted for tumor inoculation. To investigate anti-tumor efficacy and mechanisms of action in vivo, female nude/nude mice were inoculated subcutaneously at the right lower flank region with tumor cells (2xl06 cells per mouse) in 0.1 ml of PBS with 50% matrigel for tumor development. Before commencement of treatment, all animals were weighed and the tumor sizes were measured using a caliper every 2-3 days. Since the tumor size can affect the effectiveness of any given treatment, tumor size was used as numeric parameter to randomize selected animals into specified groups to minimize the systematic error. The randomization was performed using matched distribution method. The treatments were started when the mean tumor size reached 30-40mm2. The test article administration and the animal numbers in each study group were shown in the experimental design Table 3. The date of tumor cell inoculation was denoted as day 0.
Table 3. Experimental design
Figure imgf000061_0001
After inoculation of tumor cells, the animals were checked daily for morbidity and mortality. At the time of routine monitoring, the animals were checked for any effects of tumor growth and treatments on normal behavior such as mobility, visual estimation of food and water consumption, body weight gain/loss (body weights were measured thrice weekly), eye/hair matting and any other abnormal effect. Death and observed clinical signs were recorded. Tumor volumes were measured every 2-3 days in two dimensions using a caliper, and the size was expressed in mm2 using the formula: tumor area = long diameter of the tumor x short diameter of the tumor. The entire procedures of dosing as well as tumor and body weight measurement were conducted in a Laminar Flow Cabinet.
The anti-tumor activity of Compound A and Compound B3 was assessed in the ovarian cancer model OVCAR-8. Experimenet was performed as described above. Tumor growth curves (Figure 3A), tumor response (Figure 3B) and treatement over control (Figure 3B) were used as anti tumor activity endpoints. The tolerability was assessed by maximal body weight change Figure 3B).
Figure 3A shows tumor growth inhibition in the ovarian cancer model OVCAR-8 : the y-axis shows the tumor size in mm2 measured by caliper. The X-axis shows the days after start of treatment. Figure 3B shows responses in the OVCAR-3 ovarian cancer model treated with Cpd A and/or Cpd B3 : PR: partial response ( >30% tumor shrinkage); CR: complete response;
SD: stable disease (less than 30% tumor shrinkage and less than 20% tumor growth); PD: progressive disease (>20% tumor growth), Response rate: %CR+%PR Figure 3A and 3B show very little antitumor activity of compound A alone with T/C of 0.68 and no tumor shrinkage. The best tumor response with compound A monotherapy was stable disease (Figure 3B). Compound B3 showed no anti-tumor activity as monotherapy with T/C of 0.94 but only progressive disease as best response (Figure 3B). Combined treatment of compound A and compound B3 showed improved tumor activity resulting in T/C=0.49 (Figure 3B) and 1/9 partial response (PR) shown in Figure 3B. A clear trend towards improved tumor therapy of Cpd A combined with Cpd B3 was seen in the ovarian cancer model OVCAR-8. The combination of Cpd A plus Cpd B3 showed better therapeutic efficacy (PR=11%, SD=33%, PD=55%) than either Cpd B3 alone (PD=100%) or Cpd A alone (PR=0%, SD=10%, PD=90%). SEQUENCE LISTINGS :
>Anetumab-VH (SEQ ID NO: 1)
QVELVQSGAE VKKPGESLKI SCKGSGYSFT SYWIGWVRQA PGKGLEWMGI IDPGDSRTRY SPSFQGQVTI SADKSI STAY LQWSSLKASD TAMYYCARGQ LYGGTYMDGW GQGTLVTVSS
>Anetumab-VL (SEQ ID NO: 2)
DIALTQPASV SGSPGQSITI SCTGTSSDIG GYNSVSWYQQ HPGKAPKLMI YGVNNRPSGV SNRFSGSKSG NTASLTI SGL QAEDEADYYC SSYDIESATP VFGGGTKLTV LGQ
>Anetumab Heavy Chain (SEQ ID NO: 3)
QVELVQSGAE VKKPGESLKI SCKGSGYSFT SYWIGWVRQA PGKGLEWMGI IDPGDSRTRY SPSFQGQVTI SADKSI STAY LQWSSLKASD TAMYYCARGQ LYGGTYMDGW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMI SRTP EVTCWVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRWSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK
>Anetumab Light Chain (SEQ ID NO: 4)
DIALTQPASV SGSPGQSITI SCTGTSSDIG GYNSVSWYQQ HPGKAPKLMI YGVNNRPSGV
SNRFSGSKSG NTASLTI SGL QAEDEADYYC SSYDIESATP VFGGGTKLTV LGQPKAAPSV
TLFPPSSEEL QANKATLVCL ISDFYPGAVT VAWKGDSSPV KAGVETTTPS KQSNNKYAAS
SYLSLTPEQW KSHRSYSCQV THEGSTVEKT VAPTECS
> Bevacizumab Heavy Chain (SEQ ID NO: 5)
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFS LDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTS GGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWY VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPGK
> Bevacizumab Light Chain (SEQ ID NO: 6)
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGTDF TLTI SSLQPEDFATYYCQQYSTVPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGE C

Claims

1. A combination of :
component A : anetumab ravtansine ;
and
component B1 : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Al) :
Figure imgf000064_0001
wherein
X represents CR5R6 or NH; Y1 represents CR3 or N;
Chemical bond between y2— y3 represents a single bond or double bond, with the proviso that when theY2— Y3 represents a double bond,
Y2 and Y3 independently represent CR4 or N, and when Y2— Y3 represents a single bond, Y2 and Y3 independently represent CR3R4 or NR4; Z1, Z2, Z3 and Z4 independently represent CH , CR2 or N;
R1 represents aryl optionally having 1 to 3 substituents selected from R , C3-s cycloalkyl optionally having 1 to 3 substituents selected from R ,
Ci-6 alkyl optionally substituted by aryl, heteroaryl, Ci-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,
Ci-6 alkoxy optionally substituted by
carboxy, aryl, heteroaryl, Ci-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen, or
a 3 to 15 membered mono- or bi-cyclic heterocyclic ring that is saturated or unsaturated, and contains 1 to 3 heteroatoms selected from the group consisting of N, O and S, and optionally having 1 to 3 substituents selected from R
wherein
R represents
halogen, nitro, hydroxy, cyano, carboxy, amino, N-(Ci-6alkyl)amino, N-(hydroxyCi- 6alkyl)amino, N,N-di(Ci-6alkyl)amino, N-(Ci-6acyl)amino, N-(formyl)-N-(Ci-6alkyl)amino, N- (Ci-6alkanesulfonyl) amino, N-(carboxyCi-6alkyl)-N-(Ci-6alkyl)amino, N-(Ci- 6alkoxycabonyl)amino, N-[N,N-di(Ci-6alkyl)amino methylene]amino, N-[N,N-di(Ci- 6alkyl)amino (Ci-6 alkyl)methylene]amino, N-[N,N-di(Ci-6alkyl)amino C2-6alkenyl]amino, aminocarbonyl, N-(Ci-6alkyl)aminocarbonyl, N,N-di(Ci-6alkyl)aminocarbonyl, C3- scycloalkyl, Ci-6 alkylthio, Ci-6alkanesulfonyl, sulfamoyl, Ci-6alkoxycarbonyl,
N-arylamino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101, N-(aryl Ci-6alkyl)amino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101, aryl Ci-6alkoxycarbonyl wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101,
Ci-galkyl optionally substituted by
mono-, di- or tri- halogen, amino, N-(Ci-6alkyl)amino or N,N-di(Ci-6alkyl)amino,
Ci-6alkoxy optionally substituted by
mono-, di- or tri- halogen, N-(Ci-6alkyl)sulfonamide, or N-(aryl)sulfonamide, or
a 5 to 7 membered saturated or unsaturated ring having 1 to 3 heteroatoms selected from the group consisting of O, S and N, and optionally having 1 to 3 substituents selected from R101
wherein
R101 represents
halogen, carboxy, amino, N-(CI-6 alkyl)amino, N,N-di(Ci-6alkyl)amino, aminocarbonyl, N- (Ci-6alkyl)aminocarbonyl, N,N-di(Ci-6alkyl)aminocarbonyl, pyridyl,
Ci-6 alkyl optionally substituted by cyano or mono- di- or tri- halogen, or
Ci-galkoxy optionally substituted by cyano, carboxy, amino, N-(CI-6 alkyl)amino, N,N- di(Ci-6alkyl)amino, aminocarbonyl, N-(Ci-6alkyl)aminocarbonyl, N,N-di(Ci- 6alkyl)aminocarbonyl or mono-, di- or tri- halogen;
R2 represents hydroxy, halogen, nitro, cyano, amino, N-(Ci-6alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(hydroxyCi-6alkyl)amino, N-(hydroxyCi-6alkyl)-N-(Ci-6alkyl)amino, Ci- 6 acyloxy, aminoCi-6 acyloxy, C2-6alkenyl, aryl,
a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, Ci-6 alkyl, Ci-6 alkoxy, oxo, amino, amino Ci_6al kyl, N-(Ci-6alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(CI-6 acyl)amino, N-(Ci-6alkyl)carbonylamino, phenyl, phenyl Ci-6 alkyl, carboxy, Ci-6alkoxycarbonyl, aminocarbonyl, N-(Ci-6alkyl)aminocarbonyl, or N,N-di(Ci- 6alkyl)amino,
-C(O)- R20
wherein
R20 represents Ci-6 alkyl, Ci-6 alkoxy, amino, N-(Ci-6alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(CI-6 acyl)amino, or a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by
Ci-6 alkyl, Ci-6 alkoxy, oxo, amino, N-(Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N- (Ci-6 acyl)amino, phenyl, or benzyl,
Ci-6 alkyl optionally substituted by R21
or
Ci-6 alkoxy optionally substituted by R21
wherein
R21 represents cyano, mono-, di or tri- halogen, hydroxy, amino, N-(Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N- (hydroxyCi-6 alkyl) amino, N- (halophenylCi-6 alkyl) amino, amino C2.6 alkylenyl, Ci-6 alkoxy, hydroxyCi-s alkoxy, -C(O)- R201, NHC(O)- R201, C -ecycloalkyl, isoindolino, phthalimidyl, 2-oxo-l,3-oxazolidinyl, aryl or a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N optionally substituted by
hydroxy, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxycarbonyl, hydroxyCi-6 alkoxy, oxo, amino, aminoCi-6alkyl, N-(Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N-(CI-6 acyl)amino, or benzyl, wherein
R201 represents hydroxy, amino, N-(Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N- (halophenylCi-6 alkyl) amino, Ci_6al kyl, aminoCi-6 alkyl, aminoC2-6 alkylenyl, Ci-6 alkoxy, a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N optionally substituted by
hydroxy, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxycarbonyl, hydroxyCi-6 alkoxy, oxo, amino, N-(Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N-(CI-6 acyl)amino or benzyl;
R3 represents hydrogen, halogen, aminocarbonyl, or Ci-6 alkyl optionally substituted by aryl Ci-6 alkoxy or mono-, di- or tri- halogen;
R4 represents hydrogen or Ci-6 alkyl;
R5 represents hydrogen or Ci-6 alkyl; and
R6 represents halogen, hydrogen or Ci-6 alkyl ; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
2. The combination according to claim 1, wherein : said component B1 is one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (B2) :
Figure imgf000068_0001
in which :
X represents CR5R6or NH;
Y1 represents CR3 or N; the chemical bond between y2— y3 represents a single bond or double bond,
with the proviso that when theY2— Y3 represents a double bond, Y2 and Y3 independently represent CR4 or N, and
when Y2— Y3 represents a single bond, Y2 and Y3 independently represent CR3R4 or NR4;
Z1, Z2, Z3 and Z4 independently represent CH , CR2 or N;
R1 represents aryl optionally having 1 to 3 substituents selected from R , C3-s cycloalkyl optionally having 1 to 3 substituents selected from R , Ci-6 alkyl optionally substituted by aryl, heteroaryl, Ci-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,
Ci-6 alkoxy optionally substituted by carboxy, aryl, heteroaryl, Ci-6 alkoxyaryl, aryloxy, heteroaryloxy or one or more halogen,
or
a 3 to 15 membered mono- or bi-cyclic heterocyclic ring that is saturated or unsaturated, optionally having 1 to 3 substituents selected from R , and contains 1 to 3 heteroatoms selected from the group consisting of N, O and S, wherein
R represents halogen, nitro, hydroxy, cyano, carboxy, amino, N- (Ci-6alkyl)amino, N-(hydroxyCi-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N-(Ci- 6acyl)amino, N-(formyl)-N-(Ci-6alkyl)amino, N-(Ci-6alkanesulfonyl) amino, N- (carboxyCi-6alkyl)-N-(Ci-6alkyl)amino, N-(Ci-6alkoxycabonyl)amino, N-[N,N-di(Ci- 6alkyl)amino methylene]amino, N-[N,N-di(Ci-6alkyl)amino (Ci_ 6alkyl)methylene]amino, N-[N,N-di(Ci-6alkyl)amino C2-6alkenyl]amino, aminocarbonyl, N-(Ci-6alkyl)aminocarbonyl, N,N-di(Ci-6alkyl)aminocarbonyl, C3-8cycloalkyl, Ci-6 alkylthio, Ci-6alkanesulfonyl, sulfamoyl, Ci-6alkoxycarbonyl, N-arylamino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101, N-(aryl Ci-6alkyl)amino wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101, aryl Ci-6alkoxycarbonyl wherein said aryl moiety is optionally having 1 to 3 substituents selected from R101,
Ci-6al kyl optionally substituted by mono-, di- or tri- halogen, amino, N-(Ci- 6alkyl)amino or N,N-di(Ci-6alkyl)amino,
Ci-6alkoxy optionally substituted by mono-, di- or tri- halogen, N- (Ci-6alkyl)sulfonamide, or N-(aryl)sulfonamide,
or
a 5 to 7 membered saturated or unsaturated ring having 1 to 3 heteroatoms selected from the group consisting of O, S and N, and optionally having 1 to 3 substituents selected from R101 wherein
R101 represents halogen, carboxy, amino, N-(CI-6 alkyl)amino, N,N-di(Ci- 6alkyl)amino, aminocarbonyl, N-(Ci-6alkyl)aminocarbonyl, N,N-di(Ci- 6alkyl)aminocarbonyl, pyridyl,
Ci-6 alkyl optionally substituted by cyano or mono- di- or tri- halogen, and
Ci-6alkoxy optionally substituted by cyano, carboxy, amino, N-(CI-6 alkyl)amino, N,N-di(Ci-6alkyl)amino, aminocarbonyl, N-(Ci- 6alkyl)aminocarbonyl, N,N-di(Ci-6alkyl)aminocarbonyl or mono-, di- or tri- halogen;
R2 represents hydroxy, halogen, nitro, cyano, amino, N-(Ci-6alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(hydroxyCi-6alkyl)amino, N-(hydroxyCi-6alkyl)-N-(Ci-6alkyl)amino, Ci-6 acyloxy, aminoCi-6 acyloxy, C2-6alkenyl, aryl, a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, Ci-6 alkyl, Ci-6 alkoxy, oxo, amino, amino Ci_6al kyl, N-(Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N-(CI-6 acyl)amino, N-(Ci-6alkyl)carbonylamino, phenyl, phenyl Ci-6 alkyl, carboxy, Ci-6alkoxycarbonyl, aminocarbonyl, N-(Ci- 6alkyl)aminocarbonyl, or N,N-di(Ci-6alkyl)amino, -C(O)- R20
wherein
R20 represents Ci-6 alkyl, Ci-6 alkoxy, amino, N-(Ci-6alkyl)amino, N,N-di(Ci- 6alkyl)amino, N-(CI-6 acyl)amino, or a 5-7 membered saturated or unsaturated heterocyclic ring having 1 to 3 heteroatoms selected from the group consisting O, S and N, and optionally substituted by Ci-6 alkyl, Ci-6 alkoxy, oxo, amino, N-(Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N-(Ci- 6 acyl)amino, phenyl, or benzyl,
Ci-6 alkyl optionally substituted by R21,
or
Ci-6 alkoxy optionally substituted by R21,
wherein
R21 represents cyano, mono-, di or tri- halogen, hydroxy, amino, N- (Ci-6alkyl)amino, N,N-di(Ci-6alkyl)amino, N- (hydroxyCi-s alkyl) amino, N- (halophenylCi-s alkyl) amino, amino C2.6 alkylenyl, Ci-6 alkoxy, hydroxyCi-6 alkoxy, -C(O)- R201, -NHC(O)- R201, C3- scycloalkyl, isoindolino, phthalimidyl, 2-oxo-l,3-oxazolidinyl, aryl or a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N , and optionally substituted by hydroxy, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxycarbonyl, hydroxyCi-6 alkoxy, oxo, amino, aminoCi-6alkyl, N-(Ci-6alkyl)amino, N,N- di(Ci-6alkyl)amino, N-(CI-6 acyl)amino, or benzyl, wherein
R201 represents hydroxy, amino, N-(Ci-6alkyl)amino, N,N-di(Ci- 6alkyl)amino, N- (halophenylCi-6 alkyl) amino, Ci-6alkyl, aminoCi-6 alkyl, aminoC2-6 alkylenyl, Ci-6 alkoxy, a 5 or 6 membered saturated or unsaturated heterocyclic ring having 1 to 4 heteroatoms selected from the group consisting O, S and N, and optionally substituted by hydroxy, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkoxycarbonyl, hydroxyCi-6 alkoxy, oxo, amino, N-(Ci-6alkyl)amino, N,N- di(Ci-6alkyl)amino, N-(CI-6 acyl)amino or benzyl;
R3 represents hydrogen, halogen, aminocarbonyl, or Ci-6 alkyl optionally substituted by aryl Ci-6 alkoxy or mono-, di- or tri- halogen;
R4 represents hydrogen or Ci-6 alkyl;
R5 represents hydrogen or Ci-6 alkyl; and
R6 represents halogen, hydrogen or Ci-6 alkyl ;
or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ;
optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
3. The combination according to claim 1, wherein : said component B1 is one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) according to claim 1, which is selected from the list consisting of specific compound Examples 1-1 to 1-210 on pp. 47 to 106, specific compound Examples 2-1 to 2-368 on pp. 107 to 204, specific compound Examples 3-1 to 3-2 on pp. 205 to 207, specific compound Examples 4-1 to 4-2 on pp. 208 to 210, of in International patent application PCT/EP2003/010377, published as WO 04/029055 A1 on April 08, 2004 and 2-amino-N-[7- methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimid-azo[l,2-c]quinazolin-5-yl]pyrimidine-5- carboxamide dihydrochloride, published in international patent application PCT/EP2012/055600, published as WO 2012/136553 ; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
4. The combination according to claim 2, wherein : said component Bl is one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (B2) according to claim 2, which is selected from the list consisting of :
Example 1 N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2- c]quinazolin-5-yl]pyrimidine-5-carboxamide
Example 2 : N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-
2.3-dihydroimidazo[l,2-c]quinazolin-5-yl)nicotinamide
Example 3 : N-(8-{3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]propoxy}-7-methoxy-
2.3-dihydroimidazo[l,2-c]quinazolin-5-yl)-2,4-dimethyl-l,3-thiazole-5-carboxamide
Example 4 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]-l,3-thiazole-5-carboxamide.
Example 5 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl] isonicotinamide
Example 6 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]-4-methyl-l,3-thiazole-5-carboxamide Example 7 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2- c]quinazolin-5-yl]-4-propylpyrimidine-5-carboxamide
Example 8 : N-{8-[2-(4-ethylmorpholin-2-yl)ethoxy]-7-methoxy-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl}nicotinamide
Example 9 : N-{8-[2-(dimethylamino)ethoxy]-7-methoxy-2,3-dihydrc>imidazo[l,2- c]quinazolin-5-yl}pyrimidine-5-carboxamide
Example 10 : N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy-
2.3-dihydroimidazo[l,2-c]quinazolin-5-yl)nicotinamide
Example 11 : N-(8-{3-[2-(hydroxymethyl)morpholin-4-yl]propoxy}-7-methoxy- 2,3-dihydroimidazo[l,2-c]quinazolin-5-yl)nicotinamide
Example 12 : N-{8-[3-(dimethylamino)propoxy]-7-methoxy-2,3-dihydroimidazo[l,2-c]quinazolin- 5-yl}nicotinamide 1-oxide
Example 13 : 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2- c]quinazolin-5-yl]pyrimidine-5-carboxamide.
Example 14 : N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2- c]quinazolin-5-yl]-6-(2-pyrrolidin-l-ylethyl)nicotinamide.
Example 15 : 6-(cyclopentylamino)-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-
2.3-dihydroimidazo[l,2-c]quinazolin-5-yl]nicotinamide
Figure imgf000073_0001
73
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
76
Figure imgf000077_0001
77
Figure imgf000078_0001

Figure imgf000079_0001

Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
83
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimid-azo[l,2-c]quinazolin-5- yl] pyrimidine-5-carboxamide dihydrochloride; or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
5. The combination according to any one of claims 1 to 4, wherein : said component A is anetumab ravtansine; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
6. The combination according to any one of claims 1 to 5, wherein said component B1 is 2- amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2-c]quinazolin-5- yl] pyrimidine-5-carboxamide or 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimid-azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride.
7. A combination of a component A and a component Bl, wherein: said component A is anetumab ravtansine, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially ; and wherein: said component Bl is 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide, or 2-amino-N-[7-methoxy-8- (3-morpholin-4-ylpropoxy)-2,3-dihydroimid-azo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride; optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
8. The combination according to claim 7, wherein: said component B is anetumab ravtansine ;
and
said component B1 is 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide.
9. The combination according to claim 7, wherein: said component B is anetumab ravtansine ;
and
said component B1 is 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride.
10. Use of a combination according to any one of claims 1 to 9 for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly ovarian cancer, colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia.
11. Use according to claim 10, wherein said cancer is ovarian cancer.
12. A method of treatment or prophylaxis of a cancer, particularly ovarian cancer, colorectal cancer, lung cancer, breast cancer, prostate cancer, bladder cancer, gastric cancer, head and neck cancer, liver cancer, brain cancer, melanoma, endometrial cancer, lymphoma, leukemia, in a subject, comprising administering to said subject a therapeutically effective amount of a combination accoring to any one of claims 1 to 9.
13. A kit comprising a combination of : component A : anetumab ravtansine, according to any one of claims 1 to 9 ;
and
component B1 : one or more 2,3-dihydroimidazo[l,2-c]quinazoline compounds of general formula (Bl) or (B2) as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, according to any one of claims 1 to 9 ; in which optionally both or either of said components A) and Bl) are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
14. The kit according to claim 13, wherein: said component A is anetumab ravtansine;
and
said component Bl is 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide, or 2-amino-N-[7-methoxy-8- (3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride.
15. The kit according to claim 13 or 14, wherein: said component A is anetumab ranvastine ;
and
said component Bl is 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3- dihydroimidazo[l,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride.
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004029055A1 (en) 2002-09-30 2004-04-08 Bayer Pharmaceuticals Corporation Fused azole-pyrimidine derivatives
WO2004103272A2 (en) 2003-05-20 2004-12-02 Immunogen, Inc. Improved cytotoxic agents comprising new maytansinoids
WO2005020883A2 (en) 2003-05-08 2005-03-10 Immunogen, Inc. Methods for the production of ansamitocins
WO2007024536A2 (en) 2005-08-24 2007-03-01 Immunogen, Inc. Process for preparing maytansinoid antibody conjugates
WO2008070150A1 (en) 2006-12-05 2008-06-12 Bayer Schering Pharma Aktiengesellschaft Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
WO2009068204A1 (en) 2007-11-26 2009-06-04 Bayer Schering Pharma Aktiengesellschaft Anti-mesothelin antibodies and uses therefor
WO2010124797A1 (en) 2009-04-29 2010-11-04 Bayer Schering Pharma Aktiengesellschaft Anti-mesothelin immunoconjugates and uses therefor
WO2012136553A1 (en) 2011-04-05 2012-10-11 Bayer Pharma Aktiengesellschaft Substituted 2,3-dihydroimidazo[1,2-c]quinazoline salts

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004029055A1 (en) 2002-09-30 2004-04-08 Bayer Pharmaceuticals Corporation Fused azole-pyrimidine derivatives
WO2005020883A2 (en) 2003-05-08 2005-03-10 Immunogen, Inc. Methods for the production of ansamitocins
WO2004103272A2 (en) 2003-05-20 2004-12-02 Immunogen, Inc. Improved cytotoxic agents comprising new maytansinoids
WO2007024536A2 (en) 2005-08-24 2007-03-01 Immunogen, Inc. Process for preparing maytansinoid antibody conjugates
WO2008070150A1 (en) 2006-12-05 2008-06-12 Bayer Schering Pharma Aktiengesellschaft Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
WO2009068204A1 (en) 2007-11-26 2009-06-04 Bayer Schering Pharma Aktiengesellschaft Anti-mesothelin antibodies and uses therefor
WO2010124797A1 (en) 2009-04-29 2010-11-04 Bayer Schering Pharma Aktiengesellschaft Anti-mesothelin immunoconjugates and uses therefor
WO2012136553A1 (en) 2011-04-05 2012-10-11 Bayer Pharma Aktiengesellschaft Substituted 2,3-dihydroimidazo[1,2-c]quinazoline salts

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
BADER, A. G.; KANG, S.; VOGT, P. K.: "Cancer-Specific Mutations in PI3KCA are Oncogenic In Vivo", PROC. NAT. ACAD. SCI., vol. 103, 2006, pages 1475 - 1479, XP002687647, DOI: doi:10.1073/PNAS.0510857103
CANCER RESEARCH 20180701 AMERICAN ASSOCIATION FOR CANCER RESEARCH INC. NLD, vol. 78, no. 13, Supplement 1, 1 July 2018 (2018-07-01), ISSN: 1538-7445 *
DATABASE EMBASE [online] ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL; 1 July 2018 (2018-07-01), SCHATZ C A ET AL: "Anetumab ravtansine has single-agent activity in mesothelin-expressing human ovarian cancer models and potentiates the activity of chemotherapeutics and targeted agents", XP002788564, Database accession no. EMB-623504859 *
F. MORGILLO; C. DELIA CORTE; A. DIANA; C. DI MAURO; V. CIARAMELLA; G. BARRA; V. BELLI; E. FRANZESE; R.BIANCO; E. MAIELLO: "Phosphatidylinositol 3-kinase (PI3Ka)/AKT axis blockade with taselisib or ipatasertib enhances the efficacy of anti-microtubule drugs in human breast cancer cells", ONCOTARGET, vol. 8, no. 44, 22 August 2017 (2017-08-22), pages 76479 - 76491
LUX MP; FASCHING PA; SCHRAUDER MG; HEIN A; JUD SM; RAUH C; BECKMANN MW: "The PI3K Pathway: Background and Treatment Approaches", BREAST CARE, vol. 11, 2016, pages 398 - 404, Retrieved from the Internet <URL:https://doi.org/10.1159/000453133>
MARIA QUANZ ET AL: "Anetumab ravtansine inhibits tumor growth and shows additive effect in combination with targeted agents and chemotherapy in mesothelin-expressing human ovarian cancer models", ONCOTARGET, vol. 9, no. 75, 25 September 2018 (2018-09-25), XP055550357, DOI: 10.18632/oncotarget.26135 *
NINGSHU LIU ET AL: "BAY 80-6946 Is a Highly Selective Intravenous PI3K Inhibitor with Potent p110[alpha] and p110[delta] Activities in Tumor Cell Lines and Xenograft Models", MOLECULAR CANCER THERAPEUTICS, vol. 12, no. 11, 29 October 2013 (2013-10-29), US, pages 2319 - 2330, XP055550697, ISSN: 1535-7163, DOI: 10.1158/1535-7163.MCT-12-0993-T *
S. GOLFIER ET AL: "Anetumab Ravtansine: A Novel Mesothelin-Targeting Antibody-Drug Conjugate Cures Tumors with Heterogeneous Target Expression Favored by Bystander Effect", MOLECULAR CANCER THERAPEUTICS, vol. 13, no. 6, 1 June 2014 (2014-06-01), US, pages 1537 - 1548, XP055550551, ISSN: 1535-7163, DOI: 10.1158/1535-7163.MCT-13-0926 *
S. M. BERGE: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: doi:10.1002/jps.2600660104
STEELMAN LS; NAVOLANIC P; CHAPPELL WH; ABRAMS SL; WONG EW; MARTELLI AM; COCCO L; STIVALA F; LIBRA M; NICOLETTI F: "Involvement of Akt and mTOR in chemotherapeutic- and hormonal-based drug resistance and response to radiation in breast cancer cells", CELL CYCLE, vol. 10, 2011, pages 3003 - 3015, Retrieved from the Internet <URL:https://doi.org/10.4161/cc.10.17.17119>

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