WO2016087490A1 - Combination of pi3k-inhibitors - Google Patents

Combination of pi3k-inhibitors Download PDF

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Publication number
WO2016087490A1
WO2016087490A1 PCT/EP2015/078299 EP2015078299W WO2016087490A1 WO 2016087490 A1 WO2016087490 A1 WO 2016087490A1 EP 2015078299 W EP2015078299 W EP 2015078299W WO 2016087490 A1 WO2016087490 A1 WO 2016087490A1
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alkyl
dihydroimidazo
quinazolin
methoxy
carboxamide
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PCT/EP2015/078299
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French (fr)
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Ningshu Liu
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Bayer Pharma Aktiengesellschaft
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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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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 at least two components, component A and component B, component A being a PI3K-inhibitor of general formula (I) as described herein, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same,
  • component B being an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
  • 5-FU or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1
  • a platinum-based antineoplastic agent such as oxaliplatin, cisplatin or carboplatin
  • a taxane such as docetaxel or paclitaxel; or combinations thereof.
  • Another aspect of the present invention relates to the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, particurlarly for the treatment of cancer, particularly gastric cancer and/or metastases thereof.
  • Yet another aspect of the present invention relates to methods of treatment or prophylaxis of a cancer in a subject, comprising administering to said subject a therapeutically effective amount of a combination as described herein.
  • kits comprising a combination of:
  • components A and B are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • Another aspect of the present invention relates to a method of predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor comprising: a. determining, partially or completely, the genetic profile of a tumor, particularly a gastric tumor; and
  • genetic profile correlates with sensitivity to inhibition by a PI3K kinase inhibitor.
  • Another aspect of the present invention relates to a method of treating a patient suffering from cancer, comprising:
  • Another aspect of the present invention relates to a method for selecting a patient that is capable of responding to a cancer
  • therapeutic agent wherein the agent inhibits the PI3K pathway activity in a cell, comprising:
  • kits for selecting a patient that is capable of responding to a therapeutic agent comprising an inhibitor of the PI3K pathway activity in a cell comprising a means for detecting an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation, biomarker(s).
  • kits for predicting the sensitivity of tumor cell growth to a therapeutic agent comprising an inhibitor of the PI3K pathway activity in a cell, comprising a means for detecting an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation, biomarker(s).
  • Another aspect of the present invention relates to a PI3K inhibitor for use in the treatment or prophylaxis of gastric cancer and/or metastases thereof, particularly gastric cancer and/or metastases thereof comprising an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression.
  • Another aspect of the present invention relates to a combination as defined herein for use in the treatment or prophylaxis of gastric cancer and/or metastases thereof, particularly gastric cancer and/or metastases thereof comprising an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression.
  • Another aspect of the present invention relates to a combination as defined herein, for use in the treatment or prophylaxis of a cancer and/or metastases thereof, wherein said cancer is resistant and/or insensitive to treatment with standard of care drugs selected from 5-FU, or a prodrug of 5-FU, such as 5'- deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum- based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
  • standard of care drugs selected from 5-FU, or a prodrug of 5-FU, such as 5'- deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum- based antineoplastic agent, such as oxaliplatin, cisplatin or carbo
  • 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/AKT/mTOR pathway which is constitutively activated in many types of cancers, is one of the prominent pathway that promote tumor cell survival. Initial activation of the PI3K/AKT/mTOR pathway occurs at the cell membrane, where the signal for pathway activation is propagated through class I A PI3K. Activation of PI3K can occur through tyrosine kinase growth factor receptors (e.g.
  • PDGF-R platelet- derived growth factor receptor
  • EGFR human epidermal growth factor 1 /2/3 receptor
  • IGF-1 R insulin-like growth factor 1 receptor
  • ILK integrin-linked kinase
  • CaMKK Ca2+/calmodulin- dependent kinase kinase
  • DNA-PK nuclear DNA-dependent protein kinase
  • Ras Ras
  • PI3K Once PI3K is activated, it catalyzes phosphorylation of the D-3 position on phosphoinositides to generate the biologically-active phosphatidylinositol-3,4,5- triphosphate [PI(3,4,5)P3, PIP3] and phosphatidylinositol-3,4-bisphosphate [PI(3,4)P 2 , PIP2].
  • PIPs binds to the pleckstrin homology (PH) domains of phosphoinositide-dependent kinase 1 (PDK-1 ), AKT, and other PH-domain containing proteins, such as Rho and PLC. As the consequence of binding to PIP3, the proteins are translocated to the cell membrane and are subsequently activated.
  • PH pleckstrin homology
  • tumour suppressor PTEN phosphatase and tensin homolog deleted on chromosome 10. antagonizes PI3K by dephosphorylating PIP3, thereby preventing translocation and activation of PDK1 , AKT and other signaling proteins.
  • AKT is the major effecter of PI3K, which elicits a broad range of downstream signaling events. It recognizes and phosphorylates the consensus sequence RXRXX(S/T) when surrounded by hydrophobic residues. As this sequence is present in many proteins, about 50 AKT substrates have been identified and validated. 3 ' 4 These substrates control key cellular processes such as apoptosis, cell cycle progression, transcription, and translation, stress adaptation, metabolism, and metastasis of tumor cells. For instance, AKT phosphorylates the FOXO subfamily of forkhead family transcription factors, which inhibits transcription of several pro-apoptotic genes, e.g. Fas-L, IGFBP1 and Bim.
  • AKT can directly regulate apoptosis by phosphorylating and inactivating pro-apoptotic proteins such as Bad, which control the release of cytochrome c from mitochondria, and apoptosis signal-regulating kinase-1 , a mitogen-activated protein kinase kinase involved in stress-induced and cytokine- induced cell death.
  • pro-apoptotic proteins such as Bad, which control the release of cytochrome c from mitochondria
  • apoptosis signal-regulating kinase-1 a mitogen-activated protein kinase kinase involved in stress-induced and cytokine- induced cell death.
  • AKT can phosphorylate ⁇ kinase, which indirectly increases the activity of nuclear factor ⁇ and stimulates the transcription of pro-survival genes.
  • AKT cyclin dependent kinase inhibitors
  • MDM2 mouse double minute 2
  • AKT has also an important function in the control of the G2/M transition by e.g. phosphorylation of Myt1 and FOXO3a. 10 > 11
  • AKT serine/threonine kinase mTOR
  • AKT can directly phosphorylate and activate mTOR, as well as cause indirect activation of mTOR by phosphorylating and inactivating TSC2 (tuberous sclerosis complex 2, also called tuberin), which normally inhibits mTOR through the GTP-binding protein Rheb (Ras homolog enriched in brain).
  • TSC2 tuberous sclerosis complex 2, also called tuberin
  • Rheb GTP-binding protein
  • mTOR exists in two complexes: the TORC1 complex, in which mTOR is bound to Raptor, and the TORC2 complex, in which mTOR is bound to Rictor. 12
  • mTOR phosphorylates its downstream effectors S6 kinase (S6K1 ) and 4EBP-1 .
  • S6K1 can then phosphorylate its substrate, a ribosomal protein called S6.
  • 4EBP-1 when phosphorylated cannot bind effectively to its binding partner, elF4E.
  • the cumulative effect is to increase protein translation, especially of highly structured, capped mRNA species.
  • mTOR is generally considered a downstream substrate of AKT
  • mTOR in complex with Rictor can also phosphorylate AKT at S473, thereby providing a level of positive feedback on the pathway.
  • S6K1 can also regulate the pathway by catalyzing an inhibitory phosphorylation on insulin receptor substrate proteins (IRS). This prevents IRS from activating PI3K, which indirectly lowers activation of AKT.
  • IRS insulin receptor substrate proteins
  • PI3K, AKT and mTOR In addition to the well described PI3K/AKT/mTOR axis of the PI3K signaling pathway, PI3K, AKT and mTOR also receive and branch differential signaling events that are independent from the axis. For example, mTOR has the crosstalk with and is activated by MAPK pathway through ERK and RSK regulated phosphorylation of TSC2. 17 There are collective data describing the AKT/mTOR-independent PI3K-mediated signaling events.
  • PI3K downstream signaling molecule PDK1 responses to increased levels of PIP3 and activates not only AKT, but also a group of AGC kinases comprising S6K, RSK, SGK and PKC isoforms, which play essential roles in regulating tumor cell growth, proliferation, survival and metabolism.
  • AGC kinases comprising S6K, RSK, SGK and PKC isoforms.
  • many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3.
  • SGK3 undergoes PI3K- and PDK1 -dependent activation in PIK3CA mutant cancer cells.
  • PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms.
  • PI3Ks regulate also other cancer related signaling proteins such as PLC, Rac, Rho, ITK and BTK, etc.
  • class I PI3K has four isoforms of the p1 10 catalytic subunits, p1 10a, ⁇ 1 10 ⁇ , pH Oy and ⁇ 1 10 ⁇ . ⁇ 1 10 ⁇ and ⁇ 1 10 ⁇ are present in all cell types, while ⁇ 1 10 ⁇ and ⁇ 1 10 ⁇ are highly enriched in leukocytes. p1 10 subunits are divided into a class IA group ( ⁇ 1 10 ⁇ , ⁇ 1 10 ⁇ and ⁇ 1 10 ⁇ ), which bind the p85 regulatory subunit, and a class IB group ( ⁇ 1 10 ⁇ ), which does not.
  • the p85 regulatory subunits contain Src homology 2 (SH2) domains and bind phosphorylated tyrosine (pTyr), which lead to the activation of the class IA p1 10 catalytic subunits.
  • SH2 Src homology 2
  • pTyr phosphorylated tyrosine
  • p1 1 0 ⁇ is activated directly through G protein coupled receptors (GPCRs). Recent data indicated that ⁇ 1 10 ⁇ was also activated by GPCRs directly through ⁇ protein.
  • each class I PI3Ks The signaling inputs to each class I PI3Ks are diverse and well depicted in genetic analyses.
  • activation of AKT was impaired in p1 10a-deficient MEFs upon stimulation by classical RTK ligands (EGF, insulin, IGF-1 , and PDGF).
  • RTK ligands EGF, insulin, IGF-1 , and PDGF.
  • MEFs in which ⁇ 1 10 ⁇ is ablated or replaced by a kinase- dead allele of ⁇ 1 10 ⁇ respond normally to growth factor stimulation via RTKs. 22
  • ⁇ 1 10 ⁇ catalytic activity is actually required for AKT activation in response to GPCR ligands (such as LPA).
  • p1 10a appears to carry the majority of the PI3K signal in classic RTK signaling and is responsible for tumor cell growth, proliferation, survival, angiogenesis and metabolism whereas ⁇ 1 10 ⁇ mediates GPCR signaling from mitogens and chemokines and therefore may regulate tumor cell proliferation, metabolism, inflammation and invasion.
  • PI3K/AKT kinases Activation of PI3K/AKT kinases promotes increased nutrient uptake, converting cells to a glucose-dependent metabolism that redirects lipid precursors and amino acids to anabolic processes that support cell growth and proliferation.
  • These metabolic phenotype with overactivated AKT lead to malignancies that display a metabolic conversion to aerobic glycolysis (the Warburg effect).
  • the PI3K/AKT pathway is discussed to be central for survival despite unfavourable growth conditions such as glucose depletion or hypoxia.
  • a further aspect of the activated PI3K/AKT pathway is to protect cells from programmed cell death ("apoptosis") and is hence considered to transduce a survival signal.
  • apoptosis programmed cell death
  • the PI3K/AKT pathway By acting as a modulator of anti-apoptotic signalling in tumor cells, the PI3K/AKT pathway, particular PI3K itself is a target for cancer therapy.
  • Activated PI3K/AKT phosphorylates and regulates several targets, e.g. BAD, GSK3 or FKHRL1 , that affect different signalling pathways like cell survival, protein synthesis or cell movement.
  • This PI3K/AKT pathway also plays a major part in resistance of tumor cells to conventional anti-cancer therapies.
  • Blocking the PI3K/AKT pathway could therefore simultaneously inhibit the proliferation of tumor cells (e.g. via the inhibition of the metabolic effect) and sensitize towards pro-apoptotic agents.
  • PI3K inhibition selectively sensitized tumor cells to apoptotic stimuli like Trail, Campthothecin and Doxorubicin.
  • the PI3K/AKT pathway is linked to resistance to both chemo- and targeted therapeutics.
  • the inhibition of ⁇ 3 ⁇ might present a promising strategy to overcome the resistance to radiation and DNA targeting therapy.
  • Nuclear PI3Kb can induce nuclear AKT phosphorylated on both T308 and S473 in response to either IR or the DNA-damaging agent doxorubicin.
  • PI3K plays central role downstream of many cancer related signaling pathways that are critical for tumorigenesis, tumor growth / proliferation and survival, tumor cell adhesion, invation and metastasis, as well as tumor angiogenesis.
  • gain-function mutation of PIK3CA is common in several human cancers and the link between tumor suppressor gene PTEN and ⁇ 3 ⁇ has been observed in some tumors such as prostate cancer.
  • An increased expression of the ⁇ 1 10 ⁇ and ⁇ 1 1 0 ⁇ isoforms has been observed in some colon and bladder tumors, and in glioblastoma.
  • nuclear ⁇ 3 ⁇ plays roles in DNA synthesis and repair.
  • ⁇ 1 10 ⁇ controls proliferation in acute myeloid leukemia (AML) and migration of breast cancer cells, 36 whereas ⁇ 1 10 ⁇ plays roles in tumor angiogenesis, drug resistance of CML cells, and pancreatic tumor growth and survival. 37
  • AML acute myeloid leukemia
  • inhibitors of PI3K represent valuable compounds that should complement therapeutic options not only as single agents but also in combination with other drugs, e.g. anti-hyperproliferative, cytotoxic, cytostatic and/or DNA targeting agents and radiation therapy, which are currently used as standard of care in the treatment of cancer and/or metastases thereof, particularly the standard of care drugs used for the treatment of gastric cancer and/or metastases thereof.
  • drugs e.g. anti-hyperproliferative, cytotoxic, cytostatic and/or DNA targeting agents and radiation therapy, which are currently used as standard of care in the treatment of cancer and/or metastases thereof, particularly the standard of care drugs used for the treatment of gastric cancer and/or metastases thereof.
  • Gastric cancer is the second most common cause of cancer death in the world. Despite considerable improvements in surgical techniques, diagnostics, and recent approval of trastuzumab and ramucirumab, the clinical outcome for patients with advanced gastric cancer is still generally poor. Activation of the PI3K pathway occurs at a high rate and contributes to the malignant progression of gastric tumors likely via various mechanisms.
  • PI3K inhibitors are disclosed in e.g. WO2008/070150, WO2012/062743, WO2012/062745, WO2012/062748.
  • an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
  • an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof, a synergistic effect on tumor growth inhibition and apoptosis induction was obtained over the respective monotherapies. Furthermore, certain combinations of the present invention have shown surprising therapeutic efficacy in cancer models, which are resistant/insensitive to treatment with the standard of care drugs.
  • the present invention provides combinations of at least two components, component A and component B, component A being an inhibitor of PI3K of general formula (I),
  • Fi 1 represents -(CH 2 )n-(CHR 4 )-(CH 2 )m
  • R 2 represents a heteroaryl of structure o o ptionally substituted with 1 , 2 or 3 R 6 groups,
  • X represents N or C-R 6 .
  • X' represents O, S, NH, N-R 6 , N or C-R 6 ,
  • R 3 is methyl
  • R 4 is hydroxy
  • R 5 and R 5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci-Ce-alkyl, Ca-Ce-cycloalkyl-Ci -Ce-alkyl, or Ci-Ce-alkoxy- Ci-Ce-alkyl,
  • R 5 and R 5' taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R 6' groups ; each occurrence of R 6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3- Ce-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, aryl, aryl-Ci -Ce-alkyl, heteroaryl, heteroaryl-Ci -Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, -Ci-Ce-alkyl-OR 7 ,
  • component B being an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
  • 5-FU or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1
  • a platinum-based antineoplastic agent such as oxaliplatin, cisplatin or carboplatin
  • a taxane such as docetaxel or paclitaxel; or combinations thereof.
  • the first aspect component B is selected from 5-FU, capecitabine, oxaliplatin and paclitaxel, or combinations thereof.
  • kits comprising :
  • Component A one or more PI3K-kinase inhibitors as described herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ;
  • Component B one or more anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from 5-FU, capecitabine, oxaliplatin and paclitaxel, or combinations thereof,
  • 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/composition 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.
  • the present invention covers the combinations as described herein for the treatment or prophylaxis of a cancer, particularly gastric cancer and/or metastases thereof.
  • the present invention covers the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly gastric cancer and/or metastases thereof.
  • the present invention covers methods of treatment or prophylaxis of a cancer, particularly gastric cancer and/or metastases thereof in a subject, comprising administering to said subject a therapeutically effective amount of a combination as described herein.
  • compositions containing a combination as described herein together with pharmaceutically acceptable ingredients in accordance with another aspect, covers compositions containing a combination as described herein together with pharmaceutically acceptable ingredients.
  • the Combination as defined herein consists of component A as defined herein and component B as defined herein.
  • tumors with determined genetic profile showed to be particularly sensitive to the PI3K kinase of general formula (I) as described herein (or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same), or to the combinations described herein.
  • another aspect of the present invention covers a method of predicting the sensitivity of tumor cell growth to inhibition
  • genetic profile correlates with sensitivity to inhibition by a PI3K kinase inhibitor.
  • an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or overexpression and/or activation of HER2/HER3/FGFR correlates with sensitivity of a tumor cell growth to inhibition by a PI3K kinase inhibitor.
  • a co-existing KRAS mutation and/or overexpressing EGFR correlates with insensitivity or reduced responsiveness of a tumor cell growth to inhibition by a PI3K kinase inhibitor.
  • the absence of a KRAS mutation and/or overexpressing EGFR correlates with sensitivity of a tumor cell growth to inhibition by a PI3K kinase inhibitor.
  • the method is an in vitro method.
  • Suitable methods to determine the genetic profile of a tumor according to the present invention are readily available to the skilled person.
  • the present invention covers a method of treating a patient suffering from cancer, comprising:
  • the present invention covers a method of treating a patient suffering from cancer, comprising:
  • the present invention covers a method for selecting a patient that is capable of responding to a cancer
  • therapeutic agent wherein the agent inhibits the PI3K pathway activity in a cell, comprising:
  • the present invention covers a method for selecting a patient that is capable of responding to a cancer
  • therapeutic agent wherein the agent inhibits the PI3K pathway activity in a cell, comprising:
  • the patient is selected when an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation are present, and no co-existing KRAS mutation and/or overexpressing EGFR are present, in said tumor sample.
  • the agent that inhibits the PI3K pathway activity in a cell is a component A or a combination of component A and component B as defined herein.
  • the agent that inhibits the PI3K pathway activity in a cell is compound A1 or a combination of compound A1 and component B as defined herein.
  • the method is an in vitro method.
  • the tumor is a gastric tumor and/or metastases thereof.
  • the tumor is an advanced gastric tumor and/or metastases thereof.
  • the present invention covers a kit for selecting a patient that is capable of responding to a therapeutic agent comprising an inhibitor of the PI3K pathway activity in a cell, such as a Component A as defined herein (or in any of claims 1 and 3 to 8) or a Combination as defined herein (or in any of claims 1 to 16), comprising a means for detecting an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation, biomarker(s).
  • a therapeutic agent comprising an inhibitor of the PI3K pathway activity in a cell, such as a Component A as defined herein (or in any of claims 1 and 3 to 8) or a Combination as defined herein (or in any of claims 1 to 16), comprising a means for detecting an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation,
  • the present invention covers a kit for predicting the sensitivity of tumor cell growth to a therapeutic agent comprising an inhibitor of the PI3K pathway activity in a cell, such as a Component A as defined herein (or in any of claims 1 and 3 to 8) or by a Combination as defined herein (or in any of claims 1 to 16), comprising a means for detecting an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation biomarker(s).
  • the kits further comprise means for detecting a KRAS mutation and/or overexpressing EGFR.
  • the tumor is a gastric tumor and/or metastases thereof.
  • the tumor is an advanced gastric tumor and/or metastases thereof.
  • the present invention covers a Component A as defined herein (or in any of claims 1 and 3 to 8) for use in the treatment or prophylaxis of gastric cancer and/or metastases thereof, particularly gastric cancer and/or metastases thereof comprising an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression.
  • the gastric cancer and/or metastases thereof does not comprise a KRAS mutation and/or overexpressing EGFR.
  • gastric cancer and/or metastases thereof further comprise a KRAS mutation and/or overexpressing EGFR.
  • the present invention covers a Combination as defined herein (or in any of claims 1 to 16) for use in the treatment or prophylaxis of gastric cancer and/or metastases thereof, particularly gastric cancer and/or metastases thereof comprising an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression.
  • gastric cancer and/or metastases thereof further comprises a KRAS mutation and/or overexpressing EGFR.
  • the gastric cancer and/or metastases thereof does not comprise a KRAS mutation and/or overexpressing EGFR.
  • the present invention covers the use of a Component A as defined herein (or in any of claims 1 and 3 to 8) or Combination as defined herein (or in any of claims 1 to 1 6) for the manufacture of a medicament for treating cancer and/or metastases thereof in a subject, particularly gastric cancer and/or metastases in a subject, wherein the cancer is characterized by comprising an alteration of PIK3CA and/or PIK3CB, PTEN- loss, and/or HER2/HER3/FGFR overexpression.
  • the subject who shall be treated is one for whom the alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression has been determined positively in tumor cells from the subject.
  • the present invention covers a method for identifying a subject having a cancer, particularly a gastric cancer, disposed to respond favorably to Component A as defined herein or to a Combination as defined herein wherein the method comprises the detection of an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression in a sample derived for a tumor cell (from the subject).
  • the alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression is detected in tumor cells.
  • the present invention covers a method for identifying a subject having a cancer, particularly gastric cancer, is more likely to respond to a therapy comprising a Component A as defined herein or a Combination as defined herein the method comprising
  • the present invention covers a method for identifying a subject having a cancer, particularly gastric cancer, is less likely to respond to a therapy comprising a Component A as defined herein or a Combination as defined herein the method comprising
  • identifying the subject being less likely to respond to a therapy comprising a Component A as defined herein or a Combination as defined herein when PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression is absent.
  • the present invention covers the use of an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression for stratifying in vitro a cancer, particularly gastric cancer, subject or a sample derived from a tumor cell from a cancer subject disposed to respond favorably to a Component A as defined herein or a Combination as defined herein.
  • the present invention covers a Kit comprising a Component A as defined herein or a Combination as defined herein together with means to detect/determine an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression.
  • the present invention covers a method of predicting/determining whether a subject having a cancer, particularly gastric cancer, disease will be responsive to the treatment with a Component A as defined herein or a Combination as defined herein wherein the method comprises the detection of an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression in a a sample derived from a tumor cell from the subject.
  • the sample is a tumor cell sample.
  • the present invention covers a Component A as defined herein or a Combination as defined herein for the use in a method of treating a cancer, particularly gastric cancer, characterized by an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression in a subject.
  • the present invention covers the use of a Component A as defined herein or a Combination as defined herein for the treatment and/or prophylaxis of a cancer, particularly gastric cancer, characterized by an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression.
  • the subject who shall be treated is one for whom an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression has been determined in a sample containing tumor cells from the subject.
  • the present invention covers a method for the treatment and/or prophylaxis of a cancer, particularly gastric cancer, characterized by an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression using an effective amount of a Component A as defined herein or a Combination as defined herein.
  • the present invention covers the use of a Component A as defined herein or a Combination as defined herein for the preparation/manufacture of a medicament/composition for treating disease XY in a subject wherein the subject is selected by an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression.
  • the alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression has been determined (in vitro) in a sample containing body fluid, blood or cells from the subject.
  • the cancer is characterized by an alteration of PIK3CA and PTEN-loss. Accordingly, in the particular embodiments the methods of treatment, methods of characterization/determination of a cancer and uses according to the above aspects relate exclusively to an alteration of PIK3CA and PTEN.
  • the cancer is characterized by an alteration of PIK3CB and PTEN-loss. Accordingly, in the particular embodiments the methods of treatment, methods of characterization/determination of a cancer and uses according to the above aspects relate exclusively to an alteration of PIK3CB and PTEN. In a preferred embodiment of the above aspects, the cancer is characterized by overexpression of Her2, Her3 and/or FGFR. Accordingly, in the particular embodiments the methods of treatment, methods of characterization/determination of a cancer and uses according to the above aspects relate exclusively to overexpression of Her2, Her3 and/or FGFR.
  • the (genetic) alteration of PIK3CA is a mutation and/or amplification.
  • the (genetic) alteration of PIK3CB is a mutation and/or amplification.
  • the present invention covers a combination as described herein, for use in the treatment or prophylaxis of a cancer and/or metastases thereof, wherein said cancer is resistant and/or insensitive to treatment with standard of care drugs selected from 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
  • standard of care drugs selected from 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a
  • the cancer is gastric cancer and/or metastases thereof, particularly advanced gastric cancer and/or metastases thereof.
  • the cancer is resistant and/or insensitive to treatment with 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 .
  • 5-FU or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 .
  • the cancer is resistant and/or insensitive to treatment with a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin .
  • a platinum-based antineoplastic agent such as oxaliplatin, cisplatin or carboplatin .
  • the cancer is resistant and/or insensitive to treatment with a taxane, such as docetaxel or paclitaxel.
  • a taxane such as docetaxel or paclitaxel.
  • the cancer is resistant and/or insensitive to treatment with oxaliplatin and capecitabine.
  • the present invention covers the use of a combination as described herein, for the manufacture of a medicament for the treatment or prophylaxis of a cancer and/or metastases thereof, wherein said cancer is resistant and/or insensitive to treatment with standard of care drugs selected from 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
  • standard of care drugs selected from 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carb
  • the present invention covers a method of treatment or prophylaxis of a cancer and/or metastases thereof, particularly gastric cancer and/or metastases thereof, in a subject, wherein said cancer is resistant and/or insensitive to treatment with standard of care drugs selected from 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof, comprising administering to said subject a therapeutically effective amount of a combination as described herein.
  • standard of care drugs selected from 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 ; a platinum-
  • the tumor is a gastric tumor at Stage 0, Stage IA, Stage IB, Stage I IA, Stage MB, Stage IMA, Stage NIB, Stage N IC, Stage IV according to the TNM Staging Classification for Carcinoma of the Stomach (7 th ed., 2010).
  • the tumor is a gastric tumor at Stage 0, Stage I, Stage II, Stage III or Stage IV according to the Number stages of stomach cancer (aka Overall Stage Grouping or Roman Numeral Staging).
  • halogen atom or halo is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.
  • Ci -Ce-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso- butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1 ,1 -dimethylpropyl, 4-methylpentyl, 3- methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2-ethylbutyl, 1 -ethylbutyl, 3,3- dimethylbutyl, 2,2-dimethylbutyl, 1 ,1
  • Ci -Ce-alkoxy is to be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term “alkyl” is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso- propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof.
  • Ci -Ce-alkoxy-Ci -Ce-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a Ci -Ce-alkoxy group, as defined supra, e.g.
  • C2-C6-alkenyl is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C2-C3-alkenyl”), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other.
  • Said alkenyl group is, for example, a vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2- enyl, (Z)-but-2-enyl, (E)-buM-enyl, (Z)-buM-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-penM-enyl, (Z)-penM- enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-he
  • C2-C6-alkynyl is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkynyl").
  • Said C2-C6-alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl, but-1 -ynyl, but-2-ynyl, but-3-ynyl, pent-1 -ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1 -ynyl, hex-2-inyl, hex-3-inyl, hex-4- ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1 - methylbut-2-ynyl, 3-methylbut-1 -ynyl, 1 -ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2- methylpent-4-ynyl, 1 -
  • C3-C6-cycloalkyl is to be understood as preferably meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5, or 6 carbon atoms.
  • Said C3-C6-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, or a bicyclic hydrocarbon ring, e.g. a perhydropentalenylene or decalin ring.
  • Said cycloalkyl ring can optionally contain one or more double bonds e.g.
  • alkylene is understood as preferably meaning an optionally substituted hydrocarbon chain (or "tether”) having 1 , 2, 3, 4, 5, or 6 carbon atoms, i.e.
  • -CH2- an optionally substituted -CH2- ("methylene” or “single membered tether” or, for example -C(Me)2-), -CH2-CH2- ("ethylene”, “dimethylene”, or “two- membered tether"), -CH2-CH2-CH2- ("propylene”, “trimethylene”, or “three- membered tether"), -CH2-CH2-CH2- ("butylene”, “tetramethylene”, or “four- membered tether"), -CH2-CH2-CH2-CH2- (“pentylene”, “pentamethylene” or “five-membered ether"), or -CH2-CH2-CH2-CH2-CH2- ("hexylene”, “hexamethylene”, or six-membered tether”) group.
  • said alkylene tether has 1 , 2, 3, 4, or 5 carbon atoms, more particularly 1 or 2 carbon atoms.
  • said 3- to 8-membered heterocycloalkyl can contain 2, 3, 4, 5, 6 or 7 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "3- to 8-membered heterocycloalkyl"), more particularly said heterocycloalkyl can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "5- to 7-membered heterocycloalkyl").
  • said heterocycloalkyl can be a 4- membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanyl ring, for example.
  • said heterocycloalkyl can be benzo fused.
  • Said heterocyclyl can be bicyclic, such as, without being limited thereto, a 5,5- membered ring, e.g. a hexahydrocyclopenta[c]pyrrol-2(1 H)-yl) ring, or a 5,6- membered bicyclic ring, e.g. a hexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl ring, or 8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl ring, for example.
  • said nitrogen atom-containing ring can be partially unsaturated, i.e.
  • it can contain one or more double bonds, such as, without being limited thereto, a 2,5-dihydro-1 H-pyrrolyl, 4H-[1 ,3,4]thiadiazinyl, 4,5- dihydrooxazolyl, or 4H-[1 ,4]thiazinyl ring, for example, or, it may be benzo-fused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.
  • double bonds such as, without being limited thereto, a 2,5-dihydro-1 H-pyrrolyl, 4H-[1 ,3,4]thiadiazinyl, 4,5- dihydrooxazolyl, or 4H-[1 ,4]thiazinyl ring, for example, or, it may be benzo-fused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.
  • aryl is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 carbon atoms (a "C6-Ci -aryl” group), particularly a ring having 6 carbon atoms (a "Ce-aryl” group), e.g. a phenyl group; or a biphenyl group, or a ring having 9 carbon atoms (a "Cg-aryl” group), e.g. an indanyl or indenyl group, or a ring having 1 0 carbon atoms (a "Cio-aryl” group), e.g.
  • a particular example of an ar l group is one of the following possible structures : in which z represents O, S, NH or N(Ci-C6-alkyl), and * indicates the point of attachment of said aryl group with the rest of the molecule.
  • heteroaryl is understood as preferably meaning a monovalent, monocyclic- , bicyclic- or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl” group), particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and in addition in each case can be benzocondensed.
  • heteroaryl is of structure : optionally substituted with 1 , 2 or 3 R 6 groups,
  • X represents N or C-R 6 .
  • X' represents O, S, N H , N-R 6 , N or C- R 6 ,
  • R 7 and R 7' may be the same or different and is independently a hydrogen atom, or a Ci -Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci -Ce-alklyl, C3-C6-cycloalkenyl, aryl, aryl-Ci - Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci -Ce-alkyl, or heteroaryl-Ci -Ce-alkyl ;
  • R 8 is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci -Ce-alkyl, Ci -Ce-alkoxy, C2-C6-alkenyl, C2-C6- alkynyl, C3-C6-cycloalkyl, Cs-Ce-cycloalkyl-Ci -Ce-alkyl, Ci -Ce-cycloalkenyl, aryl, aryl-Ci -Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci - Ce-alkyl, or heteroaryl-Ci -Ce-alkyl.
  • said heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.
  • the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof.
  • the term pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.
  • Ci -Ce as used throughout this text, e.g. in the context of the definition of "Ci -Ce-alkyI” or “Ci -Ce-alkoxy” is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “Ci -Ce” is to be interpreted as any sub-range comprised therein, e.g.
  • C2-Ce as used throughout this text, e.g.
  • C2-Ce-alkenyl and “C2-Ce-alkynyl”
  • C2-Ce-alkynyl is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms.
  • said term "C2-Ce” is to be interpreted as any sub-range comprised therein, e.g. C2-C6 , C3-C5 , C3-C , C2-C3 , C2-C , C2-C5 ; particularly
  • C3-C6 as used throughout this text, e.g. in the context of the definition of "C3-Ce-cycloalkyl”, is to be understood as meaning a cycloalkyi group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3-C6” is to be interpreted as any sub-range comprised therein, e.g. C3-C6 , C -Cs , C3-C5 , C3-C , C -Ce, C5-C6 ; particularly C3-C6.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • prodrug of 5-FU is to be understood as meaning a prodrug of 5-FU such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2 and tegafur, or a combination comprising a prodrug of 5-FU such as UFT or S-1 in combination with one or more other pharmaceutical agents.
  • Such combination may be a fixed dose combination or a combination in which the prodrug of 5-FU and the one or more pharmaceutical agents may be administered simultaneously, concurrently, separately or sequentially.
  • Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • the term "one or more times”, e.g. in the definition of the substituents of the compounds of the present invention (e.g. component A, B or C), is understood as meaning “one, two, three, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times".
  • the plural form of the word components, compounds, salts, polymorphs, hydrates, solvates and the like is used herein, this is taken to mean also a single component, compound, salt, polymorph, isomer, hydrate, solvate or the like.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • carbonyl refers to an oxygen atom bound to a carbon atom of the molecule by a double bond.
  • the compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms may be present in the (f?)- and/or (SJ-configuration, resulting in racemic mixtures in the case of a single asymmetric center, and diastereomeric mixtures in the case of multiple asymmetric centers.
  • asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.
  • Preferred compounds are those, which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • Tautomers are two or more compounds that are related by the migration of a hydrogen atom accompanied by the switch of one or more single bonds and one or more adjacent double bonds.
  • the compounds of this invention may exist in one or more tautomeric forms.
  • a compound of Formula I may exist in tautomeric form la, tautomeric form lb, or tautomeric form Ic, or may exist as a mixture of any of these forms. It is intended that all such tautomeric forms are included within the scope of the present invention.
  • the present invention also relates to useful forms of the compounds as disclosed herein, 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; dialkyi 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.
  • heteroarylic, or heterocyclic groups mentioned herein can be substituted by their given substituents or parent molecular groups, unless otherwise noted, at any possible position, such as e.g. at any substitutable ring carbon or ring nitrogen atom. Analogously it is being understood that it is possible for any heteroaryl or heterocyclyl group to be attached to the rest of the molecule via any suitable atom if chemically suitable. Unless otherwise noted, any heteroatom of a heteroarylic ring with unsatisfied valences mentioned herein is assumed to have the hydrogen atom(s) to satisfy the valences.
  • rings containing quaternizable amino- or imino-type ring nitrogen atoms may be preferably not quaternized on these amino- or imino-type ring nitrogen atoms by the mentioned substituents or parent molecular groups.
  • Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques already known in the art.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
  • isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 CI, 82 Br, 123 l, 124 l, 129 l and 131 1, respectively.
  • Certain isotopic variations of a compound of the invention for example, those in which one or more radioactive isotopes such as 3 H or 14 C are incorporated, are useful in drug and/or substrate tissue distribution studies.
  • Tritiated and carbon-14, i.e., 1 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio. Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio.
  • standard of care drug(s) is meant to be understood a drug selected from 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
  • a drug selected from 5-FU or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
  • alteration is to be understood as genetic alteration (e.g. mutation).
  • PTENnull includes “PTENlow”.
  • resistant or insensitive to "treatment with stardard of care drugs” is meant to define a cancer disease, particularly gastric cancer, in which the treatment with a drug selected from 5-FU, or a prodrug of 5-FU, such as 5'- deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 ; a platinum- based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof, is not therapeutically effective, for failing to:
  • the resistance and/or insensitivity may be intrinsic (to the patient) or acquired.
  • the methods, combinations, uses and kits of the present invention cover both intrinsic and acquired resistance and/or insensitivity to standard of care drugs as defined herein. Methods to determine whether a cancer is resistant and/or insensitive to treatment with standard of care drugs are readily available ot the skilled person, such as in the Examples provided herein, as well as in the prior art.
  • HER2/HER3/FGFR means HER2, HER3 and/or FGFR and any particular subcombinations thereof, such as, for example HER2; HER3; FGFR, HER2 and HER3; HER2 and FGFR; HER3 and FGFR; HER2, HER3 and FGFR; etc.
  • Component A can be selected from the group of PI3K inhibitors generically or specifically disclosed in WO 201 2/062748 A1 , which are incorporated by reference herein.
  • the component A being an inhibitor of PI3K is selected from the group of compounds of general formula (I) :
  • R 1 represents -(CH 2 )n-(CHR 4 )-(CH 2 )m
  • R 2 represents a heteroaryl of structure o o ptionally substituted with 1 , 2 or 3 R 6 groups,
  • X represents N or C-R 6 .
  • X' represents O, S, NH, N-R 6 , N or C-R 6 ,
  • R 3 is methyl
  • R 4 is hydroxy
  • R 5 and R 5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci-Ce-alkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci -Ce-alkoxy- Ci-Ce-alkyl,
  • R 5 and R 5' taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R 6' groups ; each occurrence of R 6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3- Ce-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, aryl, aryl-Ci -Ce-alkyl, heteroaryl, heteroaryl-Ci -Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, -Ci -Ce-alkyl-OR 7 ,
  • each occurrence of R 8 is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci-Ce-alkyl, Ci-Ce-alkoxy, C2-C6-alkenyl, C2-C6- alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alklyl, C3-C6-cycloalkenyl, aryl, aryl-Ci- Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; each occurrence of R 8 is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci-Ce-alky
  • * represents the point of attachment with the rest of the structure of general formula (I). or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
  • component A is selected from the group of compounds of general formula (I), supra, wherein
  • R 1 represents -(CH 2 )n-(CHR 4 )-(CH2)m-N(R 5 )(R 5 ) ;
  • R 2 represents a heteroaryl of structure :
  • R 3 is methyl
  • R 4 is hydroxy
  • R 5 and R 5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci-Ce-alkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkoxy- Ci-Ce-alkyl,
  • R 5 and R 5' taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R 6' groups ; each occurrence of R 6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3- Ce-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, heteroaryl-Ci-Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-O-Ce-alkyl, -Ci-Ce-alkyl-OR 7 , -Ci
  • * represents the point of attachment with the rest of the structure of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
  • said component A is a compound of general formula (I) selected from the group consisting of
  • said component A is a compound of general formula (I) selected from the group consisting of
  • component A is selected from the group of compounds of general formula (I), supra, wherein
  • R 1 represents -(CH 2 )n-(CHR 4 )-(CH2)m-N(R 5 )(R 5 ) ;
  • R 2 represents a heteroaryl of structure :
  • X represents N or C-R 6 ;
  • R 3 is methyl
  • R 4 is hydroxy
  • R 5 and R 5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci-Ce-alkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkoxy- Ci-Ce-alkyl,
  • R 5 and R 5' taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R 6' groups ; each occurrence of R 6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3- Ce-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, heteroaryl-Ci-Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-O-Ce-alkyl, -Ci-Ce-alkyl-OR 7 , -Ci
  • said component A is a compound of general formula (I) selected from the group consisting of
  • said component A is N-(8- ⁇ [(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7-methoxy- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
  • said component A is N-(8- ⁇ [(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7-methoxy- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide or a physiologically acceptable salt thereof, or a mixture of same.
  • component A is N-(8- ⁇ [(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7-methoxy- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide.
  • the asymmetric carbon to which R 4 is bonded has the (/ ⁇ -configuration in the compound of formula (I), as described herein.
  • component A is selected from the group of PI3K inhibitors consisting of buparlisib, idelalisib, BYL-719, dactolisib, PF-05212384, pictilisib, copanlisib, copanlisib dihydrochloride, ZSTK-474, GSK-2636771 , duvelisib, GS- 9820, PF-04691502, SAR-245408, SAR-245409, sonolisib, Archexin, GDC- 0032, GDC-0980, apitolisib, pilaralisib, DLBS 1425, PX-866, voxtalisib, AZD- 81 86, BGT-226, DS-7423, GDC-0084, GSK-2126458, I
  • PI3K-inhibitors mentioned in the prior art as well as in the lists above have been disclosed for the treatment or prophylaxis of different diseases, especially cancer.
  • the specific compounds of the lists as disclosed above are preferred as being component A of the combination, most preferred is the compound used in the experimental section.
  • the synergistic behavior of a combination of the present invention is demonstrated herein with one of the PI3K inhibitors specifically disclosed in the Examples section, as example 14, of WO 2012/062748, referrred to as Compound A1 (or as Compd A1 ) below.
  • a combination of the present invention comprises is a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and 5-FU.
  • a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and capecitabine.
  • a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and a prodrug of 5-FU, such as 5'-deoxy- 5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 or a combination thereof.
  • 5-FU such as 5'-deoxy- 5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 or a combination thereof.
  • a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin or a combination thereof.
  • a platinum-based antineoplastic agent selected from oxaliplatin, cisplatin and carboplatin, or a combination thereof.
  • a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and oxaliplatin.
  • a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and cisplatin.
  • a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and carboplatin.
  • a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and capecitabine and oxaliplatin.
  • a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and a taxane, such as docetaxel or paclitaxel, or a combination thereof.
  • the taxane is selected from docetaxel and paclitaxel or a combination thereof.
  • a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and paclitaxel.
  • a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and docetaxel.
  • a combination of the present invention comprising Compound A1 or a pharmaceutically acceptable salt as mentioned above and 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin and/or a taxane, such as docetaxel or paclitaxel, is a preferred aspect of the invention.
  • Particularly preferred is a combination of the present invention comprising Compound A1 as mentioned above and 5-FU, capecitabine, oxaliplatin and/or paclitaxel.
  • a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and 5-FU.
  • a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and capecitabine.
  • a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 or a combination thereof.
  • 5-FU such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 or a combination thereof.
  • a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin or a combination thereof.
  • a platinum-based antineoplastic agent such as oxaliplatin, cisplatin or carboplatin or a combination thereof.
  • a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and oxaliplatin. In another aspect a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and cisplatin.
  • a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and carboplatin. In another aspect a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and capecitabine and oxaliplatin.
  • a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and a taxane, such as docetaxel or paclitaxel, or a combination thereof.
  • a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and paclitaxel.
  • a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof and docetaxel. It is to be understood that the present invention relates also to any combination of the embodiments of component A described above.
  • Component A may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. In accordance with a preferred embodiment, the component A is administered by the oral route.
  • Component B of the Combination Component B is an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
  • 5-FU or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1
  • a platinum-based antineoplastic agent such as oxaliplatin, cisplatin or carboplatin
  • a taxane such as docetaxel or paclitaxel; or combinations thereof.
  • Component B is an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from 5-FU, capecitabine, oxaliplatin and paclitaxel, or combinations thereof.
  • 5-FU may be administered as a prodrug, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, ftorafur, UFT (ftorafur plus uracil), and S-1 (ftorafur plus 5-chloro-2,4-dihydroxypyridine plus potassium oxonate).
  • a prodrug such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, ftorafur, UFT (ftorafur plus uracil), and S-1 (ftorafur plus 5-chloro-2,4-dihydroxypyridine plus potassium oxonate).
  • S-1 is an oral anticancer medicament based on 5-Fluorouacil as active substance combining three components: Tegafur, a prodrug of 5-FU, Gimeracil (aka 5-chloro-2,4-dihydroxypyridine, CHDP (CAS 103766-25-2)) and Oteracil potassium (potassium oxonate).
  • S-1 consists of a fixed dose combination of the three above-mentioned components which complement/support each other at the pharmacokintiec and pharmacodynamics level: Tegafur is a prodrug of 5-FU, the active substance, which is converted into 5-FU following administration.
  • the Gimeracil component of S-1 inhibits the enzyme dihydropyrimidin- dehydrogenase (DPD), the rate-limiting enzyme in the catabolic pathway of 5- FU. Gimeracil prevents in such way the conversion of 5-FU into the toxic metabolite F-b-alanine.
  • F-b-alanine (FBAL) is a main metabolite of 5-FU.
  • F-b- alanine and fluorocitrate are thought to cause the cardiotoxic and neurotoxic effects of 5-FU by inhibiting the tricarboxylic acid cycle (Koenig and Patel, 1970; Okeda et al, 1990; Robben et al, 1993; Diasio, 1998; Kuwata et al, 2000; Kato et al, 2001 ). Consequently, the plasma FBAL concentration after oral administration of S-1 is significantly lower than that after protracted intravenous infusion (PVI) of 5-FU thus leading to reduced side effects and simultaneously a higher concentration of 5-FU available to produce the desired cytotoxic effects. Oteracil potassium prevents gastrointestinal side effects.
  • Oteracil potassium is an orotate phosphoribosyl transferase inhibitor that is distributed primarily to the gastrointestinal tract. This component of S-1 decreases the incorporation of 5- fluorouridine triphosphate into RNA in the gastrointestinal mucosa and reduces the incidence of diarrhoea.
  • UFT is an oral agent combining two components : uracil, a competitive inhibitor of DPD, with tegafur, a prodrug of 5-FU, in a 4:1 molar ratio.
  • the tegafur is taken up by the cancer cells and breaks down into 5-FU.
  • Excess uracil competes with 5-FU for DPD, thus inhibiting 5-FU catabolism and allowing higher amounts of 5- FU to stay inside the cells for its cytotoxic effects.
  • the uracil has also been stated to help protect the gastrointestinal tract from 5-FU toxicity and of its metabolites.
  • Paclitaxel is a member of the taxane drug class, which also includes docetaxel.
  • Oxaliplatin is a member of the platinum-based antineoplastic agents, which also includes cisplatin and carboplatin.
  • Suitable dose(s), administration regime(s) and administration route(s) for taxanes and platinum-based antineoplastic agents include those described in the NCCN Clinical Practice Guidelines in Oncology (NCCN guidelines), in particular in the NCCN Guidelines for Gastric Cancer Version 1 .2014 which is included herein by reference in its entirety.
  • Component B is an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, ftorafur (INN: tegafur), UFT, and S-1 , a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin and carboplatin, and a taxane, such as docetaxel and paclitaxel ; or combinations thereof.
  • 5-FU or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, ftorafur (INN: tegafur), UFT, and S-1
  • a platinum-based antineoplastic agent such as oxaliplatin, cisplatin and carboplatin
  • a taxane such as docetaxel and paclitaxel ; or
  • cytotoxic refers to an agent which can be administered to kill or eliminate a cancer cell.
  • cytostatic refers to an agent which can be administered to restrain tumor proliferation rather than induce cytotoxic cytoreduction yielding an elimination of the cancer cell from the total viable cell population of the patient.
  • anti-hyperproliferative refers to an agent which can inhibit the survival or multiplication of the tumor cells with high proliferation rate.
  • chemotherapeutic agents described herein e.g., paclitaxel, 5-FU, capecitabine, oxaliplatin are considered cytotoxic, cytostatic agent, or anti- hyper-proliferative agent depending on individual tumor types. These anti- hyperproliferative, cytotoxic and cytostatic agents have gained wide spread use as chemotherapeutics in the treatment of various cancer types and are well known.
  • Component B may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • Paclitaxel is sold under the tradename Taxol® by the Bristol-Myers Squibb Company.
  • Paclitaxel ((2 ⁇ ,4 ⁇ ,5 ⁇ ,7 ⁇ ,10 ⁇ ,1 3 ⁇ )-4,1 0-bis(acetyloxy)-13- ⁇ [(2R,3S)- 3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy ⁇ - 1 ,7-dihydroxy-9-oxo-5,20- epoxytax-1 1 -en-2-yl benzoate - CAS No: 33069-62-4) has the empirical formula C47H51 N014 and a molecular weight of 853.9. It is highly lipophilic in water.
  • Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubles from tubulin dimers and stabilizes microtubules by preventing depolymerization. While not bound by a theory, it is believed that this stability results in the inhibition in the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. Also, paclitaxel is believed to induce abnormal arrays or bundles of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. Paclitaxel is administered by intravenous injection or by other appropriate infusion techniques.
  • Docetaxel is sold under the tradename Taxotere® by Sanofi-Aventis (1 ,7 ⁇ ,10 ⁇ - trihydroxy-9-oxo-53,20-epoxytax-1 1 -ene-2a,4,13a-triyl 4-acetate 2-benzoate 13- ⁇ (2f?,3S)-3-[(ieri-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate ⁇ , CAS No. 1 14977-28-5).
  • Docetaxel belongs to the taxanes chemotherapy drug class and is a semi-synthetic analogue of paclitaxel (Taxol®). It is an anti-mitotic chemotherapy medication that works by interfering with cell division.
  • cytotoxic activity of docetaxel is believed to be exerted by promoting and stabilising microtubule assembly, while preventing physiological microtubule depolymerisation/disassembly in the absence of GTP. This leads to a significant decrease in free tubulin, needed for microtubule formation and results in inhibition of mitotic cell division between metaphase and anaphase, preventing further cancer cell progeny. Because microtubules do not disassemble in the presence of docetaxel, they accumulate inside the cell and cause initiation of apoptosis. Docetaxel is administered by intravenous injection or by other appropriate infusion techniques.
  • Fluorouracil or 5-FU (tradenames Adrucil® (IV), Carac® (topical), Efudex® and Efudix® (topical)) is a drug that is a pyrimidine analog which is used in the treatment of cancer. It is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase. It belongs to the family of drugs called the antimetabolites. 5-FU acts in several ways, but principally as a thymidylate synthase (TS) inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidine, which is a nucleoside required for DNA replication.
  • TS thymidylate synthase
  • Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) to form thymidine monophosphate (dTMP).
  • dUMP deoxyuridine monophosphate
  • dTMP thymidine monophosphate
  • 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death via thymineless death.
  • Capecitabine (INN) (tradename Xeloda®, Roche) is an orally-administered chemotherapeutic agent used in the treatment of numerous cancers.
  • Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil (5- FU) in the body.
  • Oxaliplatin (tradename Eloxatin® by Sanofi) is a platinum-based antineoplastic agent used in cancer chemotherapy. Oxaliplatin fights carcinoma through non- targeted cytotoxic effects. Like other platinum compounds, its cytotoxicity is thought to result from inhibition of DNA synthesis in cells. In particular, oxaliplatin forms both inter- and intra-strand cross links in DNA, which prevent DNA replication and transcription, causing cell death.
  • Cisplatin (aka cisplatinum) (SP-4-2)-diamminedichloroplatinum(ll), CAS No. 15663-27-1 ) was the first member of the drug class of platinum-based antineoplastic agents, which also includes carboplatin and oxaliplatin. Cisplatin crosslinks DNA in several different ways, interfering with cell division by mitosis. The damaged DNA elicits DNA repair mechanisms, which in turn activate apoptosis when repair proves impossible. Cisplatin is administered intravenously.
  • Carboplatin sold under the trade name Paraplatin® (c/ ' s-diammine(cyclobutane- 1 ,1 -dicarboxylate-0,0)platinum(ll), CAS No. 41575-94-4) is a platinum-based antineoplastic agent used in cancer chemotherapy. Carboplatin interacts with DNA to interfere with DNA repair. Carboplatin is administered intravenously.
  • anti-hyperproliferative/cytotoxic/cytostatic agents may be administered in the conventional formulations and regimens in which they are known for use in monotherapy or in combinations thereof.
  • the present invention relates to a combination of a component A with a component B, optionally with a component C, as mentioned in the Examples Section herein.
  • kits comprising :
  • component A one or more PI3K-kinase inhibitors, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof
  • component B one or more anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1
  • a platinum-based antineoplastic agent such as oxaliplatin, cisplatin or carboplatin
  • a taxane such as docetaxel or paclitaxel; or combinations thereof
  • component C one or more further pharmaceutical agents ;
  • component B is selected from 5-FU, capecitabine, oxaliplatin and paclitaxel, or combinations thereof.
  • kit can be used to treat a patient with a PI3K stimulated cancer as well as cancers not stimulated through PI3K kinase. Particularly such kit can be used to treat gastric cancer and/or metastases thereof.
  • component C being at least one pharmaceutical agent includes the effective compound itself as well as its pharmaceutically acceptable salts, solvates, hydrates or stereoisomers as well as any composition or pharmaceutical formulation comprising such effective compound or its pharmaceutically acceptable salts, solvates, hydrates or stereoisomers.
  • the components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • Component A is administered intravenously, intraperitoneal ⁇ , preferably it is administered orally.
  • Component B preferably is administered by the more appropriate route within the knowledge of the skilled person. Suitable route(s) are included in NCCN Guidelines for Gastric Cancer Version 1 .2014, which is included herein by reference in its entirety.
  • Component C being administered as the case may be.
  • composition A refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • 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.
  • an appropriate base 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 a component A 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-
  • 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; dialkyi 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.
  • Components of this invention can be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break- up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • binders such as acacia, corn starch or gelatin
  • disintegrating agents intended to assist the break- up and dissolution of the tablet following administration such as potato starch, alginic acid, corn
  • Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present.
  • Components of this invention can also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (1 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
  • the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs can be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • Components of this invention can also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the component in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1 -dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable sur
  • Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl- beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
  • suitable detergents include cationic detergents, for example dimethyl dial
  • compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 1 5% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • compositions can be in the form of sterile injectable aqueous suspensions.
  • suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can be used in the preparation of injectables.
  • Components of the invention can also be administered in the form of suppositories for rectal administration of the drug.
  • These components can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are, for example, cocoa butter and polyethylene glycol.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 1 1 , 1991 , incorporated herein by reference).
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art. It can be desirable or necessary to introduce a component of the present invention to the patient via a mechanical delivery device.
  • compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired.
  • Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al, "Compendium of Excipients for Parenteral Formulations " PDA Journal of Pharmaceutical Science & Technology 1 998, 52(5), 238-31 1 ; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1 " PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S.
  • compositions for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CCI2F2, F2CIC-CCIF2 and CCIF3) air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservative
  • clarifying agents include but are not limited to bentonite
  • emulsifying agents include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate
  • encapsulating agents include but are not limited to gelatin and cellulose acetate phthalate
  • flavorants include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
  • humectants include but are not limited to glycerol, propylene glycol and sorbitol
  • levigating agents include but are not
  • compositions according to the present invention can be illustrated as follows:
  • Sterile IV Solution A 5 mg/mL solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over about 60 minutes.
  • a sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lypholized powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 - 3000 mg Dextran 40.
  • the formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 minutes.
  • Intramuscular suspension The following solution or suspension can be prepared, for intramuscular injection:
  • Hard Shell Capsules A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
  • Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 1 00 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
  • Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 1 1 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption. Immediate Release Tablets/Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners.
  • a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners.
  • the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • the compounds of formula (I) and the stereoisomers thereof according to the combination as referred to above are components A.
  • the compounds according to the combination have valuable pharmaceutical properties, which make them commercially utilizable. In particular, they inhibit the PI3K/AKT pathway and exhibit cellular activity. They are expected to be commercially applicable in the therapy of diseases (e.g. diseases dependent on overactivated PI3K/AKT).
  • diseases e.g. diseases dependent on overactivated PI3K/AKT.
  • An abnormal activation of the PI3K/AKT pathway is an essential step towards the initiation and maintenance of human tumors and thus its inhibition, for example with PI3K inhibitors, is understood to be a valid approach for treatment of human tumors.
  • PI3K inhibitors for example see Garcia-Echeverria et al (Oncogene, 2008, 27, 551 -5526).
  • component B is especially suitable to have effects on tumor diseases.
  • the combinations of the present invention thus can be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g.
  • leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
  • One embodiment relates to the use of a combination as described herein (e.g. according to any one of claims 1 to 12) for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly gastric cancer and/or metastases thereof.
  • the invention relates to combinations comprising component A or a pharmaceutically acceptable salt thereof and Component B being an anti- hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof, for use in the treatment of cancer indications, particularly gastric cancer and/or metastases thereof.
  • 5-FU or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1
  • a platinum-based antineoplastic agent such as oxaliplatin, cisplatin or carboplatin
  • the invention in another embodiment relates to combinations comprising component A or a pharmaceutically acceptable salt thereof and Component B being an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from 5-FU, capecitabine, oxaliplatin and paclitaxel, or combinations thereof, for use in the treatment of cancer indications, particularly gastric cancer and/or metastases thereof.
  • cancer types include, but are not limited to, gastric cancer and/or metastases thereof.
  • Such cancer types include, but are not limited to, advanced gastric cancer and/or metastases thereof.
  • the invention relates to a method of treatment or prophylaxis of a cancer, particularly gastric cancer and/or metastases thereof, in a subject, comprising administering to said subject a therapeutically effective amount of a combination according to any one of claims 1 to 16.
  • Preferred uses of the combinations of the invention are the treatment of gastric cancer and/or metastases thereof.
  • Preferred uses of the combinations of the invention are the treatment of advanced gastric cancer and/or metastases thereof.
  • inappropriate within the context of the present invention, in particular in the context of "inappropriate cellular immune responses, or inappropriate cellular inflammatory responses", as used herein, is to be understood as preferably meaning a response which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases.
  • Combinations of the present invention might be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
  • This invention includes a method comprising administering to a mammal in need thereof, including a human, an amount of a component A and an amount of component B of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; etc. which is effective to treat the disorder.
  • Hyper-proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), as well as malignant neoplasia.
  • malignant neoplasia treatable with the compounds according to the present invention include solid and hematological tumors.
  • Solid tumors can be exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, anum, endocrine glands (e.g. thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva.
  • Malignant neoplasias include inherited cancers exemplified by Retinoblastoma and Wilms tumor.
  • malignant neoplasias include primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases").
  • Hematological tumors can be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma.
  • breast cancer 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 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, 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. These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
  • 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.
  • Combinations of the present invention might also be used for treating disorders and diseases associated with excessive and/or abnormal angiogenesis.
  • Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism.
  • a number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al. New Engl. J. Med. 1994, 331 , 1480 ; Peer et al. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD ; see, Lopez et al. Invest. Opththalmol. Vis. Sci.
  • neovascular glaucoma neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc.
  • RA rheumatoid arthritis
  • restenosis in-stent restenosis
  • vascular graft restenosis etc.
  • the increased blood supply associated with cancerous and neoplastic tissue encourages growth, leading to rapid tumor enlargement and metastasis.
  • the growth of new blood and lymph vessels in a tumor provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer.
  • combinations of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation ; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
  • Component A Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, 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 compounds of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredients to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound 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 ingredients 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 of a compound 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 hyper-proliferative, cytotoxic or cytostatic agent, 5-FU, or a prodrug of 5-FU such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin, and a taxane, such as docetaxel or paclitaxel; or combinations thereof, particularly 5-FU, paclitaxel, oxaliplatin, capecitabine and combinations thereof, can be administered to a patient at a dosage which can range from about 0.1 to about 300 mg/kg of total body weight.
  • the agents can also be administered in conventional amounts routinely used in cancer chemotherapy, particularly in gastric cancer and advanced gastric cancer and/or metastases thereof.
  • 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 compounds 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 compound 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.
  • suitable dose(s), administration regime(s) and administration route(s) for 5-FU, or a prodrug of 5-FU such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 ; for a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and for a taxane, such as docetaxel or paclitaxel; or combinations thereof may be readily determined by standard techniques known to the skilled person.
  • the dose(s), administration regime(s) and administration route(s) may have to be adapted according to, inter alia, the indication, the indication stage, the patient age and/or the patient gender, among other factors. Such adaptations can be readily determined by standard techniques known to the skilled person.
  • Suitable dose(s), administration regime(s) and administration route(s) for 5-FU, paclitaxel, oxaliplatin, capecitabine and combinations thereof include those described in the NCCN Clinical Practice Guidelines in Oncology (NCCN guidelines), in particular in the NCCN Guidelines for Gastric Cancer Version 1 .2014 which is included herein by reference in its entirety.
  • the hyper-proliferative, cytotoxic or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof (particularly 5-FU, paclitaxel, oxaliplatin, capecitabine and combinations thereof), the administered dosage of the compound(s) may be modified depending on any superior or unexpected results which may be obtained as routinely determined with this invention.
  • 5-FU or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1
  • a platinum-based antineoplastic agent such as oxaliplatin, c
  • the hyper-proliferative, cytotoxic or cytostatic agent can be administered to a patient orally, topically, parenterally, rectally, by inhalation, and by injection.
  • Administration by injection includes intravenous, intramuscular, subcutaneous, and parenterally as well as by infusion techniques.
  • the agents can be administered by any of the conventional routes of administration for these compounds.
  • the preferred route of administration for the hyper- proliferative/cytotoxic/cytostatic agents using this invention is typically by injection which is the same route of administration used for the agent alone.
  • hyper-proliferative, cytotoxic or cytostatic agents can be administered in combination with an aminoalcohol substituted 2,3-dihydroimidazo[1 ,2- c]quinazoline derivative of general formula (I) by any of the mentioned routes of administration.
  • the aminoalcohol substituted 2,3-dihydroimidazo[1 ,2- c]quinazoline derivative of general formula (I) can be administered simultaneously with the hyper-proliferative, cytotoxic or cytostatic agent.
  • the aminoalcohol substituted 2,3-dihydroimidazo[1 ,2- c]quinazoline derivative of general formula (I) can be administered in tandem with the hyper-proliferative/cytotoxic/cytostatic agent.
  • the aminoalcohol substituted 2,3-dihydroimidazo[1 ,2-c]quinazoline derivative of general formula (I) can be administered prior to the hyper-proliferative/cytotoxic/cytostatic agent.
  • the aminoalcohol substituted 2,3-dihydroimidazo[1 ,2-c]quinazoline derivative of general formula (I) can be administered once or more times per day up to 28 consecutive days, or once or more times per week up to 4 consecutive weeks followed by administration of the hyper-proliferative, cytotoxic or cytostatic agent.
  • the hyper-proliferative, cytotoxic or cytostatic agent can be administered first followed by adminstration of the aminoalcohol substituted 2,3-dihydroimidazo[1 ,2-c]quinazoline derivative of general formula (I).
  • the choice of sequence administration of the aminoalcohol substituted 2,3- dihydroimidazo[1 ,2-c]quinazoline derivative of general formula (I) relative to the hyper-proliferative/cytotoxic/cytostatic agent may vary for different agents. Also, the hyper-proliferative/cytotoxic or cytostatic agent can be administered using any regimen which is conventionally used for these agents.
  • the aminoalcohol substituted 2,3- dihydroimidazo[1 ,2-c]quinazoline derivative of general formula (I) and the hyper- proliferative/cytotoxic/cytostatic agent can be administered once or more times per day on the day of administration.
  • the combinations of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth, more especially on gastric tumours and/or metastases thereof.
  • component A and component B of this invention can be administered as the sole pharmaceutical agent or in combination with one or more further pharmaceutical agents C where the resulting combination of components A, B and C causes no unacceptable adverse effects.
  • the combinations of components A and B 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 131 l-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate,amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, b
  • said component C can be one or more further pharmaceutical agents selected from gemcitabine, paclitaxel, oxaliplatin, cisplatin, carboplatin, sodium butyrate, 5-FU, doxirubicin, tamoxifen, etoposide, trastumazab, gefitinib, intron A, rapamycin, 17-AAG, U0126, insulin, an insulin derivative, a PPAR ligand, a sulfonylurea drug, an a-glucosidase inhibitor, a biguanide, a PTP-1 B inhibitor, a DPP-IV inhibitor, a 1 1 -beta-HSD inhibitor, GLP-1 , a GLP-1 derivative, GIP, a GIP derivative, PACAP, a PACAP derivative, secretin or a secretin derivative.
  • gemcitabine gemcitabine, paclitaxel, oxaliplatin, cisplatin, carboplatin, sodium butyrate, 5-
  • Optional anti-hyper-proliferative agents which can be added as component C to the combination of components A and B of the present invention include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 1 1 th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5- fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone
  • anti-hyper-proliferative agents suitable for use as component C with the combination of components A and B of the present invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ.
  • anti-hyper-proliferative agents suitable for use as component C with the combination of components A and B of the present invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan.
  • cytotoxic and/or cytostatic agents as component C in combination with a combination of components A and B of the present invention will serve to:
  • Compound A1 is a PI3K inhibitor as disclosed in the experimental section of WO2012/062748 in example 14 (N-(8- ⁇ [(2R)-2-hydroxy-3-(morpholin-4- yl)propyl]oxy ⁇ -7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2- methylpyridine-3-carboxamide).
  • Component B is available from commercial sources. Alternatively Component B may be prepared using any of the methods available in the art.
  • Example 1 COMPOUND A1 was profiled in 7 gastric tumor cell lines with known mutation status of PIK3CA and PTEN.
  • Cell lines with either PIK3CA mutation and/or PTEN nuN are sensitive to COMPOUND A1
  • tumor cell lines with wild type PIK3CA or PTEN are insensitive or resistant to COMPOUND A1 in vitro.
  • HGC27 harboring both PIK3CA and PTEN mutations is the most sensitive cell line to COMPOUND A1 . This result confirmed our hypothesis that the balanced ⁇ 3 ⁇ / ⁇ inhibitor is more effective in tumors with both PIK3CA and PTEN alterations.
  • Table 1 Anti- rol iterative activity of COMPOUND A1 in gastric cancer cell lines.
  • COMPOUND A 1 is active in chemo-resistant gastric cancer models.
  • Example 2 COMPOUND A1 was profiled in vivo in 17 gastric tumor models (2 cell lines and 15 patient-derived primary tumors) with known molecular features as single agent.
  • the monotherapy efficacy of COMPOUND A1 was tested in two sets of studies with both tumor cell line and patient-derived primary tumor models.
  • the first set of study was conducted in gastric tumor models established in Oncotest GmbH (Freiburg, Germany). This study includes 2 cell-line derived Asian gastric cancer models (GXA IM95LX and GXA MKN45LX) as well as 3 Asian patient and 3 Caucasian patient-derived gastric cancer xenografts in female NMRI nu/nu mice.
  • the second set of studies was performed in National Cancer Centre Singapore in 8 Asian patient-derived gastric cancer xenografts in male SCID mice.
  • COMPOUND A1 was administered p.o. once daily at a dose of 75 mg/kg. Anti-tumor activity was determined as tumor growth inhibition relative to the vehicle control group and was expressed as the ratio of group median relative tumor volumes (treatment/control; T/C [%]).
  • COMPOUND A1 is active in chemo-resistant tumor models, e.g. 5-FU- and cisplatin-resistant GXF602, and 5-FU-, cisplatin- and taxol- resistant GXA3002 with T/C values of 17.1 % and 13.5%, respectively.
  • Table 2 Summary of in vivo efficacy of COMPOUND A1 in a set of gastric cancer models
  • COMPOUND A1 75 mg/kg and its vehicle (0.1 N HCI pH4.0) were administered orally once daily. Dosing holidays were taken when animals lost more than 20% of their body weight and until they had regained at least 85% of their original body weight.
  • Ad Adenocarcinoma; tbd: to be determined; 0 E : Overexpression; am P: amplification; CR: complete regression, final tumor volume is ⁇ 10% of tumor volume on day 0; PR: partial regression, final tumor volume is ⁇ 70% of tumor volume on day 0; SD: stable disease, final tumor volume is ⁇ 130% of tumor volume on day 0; PD: progressive disease, final tumor volume is >130% of tumor volume on day 0; a : T/C (treatment vs vehicle control); b : non-parametric Mann-parametric Mann-Whitney test on the day which the minimum T/C value was recorded for each group.
  • COMPOUND A1 was tested in 9 Asian gastric cancer patient-derived tumor models in comparison to the standard of care of the 1 st line treatment, Oxaliplatin plus Capecitabine (tradename: Xeloda®). COMPOUND A1 demonstrated significant tumor growth inhibition in all gastric tumor models tested and highly efficacious in 8 out of 9 tumor models at a dose of 75 mg/kg/d of COMPOUND A1 . Importantly, in 3 out of 6 Oxaliplatin + Capecitabine resistant models (TGI 14-45%), COMPOUND A1 demonstrated a clear superiority with tumor growth inhibition ranging from 66-79% (Table 3). Sequenome analysis of 19 oncogenes (240 mutations, including KRAS, PIK3CA, etc.) indicated that
  • ⁇ tumors bearing a KRAS mutation e.g. GC05-0208B are most
  • mice are sacrificed with body and tumor weights being recorded and presented with means and standard errors.
  • SE standard error
  • T/C tumor weight of treatment group vs vehicle control group
  • TGI tumor growth inhibition.
  • Example 3 Synergistic combination with 1 st line Standard of Care (SoC) Oxaliplatin plus Capecitabine (tradename of Capecitabine: Xeloda®)
  • Oxaliplatin and Capecitabine in both chemo resistant and chemo sensitive tumor models were dosed at the MTD (4 mg/kg/week and 1 00 mg/kg/day, respectively) and COMPOUND A1 was dosed at the 67% of the monotherapy MTD.
  • the combination effects were summarized in Table 4, thus
  • COMPOUND A1 50 mg/kg, QD 1 .7297 0.10454 0.585 41.53 COMPOUND A1 50 + Oxaliplatin 4 +
  • mice are sacrificed with body and tumor weights being recorded and presented with means and standard errors. SE: standard error; T/C: tumor weight of treatment group vs vehicle control group; TGI : tumor growth inhibition.
  • Paclitaxel in combination with weekly COMPOUND A1 (500/400 mg/kg) was highly active with an optimal T/C value of 9.1 % and an overall tumor stasis with 3/8 partial tumor remissions.
  • the combination effect of paclitaxel plus intermittent weekly COMPOUND A1 therefore has to be assessed by tumor growth delay.
  • PI3Ka/b balanced PI3K inhibitor Compound A1 is effective for the treatment of GC, particularly those with activation of PI3Ka and/or PI3Kb isoforms, e.g. genetic alteration of PIK3CA and PIK3CB, PTEN-loss, and/or HER2/HER3 overexpression
  • Compound A1 demonstrated potent PI3K pathway inhibition, strong anti- angiogenesis and tumor killing effects.
  • Compound A1 was active in multiple tumor models resistant to the standard of care chemotherapy. Combination with paclitaxel and capecitabine/oxaliplatin demonstrated synergistic or additive effects on tumor growth inhibition, apoptosis induction and preventing tumor regrowth.
  • Example 5 In vivo efficacy of Compound A1 dosed continuously or intermittently in GXA3027 patient derived gastric tumor model in mice as a single agent and in combination with cisplatin and capecitabine.
  • Compound A1 was administered p.o. once daily at 60 mg/kg, 20n/50ff at 210 mg/kg, or once weekly at 420 mg/kg with the same weekly cumulative dose of 420 mg/kg in GXA3027 patient derived gastric tumor model in NMRI nu/nu mice.
  • Anti-tumor activity was determined as tumor growth inhibition relative to the vehicle control group and starting tumor volumes and is expressed as the ratio of group median relative tumor volumes (Vtreatment-Vinitiai)/(V C ontroi- Vinitiai)%; T/C [%]).
  • the animal body weight was monitored as a measure for treatment-related toxicity. Measurements of tumor size and body weight were performed 2-3 times weekly.
  • Statistical analysis was assessed using SigmaStat software. A one-way analysis of variance was performed and differences to the control are compared by a pair-wise comparison procedure (Dunn's method). Relative T/C ratios were calculated with final tumor areas at study end, if not mentioned otherwise.
  • COMPOUND A1 tumors were harvested for analysis at the end of the study.
  • western blot analysis of GC22-0808 tumor lysates with antibodies against PI3K and MAPK pathways indicated that COMPOUND A1 and COMPOUND A1 plus Oxaliplatin/Xeloda significantly inhibited the phosphorylation of p70S6K, AKT, 4EBP1 , and S6R without affecting the p-ERK1 /2 (p ⁇ 0.05, Figure 1 ).
  • FIG. 1 Effects of COMPOUND A1 , Oxaliplatin/Xeloda, and COMPOUND A1 plus Oxaliplatin/Xeloda on the phosphorylation of AKT/mTOR and ERK1/2 pathways, and apoptosis of GC22-0808. Lysates of 3-4 tumors from one group were pooled. Each lane represented one protein pool and two pools per group were subjected to Western blot analysis. Representative blots are shown.
  • FIG. 1 Effects of COMPOUND A1 and COMPOUND A1 plus Oxaliplatin/Xeloda on angiogenesis, cell proliferation and apoptosis in GC 22-0808 xenografts.
  • GC22-0808 tumors were s.c. implanted in SCID mice.
  • Mice bearing tumor xenografts were daily treated with vehicle or 50 mg/kg COMPOUND A1 or Oxaliplatin Xeloda (4 mg/kg/100 mg/kg) 50 mg/kg COMPOUND A1 plus Oxaliplatin/Xeloda for 1 5 days.
  • Each treatment arm involved 15 independent tumor-bearing mice.
  • ⁇ tumors bearing an activating mutation of PIK3CA are most sensitive to Compound A1 ;
  • ⁇ tumors bearing a KRAS mutation are most resistant to Compound A1 ;
  • Tumors bearing both PIK3CA and KRAS mutations (e.g. GC23-0909) showed moderate sensitivity to Compound A1 .
  • PI3Ka/b balanced inhibitor Compound A1 showed potent in vivo anti-tumor efficacy in
  • PI3Ka via overexpression of Her3 and EGFR
  • PI3Kb via PTEN-Low
  • Compound A1 showed potent pathway inhibition and induction of apoptosis in GC28-1 107 GC model Figure 7.
  • Compound A1 showed strong anti-angiogenesis effect (CD31 staining, Figure 5B) in highly vascularized GC10-0608 and GC22-0808 GC PDx models
  • PI3K inhibitor Compound A1 showed synergistic anti-tumor effects with the 1 st line SoC therapy (XELOX, capecitabine+oxaliplatin, Figure 8A) and 2 nd line SoC therapy (paclitaxel, Figure 8B) in chemo resistant GC PDx models.
  • Compound A1 could further significantly enhance tumor killing effects compared to chemo treatment alone.
  • Figure 10 Efficacy of Compound A1 in patient derived GXA 3027 gastric cancer xenograft model in nude mice.
  • TGI tumor growth inhibition
  • response rates were calculated as the percentage of animals with a complete or partial response.
  • COMPOUND A1 a potent and balanced ⁇ 3 ⁇ / ⁇ inhibitor.
  • PDx patient-derived xenograft tumor models
  • COMPOUND A1 was completely inactive against MKN45 human gastric tumor cell line in an in vitro cell proliferation assay (ICso>10 ⁇ ), it induced tumor stasis in vivo in MKN45 xenograft, a highly vascularized tumor model, likely through blocking tumor angiogenesis signaling. This was further confirmed by ex vivo IHC staining of tumors treated with COMPOUND A1 using CD31 antibody. In addition, COMPOUND A1 was active in multiple tumor models resistant to the standard of care chemotherapy.
  • COMPOUND A1 with equipotent activity against ⁇ 3 ⁇ / ⁇ demonstrated unexpected and impressive efficacy cross a panel of PI3Ka/ -driven gastric cancer models, including apoptosis induction and tumor regression in a panel of gastric tumor models as a single agent or in combination with chemotherapy. These results strongly support clinical development of COMPOUND A1 for the treatment of advanced gastric cancer.

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Abstract

The present invention relates to combinations of at least two components, component A and component B, component A being a PI3K-inhibitor of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, and component B being an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin; and a taxane, such as docetaxel or paclitaxel, or combinations thereof. 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 disease, particurlarly for the treatment of gastric cancer and/or metastases thereof. Another aspect of the present invention relates to methods of predicting the sensitivity of tumor cell growth to inhibition by PI3K inhibitors, methods of selecting and/or treating patients responsive to PI3K inhibitors, and/or their combinations with other therapeutic agents, as well as means (e.g. a kit) to carry out those methods.

Description

Combination of PI3K-lnhibitors
The present invention relates to combinations of at least two components, component A and component B, component A being a PI3K-inhibitor of general formula (I) as described herein, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same,
and component B being an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
Another aspect of the present invention relates to the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, particurlarly for the treatment of cancer, particularly gastric cancer and/or metastases thereof.
Yet another aspect of the present invention relates to methods of treatment or prophylaxis of a cancer in a subject, comprising administering to said subject a therapeutically effective amount of a combination as described herein.
Further, the present invention relates to a kit comprising a combination of:
- one or more components A, as defined herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ;
- a component B, as defined supra, or a solvate or hydrate thereof ; and optionally
- one or more pharmaceutical agents C;
in which optionally either or both of said components A and B are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
Another aspect of the present invention relates to a method of predicting the sensitivity of tumor cell growth to inhibition by a PI3K inhibitor comprising: a. determining, partially or completely, the genetic profile of a tumor, particularly a gastric tumor; and
b. identifying an alteration of PIK3CA, PIK3CB, PTEN-loss, overexpression and/or activation of HER2/HER3/FGFR, KRAS mutation and/or overexpression of EGFR of said tumor,
wherein said genetic profile correlates with sensitivity to inhibition by a PI3K kinase inhibitor.
Another aspect of the present invention relates to a method of treating a patient suffering from cancer, comprising:
a. obtaining a tumor sample from the patient, particularly a gastric tumor sample; b. determining, partially or completely, the genetic profile of said tumor, comprising identifying the presence of an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation, in said tumor sample;
c. optionally identifying the presence of a co-existing KRAS mutation and/or overexpressing EGFR; and
d1 . administering a PI3K inhibitor as defined herein to the patient, or
d2. administering a Combination as defined herein to the patient.
Another aspect of the present invention relates to a method for selecting a patient that is capable of responding to a cancer
therapeutic agent, wherein the agent inhibits the PI3K pathway activity in a cell, comprising:
a. obtaining a tumor sample from a patient, particularly a gastric tumor sample; b. determining, partially or completely, the genetic profile of said tumor;
c. identifying the presence of an alteration of PIK3CA and/or PIK3CB, PTEN- loss, and/or HER2/HER3/FGFR overexpression and/or activation, in said tumor sample;
d. optionally identifying the presence of a co-existing KRAS mutation and/or overexpressing EGFR; and
e. selecting said patient when an alteration of PIK3CA and/or PIK3CB, PTEN- loss, and/or HER2/HER3/FGFR overexpression and/or activation, and optionally a co-existing KRAS mutation and/or overexpressing EGFR are present in said tumor sample.
Another aspect of the present invention relates to a kit for selecting a patient that is capable of responding to a therapeutic agent comprising an inhibitor of the PI3K pathway activity in a cell, comprising a means for detecting an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation, biomarker(s). Another aspect of the present invention relates to a kit for predicting the sensitivity of tumor cell growth to a therapeutic agent comprising an inhibitor of the PI3K pathway activity in a cell, comprising a means for detecting an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation, biomarker(s).
Another aspect of the present invention relates to a PI3K inhibitor for use in the treatment or prophylaxis of gastric cancer and/or metastases thereof, particularly gastric cancer and/or metastases thereof comprising an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression.
Another aspect of the present invention relates to a combination as defined herein for use in the treatment or prophylaxis of gastric cancer and/or metastases thereof, particularly gastric cancer and/or metastases thereof comprising an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression.
Another aspect of the present invention relates to a combination as defined herein, for use in the treatment or prophylaxis of a cancer and/or metastases thereof, wherein said cancer is resistant and/or insensitive to treatment with standard of care drugs selected from 5-FU, or a prodrug of 5-FU, such as 5'- deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum- based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
BACKGROUND
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/AKT/mTOR pathway, which is constitutively activated in many types of cancers, is one of the prominent pathway that promote tumor cell survival. Initial activation of the PI3K/AKT/mTOR pathway occurs at the cell membrane, where the signal for pathway activation is propagated through class I A PI3K. Activation of PI3K can occur through tyrosine kinase growth factor receptors (e.g. platelet- derived growth factor receptor (PDGF-R), human epidermal growth factor 1 /2/3 receptor (EGFR, HER2/3), or the insulin-like growth factor 1 receptor (IGF-1 R)), cell adhesion molecules through integrin-linked kinase (ILK), Ca2+/calmodulin- dependent kinase kinase (CaMKK), nuclear DNA-dependent protein kinase (DNA-PK), G-protein-coupled receptors, and oncogenic proteins, such as Ras. Once PI3K is activated, it catalyzes phosphorylation of the D-3 position on phosphoinositides to generate the biologically-active phosphatidylinositol-3,4,5- triphosphate [PI(3,4,5)P3, PIP3] and phosphatidylinositol-3,4-bisphosphate [PI(3,4)P2, PIP2]. PIPs binds to the pleckstrin homology (PH) domains of phosphoinositide-dependent kinase 1 (PDK-1 ), AKT, and other PH-domain containing proteins, such as Rho and PLC. As the consequence of binding to PIP3, the proteins are translocated to the cell membrane and are subsequently activated. The tumour suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) antagonizes PI3K by dephosphorylating PIP3, thereby preventing translocation and activation of PDK1 , AKT and other signaling proteins.1 2
AKT is the major effecter of PI3K, which elicits a broad range of downstream signaling events. It recognizes and phosphorylates the consensus sequence RXRXX(S/T) when surrounded by hydrophobic residues. As this sequence is present in many proteins, about 50 AKT substrates have been identified and validated.3' 4 These substrates control key cellular processes such as apoptosis, cell cycle progression, transcription, and translation, stress adaptation, metabolism, and metastasis of tumor cells. For instance, AKT phosphorylates the FOXO subfamily of forkhead family transcription factors, which inhibits transcription of several pro-apoptotic genes, e.g. Fas-L, IGFBP1 and Bim.5> 6 Additionally, AKT can directly regulate apoptosis by phosphorylating and inactivating pro-apoptotic proteins such as Bad, which control the release of cytochrome c from mitochondria, and apoptosis signal-regulating kinase-1 , a mitogen-activated protein kinase kinase involved in stress-induced and cytokine- induced cell death.7 In contrast, AKT can phosphorylate ΙκΒ kinase, which indirectly increases the activity of nuclear factor κΒ and stimulates the transcription of pro-survival genes.8 Cell cycle progression can also be affected at the G1 /S transition by AKT through its inhibitory phosphorylation of the cyclin dependent kinase inhibitors, p21 WAF1 /CIP1 and p27KIP1 . In addition AKT can phosphorylate mouse double minute 2 (MDM2) leading to its nuclear translocation and promotion of degradation of p53. This in consequence leads to an decrease in p21 Cip1 mRNA.9 Furthermore AKT has also an important function in the control of the G2/M transition by e.g. phosphorylation of Myt1 and FOXO3a.10> 11
The best-studied downstream substrate of AKT is the serine/threonine kinase mTOR. AKT can directly phosphorylate and activate mTOR, as well as cause indirect activation of mTOR by phosphorylating and inactivating TSC2 (tuberous sclerosis complex 2, also called tuberin), which normally inhibits mTOR through the GTP-binding protein Rheb (Ras homolog enriched in brain). When TSC2 is inactivated by phosphorylation, the GTPase Rheb is maintained in its GTP- bound state, allowing for increased activation of mTOR. mTOR exists in two complexes: the TORC1 complex, in which mTOR is bound to Raptor, and the TORC2 complex, in which mTOR is bound to Rictor.12 In the TORC1 complex, mTOR phosphorylates its downstream effectors S6 kinase (S6K1 ) and 4EBP-1 . S6K1 can then phosphorylate its substrate, a ribosomal protein called S6. 4EBP-1 , when phosphorylated cannot bind effectively to its binding partner, elF4E. The cumulative effect is to increase protein translation, especially of highly structured, capped mRNA species.13 Although mTOR is generally considered a downstream substrate of AKT, mTOR in complex with Rictor can also phosphorylate AKT at S473, thereby providing a level of positive feedback on the pathway.14 Finally, S6K1 can also regulate the pathway by catalyzing an inhibitory phosphorylation on insulin receptor substrate proteins (IRS). This prevents IRS from activating PI3K, which indirectly lowers activation of AKT. This feedback pathway is very important for developing PI3K/AKT/mTOR pathway inhibitors, as the re-activation of PI3K has to be taken into consideration during the evaluation of the anti-tumor efficacy of the PI3K pathway inhibitors.15' 16
In addition to the well described PI3K/AKT/mTOR axis of the PI3K signaling pathway, PI3K, AKT and mTOR also receive and branch differential signaling events that are independent from the axis. For example, mTOR has the crosstalk with and is activated by MAPK pathway through ERK and RSK regulated phosphorylation of TSC2.17 There are collective data describing the AKT/mTOR-independent PI3K-mediated signaling events. First of all, PI3K downstream signaling molecule PDK1 responses to increased levels of PIP3 and activates not only AKT, but also a group of AGC kinases comprising S6K, RSK, SGK and PKC isoforms, which play essential roles in regulating tumor cell growth, proliferation, survival and metabolism.18 Furthermore, many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1 -dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms.19 In addition to PDK1 and AGC kinases, PI3Ks regulate also other cancer related signaling proteins such as PLC, Rac, Rho, ITK and BTK, etc.
In humans, class I PI3K has four isoforms of the p1 10 catalytic subunits, p1 10a, ρ1 10β, pH Oy and ρ1 10δ. ρ1 10α and ρ1 10β are present in all cell types, while ρ1 10δ and ρ1 10γ are highly enriched in leukocytes. p1 10 subunits are divided into a class IA group (ρ1 10α, ρ1 10β and ρ1 10δ), which bind the p85 regulatory subunit, and a class IB group (ρ1 10γ), which does not. The p85 regulatory subunits contain Src homology 2 (SH2) domains and bind phosphorylated tyrosine (pTyr), which lead to the activation of the class IA p1 10 catalytic subunits. On the other hand, p1 1 0γ is activated directly through G protein coupled receptors (GPCRs). Recent data indicated that ρ1 10β was also activated by GPCRs directly through ΰβγ protein.20
The signaling inputs to each class I PI3Ks are diverse and well depicted in genetic analyses. Thus, activation of AKT was impaired in p1 10a-deficient MEFs upon stimulation by classical RTK ligands (EGF, insulin, IGF-1 , and PDGF).21 On the other hand, MEFs in which ρ1 10β is ablated or replaced by a kinase- dead allele of ρ1 10β respond normally to growth factor stimulation via RTKs.22 Instead, ρ1 10β catalytic activity is actually required for AKT activation in response to GPCR ligands (such as LPA). As such, p1 10a appears to carry the majority of the PI3K signal in classic RTK signaling and is responsible for tumor cell growth, proliferation, survival, angiogenesis and metabolism whereas ρ1 10β mediates GPCR signaling from mitogens and chemokines and therefore may regulate tumor cell proliferation, metabolism, inflammation and invasion.23 24
Although the differences in signaling outputs from the four class I PI3K isoforms are still largely unknown, it seems that ΡΙ3Κβ together with PTEN determines the basal levels of PIP3 in tumor cells, while RTK stimulated elevation of PIP3 is controlled mainly by PI3Ka. The potential for differential signaling outputs downstream of specific PI3K isoforms, in parallel with a possibly more universal Akt activation are yet to be discovered.
Activation of PI3K/AKT kinases promotes increased nutrient uptake, converting cells to a glucose-dependent metabolism that redirects lipid precursors and amino acids to anabolic processes that support cell growth and proliferation. These metabolic phenotype with overactivated AKT lead to malignancies that display a metabolic conversion to aerobic glycolysis (the Warburg effect). In that respect the PI3K/AKT pathway is discussed to be central for survival despite unfavourable growth conditions such as glucose depletion or hypoxia.
A further aspect of the activated PI3K/AKT pathway is to protect cells from programmed cell death ("apoptosis") and is hence considered to transduce a survival signal. By acting as a modulator of anti-apoptotic signalling in tumor cells, the PI3K/AKT pathway, particular PI3K itself is a target for cancer therapy. Activated PI3K/AKT phosphorylates and regulates several targets, e.g. BAD, GSK3 or FKHRL1 , that affect different signalling pathways like cell survival, protein synthesis or cell movement. This PI3K/AKT pathway also plays a major part in resistance of tumor cells to conventional anti-cancer therapies. Blocking the PI3K/AKT pathway could therefore simultaneously inhibit the proliferation of tumor cells (e.g. via the inhibition of the metabolic effect) and sensitize towards pro-apoptotic agents. PI3K inhibition selectively sensitized tumor cells to apoptotic stimuli like Trail, Campthothecin and Doxorubicin.
The resistance of many types of cancer to chemo- and targeted therapeutics represents the major hurdle in successful cancer treatment. Cancer cells can escape the effect of most commonly used drugs despite their different chemical structure and intracellular targets. Many mechanisms underlying the failure of therapeutic drugs have been well studied. Activation of PI3K/AKT pathway plays a key role in different cellular functions such as growth, migration, survival and differentiation. Data accumulated in the last decade have established that this pathway plays also a key role in resistance to both chemo-, radiation- and targeted therapeutics. Collective data describing constitutive or residual pathway activation in cells that have developed resistance to conventional chemotherapy and radiation, as well as to other targeted therapies such as EGFR antagonism. For example, experiments in doxorubicin-resistant CML cell lines demonstrated high levels of PI3K/ AKT activity; importantly, doxorubicin resistance could be overcome by decreasing PI3K/ AKT activity. Further experimental evidence was observed in two pancreatic cancer cell lines in which decreased levels of phosphorylated AKT can increase gemcitabine-induced apoptosis. Synergistic antitumor activity with cisplatin was also demonstrated in xenograft models of lung cancer.
The PI3K/AKT pathway is linked to resistance to both chemo- and targeted therapeutics. The inhibition of ΡΙ3Κβ might present a promising strategy to overcome the resistance to radiation and DNA targeting therapy. Nuclear PI3Kb can induce nuclear AKT phosphorylated on both T308 and S473 in response to either IR or the DNA-damaging agent doxorubicin.
In summary, PI3K plays central role downstream of many cancer related signaling pathways that are critical for tumorigenesis, tumor growth / proliferation and survival, tumor cell adhesion, invation and metastasis, as well as tumor angiogenesis. In addition, gain-function mutation of PIK3CA is common in several human cancers and the link between tumor suppressor gene PTEN and ΡΙ3Κβ has been observed in some tumors such as prostate cancer. An increased expression of the ρ1 10β and ρ1 1 0δ isoforms has been observed in some colon and bladder tumors, and in glioblastoma. In addition, nuclear ΡΙ3Κβ plays roles in DNA synthesis and repair.35 Furthermore, ρ1 10δ controls proliferation in acute myeloid leukemia (AML) and migration of breast cancer cells,36 whereas ρ1 10γ plays roles in tumor angiogenesis, drug resistance of CML cells, and pancreatic tumor growth and survival.37 Thus, developing PI3K inhibitors for treatment in mono- and combination therapy is a promising strategy to treat cancer and overcome cancer treatment resistance.
Thus inhibitors of PI3K represent valuable compounds that should complement therapeutic options not only as single agents but also in combination with other drugs, e.g. anti-hyperproliferative, cytotoxic, cytostatic and/or DNA targeting agents and radiation therapy, which are currently used as standard of care in the treatment of cancer and/or metastases thereof, particularly the standard of care drugs used for the treatment of gastric cancer and/or metastases thereof.
Gastric cancer is the second most common cause of cancer death in the world. Despite considerable improvements in surgical techniques, diagnostics, and recent approval of trastuzumab and ramucirumab, the clinical outcome for patients with advanced gastric cancer is still generally poor. Activation of the PI3K pathway occurs at a high rate and contributes to the malignant progression of gastric tumors likely via various mechanisms.
There is thus an acute medical need for additional therapeutic options for the treatment of gastric tumours, particularly advanced gastric tumours. Furthermore, there is also a critical medical need for methods of predicting the sensitivity of tumor cell growth to inhibition by PI3K inhibitors, methods of selecting and/or treating patients responsive to PI3K inhibitors, and/or their combinations with other therapeutic agents, as well as means (e.g. a kit) to carry out those methods, particularly when said tumors are gastric tumors
Different PI3K inhibitors are disclosed in e.g. WO2008/070150, WO2012/062743, WO2012/062745, WO2012/062748.
However, the state of the art does not disclose the combinations of the present invention comprising an inhibitor of PI3K kinase of general formula (I) as described herein, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same,
and an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof. SUMMARY of the INVENTION
Surprisingly it was observed that by administering a PI3K kinase of general formula (I) as described herein, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same,
in combination with an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof, a synergistic effect on tumor growth inhibition and apoptosis induction was obtained over the respective monotherapies. Furthermore, certain combinations of the present invention have shown surprising therapeutic efficacy in cancer models, which are resistant/insensitive to treatment with the standard of care drugs.
Therefore, in accordance with a first aspect, the present invention provides combinations of at least two components, component A and component B, component A being an inhibitor of PI3K of general formula (I),
Figure imgf000012_0001
(I)
in which :
Fi1 represents -(CH2)n-(CHR4)-(CH2)m
R2 represents a heteroaryl of structure o optionally substituted with 1 , 2 or 3 R6 groups,
in which :
* represents the point of attachment of said heteroaryl with the rest of the compound of general formula (I),
X represents N or C-R6,
X' represents O, S, NH, N-R6, N or C-R6,
with the proviso that when X and X' are both C-R6, then one C-R6 is C-H ;
R3 is methyl ;
R4 is hydroxy ;
R5 and R5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci-Ce-alkyl, Ca-Ce-cycloalkyl-Ci -Ce-alkyl, or Ci-Ce-alkoxy- Ci-Ce-alkyl,
or
R5 and R5', taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R6' groups ; each occurrence of R6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3- Ce-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, aryl, aryl-Ci -Ce-alkyl, heteroaryl, heteroaryl-Ci -Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, -Ci-Ce-alkyl-OR7, -Ci-Ce-alkyl-SR7, -Ci -Ce-alkyl- N(R7)(R7 ),
Figure imgf000013_0001
), -OR7, -SR7, -N(R7)(R7'), or -N R7C(=0)R7 each of which may be optionally substituted with 1 or more R8 groups ; each occurrence of R6' may be the same or different and is independently Ci -Ce- alkyl, Cs-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkyl-OR7; each occurrence of R7 and R7' may be the same or different and is independently a hydrogen atom, or a Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alklyl, C3-C6-cycloalkenyl, aryl, aryl-Ci- Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; each occurrence of R8 is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci-Ce-alkyl, Ci-Ce-alkoxy, C2-C6-alkenyl, C2-C6- alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, Ci-Ce-cycloalkenyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci- Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; n is an integer of 1 and m is an integer of 1 ; with the proviso that when :
- said R5 and R5', taken together with the nitrogen atom to which they are bound, represent :
Figure imgf000014_0001
in which * represents the point of attachment with the rest of the structure of general formula (I),
then
eteroaryl of structure :
Figure imgf000014_0002
is not :
Figure imgf000014_0003
in which * represents the point of attachment with the rest of the structure of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same,
and component B being an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
In one embodiment of the first aspect component B is selected from 5-FU, capecitabine, oxaliplatin and paclitaxel, or combinations thereof.
The combinations comprising at least two components, component A and component B, as decribed and defined herein, are also referred to as "combinations of the present invention".
Further, the present invention relates to : a kit comprising :
- a combination of :
Component A: one or more PI3K-kinase inhibitors as described herein, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ;
Component B : one or more anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from 5-FU, capecitabine, oxaliplatin and paclitaxel, or combinations thereof,
Component C : one or more further pharmaceutical agents ;
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/composition 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 aspect, the present invention covers the combinations as described herein for the treatment or prophylaxis of a cancer, particularly gastric cancer and/or metastases thereof.
In accordance with another aspect, the present invention covers the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly gastric cancer and/or metastases thereof.
In accordance with another aspect, the present invention covers methods of treatment or prophylaxis of a cancer, particularly gastric cancer and/or metastases thereof in a subject, comprising administering to said subject a therapeutically effective amount of a combination as described herein.
In accordance with another aspect, the present invention covers compositions containing a combination as described herein together with pharmaceutically acceptable ingredients.
According to certain embodiments of the aspects of the present invention, the Combination as defined herein consists of component A as defined herein and component B as defined herein.
Patient selection
Furthermore, surprisingly it was observed that tumors with determined genetic profile showed to be particularly sensitive to the PI3K kinase of general formula (I) as described herein (or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same), or to the combinations described herein. In accordance with this, another aspect of the present invention covers a method of predicting the sensitivity of tumor cell growth to inhibition
by Component A as defined herein (or in any of claims 1 and 3 to 8) or by a Combination as defined herein (or in any of claims 1 to 16), comprising:
a. determining, partially or completely, the genetic profile of a tumor, particularly a gastric tumor; and
b. identifying an alteration of PIK3CA, PIK3CB, PTEN-loss, overexpression and/or activation of HER2/HER3/FGFR, KRAS mutation and/or overexpression of EGFR of said tumor,
wherein said genetic profile correlates with sensitivity to inhibition by a PI3K kinase inhibitor.
In accordance with an embodiment, an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or overexpression and/or activation of HER2/HER3/FGFR, correlates with sensitivity of a tumor cell growth to inhibition by a PI3K kinase inhibitor.
In accordance with an embodiment, a co-existing KRAS mutation and/or overexpressing EGFR correlates with insensitivity or reduced responsiveness of a tumor cell growth to inhibition by a PI3K kinase inhibitor.
In accordance with an embodiment, the absence of a KRAS mutation and/or overexpressing EGFR correlates with sensitivity of a tumor cell growth to inhibition by a PI3K kinase inhibitor.
In accordance with an embodiment, the method is an in vitro method.
Suitable methods to determine the genetic profile of a tumor according to the present invention are readily available to the skilled person.
In accordance with another aspect, the present invention covers a method of treating a patient suffering from cancer, comprising:
a. obtaining a tumor sample from the patient, particularly a gastric tumor sample; b. determining, partially or completely, the genetic profile of said tumor, comprising identifying the presence of an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation, in said tumor sample;
c. optionally identifying the presence of a co-existing KRAS mutation and/or overexpressing EGFR; and
d1 . administering a Component A as defined herein (or in any of claims 1 and 3 to 8) to the patient, or
d2. administering a Combination as defined herein (or in any of claims 1 to 16) to the patient.
In accordance with another aspect, the present invention covers a method of treating a patient suffering from cancer, comprising:
a. obtaining a tumor sample from the patient, particularly a gastric tumor sample; b. determining, partially or completely, the genetic profile of said tumor, comprising identifying the presence of an alteration of PIK3CA and/or PIK3CB,
PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation, in said tumor sample;
c. optionally identifying the absence of a co-existing KRAS mutation and/or overexpressing EGFR; and
d1 . administering a Component A as defined herein (or in any of claims 1 and 3 to 8 to the patient), or
d2. administering a Combination as defined herein (or in any of claims 1 to 16) to the patient.
In accordance with another aspect, the present invention covers a method for selecting a patient that is capable of responding to a cancer
therapeutic agent, wherein the agent inhibits the PI3K pathway activity in a cell, comprising:
a. obtaining a tumor sample from a patient, particularly a gastric tumor sample; b. determining, partially or completely, the genetic profile of said tumor; c. identifying the presence of an alteration of PIK3CA and/or PIK3CB, PTEN- loss, and/or HER2/HER3/FGFR overexpression and/or activation, in said tumor sample;
d. optionally identifying the presence of a co-existing KRAS mutation and/or overexpressing EGFR; and
e. selecting said patient when an alteration of PIK3CA and/or PIK3CB, PTEN- loss, and/or HER2/HER3/FGFR overexpression and/or activation, and optionally a co-existing KRAS mutation and/or overexpressing EGFR are present in said tumor sample.
In accordance with another aspect, the present invention covers a method for selecting a patient that is capable of responding to a cancer
therapeutic agent, wherein the agent inhibits the PI3K pathway activity in a cell, comprising:
a. obtaining a tumor sample from a patient, particularly a gastric tumor sample; b. determining, partially or completely, the genetic profile of said tumor;
c. identifying the presence of an alteration of PIK3CA and/or PIK3CB, PTEN- loss, and/or HER2/HER3/FGFR overexpression and/or activation, in said tumor sample;
d. optionally identifying the presence of a co-existing KRAS mutation and/or overexpressing EGFR; and
e. selecting said patient when an alteration of PIK3CA and/or PIK3CB, PTEN- loss, and/or HER2/HER3/FGFR overexpression and/or activation, and optionally no co-existing KRAS mutation and/or overexpressing EGFR are present in said tumor sample.
In accordance with a preferred embodiment the patient is selected when an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation are present, and no co-existing KRAS mutation and/or overexpressing EGFR are present, in said tumor sample. In an embodiment, the agent that inhibits the PI3K pathway activity in a cell is a component A or a combination of component A and component B as defined herein. In a preferred embodiment, the agent that inhibits the PI3K pathway activity in a cell is compound A1 or a combination of compound A1 and component B as defined herein.
In accordance with an embodiment, the method is an in vitro method.
In accordance with an embodiment of the above methods the tumor is a gastric tumor and/or metastases thereof.
In accordance with an embodiment of the above methods the tumor is an advanced gastric tumor and/or metastases thereof.
In accordance with another aspect, the present invention covers a kit for selecting a patient that is capable of responding to a therapeutic agent comprising an inhibitor of the PI3K pathway activity in a cell, such as a Component A as defined herein (or in any of claims 1 and 3 to 8) or a Combination as defined herein (or in any of claims 1 to 16), comprising a means for detecting an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation, biomarker(s). In accordance with another aspect, the present invention covers a kit for predicting the sensitivity of tumor cell growth to a therapeutic agent comprising an inhibitor of the PI3K pathway activity in a cell, such as a Component A as defined herein (or in any of claims 1 and 3 to 8) or by a Combination as defined herein (or in any of claims 1 to 16), comprising a means for detecting an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation biomarker(s). In accordance with an embodiment of the above kits, the kits further comprise means for detecting a KRAS mutation and/or overexpressing EGFR.
In accordance with an embodiment of the above kits, the tumor is a gastric tumor and/or metastases thereof.
In accordance with an embodiment the of the above kits, the tumor is an advanced gastric tumor and/or metastases thereof. In accordance with another aspect, the present invention covers a Component A as defined herein (or in any of claims 1 and 3 to 8) for use in the treatment or prophylaxis of gastric cancer and/or metastases thereof, particularly gastric cancer and/or metastases thereof comprising an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression.
In accordance with an embodiment the gastric cancer and/or metastases thereof does not comprise a KRAS mutation and/or overexpressing EGFR.
In accordance with an embodiment the gastric cancer and/or metastases thereof further comprise a KRAS mutation and/or overexpressing EGFR.
In accordance with another aspect, the present invention covers a Combination as defined herein (or in any of claims 1 to 16) for use in the treatment or prophylaxis of gastric cancer and/or metastases thereof, particularly gastric cancer and/or metastases thereof comprising an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression.
In accordance with an embodiment the gastric cancer and/or metastases thereof further comprises a KRAS mutation and/or overexpressing EGFR.
In accordance with an embodiment the gastric cancer and/or metastases thereof does not comprise a KRAS mutation and/or overexpressing EGFR. In accordance with another aspect, the present invention covers the use of a Component A as defined herein (or in any of claims 1 and 3 to 8) or Combination as defined herein (or in any of claims 1 to 1 6) for the manufacture of a medicament for treating cancer and/or metastases thereof in a subject, particularly gastric cancer and/or metastases in a subject, wherein the cancer is characterized by comprising an alteration of PIK3CA and/or PIK3CB, PTEN- loss, and/or HER2/HER3/FGFR overexpression.
In an embodiment the subject who shall be treated is one for whom the alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression has been determined positively in tumor cells from the subject.
In accordance with another aspect, the present invention covers a method for identifying a subject having a cancer, particularly a gastric cancer, disposed to respond favorably to Component A as defined herein or to a Combination as defined herein wherein the method comprises the detection of an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression in a sample derived for a tumor cell (from the subject).
In accordance with an embodiment, the alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression is detected in tumor cells.
In accordance with another aspect, the present invention covers a method for identifying a subject having a cancer, particularly gastric cancer, is more likely to respond to a therapy comprising a Component A as defined herein or a Combination as defined herein the method comprising
a) determining PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression (in-vitro) in a sample derived from a tumor cell (from said subject) b) identifying the subject being more likely to respond to a therapy comprising a Component A as defined herein or a Combination as defined herein when PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression is present.
In accordance with another aspect, the present invention covers a method for identifying a subject having a cancer, particularly gastric cancer, is less likely to respond to a therapy comprising a Component A as defined herein or a Combination as defined herein the method comprising
a) determining PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression (in-vitro) in a sample derived from a tumor cell (from said subject)
b) identifying the subject being less likely to respond to a therapy comprising a Component A as defined herein or a Combination as defined herein when PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression is absent.
In accordance with another aspect, the present invention covers the use of an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression for stratifying in vitro a cancer, particularly gastric cancer, subject or a sample derived from a tumor cell from a cancer subject disposed to respond favorably to a Component A as defined herein or a Combination as defined herein.
In accordance with another aspect, the present invention covers a Kit comprising a Component A as defined herein or a Combination as defined herein together with means to detect/determine an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression. In accordance with another aspect, the present invention covers a method of predicting/determining whether a subject having a cancer, particularly gastric cancer, disease will be responsive to the treatment with a Component A as defined herein or a Combination as defined herein wherein the method comprises the detection of an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression in a a sample derived from a tumor cell from the subject.
According to an embodiment, the sample is a tumor cell sample.
In accordance with another aspect, the present invention covers a Component A as defined herein or a Combination as defined herein for the use in a method of treating a cancer, particularly gastric cancer, characterized by an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression in a subject.
In accordance with another aspect, the present invention covers the use of a Component A as defined herein or a Combination as defined herein for the treatment and/or prophylaxis of a cancer, particularly gastric cancer, characterized by an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression.
In accordance to an embodiment, the subject who shall be treated is one for whom an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression has been determined in a sample containing tumor cells from the subject.
In accordance with another aspect, the present invention covers a method for the treatment and/or prophylaxis of a cancer, particularly gastric cancer, characterized by an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression using an effective amount of a Component A as defined herein or a Combination as defined herein. In accordance with another aspect, the present invention covers the use of a Component A as defined herein or a Combination as defined herein for the preparation/manufacture of a medicament/composition for treating disease XY in a subject wherein the subject is selected by an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression.
In accordance with an embodiment, the alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression has been determined (in vitro) in a sample containing body fluid, blood or cells from the subject.
In a preferred embodiment of the above aspects, the cancer is characterized by an alteration of PIK3CA and PTEN-loss. Accordingly, in the particular embodiments the methods of treatment, methods of characterization/determination of a cancer and uses according to the above aspects relate exclusively to an alteration of PIK3CA and PTEN.
In a preferred embodiment of the above aspects, the cancer is characterized by an alteration of PIK3CB and PTEN-loss. Accordingly, in the particular embodiments the methods of treatment, methods of characterization/determination of a cancer and uses according to the above aspects relate exclusively to an alteration of PIK3CB and PTEN. In a preferred embodiment of the above aspects, the cancer is characterized by overexpression of Her2, Her3 and/or FGFR. Accordingly, in the particular embodiments the methods of treatment, methods of characterization/determination of a cancer and uses according to the above aspects relate exclusively to overexpression of Her2, Her3 and/or FGFR.
According to embodiments of the above aspects the (genetic) alteration of PIK3CA is a mutation and/or amplification. According to embodiments of the above aspects the (genetic) alteration of PIK3CB is a mutation and/or amplification.
Treatment of a cancer resistant/insensitive to SoC drugsln accordance with another aspect, the present invention covers a combination as described herein, for use in the treatment or prophylaxis of a cancer and/or metastases thereof, wherein said cancer is resistant and/or insensitive to treatment with standard of care drugs selected from 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
In accordance with an embodiment the cancer is gastric cancer and/or metastases thereof, particularly advanced gastric cancer and/or metastases thereof.
In accordance with an embodiment the cancer is resistant and/or insensitive to treatment with 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 .
In accordance with an embodiment the cancer is resistant and/or insensitive to treatment with a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin .
In accordance with an embodiment the cancer is resistant and/or insensitive to treatment with a taxane, such as docetaxel or paclitaxel.
In accordance with an embodiment the cancer is resistant and/or insensitive to treatment with oxaliplatin and capecitabine.
In accordance with another aspect, the present invention covers the use of a combination as described herein, for the manufacture of a medicament for the treatment or prophylaxis of a cancer and/or metastases thereof, wherein said cancer is resistant and/or insensitive to treatment with standard of care drugs selected from 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
In accordance with another aspect, the present invention covers a method of treatment or prophylaxis of a cancer and/or metastases thereof, particularly gastric cancer and/or metastases thereof, in a subject, wherein said cancer is resistant and/or insensitive to treatment with standard of care drugs selected from 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof, comprising administering to said subject a therapeutically effective amount of a combination as described herein.
In accordance with an embodiment of the combinations, uses, methods and kits described herein the tumor is a gastric tumor at Stage 0, Stage IA, Stage IB, Stage I IA, Stage MB, Stage IMA, Stage NIB, Stage N IC, Stage IV according to the TNM Staging Classification for Carcinoma of the Stomach (7th ed., 2010).
In accordance with an embodiment of the combinations, uses, methods and kits described herein the tumor is a gastric tumor at Stage 0, Stage I, Stage II, Stage III or Stage IV according to the Number stages of stomach cancer (aka Overall Stage Grouping or Roman Numeral Staging).
DETAILED DESCRIPTION
A. Definitions The terms as mentioned in the present text have preferably the following meanings :
The term "halogen atom" or "halo" is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.
The term "Ci -Ce-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso- butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1 ,1 -dimethylpropyl, 4-methylpentyl, 3- methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2-ethylbutyl, 1 -ethylbutyl, 3,3- dimethylbutyl, 2,2-dimethylbutyl, 1 ,1 -dimethylbutyl, 2,3-dimethylbutyl, 1 ,3- dimethylbutyl, or 1 ,2-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1 , 2 or 3 carbon atoms ("Ci -C3-alkyl"), methyl, ethyl, n-propyl- or iso- propyl.
The term "Ci -Ce-alkoxy" is to be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term "alkyl" is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso- propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof.
The term "Ci -Ce-alkoxy-Ci -Ce-alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a Ci -Ce-alkoxy group, as defined supra, e.g. methoxyalkyl, ethoxyalkyl, propyloxyalkyl, iso-propoxyalkyl, butoxyalkyl, iso-butoxyalkyl, tert-butoxyalkyl, sec-butoxyalkyl, pentyloxyalkyl, iso-pentyloxyalkyl, hexyloxyalkyl group, in which the term "Ci -Ce-alkyl" is defined supra, or an isomer thereof.
The term "C2-C6-alkenyl" is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkenyl"), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other. Said alkenyl group is, for example, a vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2- enyl, (Z)-but-2-enyl, (E)-buM-enyl, (Z)-buM-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-penM-enyl, (Z)-penM- enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-l-enyl, (Z)-hex-l-enyl, isopropenyl, 2- methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-l-methylprop- 1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1- methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2- enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)- 3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1- methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-
1- enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl,
2- methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, (E)-3- methylpent-3-enyl, (Z)-3-methylpent-3-enyl, (E)-2-methylpent-3-enyl, (Z)-2- methylpent-3-enyl, (E)-1-methylpent-3-enyl, (Z)-1-methylpent-3-enyl, (E)-4- methylpent-2-enyl, (Z)-4-methylpent-2-enyl, (E)-3-methylpent-2-enyl, (Z)-3- methylpent-2-enyl, (E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl, (E)-1- methylpent-2-enyl, (Z)-1-methylpent-2-enyl, (E)-4-methylpent-1-enyl, (Z)-4- methylpent-1-enyl, (E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl, (E)-2- methylpent-1-enyl, (Z)-2-methylpent-1-enyl, (E)-1-methylpent-1-enyl, (Z)-1- methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1 -ethylbut-3-enyl, (E)-3- ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2- enyl, (E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl, (Z)-3- ethylbut-1-enyl, 2-ethylbut-1-enyl, (E)-1 -ethylbut-1 -enyl, (Z)-1 -ethylbut-1 -enyl, 2- propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl, 1-isopropylprop- 2-enyl, (E)-2-propylprop-1-enyl, (Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl, (Z)-1 -propylprop-1 -enyl, (E)-2-isopropylprop-1 -enyl, (Z)-2-isopropylprop-1 -enyl, (E)-1 -isopropylprop-1 -enyl, (Z)-1 -isopropylprop-1 -enyl, (E)-3,3-dimethylprop-1 - enyl, (Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl, buta-1 ,3-dienyl, penta-1 ,4-dienyl, hexa-1 ,5-dienyl, or methylhexadienyl group. Particularly, said group is vinyl or allyl.
The term "C2-C6-alkynyl" is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkynyl"). Said C2-C6-alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl, but-1 -ynyl, but-2-ynyl, but-3-ynyl, pent-1 -ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1 -ynyl, hex-2-inyl, hex-3-inyl, hex-4- ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1 - methylbut-2-ynyl, 3-methylbut-1 -ynyl, 1 -ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2- methylpent-4-ynyl, 1 -methylpent-4-ynyl, 2-methylpent-3-ynyl, 1 -methylpent-3- ynyl, 4-methylpent-2-ynyl, 1 -methylpent-2-ynyl, 4-methylpent-1 -ynyl, 3- methylpent-1 -ynyl, 2-ethylbut-3-ynyl, 1 -ethylbut-3-ynyl, 1 -ethylbut-2-ynyl, 1 - propylprop-2-ynyl, 1 -isopropylprop-2-ynyl, 2,2-dimethylbut-3-inyl, 1 ,1 - dimethylbut-3-ynyl, 1 , 1 -dimethylbut-2-ynyl, or 3,3-dimethylbut-1 -ynyl group. Particularly, said alkynyl group is ethynyl, prop-1 -ynyl, or prop-2-inyl.
The term "C3-C6-cycloalkyl" is to be understood as preferably meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5, or 6 carbon atoms. Said C3-C6-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, or a bicyclic hydrocarbon ring, e.g. a perhydropentalenylene or decalin ring. Said cycloalkyl ring can optionally contain one or more double bonds e.g. cycloalkenyl, such as a cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, wherein the bond between said ring with the rest of the molecule may be to any carbon atom of said ring, be it saturated or unsaturated. The term "alkylene" is understood as preferably meaning an optionally substituted hydrocarbon chain (or "tether") having 1 , 2, 3, 4, 5, or 6 carbon atoms, i.e. an optionally substituted -CH2- ("methylene" or "single membered tether" or, for example -C(Me)2-), -CH2-CH2- ("ethylene", "dimethylene", or "two- membered tether"), -CH2-CH2-CH2- ("propylene", "trimethylene", or "three- membered tether"), -CH2-CH2-CH2-CH2- ("butylene", "tetramethylene", or "four- membered tether"), -CH2-CH2-CH2-CH2-CH2- ("pentylene", "pentamethylene" or "five-membered ether"), or -CH2-CH2-CH2-CH2-CH2-CH2- ("hexylene", "hexamethylene", or six-membered tether") group. Particularly, said alkylene tether has 1 , 2, 3, 4, or 5 carbon atoms, more particularly 1 or 2 carbon atoms.
The term "3- to 8-membered heterocycloalkyl", is to be understood as meaning a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 2, 3, 4, 5, 6 or 7 carbon atoms, and one or more heteroatom-containing groups selected from C(=0), O, S, S(=0), S(=0)2, NRa, in which Ra represents a hydrogen atom, or a Ci-Ce-alkyl- or halo-Ci-Ce-alkyl- group ; it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom.
Particularly, said 3- to 8-membered heterocycloalkyl can contain 2, 3, 4, 5, 6 or 7 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "3- to 8-membered heterocycloalkyl"), more particularly said heterocycloalkyl can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "5- to 7-membered heterocycloalkyl").
Particularly, without being limited thereto, said heterocycloalkyl can be a 4- membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanyl ring, for example. Optionally, said heterocycloalkyl can be benzo fused.
Said heterocyclyl can be bicyclic, such as, without being limited thereto, a 5,5- membered ring, e.g. a hexahydrocyclopenta[c]pyrrol-2(1 H)-yl) ring, or a 5,6- membered bicyclic ring, e.g. a hexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl ring, or 8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl ring, for example. As mentioned supra, said nitrogen atom-containing ring can be partially unsaturated, i.e. it can contain one or more double bonds, such as, without being limited thereto, a 2,5-dihydro-1 H-pyrrolyl, 4H-[1 ,3,4]thiadiazinyl, 4,5- dihydrooxazolyl, or 4H-[1 ,4]thiazinyl ring, for example, or, it may be benzo-fused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.
The term "aryl" is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 carbon atoms (a "C6-Ci -aryl" group), particularly a ring having 6 carbon atoms (a "Ce-aryl" group), e.g. a phenyl group; or a biphenyl group, or a ring having 9 carbon atoms (a "Cg-aryl" group), e.g. an indanyl or indenyl group, or a ring having 1 0 carbon atoms (a "Cio-aryl" group), e.g. a tetralinyl, dihydronaphthyl, or naphthyl group, or a ring having 13 carbon atoms, (a "Ci3-aryl" group), e.g. a fluorenyl group, or a ring having 14 carbon atoms, (a "Ci -aryl" group), e.g. an anthranyl group. A particular example of an ar l group is one of the following possible structures :
Figure imgf000032_0001
in which z represents O, S, NH or N(Ci-C6-alkyl), and * indicates the point of attachment of said aryl group with the rest of the molecule.
The term "heteroaryl" is understood as preferably meaning a monovalent, monocyclic- , bicyclic- or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl" group), particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and in addition in each case can be benzocondensed.
Particularly, said heteroaryl is of structure :
Figure imgf000032_0002
optionally substituted with 1 , 2 or 3 R6 groups,
in which :
* represents the point of attachment of said heteroaryl with the rest of the compound of general formula (I) as defined supra,
X represents N or C-R6,
X' represents O, S, N H , N-R6, N or C- R6,
- each occurrence of R6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci -Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3- Ce-cycloalkyl, Ca-Ce-cycloalkyl-Ci -Ce-alkyl, aryl, aryl-Ci -Ce-alkyl, heteroaryl, heteroaryl-Ci -Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-O -Ce-alkyl, -Ci -Ce-alkyl-OR7, -Ci -Ce-alkyl-SR7, -Ci -Ce-alkyl- N( R7)( R7 ), -Ci -C6-alkyl-C(=0) R7,-CN , -C(=0)OR7, -C(=0)N( R7)( R7 ), -OR7, -SR7, -N(R7)(R7'), or -N R7C(=0) R7 each of which may be optionally substituted with 1 or more R8 groups ;
- each occurrence of R7 and R7' may be the same or different and is independently a hydrogen atom, or a Ci -Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci -Ce-alklyl, C3-C6-cycloalkenyl, aryl, aryl-Ci - Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci -Ce-alkyl, or heteroaryl-Ci -Ce-alkyl ;
- each occurrence of R8 is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci -Ce-alkyl, Ci -Ce-alkoxy, C2-C6-alkenyl, C2-C6- alkynyl, C3-C6-cycloalkyl, Cs-Ce-cycloalkyl-Ci -Ce-alkyl, Ci -Ce-cycloalkenyl, aryl, aryl-Ci -Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci - Ce-alkyl, or heteroaryl-Ci -Ce-alkyl.
More particularly, said heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc. ; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc..
In general, and unless otherwise mentioned, the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some illustrative non-restricting example, the term pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.
The term "Ci -Ce", as used throughout this text, e.g. in the context of the definition of "Ci -Ce-alkyI" or "Ci -Ce-alkoxy" is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "Ci -Ce" is to be interpreted as any sub-range comprised therein, e.g. Ci -Ce , C2-C5 , C3-C , C1 -C2 , C1 -C3 , Ci -C4 , C1 -C5 , Ci -Ce ; particularly C1 -C2 , C1 -C3 , Ci -C4 , C1 -C5 , Ci -Ce ; more particularly Ci -C ; in the case of "Ci -Ce-haloalkyl" or "Ci -Ce-haloalkoxy" even more particularly C1 -C2. Similarly, as used herein, the term "C2-Ce", as used throughout this text, e.g. in the context of the definitions of "C2-Ce-alkenyl" and "C2-Ce-alkynyl", is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "C2-Ce" is to be interpreted as any sub-range comprised therein, e.g. C2-C6 , C3-C5 , C3-C , C2-C3 , C2-C , C2-C5 ; particularly
Further, as used herein, the term "C3-C6", as used throughout this text, e.g. in the context of the definition of "C3-Ce-cycloalkyl", is to be understood as meaning a cycloalkyi group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term "C3-C6" is to be interpreted as any sub-range comprised therein, e.g. C3-C6 , C -Cs , C3-C5 , C3-C , C -Ce, C5-C6 ; particularly C3-C6. The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.
The term "prodrug of 5-FU" is to be understood as meaning a prodrug of 5-FU such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2 and tegafur, or a combination comprising a prodrug of 5-FU such as UFT or S-1 in combination with one or more other pharmaceutical agents. Such combination may be a fixed dose combination or a combination in which the prodrug of 5-FU and the one or more pharmaceutical agents may be administered simultaneously, concurrently, separately or sequentially. Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.
As used herein, the term "one or more times", e.g. in the definition of the substituents of the compounds of the present invention (e.g. component A, B or C), is understood as meaning "one, two, three, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times". Where the plural form of the word components, compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single component, compound, salt, polymorph, isomer, hydrate, solvate or the like. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term "carbonyl" refers to an oxygen atom bound to a carbon atom of the molecule by a double bond.
The compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (f?)- and/or (SJ-configuration, resulting in racemic mixtures in the case of a single asymmetric center, and diastereomeric mixtures in the case of multiple asymmetric centers. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention. Preferred compounds are those, which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.
Tautomers, sometimes referred to as proton-shift tautomers, are two or more compounds that are related by the migration of a hydrogen atom accompanied by the switch of one or more single bonds and one or more adjacent double bonds. The compounds of this invention may exist in one or more tautomeric forms. For example, a compound of Formula I may exist in tautomeric form la, tautomeric form lb, or tautomeric form Ic, or may exist as a mixture of any of these forms. It is intended that all such tautomeric forms are included within the scope of the present invention.
Figure imgf000037_0001
The present invention also relates to useful forms of the compounds as disclosed herein, 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; dialkyi 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.
Constituents which are optionally substituted as stated herein, may be substituted, unless otherwise noted, one or more times, independently from one another at any possible position. When any variable occurs more than one time in any constituent, each definition is independent.
The heteroarylic, or heterocyclic groups mentioned herein can be substituted by their given substituents or parent molecular groups, unless otherwise noted, at any possible position, such as e.g. at any substitutable ring carbon or ring nitrogen atom. Analogously it is being understood that it is possible for any heteroaryl or heterocyclyl group to be attached to the rest of the molecule via any suitable atom if chemically suitable. Unless otherwise noted, any heteroatom of a heteroarylic ring with unsatisfied valences mentioned herein is assumed to have the hydrogen atom(s) to satisfy the valences. Unless otherwise noted, rings containing quaternizable amino- or imino-type ring nitrogen atoms (-N=) may be preferably not quaternized on these amino- or imino-type ring nitrogen atoms by the mentioned substituents or parent molecular groups.
Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques already known in the art.
The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
If in the context of the invention "embodiment" is mentioned it should be understood to include a plurality of possible combinations. In order to limit different types of isomers from each other reference is made to lUPAC Rules Section E (Pure Appl Chem 45, 1 1 -30, 1976).
The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 11C, 13C, 14C, 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36CI, 82Br, 123l, 124l, 129l and 1311, respectively. Certain isotopic variations of a compound of the invention, for example, those in which one or more radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., 1 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example. The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio. Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio.
As defined herein the term "standard of care drug(s)" is meant to be understood a drug selected from 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
The term "alteration" is to be understood as genetic alteration (e.g. mutation). The term "PTENnull" includes "PTENlow". The term " resistant" or "insensitive" to "treatment with stardard of care drugs" is meant to define a cancer disease, particularly gastric cancer, in which the treatment with a drug selected from 5-FU, or a prodrug of 5-FU, such as 5'- deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 ; a platinum- based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof, is not therapeutically effective, for failing to:
- reduce the growth of a tumor and/or metastasis or even eliminate the tumor and/ or metastasis
- provide for a longer survival time, and/or
- provide a longer time for tumor progression.
The resistance and/or insensitivity may be intrinsic (to the patient) or acquired. The methods, combinations, uses and kits of the present invention cover both intrinsic and acquired resistance and/or insensitivity to standard of care drugs as defined herein. Methods to determine whether a cancer is resistant and/or insensitive to treatment with standard of care drugs are readily available ot the skilled person, such as in the Examples provided herein, as well as in the prior art.
For the purposes of the present invention "HER2/HER3/FGFR" means HER2, HER3 and/or FGFR and any particular subcombinations thereof, such as, for example HER2; HER3; FGFR, HER2 and HER3; HER2 and FGFR; HER3 and FGFR; HER2, HER3 and FGFR; etc.
Component A of the Combination
Component A can be selected from the group of PI3K inhibitors generically or specifically disclosed in WO 201 2/062748 A1 , which are incorporated by reference herein.
In another embodiment, the component A being an inhibitor of PI3K is selected from the group of compounds of general formula (I) :
Figure imgf000042_0001
(I)
in which :
R1 represents -(CH2)n-(CHR4)-(CH2)m
R2 represents a heteroaryl of structure o optionally substituted with 1 , 2 or 3 R6 groups,
in which :
* represents the point of attachment of said heteroaryl with the rest of the compound of general formula (I),
X represents N or C-R6,
X' represents O, S, NH, N-R6, N or C-R6,
with the proviso that when X and X' are both C-R6, then one C-R6 is C-H ;
R3 is methyl ;
R4 is hydroxy ;
R5 and R5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci-Ce-alkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci -Ce-alkoxy- Ci-Ce-alkyl,
or
R5 and R5', taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R6' groups ; each occurrence of R6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3- Ce-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, aryl, aryl-Ci -Ce-alkyl, heteroaryl, heteroaryl-Ci -Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, -Ci -Ce-alkyl-OR7, -Ci-Ce-alkyl-SR7, -Ci-Ce-alkyl- N(R7)(R7 ),
Figure imgf000043_0001
), -OR7, -SR7, -N(R7)(R7'), or -N R7C(=0)R7 each of which may be optionally substituted with 1 or more R8 groups ; each occurrence of R6' may be the same or different and is independently Ci -Ce- alkyl, Cs-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkyl-OR7; each occurrence of R7 and R7' may be the same or different and is
independently a hydrogen atom, or a Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alklyl, C3-C6-cycloalkenyl, aryl, aryl-Ci- Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; each occurrence of R8 is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci-Ce-alkyl, Ci-Ce-alkoxy, C2-C6-alkenyl, C2-C6- alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, Ci-Ce-cycloalkenyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci- Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; n is an integer of 1 and m is an integer of 1 ; with the proviso that when :
- said R5 and R5', taken together with the nitrogen atom to which they are bound, represent :
Figure imgf000044_0001
in which * represents the point of attachment with the rest of the structure of general formula (I),
then
eteroaryl of structure :
Figure imgf000044_0002
is not :
Figure imgf000044_0003
in which * represents the point of attachment with the rest of the structure of general formula (I). or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
In other embodiment, component A is selected from the group of compounds of general formula (I), supra, wherein
R1 represents -(CH2)n-(CHR4)-(CH2)m-N(R5)(R5 ) ;
R2 represents a heteroaryl of structure :
Figure imgf000045_0001
in which :
* represents the point of attachment of said heteroaryl with the rest of the structure of general formula (I) ;
R3 is methyl ;
R4 is hydroxy ;
R5 and R5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci-Ce-alkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkoxy- Ci-Ce-alkyl,
or
R5 and R5', taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R6' groups ; each occurrence of R6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3- Ce-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, heteroaryl-Ci-Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-O-Ce-alkyl, -Ci-Ce-alkyl-OR7, -Ci-Ce-alkyl-SR7, -Ci-Ce-alkyl- N(R )(R7 ),
Figure imgf000046_0001
), -OR7, -SR7, -N(R7)(R7'), or -N R7C(=O)R7 each of which may be optionally substituted with 1 or more R8 groups ; each occurrence of R6' may be the same or different and is independently Ci -Ce- alkyl, Cs-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkyl-OR7; each occurrence of R7 and R7' may be the same or different and is independently a hydrogen atom, or a Ci -Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, C3-C6-cycloalkenyl, aryl, aryl-Ci- Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; each occurrence of R8 is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci -Ce-alkyl, Ci -Ce-alkoxy, C2-C6-alkenyl, C2-C6- alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci -Ce-alkyl, Ci-Ce-cycloalkenyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci - Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; n is an integer of 1 and m is an integer of 1 ; with the proviso that when :
- said R5 and R5', taken together with the nitrogen atom to which they are bound, re resent :
Figure imgf000046_0002
in which * represents the point of attachment with the rest of the structure of general formula (I),
then
- said R2 heteroaryl of structure :
Figure imgf000047_0001
is not :
Figure imgf000047_0002
in which * represents the point of attachment with the rest of the structure of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
In other embodiment, said component A is a compound of general formula (I) selected from the group consisting of
N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)propyl]oxy}-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-{8-[2-hydroxy-3-(thiomorpholin-4-yl)propoxy]-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyridine-3-carboxamide
N-(8-{[(2R)-3-(azetidin-1 -yl)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-{8-[3-(dimethylamino)-2-hydroxypropoxy]-7-methoxy-2,3-dihydroimidazo[1 ,2- c]quinazolin-5-yl}pyridine-3-carboxamide
N-(8-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide
N-(8-{[(2R)-3-(azetidin-1 -yl)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide
N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]-2-methylpyridine-3- carboxamide
N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide
N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide
6-amino-N-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyridine-3-carboxamide
6- amino-N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide
2-amino-N-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide
2-amino-N-[8-({(2R)-3-[(2R,6S)-2,6-dimetriylmorpholin-4-yl]-2- hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5- yl]pyrimidine-5-carboxamide
2-amino-N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)propyl]oxy}-
7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide dihydrochloride
2-amino-N-(8-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6-carboxami^
N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide
N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]-1 ,3-thiazole-5-carboxamide
N-(8-{[(2R)-3-(azetidin-1 -yl)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide
N-(8-{[(2R)-2-Hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-4-methyl-1 ,3-thiazole-5-carboxamide
2-amino-N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-4-methyl-1 ,3-thiazole-5-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-oxazole-5-carboxamide
N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
In other embodiment, said component A is a compound of general formula (I) selected from the group consisting of
N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxypropyl}oxy)-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]pyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)propyl]oxy}-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-(8-{[(2R)-3-(azetidin-1 -yl)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-(8-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide
N-(8-{[(2R)-3-(azetidin-1 -yl)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide
N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-oxazole-5-carboxamide,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
In other embodiment, component A is selected from the group of compounds of general formula (I), supra, wherein
R1 represents -(CH2)n-(CHR4)-(CH2)m-N(R5)(R5 ) ; R2 represents a heteroaryl of structure :
Figure imgf000051_0001
in which :
* represents the point of attachment of said heteroaryl with the rest of the structure of general formula (I), and
X represents N or C-R6 ;
R3 is methyl ;
R4 is hydroxy ;
R5 and R5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci-Ce-alkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkoxy- Ci-Ce-alkyl,
or
R5 and R5', taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R6' groups ; each occurrence of R6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3- Ce-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, heteroaryl-Ci-Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-O-Ce-alkyl, -Ci-Ce-alkyl-OR7, -Ci-Ce-alkyl-SR7, -Ci-Ce-alkyl- N(R )(R7),
Figure imgf000051_0002
-OR7, -SR7, -N(R7)(R7'), or -NR7C(=O)R7 each of which may be optionally substituted with 1 or more R8 groups ; each occurrence of R6' may be the same or different and is independently Ci-Ce- alkyl, Cs-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkyl-OR7; each occurrence of R7 and R7' may be the same or different and is independently a hydrogen atom, or a Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, C3-C6-cycloalkenyl, aryl, aryl-Ci- Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; each occurrence of R8 is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci-Ce-alkyl, Ci-Ce-alkoxy, C2-C6-alkenyl, C2-C6- alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, Ci-Ce-cycloalkenyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci- Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; n is an integer of 1 and m is an integer of 1 ; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
In other embodiment, said component A is a compound of general formula (I) selected from the group consisting of
6-amino-N-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyridine-3-carboxamide
6-Amino-N-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
6-Amino-N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide
2-Amino-N-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide
2-Amino-N-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide
2-amino-N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2- hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5- yl]pyrimidine-5-carboxamide 2-Amino-N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)propyl]oxy}- 7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide dihydrochloride
2-Amino-N-(8-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
In a preferred embodiment of the aspects of the present invention, said component A is N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same. In a preferred embodiment of the aspects of the present invention, said component A is N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide or a physiologically acceptable salt thereof, or a mixture of same. In a more preferred embodiment of the aspects of the present invention, component A is N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide.
In some embodiments, the asymmetric carbon to which R4 is bonded has the (/^-configuration in the compound of formula (I), as described herein.
In other embodiments, the asymmetric carbon to which R4 is bonded has the (SJ-configuration in the compound of formula (I), as described herein. In other embodiment, component A is selected from the group of PI3K inhibitors consisting of buparlisib, idelalisib, BYL-719, dactolisib, PF-05212384, pictilisib, copanlisib, copanlisib dihydrochloride, ZSTK-474, GSK-2636771 , duvelisib, GS- 9820, PF-04691502, SAR-245408, SAR-245409, sonolisib, Archexin, GDC- 0032, GDC-0980, apitolisib, pilaralisib, DLBS 1425, PX-866, voxtalisib, AZD- 81 86, BGT-226, DS-7423, GDC-0084, GSK-2126458, INK-1 1 17, SAR-260301 , SF-1 126, AMG-31 9, BAY-1082439, CH-51 32799, GSK-2269557, P-71 70, PWT- 33597, CAL-263, RG-7603, LY-3023414, RP-5264, RV-1729, taselisib, TGR- 1202, GSK-418, INCB-040093, Panulisib, GSK-1059615, CNX-1351 , AMG-51 1 , PQR-309, 17beta-Hydroxywortmannin, AEZS-129, AEZS-1 36, HM-5016699, IPI-443, ONC-201 , PF-4989216, RP-6503, SF-2626, X-339, XL-499, PQR-401 , AEZS-132, CZC-24832, KAR-4141 , PQR-31 1 , PQR-316, RP-5090, VS-5584, X- 480, AEZS-126, AS-604850, BAG-956, CAL-1 30, CZC-24758, ETP-46321 , ETP-47187, GNE-317, GS-548202, HM-032, KAR-1 139, LY-294002, PF- 04979064, PI-620, PKI-402, PWT-143, RP-6530, 3-HOI-BA-01 , AEZS-134, AS- 041 164, AS-252424, AS-605240, AS-605858, AS-606839, BCCA-621 C, CAY- 10505, CH-5033855, CH-5108134, CUDC-908, CZC-19945, D-106669, D- 87503, DPT-NX7, ETP-46444, ETP-46992, GE-21 , GNE-123, GNE-151 , GNE- 293, GNE-380, GNE-390, GNE-477, GNE-490, GNE-493, GNE-614, HMPL-518, HS-104, HS-1 06, HS-1 16, HS-173, HS-196, IC-486068, INK-055, KAR 1 141 , KY-12420, Wortmannin, Lin-05, NPT-520-34, PF-04691503, PF-06465603, PGNX-01 , PGNX-02, PI 620, PI-103, PI-509, PI-516, PI-540, PIK-75, PWT-458, RO-2492, RP-5152, RP-5237, SB-2015, SB-2312, SB-2343, SHBM-1009, SN 32976, SR-13179, SRX-2523, SRX-2558, SRX-2626, SRX-3636, SRX-5000, TGR-5237, TGX-221 , UCB-5857, WAY-266175, WAY-2661 76, EI-201 , AEZS- 131 , AQX-MN100, KCC-TGX, OXY-1 1 1 A, PI-708, PX-2000, WJD-008.
Compounds of formula (I) as described and defined herein can be prepared according to the preparation methods contained in WO 2012/062748 which is incorporated herein by reference in its entirety.
The PI3K-inhibitors mentioned in the prior art as well as in the lists above have been disclosed for the treatment or prophylaxis of different diseases, especially cancer. The specific compounds of the lists as disclosed above are preferred as being component A of the combination, most preferred is the compound used in the experimental section. The synergistic behavior of a combination of the present invention is demonstrated herein with one of the PI3K inhibitors specifically disclosed in the Examples section, as example 14, of WO 2012/062748, referrred to as Compound A1 (or as Compd A1 ) below. In another aspect a combination of the present invention comprises is a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and 5-FU. In another aspect a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and capecitabine.
In another aspect a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and a prodrug of 5-FU, such as 5'-deoxy- 5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 or a combination thereof.
In another aspect a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin or a combination thereof. Particularly, a platinum-based antineoplastic agent, selected from oxaliplatin, cisplatin and carboplatin, or a combination thereof. In another aspect a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and oxaliplatin.
In another aspect a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and cisplatin.
In another aspect a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and carboplatin.
In another aspect a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and capecitabine and oxaliplatin.
In another aspect a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and a taxane, such as docetaxel or paclitaxel, or a combination thereof. Particularly, the taxane is selected from docetaxel and paclitaxel or a combination thereof.
In another aspect a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and paclitaxel. In another aspect a combination of the present invention comprises a compound of general formula (I) or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same, as described above, and docetaxel.
In addition a combination of the present invention comprising Compound A1 or a pharmaceutically acceptable salt as mentioned above and 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin and/or a taxane, such as docetaxel or paclitaxel, is a preferred aspect of the invention. Particularly preferred is a combination of the present invention comprising Compound A1 as mentioned above and 5-FU, capecitabine, oxaliplatin and/or paclitaxel. In another aspect a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and 5-FU.
In another aspect a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and capecitabine.
In another aspect a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 or a combination thereof.
In another aspect a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin or a combination thereof.
In another aspect a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and oxaliplatin. In another aspect a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and cisplatin.
In another aspect a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and carboplatin. In another aspect a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and capecitabine and oxaliplatin.
In another aspect a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and a taxane, such as docetaxel or paclitaxel, or a combination thereof.
In another aspect a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and paclitaxel.
In another aspect a combination of the present invention comprises Compound A1 or a pharmaceutically acceptable salt thereof and docetaxel. It is to be understood that the present invention relates also to any combination of the embodiments of component A described above.
Component A may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. In accordance with a preferred embodiment, the component A is administered by the oral route.
Component B of the Combination Component B is an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
According to a preferred embodiment of the aspects of the present invention, Component B is an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from 5-FU, capecitabine, oxaliplatin and paclitaxel, or combinations thereof.
Alternatively, 5-FU may be administered as a prodrug, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, ftorafur, UFT (ftorafur plus uracil), and S-1 (ftorafur plus 5-chloro-2,4-dihydroxypyridine plus potassium oxonate).
S-1 is an oral anticancer medicament based on 5-Fluorouacil as active substance combining three components: Tegafur, a prodrug of 5-FU, Gimeracil (aka 5-chloro-2,4-dihydroxypyridine, CHDP (CAS 103766-25-2)) and Oteracil potassium (potassium oxonate). S-1 consists of a fixed dose combination of the three above-mentioned components which complement/support each other at the pharmacokintiec and pharmacodynamics level: Tegafur is a prodrug of 5-FU, the active substance, which is converted into 5-FU following administration. The Gimeracil component of S-1 inhibits the enzyme dihydropyrimidin- dehydrogenase (DPD), the rate-limiting enzyme in the catabolic pathway of 5- FU. Gimeracil prevents in such way the conversion of 5-FU into the toxic metabolite F-b-alanine. F-b-alanine (FBAL) is a main metabolite of 5-FU. F-b- alanine and fluorocitrate are thought to cause the cardiotoxic and neurotoxic effects of 5-FU by inhibiting the tricarboxylic acid cycle (Koenig and Patel, 1970; Okeda et al, 1990; Robben et al, 1993; Diasio, 1998; Kuwata et al, 2000; Kato et al, 2001 ). Consequently, the plasma FBAL concentration after oral administration of S-1 is significantly lower than that after protracted intravenous infusion (PVI) of 5-FU thus leading to reduced side effects and simultaneously a higher concentration of 5-FU available to produce the desired cytotoxic effects. Oteracil potassium prevents gastrointestinal side effects. Oteracil potassium is an orotate phosphoribosyl transferase inhibitor that is distributed primarily to the gastrointestinal tract. This component of S-1 decreases the incorporation of 5- fluorouridine triphosphate into RNA in the gastrointestinal mucosa and reduces the incidence of diarrhoea.
UFT is an oral agent combining two components : uracil, a competitive inhibitor of DPD, with tegafur, a prodrug of 5-FU, in a 4:1 molar ratio. The tegafur is taken up by the cancer cells and breaks down into 5-FU. Excess uracil competes with 5-FU for DPD, thus inhibiting 5-FU catabolism and allowing higher amounts of 5- FU to stay inside the cells for its cytotoxic effects. The uracil has also been stated to help protect the gastrointestinal tract from 5-FU toxicity and of its metabolites.
Paclitaxel is a member of the taxane drug class, which also includes docetaxel.
Oxaliplatin is a member of the platinum-based antineoplastic agents, which also includes cisplatin and carboplatin.
Suitable dose(s), administration regime(s) and administration route(s) for taxanes and platinum-based antineoplastic agents include those described in the NCCN Clinical Practice Guidelines in Oncology (NCCN guidelines), in particular in the NCCN Guidelines for Gastric Cancer Version 1 .2014 which is included herein by reference in its entirety.
Therefore, all aspects of the invention as described herein provide embodiments wherein, Component B is an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, ftorafur (INN: tegafur), UFT, and S-1 , a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin and carboplatin, and a taxane, such as docetaxel and paclitaxel ; or combinations thereof.
The term "cytotoxic" refers to an agent which can be administered to kill or eliminate a cancer cell. The term "cytostatic" refers to an agent which can be administered to restrain tumor proliferation rather than induce cytotoxic cytoreduction yielding an elimination of the cancer cell from the total viable cell population of the patient. The term "anti-hyperproliferative" refers to an agent which can inhibit the survival or multiplication of the tumor cells with high proliferation rate.
The chemotherapeutic agents described herein, e.g., paclitaxel, 5-FU, capecitabine, oxaliplatin are considered cytotoxic, cytostatic agent, or anti- hyper-proliferative agent depending on individual tumor types. These anti- hyperproliferative, cytotoxic and cytostatic agents have gained wide spread use as chemotherapeutics in the treatment of various cancer types and are well known.
Component B may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
Paclitaxel is sold under the tradename Taxol® by the Bristol-Myers Squibb Company. Paclitaxel ((2α,4α,5β,7β,10β,1 3α)-4,1 0-bis(acetyloxy)-13-{[(2R,3S)- 3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}- 1 ,7-dihydroxy-9-oxo-5,20- epoxytax-1 1 -en-2-yl benzoate - CAS No: 33069-62-4) has the empirical formula C47H51 N014 and a molecular weight of 853.9. It is highly lipophilic in water. Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubles from tubulin dimers and stabilizes microtubules by preventing depolymerization. While not bound by a theory, it is believed that this stability results in the inhibition in the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. Also, paclitaxel is believed to induce abnormal arrays or bundles of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. Paclitaxel is administered by intravenous injection or by other appropriate infusion techniques.
Docetaxel is sold under the tradename Taxotere® by Sanofi-Aventis (1 ,7β,10β- trihydroxy-9-oxo-53,20-epoxytax-1 1 -ene-2a,4,13a-triyl 4-acetate 2-benzoate 13- {(2f?,3S)-3-[(ieri-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate}, CAS No. 1 14977-28-5). Docetaxel belongs to the taxanes chemotherapy drug class and is a semi-synthetic analogue of paclitaxel (Taxol®). It is an anti-mitotic chemotherapy medication that works by interfering with cell division. While not bound by a theory, the cytotoxic activity of docetaxel is believed to be exerted by promoting and stabilising microtubule assembly, while preventing physiological microtubule depolymerisation/disassembly in the absence of GTP. This leads to a significant decrease in free tubulin, needed for microtubule formation and results in inhibition of mitotic cell division between metaphase and anaphase, preventing further cancer cell progeny. Because microtubules do not disassemble in the presence of docetaxel, they accumulate inside the cell and cause initiation of apoptosis. Docetaxel is administered by intravenous injection or by other appropriate infusion techniques. Fluorouracil or 5-FU (tradenames Adrucil® (IV), Carac® (topical), Efudex® and Efudix® (topical)) is a drug that is a pyrimidine analog which is used in the treatment of cancer. It is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase. It belongs to the family of drugs called the antimetabolites. 5-FU acts in several ways, but principally as a thymidylate synthase (TS) inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidine, which is a nucleoside required for DNA replication. Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) to form thymidine monophosphate (dTMP). Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death via thymineless death.
Capecitabine (INN) (tradename Xeloda®, Roche) is an orally-administered chemotherapeutic agent used in the treatment of numerous cancers. Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil (5- FU) in the body.
Oxaliplatin (tradename Eloxatin® by Sanofi) is a platinum-based antineoplastic agent used in cancer chemotherapy. Oxaliplatin fights carcinoma through non- targeted cytotoxic effects. Like other platinum compounds, its cytotoxicity is thought to result from inhibition of DNA synthesis in cells. In particular, oxaliplatin forms both inter- and intra-strand cross links in DNA, which prevent DNA replication and transcription, causing cell death.
Cisplatin (aka cisplatinum) (SP-4-2)-diamminedichloroplatinum(ll), CAS No. 15663-27-1 ) was the first member of the drug class of platinum-based antineoplastic agents, which also includes carboplatin and oxaliplatin. Cisplatin crosslinks DNA in several different ways, interfering with cell division by mitosis. The damaged DNA elicits DNA repair mechanisms, which in turn activate apoptosis when repair proves impossible. Cisplatin is administered intravenously.
Carboplatin sold under the trade name Paraplatin® (c/'s-diammine(cyclobutane- 1 ,1 -dicarboxylate-0,0)platinum(ll), CAS No. 41575-94-4) is a platinum-based antineoplastic agent used in cancer chemotherapy. Carboplatin interacts with DNA to interfere with DNA repair. Carboplatin is administered intravenously.
These and other anti-hyperproliferative/cytotoxic/cytostatic agents may be administered in the conventional formulations and regimens in which they are known for use in monotherapy or in combinations thereof.
In a particular embodiment, the present invention relates to a combination of a component A with a component B, optionally with a component C, as mentioned in the Examples Section herein.
Further, the present invention relates to : a kit comprising :
- a combination of :
component A: one or more PI3K-kinase inhibitors, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ; component B : one or more anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof and, optionally, component C : one or more further pharmaceutical agents ;
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.
In an embodiment, component B is selected from 5-FU, capecitabine, oxaliplatin and paclitaxel, or combinations thereof.
Such kit can be used to treat a patient with a PI3K stimulated cancer as well as cancers not stimulated through PI3K kinase. Particularly such kit can be used to treat gastric cancer and/or metastases thereof.
The term "component C" being at least one pharmaceutical agent includes the effective compound itself as well as its pharmaceutically acceptable salts, solvates, hydrates or stereoisomers as well as any composition or pharmaceutical formulation comprising such effective compound or its pharmaceutically acceptable salts, solvates, hydrates or stereoisomers. A list of such readily available agents is being provided further below. The components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. Component A is administered intravenously, intraperitoneal^, preferably it is administered orally.
Component B preferably is administered by the more appropriate route within the knowledge of the skilled person. Suitable route(s) are included in NCCN Guidelines for Gastric Cancer Version 1 .2014, which is included herein by reference in its entirety.
Component C being administered as the case may be.
The term "pharmaceutically acceptable" is used synonymously to the term "physiologically acceptable".
The term "pharmaceutically or physiologically acceptable salt" of component A 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 a component A 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; dialkyi 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.
Components of this invention can be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break- up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present.
Components of this invention can also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin. Syrups and elixirs can be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents. Components of this invention can also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the component in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1 -dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants. Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl- beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 1 5% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
The pharmaceutical compositions can be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.
Components of the invention can also be administered in the form of suppositories for rectal administration of the drug. These components can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol.
Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 1 1 , 1991 , incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art. It can be desirable or necessary to introduce a component of the present invention to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,01 1 ,472, issued April 30, 1991 .
The compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al, "Compendium of Excipients for Parenteral Formulations " PDA Journal of Pharmaceutical Science & Technology 1 998, 52(5), 238-31 1 ; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1 " PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. ef al, "Excipients and Their Use in Injectable Products " PDA Journal of Pharmaceutical Science & Technology 1997, 51 (4), 166-171 . Commonly used pharmaceutical ingredients that can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CCI2F2, F2CIC-CCIF2 and CCIF3) air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene-butadiene copolymers); buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate) carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection) chelating agents (examples include but are not limited to edetate disodium and edetic acid) colorants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (examples include but are not limited to bentonite); emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas) plasticizers (examples include but are not limited to diethyl phthalate and glycerol); solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)); surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate); suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples include but are not limited to magnesium stearate and talc); tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch); tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate); tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch); tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc); tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet/capsule opaquants (examples include but are not limited to titanium dioxide); tablet polishing agents (examples include but are not limited to carnuba wax and white wax); thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin); tonicity agents (examples include but are not limited to dextrose and sodium chloride); viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth); and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).
Pharmaceutical compositions according to the present invention can be illustrated as follows:
Sterile IV Solution: A 5 mg/mL solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over about 60 minutes.
Lvophilized powder for IV administration: A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lypholized powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 - 3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 minutes.
Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection:
50 mg/mL of the desired, water-insoluble compound of this invention
5 mg/mL sodium carboxymethylcellulose
4 mg/mL TWEEN 80
9 mg/mL sodium chloride
9 mg/mL benzyl alcohol Hard Shell Capsules: A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate. Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 1 00 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 1 1 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption. Immediate Release Tablets/Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
Commercial utility
Component A
The compounds of formula (I) and the stereoisomers thereof according to the combination as referred to above are components A. The compounds according to the combination have valuable pharmaceutical properties, which make them commercially utilizable. In particular, they inhibit the PI3K/AKT pathway and exhibit cellular activity. They are expected to be commercially applicable in the therapy of diseases (e.g. diseases dependent on overactivated PI3K/AKT). An abnormal activation of the PI3K/AKT pathway is an essential step towards the initiation and maintenance of human tumors and thus its inhibition, for example with PI3K inhibitors, is understood to be a valid approach for treatment of human tumors. For a recent review see Garcia-Echeverria et al (Oncogene, 2008, 27, 551 -5526).
Component B
Due to the mechanism as discussed above component B is especially suitable to have effects on tumor diseases. Combination
The combinations of the present invention thus can be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
One embodiment relates to the use of a combination as described herein (e.g. according to any one of claims 1 to 12) for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly gastric cancer and/or metastases thereof.
In one embodiment the invention relates to combinations comprising component A or a pharmaceutically acceptable salt thereof and Component B being an anti- hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof, for use in the treatment of cancer indications, particularly gastric cancer and/or metastases thereof.
In another embodiment the invention relates to combinations comprising component A or a pharmaceutically acceptable salt thereof and Component B being an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from 5-FU, capecitabine, oxaliplatin and paclitaxel, or combinations thereof, for use in the treatment of cancer indications, particularly gastric cancer and/or metastases thereof. Such cancer types include, but are not limited to, gastric cancer and/or metastases thereof. Such cancer types include, but are not limited to, advanced gastric cancer and/or metastases thereof.
In one embodiment the invention relates to a method of treatment or prophylaxis of a cancer, particularly gastric cancer and/or metastases thereof, in a subject, comprising administering to said subject a therapeutically effective amount of a combination according to any one of claims 1 to 16.
Preferred uses of the combinations of the invention are the treatment of gastric cancer and/or metastases thereof.
Preferred uses of the combinations of the invention are the treatment of advanced gastric cancer and/or metastases thereof.
The term "inappropriate" within the context of the present invention, in particular in the context of "inappropriate cellular immune responses, or inappropriate cellular inflammatory responses", as used herein, is to be understood as preferably meaning a response which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases.
Combinations of the present invention might be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
This invention includes a method comprising administering to a mammal in need thereof, including a human, an amount of a component A and an amount of component B of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; etc. which is effective to treat the disorder. Hyper-proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), as well as malignant neoplasia. Examples of malignant neoplasia treatable with the compounds according to the present invention include solid and hematological tumors. Solid tumors can be exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, anum, endocrine glands (e.g. thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva. Malignant neoplasias include inherited cancers exemplified by Retinoblastoma and Wilms tumor. In addition, malignant neoplasias include primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases"). Hematological tumors can be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of unknown primary site as well as AIDS related malignancies. 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 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, 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. These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
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.
Combinations of the present invention might also be used for treating disorders and diseases associated with excessive and/or abnormal angiogenesis. Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al. New Engl. J. Med. 1994, 331 , 1480 ; Peer et al. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD ; see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumor enlargement and metastasis. Moreover, the growth of new blood and lymph vessels in a tumor provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer. Thus, combinations of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation ; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
Dose and administration
Component A Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, 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 compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredients to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound 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 ingredients 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 of a compound 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. Component B
The hyper-proliferative, cytotoxic or cytostatic agent, 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin, and a taxane, such as docetaxel or paclitaxel; or combinations thereof, particularly 5-FU, paclitaxel, oxaliplatin, capecitabine and combinations thereof, can be administered to a patient at a dosage which can range from about 0.1 to about 300 mg/kg of total body weight. Also, the agents can also be administered in conventional amounts routinely used in cancer chemotherapy, particularly in gastric cancer and advanced gastric cancer and/or metastases thereof.
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 compounds 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 compound 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.
Suitable dose(s), administration regime(s) and administration route(s) for 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 ; for a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and for a taxane, such as docetaxel or paclitaxel; or combinations thereof include those described in the NCCN Clinical Practice Guidelines in Oncology (NCCN guidelines), in particular in the NCCN Guidelines for Gastric Cancer Version 1 .2014 which is included herein by reference in its entirety. Further, suitable dose(s), administration regime(s) and administration route(s) for 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 ; for a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and for a taxane, such as docetaxel or paclitaxel; or combinations thereof may be readily determined by standard techniques known to the skilled person.
The dose(s), administration regime(s) and administration route(s) may have to be adapted according to, inter alia, the indication, the indication stage, the patient age and/or the patient gender, among other factors. Such adaptations can be readily determined by standard techniques known to the skilled person.
Suitable dose(s), administration regime(s) and administration route(s) for 5-FU, paclitaxel, oxaliplatin, capecitabine and combinations thereof include those described in the NCCN Clinical Practice Guidelines in Oncology (NCCN guidelines), in particular in the NCCN Guidelines for Gastric Cancer Version 1 .2014 which is included herein by reference in its entirety.
For both the aminoalcohol substituted 2,3-dihydroimidazo[1 ,2-c]quinazoline derivative of general formula (I) and the hyper-proliferative, cytotoxic or cytostatic agent, selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof (particularly 5-FU, paclitaxel, oxaliplatin, capecitabine and combinations thereof), the administered dosage of the compound(s) may be modified depending on any superior or unexpected results which may be obtained as routinely determined with this invention.
The hyper-proliferative, cytotoxic or cytostatic agent can be administered to a patient orally, topically, parenterally, rectally, by inhalation, and by injection. Administration by injection includes intravenous, intramuscular, subcutaneous, and parenterally as well as by infusion techniques. The agents can be administered by any of the conventional routes of administration for these compounds. The preferred route of administration for the hyper- proliferative/cytotoxic/cytostatic agents using this invention is typically by injection which is the same route of administration used for the agent alone. Any of the hyper-proliferative, cytotoxic or cytostatic agents can be administered in combination with an aminoalcohol substituted 2,3-dihydroimidazo[1 ,2- c]quinazoline derivative of general formula (I) by any of the mentioned routes of administration.
For administering the aminoalcohol substituted 2,3-dihydroimidazo[1 ,2- c]quinazoline derivative of general formula (I) and the hyper- proliferative/cytotoxic/cytostatic agent(s), by any of the routes of administration herein discussed, the aminoalcohol substituted 2,3-dihydroimidazo[1 ,2- c]quinazoline derivative of general formula (I) can be administered simultaneously with the hyper-proliferative, cytotoxic or cytostatic agent. This can be performed by administering a single formulation which contains both the aminoalcohol substituted 2,3-dihydroimidazo[1 ,2-c]quinazoline derivative of general formula (I) and the hyper-proliferative/cytotoxic/cytostatic agent or administering the aminoalcohol substituted 2,3-dihydroimidazo[1 ,2-c]quinazoline derivative of general formula (I) compound and the hyperproliferative/cytotoxic/cytostatic agents in independent formulations at the same time to a patient.
Alternatively, the aminoalcohol substituted 2,3-dihydroimidazo[1 ,2- c]quinazoline derivative of general formula (I) can be administered in tandem with the hyper-proliferative/cytotoxic/cytostatic agent. The aminoalcohol substituted 2,3-dihydroimidazo[1 ,2-c]quinazoline derivative of general formula (I) can be administered prior to the hyper-proliferative/cytotoxic/cytostatic agent. For example, the aminoalcohol substituted 2,3-dihydroimidazo[1 ,2-c]quinazoline derivative of general formula (I) can be administered once or more times per day up to 28 consecutive days, or once or more times per week up to 4 consecutive weeks followed by administration of the hyper-proliferative, cytotoxic or cytostatic agent. Also, the hyper-proliferative, cytotoxic or cytostatic agent can be administered first followed by adminstration of the aminoalcohol substituted 2,3-dihydroimidazo[1 ,2-c]quinazoline derivative of general formula (I). The choice of sequence administration of the aminoalcohol substituted 2,3- dihydroimidazo[1 ,2-c]quinazoline derivative of general formula (I) relative to the hyper-proliferative/cytotoxic/cytostatic agent may vary for different agents. Also, the hyper-proliferative/cytotoxic or cytostatic agent can be administered using any regimen which is conventionally used for these agents.
In another regimen of administration, the aminoalcohol substituted 2,3- dihydroimidazo[1 ,2-c]quinazoline derivative of general formula (I) and the hyper- proliferative/cytotoxic/cytostatic agent can be administered once or more times per day on the day of administration.
Any of the routes and regimens of administration may be modified depending on any superior or unexpected results which may be obtained as routinely determined with this invention.
Combinations of the present invention
The combinations of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth, more especially on gastric tumours and/or metastases thereof.
Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art. The combinations of component A and component B of this invention can be administered as the sole pharmaceutical agent or in combination with one or more further pharmaceutical agents C where the resulting combination of components A, B and C causes no unacceptable adverse effects. For example, the combinations of components A and B 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 131 l-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate,amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib , crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, 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, lanreotide, lapatinib, lasocholine, lenalidomide, 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, nedaplatin, nelarabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin, palladium- 103 seed, palonosetron, pamidronic acid, panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, 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, romidepsin, romiplostim, romurtide, roniciclib , samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, 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, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin or combinations thereof.
Alternatively, said component C can be one or more further pharmaceutical agents selected from gemcitabine, paclitaxel, oxaliplatin, cisplatin, carboplatin, sodium butyrate, 5-FU, doxirubicin, tamoxifen, etoposide, trastumazab, gefitinib, intron A, rapamycin, 17-AAG, U0126, insulin, an insulin derivative, a PPAR ligand, a sulfonylurea drug, an a-glucosidase inhibitor, a biguanide, a PTP-1 B inhibitor, a DPP-IV inhibitor, a 1 1 -beta-HSD inhibitor, GLP-1 , a GLP-1 derivative, GIP, a GIP derivative, PACAP, a PACAP derivative, secretin or a secretin derivative.
Optional anti-hyper-proliferative agents which can be added as component C to the combination of components A and B of the present invention include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 1 1 th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5- fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.
Other anti-hyper-proliferative agents suitable for use as component C with the combination of components A and B of the present invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1 287, (1996), which is hereby incorporated by reference, such as aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2',2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5- fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel (when component B is not itself paclitaxel), pentostatin, N- phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, and vinorelbine.
Other anti-hyper-proliferative agents suitable for use as component C with the combination of components A and B of the present invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan.
Generally, the use of cytotoxic and/or cytostatic agents as component C in combination with a combination of components A and B of the present invention will serve to:
(1 ) yield better efficacy in reducing the growth of a tumor and/or metastasis or even eliminate the tumor and/ or metastasis 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, provide for treating a broader spectrum of different cancer types in mammals, especially humans, provide for a higher response rate among treated patients, provide for a longer survival time among treated patients compared to standard chemotherapy treatments, provide a longer time for tumor progression, and/or 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. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
EXPERIMENTAL SECTION
The schemes and procedures described in the art as cited in the present application (see introductory part) disclose general synthetic routes and specific procedures within their experimental sections to arrive at the PI3K- compounds which are preferred components A of the present combination.
Compound A1 is a PI3K inhibitor as disclosed in the experimental section of WO2012/062748 in example 14 (N-(8-{[(2R)-2-hydroxy-3-(morpholin-4- yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2- methylpyridine-3-carboxamide).
Figure imgf000094_0001
Compound A1
Component B is available from commercial sources. Alternatively Component B may be prepared using any of the methods available in the art.
Examples demonstrating monotherapy activity of component A, the synergistic effect of the combinations of components A and B of the present invention and the sensitivity profile of GC tumour models to component A and to the combination of the invention.
Example 1 : COMPOUND A1 was profiled in 7 gastric tumor cell lines with known mutation status of PIK3CA and PTEN. Cell lines with either PIK3CA mutation and/or PTENnuN are sensitive to COMPOUND A1 , and tumor cell lines with wild type PIK3CA or PTEN are insensitive or resistant to COMPOUND A1 in vitro. HGC27 harboring both PIK3CA and PTEN mutations is the most sensitive cell line to COMPOUND A1 . This result confirmed our hypothesis that the balanced ΡΙ3Κα/β inhibitor is more effective in tumors with both PIK3CA and PTEN alterations. Table 1. Anti- rol iterative activity of COMPOUND A1 in gastric cancer cell lines.
Figure imgf000094_0002
Figure imgf000094_0003
COMPOUND A 1 is active in chemo-resistant gastric cancer models.
Example 2: COMPOUND A1 was profiled in vivo in 17 gastric tumor models (2 cell lines and 15 patient-derived primary tumors) with known molecular features as single agent.
The monotherapy efficacy of COMPOUND A1 was tested in two sets of studies with both tumor cell line and patient-derived primary tumor models. The first set of study was conducted in gastric tumor models established in Oncotest GmbH (Freiburg, Germany). This study includes 2 cell-line derived Asian gastric cancer models (GXA IM95LX and GXA MKN45LX) as well as 3 Asian patient and 3 Caucasian patient-derived gastric cancer xenografts in female NMRI nu/nu mice. The second set of studies was performed in National Cancer Centre Singapore in 8 Asian patient-derived gastric cancer xenografts in male SCID mice. In both studies, COMPOUND A1 was administered p.o. once daily at a dose of 75 mg/kg. Anti-tumor activity was determined as tumor growth inhibition relative to the vehicle control group and was expressed as the ratio of group median relative tumor volumes (treatment/control; T/C [%]).
The 8 gastric tumor models tested in Oncotest (Table 2) displayed good or excellent sensitivity to COMPOUND A1 . Final T/C values ranged from 5.4% (GXA 3027) to 39.8% (GXF 1 172). Partial regression or approximate tumor stasis was observed in most of the models, or progression at a reduced rate in the least sensitive model (less than 2-fold increase of tumor volume compared to greater than 4-fold increase in vehicle group).
Trends of correlations with genetic status were observed. Thus, tumors with over expression of Her2 or Her3, or amplification or mutation of PIK3CA or PIK3CB, or low expression of PTEN showed a correlation with the sensitivity. In contrast, tumors with overexpression of EGFR or KRAS mutation seem to correlate with the insensitivity.
Importantly, COMPOUND A1 is active in chemo-resistant tumor models, e.g. 5-FU- and cisplatin-resistant GXF602, and 5-FU-, cisplatin- and taxol- resistant GXA3002 with T/C values of 17.1 % and 13.5%, respectively. Table 2. Summary of in vivo efficacy of COMPOUND A1 in a set of gastric cancer models
Max. median Median RTV
DifferenResistance to final T/C ¾es ons - :'
Tumor model Origin Histology Genetic Status Stat. sign.b BWL [%j (day) on day21 (%) CR PR SD PD tiation SoC drugs Rate "
/Vehicle
GXA IM95LX Asian AdCa Moderate FGFR2amp HER3amp tbd 9.4% p<0.05 12.2 (17) 54.0/399.9 100% 0 6 0 0
AdCa
GXA3027 Asian Poor PIK3CA0/E, PIK3CB0/E tbd p<0.05 16.8 (28) 75.4/620.9 57% 0 4 0 3
intestinal
KRASG13D, PIK3CAE542K,
GXF602 Western AdCa Poor 5-FU, cisplatin 17.1 % p<0.05 11 .4 (14) 1 12.5/478.3 16.70% 0 1 5
GXA MKN45LX Asian AdCa Poor SMAD4mut, p-HER3high tbd 20.9% p<0.05 14.9 (10) 77.4/427.4 0% 0 0 4 3
AdCa Not PTENLow, EGFRHigh, 5-FU, cisplatin,
GXA 3002 Asian 13.5% p<0.05 17.6 (21) 96.3/504.6 0% 0 0 3
intestinal known Taxol *
EGFRhigh, HER2high,
GXF214 Western AdCa Poor 5-FU, Oxaliplatin 28.9% p<0.05 12.1 (21) 182.8/632.9 0% 0 0 5
PIK3CAE542K, FBX4G30
AdCa
GXA 3023 Asian Moderate KRASG13D, PIK3CAH1047R, Taxol, 5-FU 18.1 % p<0.05 9.2 (10) 144.8/713.8 0% 0 0 0 7
intestinal
GXF1172 Western AdCa Poor p Taxol 39.8% p<0.05 17.1 (14) 191 .2/399.9 0% 0 0 0 5
Table 2. COMPOUND A1 (75 mg/kg) and its vehicle (0.1 N HCI pH4.0) were administered orally once daily. Dosing holidays were taken when animals lost more than 20% of their body weight and until they had regained at least 85% of their original body weight. Ad: Adenocarcinoma; tbd: to be determined; 0 E: Overexpression; amP: amplification; CR: complete regression, final tumor volume is <10% of tumor volume on day 0; PR: partial regression, final tumor volume is <70% of tumor volume on day 0; SD: stable disease, final tumor volume is <130% of tumor volume on day 0; PD: progressive disease, final tumor volume is >130% of tumor volume on day 0; a: T/C (treatment vs vehicle control); b: non-parametric Mann-parametric Mann-Whitney test on the day which the minimum T/C value was recorded for each group.
In another set of studies, COMPOUND A1 was tested in 9 Asian gastric cancer patient-derived tumor models in comparison to the standard of care of the 1 st line treatment, Oxaliplatin plus Capecitabine (tradename: Xeloda®). COMPOUND A1 demonstrated significant tumor growth inhibition in all gastric tumor models tested and highly efficacious in 8 out of 9 tumor models at a dose of 75 mg/kg/d of COMPOUND A1 . Importantly, in 3 out of 6 Oxaliplatin + Capecitabine resistant models (TGI 14-45%), COMPOUND A1 demonstrated a clear superiority with tumor growth inhibition ranging from 66-79% (Table 3). Sequenome analysis of 19 oncogenes (240 mutations, including KRAS, PIK3CA, etc.) indicated that
■ tumors bearing an activating mutation of PIK3CA are most sensitive to compound A1 : GC28-1 107, the most sensitive model to COMPOUND A1 monotherapy (TGI%=94.5%), is bearing an activating mutation of
PIK3CA (H1047R);
■ tumors bearing a KRAS mutation (e.g. GC05-0208B) are most
resistant to compound A1 : GC05-0208B, the most resistant model to COMPOUND A1 monotherapy (TGI%=40.4%), is bearing a KRAS
(G12A) mutation;
■ Tumors bearing both PIK3CA and KRAS mutations showed
moderate sensitivity to compound A1 : GC23-0909, showed moderate sensitivity to COMPOUND A1 monotherapy (TGI%=78.5%), is bearing both PIK3CA (C420R) and KRAS (G12D) mutations. Taken all together, our initial molecular analysis on the 8 models from Oncotest and the 9 models from National Cancer Center Singapore suggested that PI3K pathway activation through PIK3CA mutation and/or amplification, PTEN-loss and/or PIK3CB amplification, and Her2, Her3 and/or FGFR2 overexpression correlate with the sensitivity toward COMPOUND A1 .
Table 3. Summary of in vivo efficacy of COMPOUND A1 and Oxaliplatin/Capecitabine on tumor growth inhibition of gastric cancer (GC) xenografts.
Figure imgf000099_0001
Table 3. Gastric cancer xenografts were carried out with male SCI D mice (Animal Resources Centre, Canning Vale, West Australia) aged 9-1 0 weeks. COM POUN D A1 was first dissolved in 0.1 N HCL (pH 4.0) and then the stock solution was further dissolved in 30% Captisol to obtain the desired concentration. Mice (12-15 per group) were orally administered daily either 200 μΙ of vehicle, or 50 mg/kg or 75 mg/kg of COM POUND A1 , or the standard of care Oxaliplatin (4 mg/kg, QW) plus Capecitabine (100 mg/kg, QD). Treatments started when the tumors reached the size of approximately 200-300 mm3. At the end of the study, the mice are sacrificed with body and tumor weights being recorded and presented with means and standard errors. SE: standard error; T/C: tumor weight of treatment group vs vehicle control group; TGI : tumor growth inhibition. Example 3: Synergistic combination with 1st line Standard of Care (SoC) Oxaliplatin plus Capecitabine (tradename of Capecitabine: Xeloda®)
We investigated the combination of PI3K inhibitor COMPOUND A1 with
Oxaliplatin and Capecitabine in both chemo resistant and chemo sensitive tumor models. Oxaliplatin and Capecitabine were dosed at the MTD (4 mg/kg/week and 1 00 mg/kg/day, respectively) and COMPOUND A1 was dosed at the 67% of the monotherapy MTD. The combination effects were summarized in Table 4, thus
■ in Oxaliplatin+Capecitabine resistant/insensitive models (GC30-0309, GC22-0808, and GC23-0909), very strong synergy was demonstrated with TGI% improved from 14-46% to 89-93%.
■ In Oxaliplatin+Capecitabine sensitive models (GC16-1008 and GC28- 1 107), no antagonistic but slight synergy was demonstrated.
■ In KRAS mutant COMPOUND A1 resistant model GC (GC05-0208B), synergistic to additive effect was observed (TGI% improved from 76.9% to 82.5%).
Overall, combination of COMPOUND A1 with Oxaliplatin plus Capecitabine was well tolerated. No significant body weight loss or other clinical signs of toxicity were observed in any groups. Table 4. Summary of in vivo combination effects of COMPOUND A1 and Oxaliplatin/Capecitabine on tumor growth inhibition of gastric cancer xenografts.
Figure imgf000100_0001
Control 1.5693 0.136846 1.000 0.00
Oxaliplatin 4 + Capecitabine 100 0.8517 0.050523 0.543 45.73
GC30-0303 COMPOUND A1 , 50 mg/kg, QD 0.5318 0.061461 0.339 66.11
COMPOUND A1 50 + Oxaliplatin 4 +
Capecitabine 100 0.1510 0.016809 0.096 90.38
Control 2.9583 0.06734 1.000 0.00
Oxaliplatin 4 + Capecitabine 100 1 .9800 0.21695 0.669 33.07
GC22-0808
COMPOUND A1 , 50 mg/kg, QD 1 .7297 0.10454 0.585 41.53 COMPOUND A1 50 + Oxaliplatin 4 +
Capecitabine 100 0.1991 0.037034 0.067 93.27
Control 2.2772 0.137726 1.000 0.00
Oxaliplatin 4 + Capecitabine 100 1 .4115 0.03453 0.860 14.04
GC23-0909 COMPOUND A1 , 50 mg/kg, QD 0.4515 0.019855 0.275 72.50
COMPOUND A1 50 + Oxaliplatin 4 +
Capecitabine 100 0.1799 0.004341 0.109 89.06
Table 4. Gastric cancer xenografts were carried out with male SCI D mice (Animal Resources Centre, Canning Vale, West Australia) aged 9-10 weeks. COM POUND A1 was first dissolved in 0.1 N HCL (pH 4.0) and then the stock solution was further dissolved in 30% Captisol to obtain the desired concentration. Mice (12-15 per group) were orally administered daily either 200 μΙ of vehicle, or 50 mg/kg of COM POUND A1 , or the standard of care Oxaliplatin (4 mg/kg, QW) plus Capecitabine (100 mg/kg, QD), or 50 mg/kg of COM POUN D A1 + Oxaliplatin (4 mg/kg, QW) + Capecitabine (1 00 mg/kg, QD). Treatments started when the tumors reached the size of approximately 200-300 mm3. At the end of the study, the mice are sacrificed with body and tumor weights being recorded and presented with means and standard errors. SE: standard error; T/C: tumor weight of treatment group vs vehicle control group; TGI : tumor growth inhibition.
Example 4: Anti-tumor Activity of COMPOUND A1 in Combination with Paclitaxel
The in vivo efficacy experiments assessing the combination activity of paclitaxel and COMPOUND A1 in different dosing schedule were performed in female nu/nu mice. The results of the experiments are summarized in Table 5.
Weekly paclitaxel (24 mg/kg/day) dosed i.v. on days 0, 7, 14, and 21 was combined with either continuous dosing of COMPOUND A1 at 75 mg/kg/day p.o. on days 1 -6, 8-13, 15-20, 22- 23, or with intermittent dosing of COMPOUND A1 on days 1 , 8, 15, and 22 (500/400 mg/kg/day).
In GXA 3023 tumor model, continuous dosing of COMPOUND A1 (75 mg/kg, QD) displayed good anti-tumor activity with an optimal T/C value of 31 .9%. Intermittent dosing 500/400 mg/kg, weekly of COMPOUND A1 showed very good efficacy with an optimal T/C value of 8.2% and overall tumor stasis and 3/8 partial remissions. Paclitaxel monotherapy was moderately good with an optimal T/C value of 35.0%. The combination therapy of paclitaxel with continuous COMPOUND A1 (75/50 mg/kg) resulted in very good anti-tumor activity with an optimal T/C value of 15.6%. Paclitaxel in combination with weekly COMPOUND A1 (500/400 mg/kg) was highly active with an optimal T/C value of 9.1 % and an overall tumor stasis with 3/8 partial tumor remissions. The combination effect of paclitaxel plus intermittent weekly COMPOUND A1 therefore has to be assessed by tumor growth delay.
In GXF 241 tumor model, continuous COMPOUND A1 dosing displayed good anti-tumor efficacy with an optimal T/C value of 17.9% with one partial remission observed.
Intermittent dosing of COMPOUND A1 also resulted in better activity with an optimal T/C of 13.6 and partial tumor remission observed in 4/8 mice. Paclitaxel monotherapy was highly active with an optimal T/C value of 6.6%. Tumors went into partial remission in 7/8 animals. The two paclitaxel/COMPOUND A1 combination therapies resulted in excellent and statistically significant anti-tumor efficacy with an optimal T/C value of 4.2% in both cases. Partial tumor remission was observed in 8/8 animals of both of the combination therapy groups. The very good anti-tumor activity of both combination therapy groups proved to be statistically significant.
In summary, the combination treatments were in both cases more active and beneficial than the respective COMPOUND A1 concentrations given in monotherapy.
Table 5 - Summary of Anti-tumor Efficacy of COMPOUND A1 given in Monotherapy and in Combination with Paclitaxei in Mice bearing the Gastric Cancers GXA 3023 and GXF 241
Figure imgf000103_0001
Table 5 (cont.) - Summary of Anti-tumor Efficacy of COMPOUND A1 given in Monotherapy and in Combination with Paciitaxei in Mice bearing the Gastric Cancers GXA 3023 and GXF 241
5
Figure imgf000104_0001
Table 6. Efficacy of Compound A1 in Her2 and/or Her3 overexpressing GC models
Figure imgf000105_0001
GC28-1107 O/E O/E PIK3CAmut 94.5 IM95 O/E PIK3CAmut 90.6
GC10-0608 O/E O/E wt 85.2
PIK3CAmut,
GXF602 O/E 82.9
KRASmut
MKN45 O/E wt 79.1
GC22-0808 O/E wt 78.9 Compound A1 showed potent anti-tumor efficacy in Her2 and/or Her3 overexpressing GC models
■ In vitro and in vivo profiling of Compound A1 in a panel of GC cell lines and PDx models indicated that PI3Ka/b balanced PI3K inhibitor Compound A1 is effective for the treatment of GC, particularly those with activation of PI3Ka and/or PI3Kb isoforms, e.g. genetic alteration of PIK3CA and PIK3CB, PTEN-loss, and/or HER2/HER3 overexpression
■ In vivo, Compound A1 demonstrated potent PI3K pathway inhibition, strong anti- angiogenesis and tumor killing effects.
- Compound A1 was active in multiple tumor models resistant to the standard of care chemotherapy. Combination with paclitaxel and capecitabine/oxaliplatin demonstrated synergistic or additive effects on tumor growth inhibition, apoptosis induction and preventing tumor regrowth.
■ In summary, Compound A1 with equipotent activity against ΡΙ3Κα/β demonstrated impressive efficacy in PI3Ka/3-driven gastric cancer models, strongly supporting clinical development of Compound A1 for the treatment of advanced gastric cancer.
Example 5: In vivo efficacy of Compound A1 dosed continuously or intermittently in GXA3027 patient derived gastric tumor model in mice as a single agent and in combination with cisplatin and capecitabine.
In order to compare the monotherapy and combination efficacy of Compound A1 with continuous and intermittent dosing regimens, Compound A1 was administered p.o. once daily at 60 mg/kg, 20n/50ff at 210 mg/kg, or once weekly at 420 mg/kg with the same weekly cumulative dose of 420 mg/kg in GXA3027 patient derived gastric tumor model in NMRI nu/nu mice. Anti-tumor activity was determined as tumor growth inhibition relative to the vehicle control group and starting tumor volumes and is expressed as the ratio of group median relative tumor volumes (Vtreatment-Vinitiai)/(VControi- Vinitiai)%; T/C [%]). Tumor response is assessed by determination of the tumor size (tumor volume = (width)2 x length/2) using a calliper. The animal body weight was monitored as a measure for treatment-related toxicity. Measurements of tumor size and body weight were performed 2-3 times weekly. Statistical analysis was assessed using SigmaStat software. A one-way analysis of variance was performed and differences to the control are compared by a pair-wise comparison procedure (Dunn's method). Relative T/C ratios were calculated with final tumor areas at study end, if not mentioned otherwise. Furthermore, treatment responses were evaluated by means of the clinically-used RECIST criteria (complete response, partial response, stable disease and progressive disease) (reference: Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1 .1 ). EJC 15 2009;45:228- 247) and response rates were calculated accordingly (RR = number of animals with complete and partial response).
Treatment of Compound A1 with QD, QW, or 20n/50ff schedule demonstrated strong anti-tumor efficacy with relative T/C of -2.2%, -13.8% and -8.3%, respectively. Importantly, QW dosing with 420 mg/kg/week displayed the strongest activity with 78% RR (7/9 animals), 20n/50ff schedule showed a RR of 56% (5/9 animals) and continuous QW dosing generated a RR of 1 1 % (1 /9 animals) (Fig. 10). These data confirmed that combination with 1 st line chemotherapy of gastric cancer (e.g. capecitabine and cisplatin), compoundAI could further enhance its anti-tumor activity with all three dosing schedules, with regard to both T/C and RR.
Table 7. Study design for the efficacy assessment of Compound A1 with different dosing regimens in GXA3027 patient derived gastric tumor model in NMRI nu/nu mice
Figure imgf000108_0001
5
10
15 Description of the Figures In vivo mode of action (MoA)
To investigate the MoA of COMPOUND A1 , tumors were harvested for analysis at the end of the study. For example, western blot analysis of GC22-0808 tumor lysates with antibodies against PI3K and MAPK pathways indicated that COMPOUND A1 and COMPOUND A1 plus Oxaliplatin/Xeloda significantly inhibited the phosphorylation of p70S6K, AKT, 4EBP1 , and S6R without affecting the p-ERK1 /2 (p<0.05, Figure 1 ). When tumor sections were stained with anti-CD31 , p-histone 3 (SeM O) and cleaved PARP antibodies, significant reduction in blood vessel formation, tumor cell proliferation and elevation of cleaved PARP were observed in COMPOUND A1 -treated tumors, suggesting that they caused the inhibition of tumor angiogenesis and proliferation and led to the induction of tumor cell apoptosis. The antitumor activities of COMPOUND A1 were correlated with the levels of pathway inhibition and cleaved PARP in drug- treated tumors. The addition of Oxaliplatin/Xeloda into COMPOUND A1 modestly augmented the apoptotic activity of COMPOUND A1 (Figure 2).
Figure 1. Effects of COMPOUND A1 , Oxaliplatin/Xeloda, and COMPOUND A1 plus Oxaliplatin/Xeloda on the phosphorylation of AKT/mTOR and ERK1/2 pathways, and apoptosis of GC22-0808. Lysates of 3-4 tumors from one group were pooled. Each lane represented one protein pool and two pools per group were subjected to Western blot analysis. Representative blots are shown.
Figure 2. Effects of COMPOUND A1 and COMPOUND A1 plus Oxaliplatin/Xeloda on angiogenesis, cell proliferation and apoptosis in GC 22-0808 xenografts. GC22-0808 tumors were s.c. implanted in SCID mice. Mice bearing tumor xenografts were daily treated with vehicle or 50 mg/kg COMPOUND A1 or Oxaliplatin Xeloda (4 mg/kg/100 mg/kg) 50 mg/kg COMPOUND A1 plus Oxaliplatin/Xeloda for 1 5 days. Each treatment arm involved 15 independent tumor-bearing mice. Representative pictures of blood vessels stained with anti-CD31 , proliferative cells stained with anti-p-histone 3 SeM O, and apoptotic cells stained with anti-cleaved-PARP antibodies in vehicle- and drug-treated tumors are shown (200x). Experiments were repeated twice with similar results. BAY 2439=COMPOUND A1
Figure 3. In vivo anti-tumor efficacy in Gastric Cancer PDx (patient-derived xenograft) with PIK3CAmut and/or KRASmut
Among 16 GC models screened,
■ tumors bearing an activating mutation of PIK3CA (e.g. GC-1 107) are most sensitive to Compound A1 ;
■ tumors bearing a KRAS mutation (e.g. GC05-0208B) are most resistant to Compound A1 ;
■ Tumors bearing both PIK3CA and KRAS mutations (e.g. GC23-0909) showed moderate sensitivity to Compound A1 .
■
Figure 4. In vivo anti-tumor efficacy in GC PDx models with activation of both PI3Kalpha and PI3Kbeta
PI3Ka/b balanced inhibitor Compound A1 showed potent in vivo anti-tumor efficacy in
■ GXA3027 GC PDx model (TGI% = 94.6% , 4/7 (57%) PRs)
overexpressing both PIK3CA and PIK3CB.
■ GXA3002 GC PDx model (TGI% = 86.5% , 1 /7 (14%) PRs) with the
activation of both PI3Ka (via overexpression of Her3 and EGFR) and PI3Kb (via PTEN-Low).
PR: Partial regression Figure 5. Efficacy of Compound A1 in IM95 GC model
• Compound A1 showed potent anti-tumor efficacy in Her2 and/or Her3
overexpressing GC models
• Compound A1 showed 1 00% tumor partial remission in
IM95Her3° E/PIK3CAmut GC model
Figure 6. In vivo MoA of PI3Ka/b balanced inhibitor Compound A1 in GC28- 1107 GC models
Compound A1 showed potent pathway inhibition and induction of apoptosis in GC28-1 107 GC model Figure 7. In vivo MoA of PI3Ka/b balanced inhibitor Compound A1 in GC10- 0608 and GC22-0808 GC models
Compound A1 showed strong anti-angiogenesis effect (CD31 staining, Figure 5B) in highly vascularized GC10-0608 and GC22-0808 GC PDx models
Figure 8. Combination treatment of PI3Ka/b balanced inhibitor Compound A1 overcomes chemo-resistance in GC PDx models
• PI3K inhibitor Compound A1 showed synergistic anti-tumor effects with the 1 st line SoC therapy (XELOX, capecitabine+oxaliplatin, Figure 8A) and 2nd line SoC therapy (paclitaxel, Figure 8B) in chemo resistant GC PDx models.
• Treatment of Compound A1 prevented tumor from regrowth after the completion of a 2-week XELOX + Compound A1 combination therapy (Figure 8C).
• Clear PI3K pathway inhibition and apoptosis induction by Compound A1 as single agent and in combination with XELOX was demonstrated in GC22-0808, a GC PDx with PTEN'°W and Her2+ Figure 9. Combination treatment of PI3Ka/b balanced inhibitor Compound A1 further enhanced tumor killing effects in GC models
• In chemo sensitive tumor models, combination with PI3K inhibitor
Compound A1 could further significantly enhance tumor killing effects compared to chemo treatment alone.
Figure 10. Efficacy of Compound A1 in patient derived GXA 3027 gastric cancer xenograft model in nude mice.
Patient derived GXA 3027 gastric cancer cells were implanted subcutaneously (s.c.) onto NMRI nude mice. When tumors had reached a size of approximately 140 mm3, animals were randomized and compound A1 was dosed with dosing regimens and schedules as indicated in Table 7 as single agent or in
combination with cisplatin and capecitabine. Tumor weights from each individual animal at the end of treatment were presented. In addition relative tumor growth inhibition (TGI) was calculated with the equation [1 -(T-T0/C-T0)] x 100, where T and C represent the mean size of tumors in the treated (T) and control (C) groups, respectively, and TO refers to the tumor size at the randomization.
Furthermore, treatment responses were evaluated by means of clinically used RECIST criteria; response rates (RR) were calculated as the percentage of animals with a complete or partial response.
Conclusions:
Due to the high medical need for the treatment of gastric cancer, we thus developed and characterized COMPOUND A1 , a potent and balanced ΡΙ3Κα/β inhibitor. In this invention, we describe in vitro and in vivo profiling of COMPOUND A1 in both gastric cancer tumor cell lines and patient-derived xenograft tumor models (PDx) followed with mode of action and biomarker analysis. Profiling a panel of gastric tumor cell lines in vitro indicated that tumor cells with either PIK3CA mutation and/or PTEN-null were sensitive to COMPOUND A1 . Surprisingly, in vivo profiling of a panel of xenograft models derived from both Asian and Caucasian patients revealed that tumors with genetic alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression were more sensitive to COMPOUND A1 (tumor growth inhibition >90%), while tumors harboring a co-existing KRAS mutation and/or overexpressing EGFR were insensitive or less responsive to COMPOUND A1 . Overall, COMPOUND A1 was efficacious in 16/17 models tested in vivo. Interestingly, although COMPOUND A1 was completely inactive against MKN45 human gastric tumor cell line in an in vitro cell proliferation assay (ICso>10 μΜ), it induced tumor stasis in vivo in MKN45 xenograft, a highly vascularized tumor model, likely through blocking tumor angiogenesis signaling. This was further confirmed by ex vivo IHC staining of tumors treated with COMPOUND A1 using CD31 antibody. In addition, COMPOUND A1 was active in multiple tumor models resistant to the standard of care chemotherapy. Combination with paclitaxel, 5-FU, capecitabine or oxaliplatin demonstrated synergistic effects on tumor growth inhibition and apoptosis induction assessed by p-H3 and elevated cleaved PARP/ caspase 3, respectively. In summary, COMPOUND A1 with equipotent activity against ΡΙ3Κα/β demonstrated unexpected and impressive efficacy cross a panel of PI3Ka/ -driven gastric cancer models, including apoptosis induction and tumor regression in a panel of gastric tumor models as a single agent or in combination with chemotherapy. These results strongly support clinical development of COMPOUND A1 for the treatment of advanced gastric cancer.
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Claims

1. Combination of at least two components, component A and component B, comprising a component A being an inhibitor of PI3K of general formula (I),
Figure imgf000116_0001
(I)
in which :
R1 represents -(CH2)n-(CHR4)-(CH2)m-N(R5)(R5 ) ;
2 represents a heteroaryl of structure :
Figure imgf000116_0002
optionally substituted with 1 , 2 or 3 R6 groups,
in which :
* represents the point of attachment of said heteroaryl with the rest of the compound of general formula (I),
X represents N or C-R6,
X' represents O, S, NH, N-R6, N or C-R6,
with the proviso that when X and X' are both C-R6, then one C-R6 is C-H ;
R3 is methyl ;
R4 is hydroxy ;
R5 and R5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci-Ce-alkyl, Cs-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkoxy- Ci-Ce-alkyl,
or R5 and R5', taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R6' groups ; each occurrence of R6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3- Ce-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, aryl, aryl-Ci -Ce-alkyl, heteroaryl, heteroaryl-Ci -Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-O-Ce-alkyl, -Ci-Ce-alkyl-OR7, -Ci-Ce-alkyl-SR7, -Ci -Ce-alkyl- N(R7)(R7 ),
Figure imgf000117_0001
), -OR7, -SR7, -N(R7)(R7'), or -N R7C(=O)R7 each of which may be optionally substituted with 1 or more R8 groups ; each occurrence of R6' may be the same or different and is independently Ci -Ce- alkyl, Cs-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkyl-OR7; each occurrence of R7 and R7' may be the same or different and is independently a hydrogen atom, or a Ci -Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alklyl, C3-C6-cycloalkenyl, aryl, aryl-Ci - Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; each occurrence of R8 is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci -Ce-alkyl, Ci -Ce-alkoxy, C2-C6-alkenyl, C2-C6- alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci -Ce-alkyl, Ci-Ce-cycloalkenyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci - Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; n is an integer of 1 and m is an integer of 1 ; with the proviso that when - said R5 and R5', taken together with the nitrogen atom to which they are bound, re resent :
Figure imgf000118_0001
in which * represents the point of attachment with the rest of the structure of general formula (I),
then
eteroaryl of structure :
Figure imgf000118_0002
is not :
Figure imgf000118_0003
in which * represents the point of attachment with the rest of the structure of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same,
and component B being an anti-hyperproliferative, cytotoxic and/or cytostatic agent selected from : 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5- fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
2. The combination according to claim 1 , wherein component B is selected from 5-FU, capecitabine, oxaliplatin and paclitaxel, or combinations thereof.
3. The combination according to claim 1 or 2, wherein R1 represents -(CH2)n-(CHR4)-(CH2)m
R2 represents a heteroaryl of structure
Figure imgf000119_0001
in which :
* represents the point of attachment of said heteroaryl with the rest of the structure of general formula (I) ;
R3 is methyl ;
R4 is hydroxy ;
R5 and R5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci -Ce-alkyl, Ca-Ce-cycloalkyl-Ci -Ce-alkyl, or Ci -Ce-alkoxy- Ci -Ce-alkyl,
or
R5 and R5', taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R6' groups ; each occurrence of R6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci -Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3- Ce-cycloalkyl, Ca-Ce-cycloalkyl-Ci -Ce-alkyl, aryl, aryl-Ci -Ce-alkyl, heteroaryl, heteroaryl-Ci -Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci -C6-alkyl, -Ci -Ce-alkyl-OR7, -Ci -Ce-alkyl-SR7, -Ci -Ce-alkyl- N(R7)( R7 ), -Ci -C6-alkyl-C(=0) R7,-CN , -C(=0)OR7, -C(=0)N( R7)( R7 ), -OR7, -SR7, -N(R7)(R7'), or -N R7C(=O) R7 each of which may be optionally substituted with 1 or more R8 groups ; each occurrence of R6' may be the same or different and is independently Ci -Ce- alkyl, Cs-Ce-cycloalkyl-Ci -Ce-alkyl, or Ci -Ce-alkyl-OR7; each occurrence of R7 and R7' may be the same or different and is independently a hydrogen atom, or a Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, C3-C6-cycloalkenyl, aryl, aryl-Ci- Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; each occurrence of R8 is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci-Ce-alkyl, Ci-Ce-alkoxy, C2-C6-alkenyl, C2-C6- alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, Ci-Ce-cycloalkenyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci- Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; n is an integer of 1 and m is an integer of 1 ; with the proviso that when :
- said R5 and R5', taken together with the nitrogen atom to which they are bound, represent :
Figure imgf000120_0001
in which * represents the point of attachment with the rest of the structure of general formula (I),
then
eteroaryl of structure :
Figure imgf000120_0002
is not :
Figure imgf000120_0003
in which * represents the point of attachment with the rest of the structure of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
4. The combination according to any of claims 1 to 3, wherein the component A is a compound selected from the group consisting of :
N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide N-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2- hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin- 5-yl]pyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1 ]oct-3- yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5- yl)pyridine-3-carboxamide
N-{8-[2-hydroxy-3-(thiomorpholin-4-yl)propoxy]-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyridine-3-carboxamide N-(8-{[(2R)-3-(azetidin-1 -yl)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide N-{8-[3-(dimethylamino)-2-hydroxypropoxy]-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyridine-3-carboxamide N-(8-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3- carboxamide
N-(8-{[(2R)-3-(azetidin-1 -yl)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3- carboxamide
N-[8-({(2R)-3-[(2R,6S)-2,6-dimetriylmorpholin-4-yl]-2- hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-
5- yl]-2-methylpyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3- carboxamide
N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3- carboxamide
N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3- carboxamide
6- amino-N-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyridine-3-carboxamide 6-amino-N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine- 3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide
2-amino-N-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide
2-amino-N-[8-({(2R)-3-[(2R,6S)-2,6-dimetriylmorpholin-4-yl]-2- hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-
5-yl]pyrimidine-5-carboxamide
2-amino-N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1 ]oct-3- yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5- yl)pyrimidine-5-carboxamide dihydrochloride 2-amino-N-(8-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5- carboxamide
N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-3H-imidazo[4,5-b]pyridine-6- carboxamide
N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide N-[8-({(2R)-3-[(2R,6S)-2,6-dimetriylmorpholin-4-yl]-2- hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin- 5-yl]-1 ,3-thiazole-5-carboxamide
N-(8-{[(2R)-3-(azetidin-1 -yl)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide N-(8-{[(2R)-2-Hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-4-methyl-1 ,3-thiazole-5- carboxamide
2-amino-N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-4-methyl-1 ,3- thiazole-5-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-oxazole-5-carboxamide N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5- carboxamide,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
5. The combination according to any of claims 1 to 4, wherein the component A is a compound selected from the group consisting of :
N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2- hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin- 5-yl]pyridine-3-carboxamide
N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1 ]oct-3- yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5- yl)pyridine-3-carboxamide
N-(8-{[(2R)-3-(azetidin-1 -yl)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide N-(8-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3- carboxamide
N-(8-{[(2R)-3-(azetidin-1 -yl)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3- carboxamide
N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3- carboxamide
N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3- carboxamide N-(8-{[(2R)-3-(dipropan-2-ylamino)-2-hydroxypropyl]oxy}-7-methoxy- 2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3- carboxamide
N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide N-(8-{[(2R)-2-hydroxy-3-(piperidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide N-(8-{[(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-1 ,3-oxazole-5-carboxamide, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
6. The combination according to claim 1 or 2, wherein
R1 represents -(CH2)n-(CHR4)-(CH2)m-N(R5)(R5 ) ;
R2 represents a heteroaryl of structure :
Figure imgf000125_0001
in which :
* represents the point of attachment of said heteroaryl with the rest of the structure of general formula (I), and
X represents N or C-R6 ;
R3 is methyl ;
R4 is hydroxy ;
R5 and R5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci-Ce-alkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkoxy- Ci-Ce-alkyl,
or R5 and R5', taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R6' groups ; each occurrence of R6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3- Ce-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, aryl, aryl-Ci -Ce-alkyl, heteroaryl, heteroaryl-Ci -Ce-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-O-Ce-alkyl, -Ci-Ce-alkyl-OR7, -Ci-Ce-alkyl-SR7, -Ci -Ce-alkyl- N(R7)(R7 ),
Figure imgf000126_0001
), -OR7, -SR7, -N(R7)(R7'), or -N R7C(=O)R7 each of which may be optionally substituted with 1 or more R8 groups ; each occurrence of R6' may be the same or different and is independently Ci -Ce- alkyl, Cs-Ce-cycloalkyl-Ci-Ce-alkyl, or Ci-Ce-alkyl-OR7; each occurrence of R7 and R7' may be the same or different and is independently a hydrogen atom, or a Ci -Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci-Ce-alkyl, C3-C6-cycloalkenyl, aryl, aryl-Ci- Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-Ci-Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; each occurrence of R8 is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci -Ce-alkyl, Ci -Ce-alkoxy, C2-C6-alkenyl, C2-C6- alkynyl, C3-C6-cycloalkyl, Ca-Ce-cycloalkyl-Ci -Ce-alkyl, Ci-Ce-cycloalkenyl, aryl, aryl-Ci-Ce-alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl-Ci - Ce-alkyl, or heteroaryl-Ci-Ce-alkyl ; n is an integer of 1 and m is an integer of 1 ; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
7. The combination according to any of claims 1 , 2, 4 and 6, wherein the component A is a compound selected from the group consisting of :
6-amino-N-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyridine-3-carboxamide
6-Amino-N-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
6-Amino-N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide
2-Amino-N-{8-[2-hydroxy-3-(morpholin-4-yl)propoxy]-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide
2-Amino-N-(8-{[(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide
2-amino-N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2- hydroxypropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5- yl]pyrimidine-5-carboxamide
2-Amino-N-(8-{[(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1 ]oct-3-yl)propyl]oxy}- 7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide dihydrochloride
2-Amino-N-(8-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
8. The combination according to any of claims 1 to 5, wherein the component A is
N-(8-{[(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy}-7-methoxy-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl)-2-methylpyridine-3-carboxamide, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
9. The combination according to claims 1 to 8, wherein the anti- hyperproliferative, cytotoxic and/or cytostatic agent is 5-FU, or a prodrug of 5- FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S- 1 , or combinations thereof.
10. The combination according to claims 1 to 8, wherein the anti- hyperproliferative, cytotoxic and/or cytostatic agent is 5-FU.
1 1 . The combination according to any of claims 1 to 8, wherein the anti- hyperproliferative, cytotoxic and/or cytostatic agent is capecitabine.
12. The combination according to claims 1 to 8, wherein the anti- hyperproliferative, cytotoxic and/or cytostatic agent is a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin or combinations thereof.
13. The combination according to any of claims 1 to 8, wherein the anti- hyperproliferative, cytotoxic and/or cytostatic agent is oxaliplatin.
14. The combination according to any of claims 1 to 8, wherein the anti- hyperproliferative, cytotoxic and/or cytostatic agent are capecitabine and oxaliplatin.
15. The combination according to claims 1 to 8, wherein the anti- hyperproliferative, cytotoxic and/or cytostatic agent is a taxane, such as docetaxel or paclitaxel, or combinations thereof.
16. The combination according to claims 1 to 8, wherein the anti- hyperproliferative, cytotoxic and/or cytostatic agent is paclitaxel.
17. The combination according to claims 1 to 16, for use in the treatment or prophylaxis of a cancer, particularly gastric cancer and/or metastases thereof.
18. Use of a combination according to any one of claims 1 to 16 for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly gastric cancer and/or metastases thereof.
19. A method of treatment or prophylaxis of a cancer, particularly gastric cancer, and/or metastases thereof, in a subject, comprising administering to said subject a therapeutically effective amount of a combination according to any one of claims 1 to 16.
20. A kit comprising a combination according to any one of claims 1 to 16, and, optionally, one or more further pharmaceutical agents C; in which optionally both or either of said compound of general formula (I) and anti-hyperproliferative, cytotoxic and/or cytostatic agent are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
21 . A composition containing a combination according to claims 1 to 16 together with pharmaceutically acceptable ingredients.
22. A method of predicting the sensitivity of tumor cell growth to inhibition by Component A as defined in any of claims 1 and 3 to 8 or by a Combination as defined in any of claims 1 to 16, comprising:
a. determining, partially or completely, the genetic profile of a tumor, particularly a gastric tumor; and
b. identifying an alteration of PIK3CA, PIK3CB, PTEN-loss, overexpression and/or activation of HER2/HER3/FGFR, KRAS mutation and/or overexpression of EGFR of said tumor,
wherein said genetic profile correlates with sensitivity to inhibition by a PI3K kinase inhibitor.
23. The method according to claim 22, wherein an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or overexpression and/or activation of HER2/HER3/FGFR, correlates with sensitivity of said tumor cell growth to inhibition by a PI3K kinase inhibitor.
24. The method according to claim 23, wherein a co-existing KRAS mutation and/or overexpressing EGFR correlates with insensitivity or reduced responsiveness of said tumor cell growth to inhibition by a PI3K kinase inhibitor.
25. The method according to any of claims 22 to 24, wherein the method is an in vitro method.
26. A method of treating a patient suffering from cancer, comprising:
a. obtaining a tumor sample from the patient, particularly a gastric tumor sample; b. determining, partially or completely, the genetic profile of said tumor, comprising identifying the presence of an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation, in said tumor sample;
c. optionally identifying the presence of a co-existing KRAS mutation and/or overexpressing EGFR; and
d1 . administering a Component A as defined in any of claims 1 and 3 to 8 to the patient, or
d2. administering a Combination as defined in any of claims 1 to 16 to the patient.
27. A method for selecting a patient that is capable of responding to a cancer therapeutic agent, wherein the agent inhibits the PI3K pathway activity in a cell, comprising:
a. obtaining a tumor sample from a patient, particularly a gastric tumor sample; b. determining, partially or completely, the genetic profile of said tumor;
c. identifying the presence of an alteration of PIK3CA and/or PIK3CB, PTEN- loss, and/or HER2/HER3/FGFR overexpression and/or activation, in said tumor sample;
d. optionally identifying the presence of a co-existing KRAS mutation and/or overexpressing EGFR; and e. selecting said patient when an alteration of PIK3CA and/or PIK3CB, PTEN- loss, and/or HER2/HER3/FGFR overexpression and/or activation, and optionally a co-existing KRAS mutation and/or overexpressing EGFR are present in said tumor sample.
28. The methods according to any of claims 22 to 27, wherein the tumor is gastric tumor and/or metastases thereof.
29. A kit for selecting a patient that is capable of responding to a therapeutic agent comprising an inhibitor of the PI3K pathway activity in a cell, such as a
Component A as defined in any of claims 1 and 3 to 8 or a Combination as defined in any of claims 1 to 16, comprising a means for detecting an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation, biomarker(s).
30. A kit for predicting the sensitivity of tumor cell growth to a therapeutic agent comprising an inhibitor of the PI3K pathway activity in a cell, such as a Component A as defined in any of claims 1 and 3 to 8 or by a Combination as defined in any of claims 1 to 16, comprising a means for detecting an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression and/or activation, biomarker(s).
31 . A kit according to claims 29 or 30, further comprising means for detecting a KRAS mutation and/or overexpressing EGFR.
32. A kit according to any of claims 29 to 31 , wherein the tumor is gastric tumor and/or metastases thereof.
33. A Component A as defined in any of claims 1 and 3 to 8 for use in the treatment or prophylaxis of gastric cancer and/or metastases thereof, particularly gastric cancer and/or metastases thereof comprising an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression.
34. The Component A according to claim 33, wherein the gastric cancer and/or metastases thereof further comprise a KRAS mutation and/or overexpressing EGFR.
35. A Combination as defined in any of claims 1 to 16 for use in the treatment or prophylaxis of gastric cancer and/or metastases thereof, particularly gastric cancer and/or metastases thereof comprising an alteration of PIK3CA and/or PIK3CB, PTEN-loss, and/or HER2/HER3/FGFR overexpression.
36. The Combination according to claim 35, wherein the gastric cancer and/or metastases thereof further comprises a KRAS mutation and/or overexpressing EGFR.
37. The combination according to any of claims 1 to 17, for use in the treatment or prophylaxis of a cancer and/or metastases thereof, wherein said cancer is resistant and/or insensitive to treatment with standard of care drugs selected from 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, LIFT, or S-1 ; a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin ; and a taxane, such as docetaxel or paclitaxel; or combinations thereof.
38. The combination according to claim 37, wherein the cancer is gastric cancer and/or metastases thereof, particularly advanced gastric cancer and/or metastases thereof.
39. The combination according to claims 37 or 38, wherein the cancer is resistant and/or insensitive to treatment with 5-FU, or a prodrug of 5-FU, such as 5'-deoxy-5-fluorouridine, capecitabine, BOF-A2, tegafur, UFT, or S-1 .
40. The combination according to claims 37 or 38, wherein the cancer is resistant and/or insensitive to treatment with a platinum-based antineoplastic agent, such as oxaliplatin, cisplatin or carboplatin .
41 . The combination according to claims 37 or 38, wherein the cancer is resistant and/or insensitive to treatment with a taxane, such as docetaxel or paclitaxel.
42. The combination according to claims 37 or 38, wherein the cancer is resistant and/or insensitive to treatment with oxaliplatin and capecitabine.
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