WO2019180141A1 - Combinations of rogaratinib - Google Patents

Combinations of rogaratinib Download PDF

Info

Publication number
WO2019180141A1
WO2019180141A1 PCT/EP2019/057087 EP2019057087W WO2019180141A1 WO 2019180141 A1 WO2019180141 A1 WO 2019180141A1 EP 2019057087 W EP2019057087 W EP 2019057087W WO 2019180141 A1 WO2019180141 A1 WO 2019180141A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
amino
benzothiophen
pyrrolo
triazin
Prior art date
Application number
PCT/EP2019/057087
Other languages
French (fr)
Inventor
Sylvia Grünewald
Isabel JERCHEL
Carolyn SPERL
Alexander Walter
Original Assignee
Bayer Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Publication of WO2019180141A1 publication Critical patent/WO2019180141A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to methods of combination therapy for enhancing the efficacy of rogaratinib.
  • the combination therapy of the present invention is in particular useful in the treatment of bladder cancer.
  • Fibroblast growth factors and their receptors (FGFRs) form part of a unique and diverse signaling system which plays a key role in a variety of biological processes which encompass various aspects of embryonic development and adult pathophysiology [Itoh and Omitz, J. Bio- chem. 149 (2), 121-130 (2011)].
  • FGFs stimulate through FGFR bin ding a wide range of cellular functions including migration, proliferation, differentiation, and sur vival.
  • the FGF family comprises 18 secreted polypeptidic growth factors that bind to four highly con served receptor tyrosine kinases (FGFR-1 to -4) expressed at the cell surface.
  • FGFR-5 can bind to FGFs but does not have a kinase domain, and therefore is devoid of intracellular signaling.
  • the specificity of the ligand/receptor interaction is enhanced by a number of transcriptional and translational processes which give rise to multiple isoforms by alternative transcriptional initiation, alternative splicing, and C-terminal truncations.
  • Various heparan sulfate proteoglycans e.g.
  • FGFRs are cell surface receptors consisting of three extracellular immunoglobulin-like domains, a single-pass transmembrane domain, and an intracellular dimerized tyrosine kinase domain. Binding of FGF bring the intracellular kinases into close proximity, enabling them to transphosphorylate each other. Seven phosphorylation sites have been identified (e.g., in FGFR-1 Tyr463, Tyr583, Tyr585, Tyr653, Tyr654, Tyr730, and Tyr766).
  • phosphotyrosine groups act as docking sites for downstream signalling molecules which themselves may also be directly phosphorylated by FGFR, leading to the activation of multiple signal transduction pathways.
  • the MAPK signaling cascade is implicated in cell growth and differentiation, the PI3K/Akt signaling cascade is involved in cell survival and cell fate determination, while the PI3K and PKC signaling cascades have a function in the control of cell polarity.
  • Several feedback inhibitors of FGF signaling have now been identified and include members of the Spry (Sprouty) and Sef (similar expression to FGF) families. Additionally, in certain conditions, FGFR is released from pre-Golgi membranes into the cytosol.
  • the receptor and its ligand, FGF-2 are co-transported into the nucleus by a mechanism that involves importin, and are engaged in the CREB-binding protein (CBP) complex, a common and essential transcriptional co-activator that acts as a gene activation gating factor.
  • CBP CREB-binding protein
  • Multiple correlations between the immunohistochemical expression of FGF-2, FGFR-1 and FGFR-2 and their cytoplasmic and nuclear tumor cell localizations have been observed. For instance, in lung adenocarcinomas this association is also found at the nuclear level, emphasizing an active role of the complex at the nucleus [Korc and Friesel, Curr. Cancer Drugs Targets 5, 639-651 (2009)].
  • FGFs are widely expressed in both developing and adult tissues and play important roles in a variety of normal and pathological processes, including tissue development, tissue regeneration, angiogenesis, neoplastic transformation, cell migration, cellular differentiation, and cell survival. Additionally, FGFs as pro-angiogenic factors have also been implicated in the emerging phe nomenon of resistance to vascular endothelial growth factor receptor-2 (VEGFR-2) inhibition [Bergers and Hanahan, Nat. Rev. Cancer 8, 592-603 (2008)].
  • VEGFR-2 vascular endothelial growth factor receptor-2
  • the same mutations discovered to be the cause of many developmental disorders are also found in tumor cells (e.g., the mutations found in achondroplasia and thanatophoric dysplasia, which cause dimerization and thus con stitutive activation of FGFR-3, are also frequently found in bladder cancer).
  • a mutation that pro motes dimerization is just one mechanism that can increase ligand-independent signaling from FGFRs.
  • Other mutations located inside or outside of the kinase domain of FGFRs can change the conformation of the domain giving rise to permanently active kinases.
  • Amplification of the chromosomal region 8pl 1-12, the genomic location of FGFR-1, is a common focal amplification in breast cancer and occurs in approximately 10% of breast cancers, predominantly in estrogen receptor-positive cancers.
  • FGFR-1 amplifications have also been reported in non-small cell lung squamous carcinoma and are found at a low incidence in ovarian cancer, bladder cancer and rhabdomyosarcoma.
  • approximately 10% of gastric cancers show FGFR-2 amplification, which is associated with poor prognosis, diffuse-type cancers.
  • SNPs single nucleotide polymorphisms located in FGFR-1 to -4 were found to correlate with an increased risk of developing selective cancers, or were reported to be associated with poor prognosis (e.g., FGFR-4 G388R allele in breast cancer, colon cancer and lung adenocarcinoma). The direct role of these SNPs to promote cancer is still controversial.
  • Rogaratinib has valuable pharmacological properties and can be used for the prevention and treatment of disorders in humans and other mammals.
  • Rogaratinib is a potent inhibitor of the activity or expression of receptor tyrosine kinases, particularly of the FGFR kinases, and most notably of the FGFR-1 and FGFR-3 kinases.
  • the disorders relating to the activity of FGFR kinases are proliferative disorders, in particular cancer and tumor diseases.
  • the PI3K signalling pathway is one of the prominent pathways that promote tumor cell survival.
  • PI3K is activated by many cancer related receptor tyrosine kinases (e.g. PDGFR, EGFR, HER2/3, or IGF-1R), cell adhesion molecules, GPCR, and oncogenic proteins (such as Ras).
  • PDGFR cancer related receptor tyrosine kinases
  • EGFR EGFR
  • HER2/3, or IGF-1R cell adhesion molecules
  • GPCR cell adhesion molecules
  • oncogenic proteins such as Ras.
  • the PI3K pathway activation by genetic alteration of PI3K (activation mutation and/or amplification) and/or loss-of-function of the tumour suppressor PTEN are frequently found in many tumors.
  • activation of PI3K is one of the major mechanisms causing the resistance of tumors to radio-, chemo- and targeted therapeutics.
  • PI3K Once PI3K is activated, it catalyzes the generation of PIP3 from PIP2.
  • the biological active PIP3 binds to the pleckstrin homology (PH) domains of PDK-1, AKT, and other PH-domain containing proteins, such as Rho and PLC. As the consequence of binding to PIP3, these proteins are translocated to the cell membrane and are subsequently activated to induce tumor cell proliferation, survival, invasion and migration.
  • ERK1/2 extracellular signal-regulated kinase 1/2
  • MEK mitogen-activated protein kinase
  • the MAPK signalling cascades are activated by external stimuli transmitted through membrane receptors comprising many receptor tyrosine kinases (RTKs) such as FGFRs, epidermal growth factor receptors (EGFR family) or the hepatocyte growth factor receptor (HGFR, encoded by the MET gene).
  • RTKs receptor tyrosine kinases
  • FGFRs epidermal growth factor receptors
  • HGFR hepatocyte growth factor receptor
  • Extracellular ligands binding to a specific receptor tyrosine kinase (RTK) promote receptor dimerization and autophosphorylation which enables interaction with adaptor proteins followed by recruitment and activation of small GTPases like RAS proteins and activation of RAF kinase family members.
  • Activated RAF kinases phosphorylate and thus activate mitogen-activated protein kinase kinases such as MEK1 (encoded by MAP2K1) or MEK2 (encoded by MAP2K2), which phosphorylate and activate ERK1/2.
  • MEK1 encoded by MAP2K1
  • MEK2 encoded by MAP2K2
  • ERK1/2 As the terminal master kinase of the MAPK pathway ERK1/2 has over 150 substrates including many transcription factors, thus acting as a signalling hub in influencing cellular proliferation, differentiation and survival (Lake et al. (2016) Cell. Mol. Life Sci. 73, 4397-4413).
  • RAS/RAF/MEK/ERK pathway The components of the RAS/RAF/MEK/ERK pathway are frequently mutated in cancer (Forbes et al. (2015) Nucleic Acids Res. 43, D805-D811). This leads to aberrant ERK1/2 activation resulting in deregulated proliferation, increased cell survival and resistance to apoptosis and ultimately to malignant transformation and tumor growth. Furthermore, reactivation of the ERK pathway is a common mechanism of drug resistance to receptor tyrosine kinase inhibitors such as rogaratinib. Reactivation of ERK1/2 signalling can occur either through pathway activation by upstream components e.g.
  • RTK target RTK
  • other RTKs like HGFR or EGFR family in case of rogaratinib
  • RAS activation or MEK1/2 mutations by mutation or amplification or downstream components such as RAS activation or MEK1/2 mutations.
  • PI3K/AKT signalling is upregulated as a second core resistance mechanism to BRAF inhibition (Groenendijk & Bernards (2014) Mol. Oncol. 8, 1067-1083).
  • Drug combinations that target key signalling hubs or parallel pathways are therefore a first indispensable step to overcome resistance.
  • ERK1/2, MEK1/2 inhibitors of key kinases
  • PI3K/mTOR PI3K/mTOR, EGFR family, HGFR
  • Ulixertinib (BVD-523) is a potent and selective ATP-competitive ERK1/2 inhibitor in phase I/II. It decreased proliferation and enhanced caspase activity in sensitive cancer cells such as the melanoma cell line UACC-62 or the colon cell lines Colo205.
  • ulixertinib showed activity in in vitro models of BRAF and MEK inhibitor resistance and demonstrated antitumor activity in vivo (Germann et al. (2017) Mol. Cancer Ther. 16, 2351-2363). It has the structure:
  • Trametinib is a dual specificity mitogen- activated protein kinase kinase 1 (MEK1) and 2 (MEK2) inhibitor that was assigned orphan drug designation for monotherapy of Stage lib through IV melanoma and in combination with dabrafenib for the treatment of patients with various BRAF V600E mutant positive cancers (Prous Integrity database). It has the structure:
  • Trametinib is the compound of Example 4-1. Trametinib can be prepared as described in International Application No. PCT/JP2005/011082. Trametinib can be prepared as described in United States Patent Publication No. US 2006/0014768, Published Jan. 19, 2006, the entire disclosure of which is hereby incorporated by reference.
  • BAY‘672 is a potent and selective MEK1/2 inhibitor which inhibits ERK phosphorylation with subnanomolar potency and proliferation of sensitive tumor cells with an IC 50 of about 10 nM (in- house data). It is described in Hartung, L, et al. Optimization of allosteric MEK inhibitors. Part 2: Taming the sulfamide group balances compound distribution, Bioorganic & Medicinal Chemistry Letters 26 (2016) 186-193 and shown as compound 3.
  • Apitolisib is a 1-2 digit nanomolar potent, orally bioavailable dual inhibitor of PI3K class I isoforms and mTOR kinase (TORC1/2) in phase II.
  • Apitolisib potently inhibits signal transduction downstream of both PI3K and mTOR resulting in cell-cycle inhibition and induction of apoptosis in cancer cells and induces significant antitumor responses in xenograft models.
  • Dactolisib (BEZ-235) is a 1-2 digit nanomolar potent, ATP-competitive dual inhibitor of PI3K class I isoforms and mTOR kinase in phase I/II. Dactolisib inhibits signal transduction downstream of both PI3K and mTOR resulting in inhibition of proliferation in cancer cells and induces significant antitumor responses in xenograft models (Maira et al. (2008) Mol. Cancer Ther. 7, 1851). It has the structure:
  • AZD8055 is a potent and selective ATP-competitive inhibitor of the mTORCl and mTORC2 complexes which inhibits proliferation of sensitive cancer cells at nanomolar concentrations and reduces tumor growth in in vivo models in various indications (Chresta et al. (2010) Cancer Res. 70, 288).
  • AZD8055 has the structure:
  • Lapatinib is a dual ERBB1 (EGFR) and ERBB2 (HER2) receptor tyrosine kinase inhibitor, which blocks EGF induced downstream signaling, and is approved for the treatment of advanced or metastatic HER2 -positive breast cancer. It has the structure:
  • Erlotinib is a ERBB1 (EGFR) specific receptor tyrosine kinase inhibitor that blocks EGF induced downstream signaling through EGFR and is approved for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) and in combination with gemcitabine for the treatment of pancreatic cancer (Prous Integrity database). It has the structure:
  • Cabozantinib (XL- 184) is a multikinase inhibitor that potently inhibits the two RTKs HGFR (MET) and vascular endothelial growth factor receptor 2 (VEGFR2, KDR), which are believed to have a synergistic effect in promoting tumor growth and angiogenesis.
  • cabozantinib was shown to inhibit several other RTKs that are thought to play a significant role in the pathogenesis of various cancers including the mast/stem cell growth factor receptor (KIT), FMS- like tyrosine kinase 3 (Flt-3) and tyrosine -protein kinase receptor (Tie-2).
  • cabozantinib malate prevented tumor growth and induced the regression of large tumors in a broad range of human tumor xenograft models, including breast cancer, lung cancer and glioma.
  • Cabozantinib is approved for the treatment of unresectable, locally advanced or metastatic medullary thyroid cancer, advanced renal cell carcinoma and advanced hepatocellular carcinoma (Prous Integrity database). It has the structure:
  • Example 48 is on paragraph [0353] in WO 2005/030140.
  • BAY-474 is a potent, highly selective inhibitor of HGFR (MET) which is an important receptor tyrosine kinase implicated in tumor growth, angiogenesis, and metastasis.
  • BAY-474 inhibited MET autophosphorylation as well as downstream phosphorylation of ERK1/2 and pS473 AKT with 1 -digit nanomolar potency and potently inhibited proliferation of tumor cell lines which carry an amplified MET gene.
  • the selective inhibition of MET by BAY - 474 was well tolerated in mice and translated into prolonged tumor stasis and even tumor shrinkage in selected preclinical human tumor xenografts with MET gene amplification and aberrant MET signaling (Zopf D. et al. Poster presented at the 22nd EORTC-NCI-AACR Symposium 16-19 November 2010, Berlin, Germany). It is disclosed as Example 81 in W02008071451 , along with methods of preparation the entire contents of which are incorporated by reference.
  • trametinib, lapatinib and the MET inhibitor BAY-474 were also tested in xenograft studies for combination potential with rogaratinib.
  • Urothelial bladder carcinoma has a high incidence with approximately 429700 new cases per year and a related mortality of 165000 worldwide (Gerullis et al. 2017 (Ref. 1)). It is a heterogeneous disease that can be classified as either non-muscle-invasive bladder cancer (NMIBC) with stages Ta, carcinoma in situ and T1 or muscle-invasive bladder cancer (MIBC) with stages >T2.
  • NMIBC non-muscle-invasive bladder cancer
  • MIBC muscle-invasive bladder cancer
  • UBC is referred to throughout this specification and attached claims as bladder cancer.
  • Patients with MIBC have a much less favorable prognosis with 5 year overall survival after radical cystectomy and lymph node dissection ranging from 49% to 74% depending on tumor stage.
  • Cisplatin-based chemotherapy is the current standard of care for metastatic disease.
  • many patients demonstrate intrinsic resistance and while about half of the patients initially respond to chemotherapy, duration of response is usually short and effective second-line treatments are lacking. Therefore, a clear unmet medical need for new effective therapies in both NMIBC and MIBC exists.
  • panFGFR inhibitor rogaratinib with a compound of the class selected from the list consisting of PI3K inhibitors, MAPK inhibitors, RAS inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, and RTK (e.g. MET, EGFR, HGFR, VEGFR, KDR) inhibitors.
  • PI3K inhibitors PI3K inhibitors
  • MAPK inhibitors MAPK inhibitors
  • RAS inhibitors RAF inhibitors
  • MEK inhibitors e.g. RAF inhibitors
  • MEK inhibitors e.g. MET, EGFR, HGFR, VEGFR, KDR
  • RTK e.g. MET, EGFR, HGFR, VEGFR, KDR
  • component B a compound selected from the list consisting of Ulixertinib, Trametinib, BAY‘672, AZD8055, Lapatinib, Erlotinib, Apitolisib, Dactolisib, Cabozantinib, and BAY-474 or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof, as described and defined herein; were evaluated for the treatment of bladder cancer, synergistically increased anti-tumor activities were demonstrated with these combinations compared to each monotherapy, providing a fundamental rationale for the clinical combination therapy using PI3K inhibitors-FGFR inhibitors. Surprisingly, synergism was not only observed in models with increased PI3K activation such as J82 cells but in several models (RT112, SW780, JMSU1) with no known activating genetic aberrations of the
  • component A a 6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]-triazin-4-amine compound of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein component Ba compound of the class selected from the list consisting of PI3K inhibitors, MAPK inhibitors, RAS inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, and RTK (e.g.
  • MET, EGFR, HGFR, VEGFR, KDR) inhibitors as described and defined herein; in which optionally either or both of said components A and B of any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially, would be effective in the treatment or prophylaxis of cancer, particularly bladder cancer.
  • the combinations of the present invention as described and defined herein show a beneficial effect in the treatment of cancer, particularly bladder cancer.
  • the present invention relates: to combinations of : component A: a 6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]-triazin-4-amine compound of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein component B: a compound of the class selected from the list consisting of PI3K inhibitors, MAPK inhibitors, RAS inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, and RTK (e.g.
  • MET, EGFR, HGFR, VEGFR, KDR MET, EGFR, HGFR, VEGFR, KDR inhibitors in which optionally either or both of said components A and B) of any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independently of one another by the oral, subcutaneous, intravenous, topical, local, intraperitoneal or nasal route.
  • the present invention relates: to combinations of : component A: a 6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]-triazin-4-amine compound of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein
  • component B a compound selected from the list consisting of Ulixertinib, Trametinib, BAY‘672 , AZD8055, Lapatinib, Erlotinib, Apitolisib, Dactolisib, Cabozantinib, and BAY-474 or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof, as described and defined herein; in which optionally either or both of said components A and B) of any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to
  • of the present invention relates to the use of any of such combinations as described supra for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly bladder cancer.
  • the present invention relates to a kit comprising : a combination of : component A: a 6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]-triazin-4-amine compound of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein
  • component B a compound selected from the list consisting of Ulixertinib, Trametinib, BAY‘672 , AZD8055, Lapatinib, Erlotinib, Apitolisib, Dactolisib, Cabozantinib, and BAY-474 or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof, as described and defined herein in which optionally either or both of components A and B in any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is
  • said combinations are of: component A: 6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]triazin-4-amine derivatives of the general formula (I)
  • R 1 is hydrogen, chloro, methyl or methoxy
  • R 2 is hydrogen or methoxy, with the proviso that at least one of R 1 and R 2 is other than hydrogen,
  • said (Ci-C4)-alkyl is optionally substituted with hydroxy, (Ci-C -alkoxy, hydroxycarbonyl, (Ci-C4)-alkoxy carbonyl, amino, aminocarbonyl, mono- (Ci-C4)-alkylaminocarbonyl, di-(Ci-C4)-alkylaminocarbonyl, (C3-Ce)-cyclo- alkyl or up to three fluoro atoms, and
  • said (C3-Ce)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci-C4)-alkyl, hydroxy and amino
  • said phenyl is optionally substituted with one or two substituents indepen dently selected from the group consisting of fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoromethoxy, (Ci-C -alkyl and (Ci-C 4 )-alkoxy
  • R 4 is hydrogen or (Ci-C -alkyl
  • R 5 is hydrogen, (Ci-C -alkyl, (Ci-C -alkylcarbonyl, (C 3 -C 6 )-cycloalkyl or 4- to 6- membered heterocycloalkyl, wherein
  • said (Ci-C 4 )-alkyl is optionally substituted with hydroxy, (Ci-C 4 )-alkoxy, hydroxycarbonyl, (Ci-C 4 )-alkoxy carbonyl, aminocarbonyl, mono-(Ci-C 4 )- alkylaminocarbonyl, di-(Ci-C 4 )-alkylaminocarbonyl or (C 3 -Ce)-cycloalkyl, and
  • said (C 3 -Ce)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci-C 4 )-alkyl, hydroxy and amino
  • said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci- C 4 )-alkyl, hydroxy, oxo and amino
  • R 6 is hydrogen, (Ci-C 4 )-alkyl, (C 3 -Ce)-cycloalkyl or 4- to 6-membered heterocyclo alkyl, wherein (i) said (Ci-C 4 )-alkyl is optionally substituted with hydroxy, (Ci-C 4 )-alkoxy, hydroxycarbonyl, (Ci-C 4 )-alkoxy carbonyl, amino, aminocarbonyl, mono- (Ci-C 4 )-alkylaminocarbonyl, di-(Ci-C 4 )-alkylaminocarbonyl or (C3-C6)- cycloalkyl,
  • said (C 3 -Ce)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci-C 4 )-alkyl, hydroxy and amino
  • said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci- C -alkyl, hydroxy, oxo and amino, or R 4 and R 5 , or R 4 and R 6 , respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 7-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R 7 ) and O, and which may be substituted on ring carbon atoms with one or two substituents independently selected from the group consisting of (C1-C4)- alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
  • R 7 is hydrogen, (Ci-C4)-alkyl, formyl or (Ci-C4)-alkylcarbonyl, and
  • R 8A and R 8B are independently selected from the group consisting of hydrogen, (C1-C4)- alkyl, cyclopropyl and cyclobutyl,
  • R 9 is hydrogen or (Ci-C -alkyl
  • R 10 is hydrogen, (Ci-C -alkyl, (Ci-C4)-alkylcarbonyl, (C3-C6)-cycloalkyl or 4- to 6- membered heterocycloalkyl, wherein
  • said (Ci-C4)-alkyl is optionally substituted with hydroxy, amino, amino- carbonyl, mono-(Ci-C4)-alkylaminocarbonyl or di-(Ci-C4)-alkylamino- carbonyl, and
  • said (C3-C6)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci-C4)-alkyl, hydroxy and amino
  • said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci- C -alkyl, hydroxy, oxo and amino
  • R 11 is hydrogen or (Ci-C -alkyl
  • R 12 is hydrogen, (Ci-C4)-alkyl, (C3-Ce)-cycloalkyl or 4- to 6-membered heterocyclo alkyl, wherein
  • said (Ci-C -alkyl is optionally substituted with hydroxy, amino, amino- carbonyl, mono-(Ci-C4)-alkylaminocarbonyl or di-(Ci-C4)-alkylamino- carbonyl, and
  • said (C3-Ce)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci-C4)-alkyl, hydroxy and amino, and
  • said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci- C4)-alkyl, hydroxy, oxo and amino, or
  • R 9 and R 10 , or R 11 and R 12 , respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 7-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R 13 ), O, S and S(0) 2 , and which may be substituted on ring carbon atoms with up to three substituents independently selected from the group consisting of fluoro, (Ci-C4)-alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
  • R 13 is hydrogen, (Ci-C4)-alkyl, (C3-C6)-cycloalkyl, formyl or (Ci-C4)-alkyl- carbonyl, and
  • R 15 is (Ci-C -alkyl, with the proviso that G 1 is not chloro when G 2 is chloro or cyano, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; said compounds are published as compounds of general formula I in International patent application PCT/EP2012/074977, filed on December 12, 2012, published as WO 2013/087578 A1 on June 20, 2013, which is incorporated herein by reference in its entirety.
  • said compounds of general formula I are described on pp. 5 et seq., they may be synthesized according to the methods given therein on pp. 19 et seq., and are exemplified as specific compound Examples 1 to 127 on pp. 109 to 205 therein.
  • Said component A may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independnently of one another by the oral, subcutaneous, intravenous, topical, local, intraperitoneal or nasal route.
  • (Ci-CA- Alkyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. There may be mentioned by way of example and preferably: methyl, ethyl, «-propyl, isopropyl, «-butyl, /50-butyl, sec-butyl, and /c/7-butyl.
  • (Ci-CA-Alkoxy in the context of the invention represents a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. There may be mentioned by way of example and preferably: methoxy, ethoxy, «-propoxy, isopropoxy, «-butoxy, /so-butoxy, sec-butoxy, and /c/T-butoxy. in the context of the invention represents an amino group with a
  • Di-(Ci -C 4 Valkylamino in the context of the invention represents an amino group with two identical or different straight- chain or branched alkyl substituents which each contain 1 to 4 carbon atoms.
  • Cvcloalkyl in the context of the invention represents a monocyclic, saturated carbocycle
  • cyclopropyl having 3 to 6 ring carbon atoms.
  • cyclobutyl having 3 to 6 ring carbon atoms.
  • cyclopentyl having 3 to 6 ring carbon atoms.
  • cyclohexyl having 3 to 6 ring carbon atoms.
  • Preferred are cyclopropyl and cyclobutyl.
  • 4- to 7-membered heterocvcloalkyl and 4- to 6-membered heterocvcloalkyl in the context of the invention represent a monocyclic, saturated heterocycle with 4 to 7 or, respectively, 4 to 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O, S and S(0) 2 , and which can be bonded via a ring carbon atom or via a ring nitrogen atom (if present).
  • 4- to 6-membered heterocycloalkyl containing one ring nitrogen atom and optionally one further ring heteroatom from the series N, O or S(0) 2 is preferred.
  • 5- or 6-membered hetero cvcloalkyl containing one ring nitrogen atom and optionally one further ring heteroatom from the series N or O is particularly preferred.
  • 5-membered aza-heteroaryl in the context of the invention represents an aromatic heterocyclic radical (heteroaromatic) having 5 ring atoms in total, which contains at least one ring nitrogen atom and optionally one or two further ring heteroatoms from the series N, O and/or S, and which is bonded via a ring carbon atom or optionally via a ring nitrogen atom (when allowed by valency).
  • 5-membered aza-heteroaryl containing one ring nitrogen atom and one or two further ring heteroatoms from the series N and/or O is preferred.
  • pyrrolyl pyrazolyl
  • imidazolyl oxazolyl
  • thiazolyl isoxazolyl
  • isothiazolyl triazolyl
  • oxadiazolyl thiadiazolyl
  • Preferred are pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and oxa- diazolyl.
  • An oxo substituent in the context of the invention represents an oxygen atom, which is bonded to a carbon atom via a double bond.
  • the radicals which occur several times the meaning thereof is independent of each other. If radicals in the compounds according to the invention are substituted, the radicals can be mono- or polysubstituted, unless specified otherwise. Substitution by one or by two or three identical or different substituents is preferred. Substitution by one or by two identical or different substituents is particularly preferred.
  • said combinations are of: component A : which is one or more a 6,7-disubstituted 5-(l-benzothiophen-2- yl)pyrrolo[2,l-f][l,2,4]-triazin-4-amine compounds of general formula (I), supra, which is selected from the list consisting of :
  • component A which is one or more a 6,7-disubstituted 5-(l-benzothiophen-2- yl)pyrrolo[2,l-f][l,2,4]-triazin-4-amine compounds of general formula (I), supra, which is selected from the list consisting of :
  • component A which is one or more a 6,7-disubstituted 5-(l-benzothiophen-2- yl)pyrrolo[2,l-f][l,2,4]-triazin-4-amine compounds of general formula (I), supra, which is selected from the list consisting of :
  • Example 1 is one or more a 6,7-di
  • compound A is rogaratinib (shown supra as structure II).
  • said combinations are of: component B: a compound selected from the list consisting of Ulixertinib, Trametinib, BAY‘672 , AZD8055, Lapatinib, Erlotinib, Apitolisib, Dactolisib, Cabozantinib, and BAY-474 or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof, as described and defined herein.
  • component B a compound selected from the list consisting of Ulixertinib, Trametinib, BAY‘672 , AZD8055, Lapatinib, Erlotinib, Apitolisib, Dactolisib, Cabozantinib, and BAY-474 or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof, as described and defined herein.
  • the components A or B may, independently from one another, be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independently of one another by the oral, subcutaneous, intravenous, topical, local, intraperitoneal or nasal route.
  • compositions can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes combinations in which components A and B, independently of one another, are pharmaceutical formulations compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a said component.
  • a pharmaceutically acceptable carrier is preferably a carrier that is relatively non toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of component, and/or combination.
  • a pharmaceutically effective amount of a combination is preferably that amount which produces a result or exerts an influence on the particular condition being treated.
  • the combinations of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.
  • the combinations can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and com starch.
  • the combinations of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, com starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, com 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, com starch or gelatin
  • disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid
  • 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.
  • the pharmaceutical compositions of this invention may 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 from 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 may 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 may 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.
  • the combinations of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound 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-l,l-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
  • 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 quartemary ammonium salts, as well as mixtures.
  • suitable detergents include cationic detergents, for example di
  • 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 15% 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 may 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 may 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.
  • a composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions 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.
  • 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 11, 1991, incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery
  • Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art. It may be desirable or necessary to introduce the pharmaceutical composition 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. 5,011,472, issued April 30, 1991.
  • 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 1998, 52(5), 238-311; 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. et 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
  • 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.
  • Lyophilized 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:
  • 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 100 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, 11 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.
  • cancer includes, but is not limited to, cancers of the endometrium, breast, lung, brain, reproductive organs, digestive tract, urinary tract, liver, eye, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include multiple myeloma, lymphomas, sarcomas, and leukemias. Examples of endometrial cancer include, but not limited to type I EC
  • endometriosis hormone-independent poorly differentiated endometrioid, clear cell and serous carcinomas
  • breast cancer examples include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to 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.
  • the present invention relates to a method for using the combinations of the present invention, in the treatment or prophylaxis of a cancer, particularly bladder cancer.
  • the combinations of the present invention can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis, in the treatment or prophylaxis of cancer, in particular bladder cancer.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a combination of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc. which is effective for the treatment or prophylaxis of cancer, in particular bladder cancer.
  • treating or“treatment” as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
  • the effective dosage of the combinations of this invention can readily be determined for treatment of the indication.
  • the amount of the active ingredient to be administered in the treatment of the condition can vary widely according to such considerations as the particular combination and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • "drug holidays" in which a patient is not dosed with a drug for a certain period of time may be beneficial to the overall balance between pharmacological effect and tolerability.
  • a unit dosage may contain from about 0.5 mg to about 1,500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
  • the average daily dosage for administration by injection will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific combination employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a combination of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • the combinations of component A and component B of this invention can be administered as the sole pharmaceutical agent or in combination with one or more further pharmaceutical agents where the resulting combination of components A, 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 1311-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, bicalu
  • said component C can be one or more further pharmaceutical agents selected from gemcitabine, paclitaxel (when component B is not itself paclitaxel), 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-1B inhibitor, a DPP-IV inhibitor, a 11-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 when component B is not itself paclitaxel
  • cisplatin carboplatin
  • 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 11 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 ah, 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: (1) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone,
  • Component B o a compound selected from the list consisting of Ulixertinib, Trametinib, BAY
  • RT - 112 ROGA 1 and RT - 112 ROGA2 were initially treated with
  • RT-112 ROGA1 was kept at 1 mM rogaratinib for 15 weeks, after which rogaratinib concentration was increased to 1.5mM for 2 weeks and RT-112 ROGA2 was treated with 0.3mM rogaratinib for 10 weeks, then with O. ⁇ mM for 6 weeks and with 1 mM for two weeks.. In both cell lines resistance was observed after 27 weeks in total.
  • RT-112 cells were initially treated with 20mM rogaratinib for 4 weeks, allowed to recover for one week, kept with 20mM rogaratinib for 6 weeks, then at 1 mM rogaratinib for 14 weeks and at 1 5mM rogaratinib for 2 weeks before resistance was observed (27 weeks in total).
  • RT-112 ROGA4 and RT-112 ROGA5 were generated by initially treating RT-112 cells with 15nM rogaratinib (IC50 for proliferation inhibition in RT-112 cells) or with 60nM (IC80) rogaratinib and concentrations were increased incrementally over a period of 25 weeks to 1 mM or 0.5 mM rogaratinib, respectively.
  • JMSU-1 cells were treated either for 5 weeks with rogaratinib concentrations corresponding to IC80 (80nM) resulting in JMSU-1 ROGA1 or to IC50 (30nM) resulting in JMSU-1 ROGA2 and JMSU-1 ROGA4, or for 10 weeks with rogaratinib concentrations corresponding to IC10 (5nM) resulting in JMSU-1 ROGA3.
  • Proliferation inhibition by rogaratinib was calculated as described below. Cells were considered rogaratinib-resistant when rogaratinib-induced proliferation arrest was ⁇ 50% at ImM.
  • In vitro combination assessment The effects of combinations of the present invention were evaluated using combination index isobologram analysis for in vitro assessment.
  • the efficacy parameters were the effects in a 72-hour growth assay. Briefly, cells were plated at the indicated cell density in 384-well plates in 30 pL respective medium with 10% FCS and incubated in a humidified 37°C incubator. After 24 hours, baseline cell growth respective viability was measured in a control plate using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega), while the cells in parallel plates were treated by adding 5 pL of experimental media containing:
  • IC50 isobolograms were plotted with the actual concentrations of the two compounds on the x- and y-axis, and the combination index (Cl) was calculated according to the median-effect model of Chou-Talalay (Ref. 1).
  • a Cl of ⁇ 0.8 was defined as more than additive (or synergistic) interaction, and a Cl of >1.2 was defined as antagonistic interaction.
  • the highest compound concentration applied IE-05 M or 3E-05 M was used to calculate the combination index.
  • Table 3 Formulations, route and schedule of compounds for in vivo experiments.
  • Example 1 Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) and a MAPK pathway inhibitor compound B consisting of either a ERK1/2 inhibitor
  • FGFR receptors are often overexpressed or mutated in UBC leading to increased pathway activity which often results in increased MAPK (ERK1/2) signaling.
  • MAPK MAPK1/2
  • compound A (rogaratinib) was evaluated in combination with compound B consisting of either the ERK1/2 inhibitor ulixertinib or one of the two MEK1/2 inhibitors trametinib or BAY‘672 and compared to the single agent activity in human cell lines derived from urothelial bladder cancers and rogaratinib-resistant cell lines derived thereof using the CellTiter-Glo® Luminescent Cell Viability Assay as described in the Materials and Methods section.
  • compound A (rogaratinib) and ERK1/2 inhibitor compound B for treating rogaratinib-resistant UBC cells results in synergistic inhibition of proliferation compared to single agent treatment as demonstrated in figure 1.
  • FIG. 1 Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with ERK1/2 inhibitor compound B (ulixertinib) in UBC RT-112 cells and rogaratinib-resistant RT- 112 cell-derived sublines.
  • the combination of pan-FGFR inhibitor compound A (rogaratinib) and ERK1/2 inhibitor compound B (ulixertinib) was tested and compared to the single agent activity in RT-112 cells and rogaratinib-resistant cell lines RT-112 ROGA1, RT-112 ROGA3, RT-112 ROGA4 and RT-112 ROGA5 using the CellTiter-Glo® Luminescent Cell Viability Assay.
  • the combination treatment shows synergistic effects on proliferation for almost all concentration combinations used.
  • FIG. 1 Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with MEK1/2 inhibitor compound B (trametinib) in RT-112 and JMSU-1 cells.
  • the combination of pan-FGFR inhibitor compound A (rogaratinib) and MEK1/2 inhibitor compound B (trametinib) was tested and compared to the single agent activity in RT-112 and JMSU-1 UBC cells using the CellTiter-Glo® Luminescent Cell Viability Assay.
  • the combination treatment shows synergistic effects on proliferation in both cell lines for all concentration combinations used.
  • FIG. 3 Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with MEK1/2 inhibitor compound B (BAY‘672) in RT-112 and JMSU-1 cells.
  • the combination of pan-FGFR inhibitor compound A (rogaratinib) and MEK1/2 inhibitor compound B (BAY‘672) was tested and compared to the single agent activity in RT-112 and JMSU-1 cells using the CellTiter-Glo® Luminescent Cell Viability Assay. In RT-112 and JMSU-1 cells no activating MAPK pathway mutations are known.
  • the combination treatment shows synergistic effects on proliferation in both cell lines for almost all concentration combinations used.
  • FIG. 4 Beneficial combination of FGFR inhibitor compound A (rogaratinib) and MEK inhibitor compound B (trametinib) in RT112 bladder cancer xenograft model, implanted subcutaneously in nude mice.
  • the combination of FGFR inhibitor compound A and MEK inhibitor compound B was tested and compared to the single agent activity in the urothelial bladder cancer model RT112 for which in vitro synergism was observed (see Figure 2).
  • Treatment was initiated at a tumor size of 163 mm 3 .
  • RT112-tumor bearing mice were treated once daily with 75 mg/kg (filled squares) of compound A (rogaratinib) or with 0.25 mg/kg of compound B (trametinib (closed triangles)) or with a combination of compound A and compound B at the respective doses (open squares).
  • Figure 4 displays tumor growth as mean tumor volume over time (upper panel), and the body weight loss relative to maximum body weight (lower panel). A maximal body weight loss of 3.1%, 4.3%, and 5.0% was observed compared to maximal body weight in both monotherapies and combination therapy, respectively.
  • rogaratinib and trametinib showed single agent activity and the combination of rogaratinib with trametinib led to significant treatment benefit compared to rogaratinib and trametinib monotherapy.
  • FIG. 5 Beneficial combination of FGFR inhibitor compound A (rogaratinib) and MEK inhibitor compound B (trametinib) in JMSU1 bladder cancer xenograft model, implanted subcutaneously in nude mice.
  • the combination of FGFR inhibitor compound A and MEK inhibitor compound B was tested and compared to the single agent activity in the urothelial bladder cancer model JMSU1 for which in vitro synergism was observed (see Figure 2).
  • Treatment was initiated at a tumor size of 131 mm 3 .
  • JMSUl-tumor bearing mice were treated once daily with 75 mg/kg (filled squares) of compound A (rogaratinib) or with 0.25 mg/kg of compound B (trametinib (closed triangles)) or with a combination of compound A and compound B at the respective doses (open triangles).
  • Figure 5 displays tumor growth as mean tumor volume over time (upper panel), and the relative body weight (lower panel). A maximal body weight loss of 1.0%, 4.4%, and 7.8% was observed compared to maximum body weight in both monotherapies and combination therapy, respectively.
  • rogaratinib inhibited tumor growth as single agent while trametinib alone was inactive.
  • the combination of rogaratinib with trametinib led to strong tumor regression and therefore showed a clear treatment benefit compared to the respective monotherapy.
  • Table 7 DT/AC in % for the combination or respective monotherapies of compound A (rogaratinib) and compound B (trametinib).
  • Example 2 Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) and a PI3K/AKT/mTOR pathway inhibitor compound B consisting of either a PI3K inhibitor (apitolisib or dactolisib) or a mTOR inhibitor (AZD8055) in rogaratinib-resistant urothelial bladder tumor models.
  • FGFR receptors are often overexpressed or mutated in UBC leading to increased pathway activity which often results in increased MAPK (ERK1/2) signalling or in activation of the PDK/AKT/mTOR pathway.
  • the antiproliferative activity of compound A (rogaratinib) was evaluated in combination with compound B consisting of either a PI3K inhibitor (apitolisib or dactolisib) or a mTOR inhibitor (AZD8055) and compared to the single agent activity in human cell lines derived from urothelial bladder cancers using the CellTiter- Glo® Luminescent Cell Viability Assay as described in the Materials and Methods section.
  • FIG. 6 Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with PI3K inhibitor compound B (apitolisib) in JMSU-1 cells.
  • the combination of pan-FGFR inhibitor compound A (rogaratinib) and PI3K inhibitor compound B (apitolisib) was tested and compared to the single agent activity in JMSU-1 and rogaratinib-resistant JMSU-1 ROGA1 UBC cells using the CellTiter-Glo® Luminescent Cell Viability Assay.
  • the combination treatment shows synergistic effects on proliferation in both cell lines for all concentration combinations used.
  • FIG. 7 Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with PI3K inhibitor compound B (dactolisib) in JMSU-1 cells.
  • the combination of pan-FGFR inhibitor compound A (rogaratinib) and PI3K inhibitor compound B (dactolisib) was tested and compared to the single agent activity in JMSU-1 UBC cells using the CellTiter-Glo® Luminescent Cell Viability Assay.
  • the combination treatment shows synergistic effects on proliferation for all concentration combinations used.
  • FIG. 8 Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with mTOR inhibitor compound B (AZD8055) in RT-112 and JMSU-1 cells.
  • the combination of pan-FGFR inhibitor compound A (rogaratinib) and mTOR inhibitor compound B (AZD8055) was tested and compared to the single agent activity in RT-112 and JMSU-1 UBC cells using the CellTiter- Glo® Luminescent Cell Viability Assay.
  • the combination treatment shows synergistic effects on proliferation in both cell lines for almost all concentration combinations used.
  • pan-FGFR inhibitor compound A pan-FGFR inhibitor compound A
  • an EGFR receptor tyrosine kinase inhibitor compound B lapatinib or erlotinib
  • FGFR receptors are often overexpressed or mutated in UBC leading to increased pathway activity which often results in increased MAPK (ERK1/2) signalling.
  • MAPK MAPK1/2
  • rogaratinib resistance in the RT-112 cell line did not lead to increased phosphorylation levels of either EGFR or HER2 as determined by R&D human phospho-RTK profiler arrays.
  • the antiproliferative activity of compound A (rogaratinib) was evaluated in combination with compound B consisting of either the dual ERBB 1 (EGFR) and ERBB2 (HER2) receptor tyrosine kinase inhibitor lapatinib or the ERBB1 (EGFR) receptor tyrosine kinase inhibitor erlotinib and compared to the single agent activity in human cell lines derived from urothelial bladder cancers using the CellTiter-Glo® Luminescent Cell Viability Assay as described in the Materials and Methods section.
  • EGFR EGFR
  • HER2 ERBB2 receptor tyrosine kinase inhibitor compound B
  • FIG. 9 Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with dual ERBB 1 (EGFR) and ERBB2 (HER2) receptor tyrosine kinase inhibitor compound B (lapatinib) in RT-112 UBC cells.
  • pan-FGFR inhibitor compound A (rogaratinib) and dual EGFR/HER2 inhibitor compound B (lapatinib) was tested and compared to the single agent activity in UBC RT-112 cells and rogaratinib-resistant sublines RT-112 ROGA1, RT-112 ROGA2, RT-112 ROGA3, RT-112 ROGA4, and RT-112 ROGA5 derived thereof using the CellTiter-Glo® Luminescent Cell Viability Assay.
  • the combination treatment shows synergistic effects on proliferation in all cell lines tested for all concentration combinations used.
  • FIG. 10 Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with ERBB1 (EGFR) receptor tyrosine kinase inhibitor compound B (erlotinib) in UBC RT-112 cells and rogaratinib-resistant RT-112 cell-derived sublines.
  • pan-FGFR inhibitor compound A rogaratinib
  • ERBB1 EGFR
  • erlotinib receptor tyrosine kinase inhibitor compound B
  • pan-FGFR inhibitor compound A (rogaratinib) and EGFR inhibitor compound B (erlotinib) was tested and compared to the single agent activity in UBC RT-112 cells and rogaratinib-resistant cell lines RT-112 ROGA1, RT-112 ROGA2, RT-112 ROGA3, RT-112 ROGA4 and RT-112 ROGA5 using the CellTiter-Glo® Luminescent Cell Viability Assay.
  • the combination treatment shows synergistic effects on proliferation in all cell lines tested for all concentration combinations used.
  • FGFR inhibitor compound A (rogaratinib) and dual EGFR/HER2 inhibitor compound B (lapatinib) in the RT112 bladder cancer xenograft model, implanted subcutaneously in nude mice.
  • the combination of FGFR inhibitor compound A and EGFR/HER2 inhibitor compound B was tested and compared to the single agent activity in the urothelial bladder cancer model RT112 for which in vitro synergism was observed (see Figure 9). Treatment was initiated at a tumor size of 163 mm 3 .
  • RT112-tumor bearing mice were treated twice daily with 54 mg/kg (filled squares) of compound A (rogaratinib) or once daily with 75 mg/kg of compound B (lapatinib (closed triangles)) or in combination of compound A and compound B at the respective doses and schedules (open triangles).
  • Figure 11 displays tumor growth as mean tumor volume over time (upper panel), and the relative body weight (lower panel). A maximal body weight loss of 2.5%, 1.6% and 5.0% was observed compared to starting body weight with both monotherapies and combination therapy, respectively.
  • Example 4 Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) and a HGFR (MET) inhibitor compound B (cabozantinib or BAY-474) in urothelial bladder tumor models.
  • FGFR receptors are often overexpressed or mutated in UBC leading to increased pathway activity which often results in increased MAPK (ERK1/2) signalling.
  • MAPK MAPK
  • compound A (rogaratinib) was evaluated in combination with compound B consisting either of the HGFR / VEGFR2 inhibitor capozantinib or the HGFR selective inhibitor BAY-474 and compared to the single agent activity in human UBC cell line JMSU-1 and rogaratinib-resistant sublines derived thereof using the CellTiter-Glo® Luminescent Cell Viability Assay as described in the Materials and Methods section.
  • compound A (rogaratinib) and compound B consisting of either non-selective HGFR inhibitor capozantinib or of HGFR selective BAY-474 for treating JMSU-1 UBC cells and rogaratinib-resistant sublines derived thereof results in synergistic inhibition of proliferation and viability compared to single agent treatment as demonstrated in figures 12 and 13. Data are summarized in tables 13 and 14.
  • FIG. 12 Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with HGFR non-selective receptor tyrosine kinase inhibitor compound B (capozantinib) in rogaratinib-resistant UBC cells.
  • pan-FGFR inhibitor compound A rogaratinib
  • HGFR non-selective receptor tyrosine kinase inhibitor compound B capozantinib
  • HGFR non-selective inhibitor compound B (capozantinib) was tested and compared to the single agent activity in JMSU-1 UBC cell-derived rogaratinib-resistant JMSU-1 ROGA1 and JMSU-1 ROGA3 sublines using the CellTiter-Glo® Luminescent Cell Viability Assay.
  • the combination treatment shows synergistic effects on proliferation in both cell lines tested for all concentration combinations used.
  • FIG. 13 Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with HGFR-selective receptor tyrosine kinase inhibitor compound B (BAY-474) in rogaratinib- resistant UBC cells.
  • the combination of pan-FGFR inhibitor compound A (rogaratinib) and HGFR-selective inhibitor compound B (BAY-474) was tested and compared to the single agent activity in JMSU-1 UBC cell derived rogaratinib-resistant JMSU-1 ROGA1 and JMSU-1 ROGA3 sublines using the CellTiter-Glo® Luminescent Cell Viability Assay.
  • the combination treatment shows synergistic effects on proliferation in both cell lines for all concentration combinations used.
  • FIG. 14 Beneficial combination of FGFR inhibitor compound A (rogaratinib) and MET inhibitor compound B (BAY-474) in the JMSU1 bladder cancer xenograft model, implanted subcutaneously in nude mice.
  • the combination of FGFR inhibitor compound A and MET inhibitor compound B was tested and compared to the single agent activity in the urothelial bladder cancer model JMSU1 for which in vitro synergism was observed (see Figure 13). Treatment was initiated at a tumor size of 131 mm 3 .
  • JMSUl-tumor bearing mice were treated twice daily either with 54 mg/kg (filled squares) of compound A (rogaratinib) or with 20 mg/kg of compound B (BAY-474 (closed triangles)) or in combination of compound A and compound B at the respective doses (open triangles).
  • Figure 14 displays tumor growth as mean tumor volume over time (upper panel), and the body weight loss relative to maximum body weight (lower panel). A maximal body weight loss of 7.1%%, 2.3% and 10.8% was observed compared to maximum body weight in both monotherapies and combination therapy, respectively.
  • the MET inhibitor compound B was inactive in the JMSU1 xenograft model while rogaratinib compound A alone induced tumor regression including 53% complete responses.
  • the combination benefit is corroborated by the observation that addition of the MET inhibitor compound B to compound A showed better tumor control resulting in a higher fraction of complete responses in the combination group compared to the monotherapy group.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to combinations of : component A: a 6,7-disubstituted 5-(1-benzothiophen-2-yl)pyrrolo[2,1-f][1,2,4]-triazin-4-amine compound of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein component B: a compound of the class selected from the list consisting of PI3K inhibitors, MAPK inhibitors, RAS inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, and RTK (e.g. MET, EGFR, HGFR, VEGFR, KDR) inhibitors; in which optionally some or all of the components are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially, independently of one another by the oral, subcutaneous, intravenous, topical, local, intraperitoneal or nasal route, for use in treating bladder cancer; the use of such combinations for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly bladder cancer and a kit comprising such combinations.

Description

Combinations of Rogaratinib
Field of the Invention
The present invention relates to methods of combination therapy for enhancing the efficacy of rogaratinib. The combination therapy of the present invention is in particular useful in the treatment of bladder cancer.
Background of the invention
There are many ways how cancers can arise which is one of the reasons why their therapy is difficult. One way that transformation of cells can occur is following a genetic alteration. The completion of the human genome project showed genomic instability and heterogeneity of human cancer genes. Recent strategies to identify these genetic alterations sped up the process of cancer-gene discovery. Gene abnormality can, for instance, lead to the overexpression of proteins, and hence to a non-physiological activation of these proteins. One family of proteins from which a number of oncoproteins derive are tyrosine kinases and in particular receptor tyrosine kinases (RTKs). In the past two decades, numerous avenues of research have demonstrated the importance of RTK-mediated signaling in adverse cell growth leading to cancer. In recent years, promising results have been achieved in the clinic with selective small- molecule inhibitors of tyrosine kinases as a new class of anti-tumorigenic agents [Swinney and Anthony, Nature Rev. Drug Disc. 10 (7), 507-519 (2011)].
Fibroblast growth factors (FGFs) and their receptors (FGFRs) form part of a unique and diverse signaling system which plays a key role in a variety of biological processes which encompass various aspects of embryonic development and adult pathophysiology [Itoh and Omitz, J. Bio- chem. 149 (2), 121-130 (2011)]. In a spatio-temporal manner, FGFs stimulate through FGFR bin ding a wide range of cellular functions including migration, proliferation, differentiation, and sur vival.
The FGF family comprises 18 secreted polypeptidic growth factors that bind to four highly con served receptor tyrosine kinases (FGFR-1 to -4) expressed at the cell surface. In addition, FGFR-5 can bind to FGFs but does not have a kinase domain, and therefore is devoid of intracellular signaling. The specificity of the ligand/receptor interaction is enhanced by a number of transcriptional and translational processes which give rise to multiple isoforms by alternative transcriptional initiation, alternative splicing, and C-terminal truncations. Various heparan sulfate proteoglycans (e.g. syndecans) can be part of the FGF/FGFR complex and strongly influence the ability of FGFs to induce signaling responses [Polanska et al, Developmental Dynamics 238 (2), 277-293 (2009)]. FGFRs are cell surface receptors consisting of three extracellular immunoglobulin-like domains, a single-pass transmembrane domain, and an intracellular dimerized tyrosine kinase domain. Binding of FGF bring the intracellular kinases into close proximity, enabling them to transphosphorylate each other. Seven phosphorylation sites have been identified (e.g., in FGFR-1 Tyr463, Tyr583, Tyr585, Tyr653, Tyr654, Tyr730, and Tyr766).
Some of these phosphotyrosine groups act as docking sites for downstream signalling molecules which themselves may also be directly phosphorylated by FGFR, leading to the activation of multiple signal transduction pathways. Thus, the MAPK signaling cascade is implicated in cell growth and differentiation, the PI3K/Akt signaling cascade is involved in cell survival and cell fate determination, while the PI3K and PKC signaling cascades have a function in the control of cell polarity. Several feedback inhibitors of FGF signaling have now been identified and include members of the Spry (Sprouty) and Sef (similar expression to FGF) families. Additionally, in certain conditions, FGFR is released from pre-Golgi membranes into the cytosol. The receptor and its ligand, FGF-2, are co-transported into the nucleus by a mechanism that involves importin, and are engaged in the CREB-binding protein (CBP) complex, a common and essential transcriptional co-activator that acts as a gene activation gating factor. Multiple correlations between the immunohistochemical expression of FGF-2, FGFR-1 and FGFR-2 and their cytoplasmic and nuclear tumor cell localizations have been observed. For instance, in lung adenocarcinomas this association is also found at the nuclear level, emphasizing an active role of the complex at the nucleus [Korc and Friesel, Curr. Cancer Drugs Targets 5, 639-651 (2009)].
FGFs are widely expressed in both developing and adult tissues and play important roles in a variety of normal and pathological processes, including tissue development, tissue regeneration, angiogenesis, neoplastic transformation, cell migration, cellular differentiation, and cell survival. Additionally, FGFs as pro-angiogenic factors have also been implicated in the emerging phe nomenon of resistance to vascular endothelial growth factor receptor-2 (VEGFR-2) inhibition [Bergers and Hanahan, Nat. Rev. Cancer 8, 592-603 (2008)].
Recent oncogenomic profiles of signaling networks demonstrated an important role for aberrant FGF signaling in the emergence of some common human cancers [Wesche et al., Biochem. J. 437 (2), 199-213 (2011)]. Ligand-independent FGFR constitutive signaling has been described in many human cancers, such as brain cancer, head and neck cancer, gastric cancer and ovarian cancer. FGFR-mutated forms as well as FGFR- intragenic translocations have been identified in malignancies such as myeloproliferative diseases. Interestingly, the same mutations discovered to be the cause of many developmental disorders are also found in tumor cells (e.g., the mutations found in achondroplasia and thanatophoric dysplasia, which cause dimerization and thus con stitutive activation of FGFR-3, are also frequently found in bladder cancer). A mutation that pro motes dimerization is just one mechanism that can increase ligand-independent signaling from FGFRs. Other mutations located inside or outside of the kinase domain of FGFRs can change the conformation of the domain giving rise to permanently active kinases.
Amplification of the chromosomal region 8pl 1-12, the genomic location of FGFR-1, is a common focal amplification in breast cancer and occurs in approximately 10% of breast cancers, predominantly in estrogen receptor-positive cancers. FGFR-1 amplifications have also been reported in non-small cell lung squamous carcinoma and are found at a low incidence in ovarian cancer, bladder cancer and rhabdomyosarcoma. Similarly, approximately 10% of gastric cancers show FGFR-2 amplification, which is associated with poor prognosis, diffuse-type cancers. Moreover, multiple single nucleotide polymorphisms (SNPs) located in FGFR-1 to -4 were found to correlate with an increased risk of developing selective cancers, or were reported to be associated with poor prognosis (e.g., FGFR-4 G388R allele in breast cancer, colon cancer and lung adenocarcinoma). The direct role of these SNPs to promote cancer is still controversial.
Potent FGFR inhibitors of general formula (I) were identified in WO 2013/087578, published 20 June, 2013:
6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]triazin-4-amine derivatives of the general formula (I)
Figure imgf000004_0001
More particularly, a compound of the formula (II)
Figure imgf000005_0001
4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l f]-'[l,2,4]-triazin-7-yl]methyl}piperazin-2-one or a pharmaceutically acceptable salt, hydrate, or solvate thereof, which serves for production of medicaments and for production of medicaments for treatment and/or prophylaxis of proliferative disorders, such as cancer and tumor diseases, is a particularly potent FGFR inhibitor.
4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l f]-'[l,2,4]-triazin-7-yl]methyl}piperazin-2-one has been given the INN ROGARATINIB.
Rogaratinib has valuable pharmacological properties and can be used for the prevention and treatment of disorders in humans and other mammals.
Rogaratinib is a potent inhibitor of the activity or expression of receptor tyrosine kinases, particularly of the FGFR kinases, and most notably of the FGFR-1 and FGFR-3 kinases. In certain embodiments, the disorders relating to the activity of FGFR kinases are proliferative disorders, in particular cancer and tumor diseases.
The PI3K signalling pathway is one of the prominent pathways that promote tumor cell survival. PI3K is activated by many cancer related receptor tyrosine kinases (e.g. PDGFR, EGFR, HER2/3, or IGF-1R), cell adhesion molecules, GPCR, and oncogenic proteins (such as Ras). The PI3K pathway activation by genetic alteration of PI3K (activation mutation and/or amplification) and/or loss-of-function of the tumour suppressor PTEN are frequently found in many tumors. Furthermore, activation of PI3K is one of the major mechanisms causing the resistance of tumors to radio-, chemo- and targeted therapeutics. Once PI3K is activated, it catalyzes the generation of PIP3 from PIP2. The biological active PIP3 binds to the pleckstrin homology (PH) domains of PDK-1, AKT, and other PH-domain containing proteins, such as Rho and PLC. As the consequence of binding to PIP3, these proteins are translocated to the cell membrane and are subsequently activated to induce tumor cell proliferation, survival, invasion and migration. The extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signalling pathway constitutes a central pathway in growth and differentiation and plays a critical role in oncogenesis (Lake et al. (2016) Cell. Mol. Life Sci. 73, 4397-4413; Rauch et al. (2016) Curr. Opin. Chem. Biol. 41, 151-158). The MAPK signalling cascades are activated by external stimuli transmitted through membrane receptors comprising many receptor tyrosine kinases (RTKs) such as FGFRs, epidermal growth factor receptors (EGFR family) or the hepatocyte growth factor receptor (HGFR, encoded by the MET gene). Extracellular ligands binding to a specific receptor tyrosine kinase (RTK) promote receptor dimerization and autophosphorylation which enables interaction with adaptor proteins followed by recruitment and activation of small GTPases like RAS proteins and activation of RAF kinase family members. Activated RAF kinases phosphorylate and thus activate mitogen-activated protein kinase kinases such as MEK1 (encoded by MAP2K1) or MEK2 (encoded by MAP2K2), which phosphorylate and activate ERK1/2. As the terminal master kinase of the MAPK pathway ERK1/2 has over 150 substrates including many transcription factors, thus acting as a signalling hub in influencing cellular proliferation, differentiation and survival (Lake et al. (2016) Cell. Mol. Life Sci. 73, 4397-4413).
The components of the RAS/RAF/MEK/ERK pathway are frequently mutated in cancer (Forbes et al. (2015) Nucleic Acids Res. 43, D805-D811). This leads to aberrant ERK1/2 activation resulting in deregulated proliferation, increased cell survival and resistance to apoptosis and ultimately to malignant transformation and tumor growth. Furthermore, reactivation of the ERK pathway is a common mechanism of drug resistance to receptor tyrosine kinase inhibitors such as rogaratinib. Reactivation of ERK1/2 signalling can occur either through pathway activation by upstream components e.g. activation of the target RTK (FGFRs in case of rogaratinib) or other RTKs (like HGFR or EGFR family in case of rogaratinib) by mutation or amplification or downstream components such as RAS activation or MEK1/2 mutations.
Besides pathway reactivation, activation of parallel pathways to bypass inhibition of a certain pathway also contributes to acquired or intrinsic resistance, e.g. the PI3K/AKT signalling is upregulated as a second core resistance mechanism to BRAF inhibition (Groenendijk & Bernards (2014) Mol. Oncol. 8, 1067-1083).
Drug combinations that target key signalling hubs or parallel pathways are therefore a first indispensable step to overcome resistance. We therefore generated several rogaratinib-resistant sublines from the parental UBC cell lines JMSU-1 and RT112 and tested the effect of the combination of rogaratinib with several inhibitors of key kinases (ERK1/2, MEK1/2) or parallel pathways (PI3K/mTOR, EGFR family, HGFR) on cell proliferation. In addition, we evaluated the potential for in vivo beneficial combinations of rogaratinib with seletected compounds targeting key kinases such as MEK1/2 or receptor tyrosine kinases such as EGFR or HGFR (MET), which may be potential resistance factors for rogaratinib, in JMSU-1 and RT112 bladder cell line-derived xenograft studies.
The following compounds were tested in combination with rogaratinib in cell proliferation experiments in our parental or rogaratinib-resistant JMSU-1 or RT112 cell lines:
4- [5 -chloro-2- [( 1 -methylethyl)amino] -4-pyridinyl] -N-[(lS)-l-(3 -chlorophenyl)-2 -hydroxy ethyl] - lH-pyrrole-2-carboxamide monohydrochloride, Ulixertinib (BVD-523) is a potent and selective ATP-competitive ERK1/2 inhibitor in phase I/II. It decreased proliferation and enhanced caspase activity in sensitive cancer cells such as the melanoma cell line UACC-62 or the colon cell lines Colo205. In addition, ulixertinib showed activity in in vitro models of BRAF and MEK inhibitor resistance and demonstrated antitumor activity in vivo (Germann et al. (2017) Mol. Cancer Ther. 16, 2351-2363). It has the structure:
Figure imgf000007_0001
and may be prepared according to the methods disclosed in U.S. Patent No. 7,354,939.
N-[3-[3-cyclopropyl-5-(2-fhioro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxopyrido[4,3- d]pyrimidin-l-yl]phenyl]acetamide, Trametinib (GSK-1120212) is a dual specificity mitogen- activated protein kinase kinase 1 (MEK1) and 2 (MEK2) inhibitor that was assigned orphan drug designation for monotherapy of Stage lib through IV melanoma and in combination with dabrafenib for the treatment of patients with various BRAF V600E mutant positive cancers (Prous Integrity database). It has the structure:
Figure imgf000008_0001
It is disclosed in International Application No. PCT/JP2005/011082, having an International filing date of Jun. 10, 2005; International Publication Number WO 2005/121142 and an International Publication date of Dec. 22, 2005, the entire disclosure of which is hereby incorporated by reference, Trametinib is the compound of Example 4-1. Trametinib can be prepared as described in International Application No. PCT/JP2005/011082. Trametinib can be prepared as described in United States Patent Publication No. US 2006/0014768, Published Jan. 19, 2006, the entire disclosure of which is hereby incorporated by reference.
BAY‘672 is a potent and selective MEK1/2 inhibitor which inhibits ERK phosphorylation with subnanomolar potency and proliferation of sensitive tumor cells with an IC50 of about 10 nM (in- house data). It is described in Hartung, L, et al. Optimization of allosteric MEK inhibitors. Part 2: Taming the sulfamide group balances compound distribution, Bioorganic & Medicinal Chemistry Letters 26 (2016) 186-193 and shown as compound 3.
(2S)-l-[4-[[2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6- yl]methyl]piperazin-l-yl]-2-hydroxypropan-l-one, Apitolisib (GDC-0980) is a 1-2 digit nanomolar potent, orally bioavailable dual inhibitor of PI3K class I isoforms and mTOR kinase (TORC1/2) in phase II. Apitolisib potently inhibits signal transduction downstream of both PI3K and mTOR resulting in cell-cycle inhibition and induction of apoptosis in cancer cells and induces significant antitumor responses in xenograft models. (Wallin et al. (2011) Mol.Cancer Ther. 10, 2426) It has the structure:
Figure imgf000009_0001
and may be prepared according to the methods disclosed in US8895729 B2.
2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-ylimidazo[4,5-c]quinolin-l- yl)phenyl]propanenitrile, Dactolisib (BEZ-235) is a 1-2 digit nanomolar potent, ATP-competitive dual inhibitor of PI3K class I isoforms and mTOR kinase in phase I/II. Dactolisib inhibits signal transduction downstream of both PI3K and mTOR resulting in inhibition of proliferation in cancer cells and induces significant antitumor responses in xenograft models (Maira et al. (2008) Mol. Cancer Ther. 7, 1851). It has the structure:
Figure imgf000009_0002
and may be produced according to the methods disclosed in EP1888578 Bl.
(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2- methoxyphenyl)methanol, AZD8055, is a potent and selective ATP-competitive inhibitor of the mTORCl and mTORC2 complexes which inhibits proliferation of sensitive cancer cells at nanomolar concentrations and reduces tumor growth in in vivo models in various indications (Chresta et al. (2010) Cancer Res. 70, 288). AZD8055 has the structure:
Figure imgf000010_0001
and may be produced according to the methods described in EP2303875 Bl.
N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2- methylsulfonylethylamino)methyl]furan-2-yl]quinazolin-4-amine, Lapatinib (Tykerb) is a dual ERBB1 (EGFR) and ERBB2 (HER2) receptor tyrosine kinase inhibitor, which blocks EGF induced downstream signaling, and is approved for the treatment of advanced or metastatic HER2 -positive breast cancer. It has the structure:
Figure imgf000010_0002
and may be prepared according to the methods described in U.S. Patent Nos. 8,563,719 and 8,710221.
N-(3-Ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine hydrochloride, Erlotinib (Tarceva) is a ERBB1 (EGFR) specific receptor tyrosine kinase inhibitor that blocks EGF induced downstream signaling through EGFR and is approved for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) and in combination with gemcitabine for the treatment of pancreatic cancer (Prous Integrity database). It has the structure:
Figure imgf000011_0001
and may be prepared according to the methods disclosed in WO2007138612A2.
Cabozantinib (XL- 184) is a multikinase inhibitor that potently inhibits the two RTKs HGFR (MET) and vascular endothelial growth factor receptor 2 (VEGFR2, KDR), which are believed to have a synergistic effect in promoting tumor growth and angiogenesis. In addition, cabozantinib was shown to inhibit several other RTKs that are thought to play a significant role in the pathogenesis of various cancers including the mast/stem cell growth factor receptor (KIT), FMS- like tyrosine kinase 3 (Flt-3) and tyrosine -protein kinase receptor (Tie-2). In preclinical studies designed to determine drug efficacy, cabozantinib malate prevented tumor growth and induced the regression of large tumors in a broad range of human tumor xenograft models, including breast cancer, lung cancer and glioma. Cabozantinib is approved for the treatment of unresectable, locally advanced or metastatic medullary thyroid cancer, advanced renal cell carcinoma and advanced hepatocellular carcinoma (Prous Integrity database). It has the structure:
Figure imgf000011_0002
and may be prepared according to the methods disclosed in WO 2005/030140 which describes the synthesis of cabozantinib (Example 48) and also discloses the therapeutic activity of this molecule to inhibit, regulate, and/or modulate the signal transduction of kinases, (Assays, Table 4, entry 289). Example 48 is on paragraph [0353] in WO 2005/030140. BAY-474 is a potent, highly selective inhibitor of HGFR (MET) which is an important receptor tyrosine kinase implicated in tumor growth, angiogenesis, and metastasis. In cellular assays, BAY-474 inhibited MET autophosphorylation as well as downstream phosphorylation of ERK1/2 and pS473 AKT with 1 -digit nanomolar potency and potently inhibited proliferation of tumor cell lines which carry an amplified MET gene. The selective inhibition of MET by BAY - 474 was well tolerated in mice and translated into prolonged tumor stasis and even tumor shrinkage in selected preclinical human tumor xenografts with MET gene amplification and aberrant MET signaling (Zopf D. et al. Poster presented at the 22nd EORTC-NCI-AACR Symposium 16-19 November 2010, Berlin, Germany). It is disclosed as Example 81 in W02008071451 , along with methods of preparation the entire contents of which are incorporated by reference.
Of the aforementioned compounds, trametinib, lapatinib and the MET inhibitor BAY-474 were also tested in xenograft studies for combination potential with rogaratinib.
Urothelial bladder carcinoma (UBC) has a high incidence with approximately 429700 new cases per year and a related mortality of 165000 worldwide (Gerullis et al. 2017 (Ref. 1)). It is a heterogeneous disease that can be classified as either non-muscle-invasive bladder cancer (NMIBC) with stages Ta, carcinoma in situ and T1 or muscle-invasive bladder cancer (MIBC) with stages >T2. At diagnosis, the majority of patients (— 70%) present with NMIBC while 25- 30% of the patients have muscle invasions. Although with NMIBC the 5 year survival is >90%, the recurrence rate is high (>50%), often on multiple occasions over many years leading to high prevalence, and a about 15-20% of patients progress to muscle-invasive disease. Therefore, costly long-term surveillance with invasive cystoscopies and surgery is required and makes this one of the most expensive of all cancers to treat (di Martino et al. 2016 (Ref. 2)). UBC is referred to throughout this specification and attached claims as bladder cancer. Patients with MIBC have a much less favorable prognosis with 5 year overall survival after radical cystectomy and lymph node dissection ranging from 49% to 74% depending on tumor stage. Cisplatin-based chemotherapy is the current standard of care for metastatic disease. However, many patients demonstrate intrinsic resistance and while about half of the patients initially respond to chemotherapy, duration of response is usually short and effective second-line treatments are lacking. Therefore, a clear unmet medical need for new effective therapies in both NMIBC and MIBC exists.
The successful management of these patients depends on the identification and understanding of molecular mechanisms underlying the initiation and progression of UBC to achieve a more tailored therapy, based on the biological tumor profile. Molecular studies of bladder cancers have identified several oncogenic targets that hold promise for therapy including FGFR receptors which are implicated as oncogenes (Knowles & Hurst 2015 (Ref. 3)). As described in the present text, the anti-tumor efficacy of the panFGFR inhibitor rogaratinib was investigated in preclinical tumor models in vitro in combination. The combination of the panFGFR inhibitor rogaratinib with a compound of the class selected from the list consisting of PI3K inhibitors, MAPK inhibitors, RAS inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, and RTK (e.g. MET, EGFR, HGFR, VEGFR, KDR) inhibitors. Ulixertinib, Trametinib, BAY‘672 , AZD8055, Lapatinib, Erlotinib, Cabozantinib, and BAY -474 was found to be synergistic, which led to decreased viability and reduced proliferation compared to single agent treatment.
Unexpectedly, and this represents a basis of the present invention, when combinations of : - component A: a 6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]-triazin-
4-amine compound of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein component B: a compound selected from the list consisting of Ulixertinib, Trametinib, BAY‘672, AZD8055, Lapatinib, Erlotinib, Apitolisib, Dactolisib, Cabozantinib, and BAY-474 or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof, as described and defined herein; were evaluated for the treatment of bladder cancer, synergistically increased anti-tumor activities were demonstrated with these combinations compared to each monotherapy, providing a fundamental rationale for the clinical combination therapy using PI3K inhibitors-FGFR inhibitors. Surprisingly, synergism was not only observed in models with increased PI3K activation such as J82 cells but in several models (RT112, SW780, JMSU1) with no known activating genetic aberrations of the PI3K pathway.
To the Applicant’s knowledge, no generic or specific disclosure or suggestion in the prior art is known that either combinations of : component A: a 6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]-triazin-4-amine compound of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein component Ba compound of the class selected from the list consisting of PI3K inhibitors, MAPK inhibitors, RAS inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, and RTK (e.g. MET, EGFR, HGFR, VEGFR, KDR) inhibitors, as described and defined herein; in which optionally either or both of said components A and B of any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially, would be effective in the treatment or prophylaxis of cancer, particularly bladder cancer. Based on the action of the testing compounds described in this invention, the combinations of the present invention as described and defined herein, show a beneficial effect in the treatment of cancer, particularly bladder cancer.
In accordance with a first embodiment of first aspect, the present invention relates: to combinations of : component A: a 6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]-triazin-4-amine compound of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein component B: a compound of the class selected from the list consisting of PI3K inhibitors, MAPK inhibitors, RAS inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, and RTK (e.g. MET, EGFR, HGFR, VEGFR, KDR) inhibitors in which optionally either or both of said components A and B) of any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independently of one another by the oral, subcutaneous, intravenous, topical, local, intraperitoneal or nasal route.
In accordance with a second embodiment of first aspect, the present invention relates: to combinations of : component A: a 6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]-triazin-4-amine compound of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein component B: a compound selected from the list consisting of Ulixertinib, Trametinib, BAY‘672 , AZD8055, Lapatinib, Erlotinib, Apitolisib, Dactolisib, Cabozantinib, and BAY-474 or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof, as described and defined herein; in which optionally either or both of said components A and B) of any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independently of one another by the oral, subcutaneous, intravenous, topical, local, intraperitoneal or nasal route.
In accordance with a second aspect, of the present invention relates to the use of any of such combinations as described supra for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly bladder cancer.
Further, in accordance with a third aspect, the present invention relates to a kit comprising : a combination of : component A: a 6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]-triazin-4-amine compound of general formula (I), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, as described and defined herein component B: a compound selected from the list consisting of Ulixertinib, Trametinib, BAY‘672 , AZD8055, Lapatinib, Erlotinib, Apitolisib, Dactolisib, Cabozantinib, and BAY-474 or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof, as described and defined herein in which optionally either or both of components A and B in any of the above-mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independently of one another by the oral, subcutaneous, intravenous, topical, local, intraperitoneal or nasal route.
The features of the aspects and/or embodiments indicated herein are usable individually and in combination in all aspects and embodiments of the invention where technically viable, unless otherwise indicated.
Detailed description of the invention
In accordance with an embodiment of the above-mentioned aspects of the present invention, said combinations are of: component A: 6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]triazin-4-amine derivatives of the general formula (I)
Figure imgf000016_0001
wherein R1 is hydrogen, chloro, methyl or methoxy,
R2 is hydrogen or methoxy, with the proviso that at least one of R1 and R2 is other than hydrogen,
G1 represents chloro, (Ci-C -alkyl, (Ci-C -alkoxy carbonyl, 5-membered aza-heteroaryl, or the group -CH2-OR3, -CH2-NR4R5 or -C(=0)-NR4R6, wherein R3 is hydrogen, (Ci-C -alkyl, (C3-Ce)-cycloalkyl or phenyl, wherein
(i) said (Ci-C4)-alkyl is optionally substituted with hydroxy, (Ci-C -alkoxy, hydroxycarbonyl, (Ci-C4)-alkoxy carbonyl, amino, aminocarbonyl, mono- (Ci-C4)-alkylaminocarbonyl, di-(Ci-C4)-alkylaminocarbonyl, (C3-Ce)-cyclo- alkyl or up to three fluoro atoms, and
(ii) said (C3-Ce)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci-C4)-alkyl, hydroxy and amino, and (iii) said phenyl is optionally substituted with one or two substituents indepen dently selected from the group consisting of fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoromethoxy, (Ci-C -alkyl and (Ci-C4)-alkoxy,
R4 is hydrogen or (Ci-C -alkyl, R5 is hydrogen, (Ci-C -alkyl, (Ci-C -alkylcarbonyl, (C3-C6)-cycloalkyl or 4- to 6- membered heterocycloalkyl, wherein
(i) said (Ci-C4)-alkyl is optionally substituted with hydroxy, (Ci-C4)-alkoxy, hydroxycarbonyl, (Ci-C4)-alkoxy carbonyl, aminocarbonyl, mono-(Ci-C4)- alkylaminocarbonyl, di-(Ci-C4)-alkylaminocarbonyl or (C3-Ce)-cycloalkyl, and
(ii) said (C3-Ce)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci-C4)-alkyl, hydroxy and amino, and (iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci- C4)-alkyl, hydroxy, oxo and amino,
R6 is hydrogen, (Ci-C4)-alkyl, (C3-Ce)-cycloalkyl or 4- to 6-membered heterocyclo alkyl, wherein (i) said (Ci-C4)-alkyl is optionally substituted with hydroxy, (Ci-C4)-alkoxy, hydroxycarbonyl, (Ci-C4)-alkoxy carbonyl, amino, aminocarbonyl, mono- (Ci-C4)-alkylaminocarbonyl, di-(Ci-C4)-alkylaminocarbonyl or (C3-C6)- cycloalkyl,
Figure imgf000017_0001
(ii) said (C3-Ce)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci-C4)-alkyl, hydroxy and amino, and (iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci- C -alkyl, hydroxy, oxo and amino, or R4 and R5, or R4 and R6, respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 7-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R7) and O, and which may be substituted on ring carbon atoms with one or two substituents independently selected from the group consisting of (C1-C4)- alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
R7 is hydrogen, (Ci-C4)-alkyl, formyl or (Ci-C4)-alkylcarbonyl, and
G2 represents chloro, cyano, (Ci-C -alkyl, or the group -CR8AR8B-OH, -CH2- NR9R10, -C(=0)-NRnR12 or -CH2-OR15, wherein
R8A and R8B are independently selected from the group consisting of hydrogen, (C1-C4)- alkyl, cyclopropyl and cyclobutyl,
R9 is hydrogen or (Ci-C -alkyl,
R10 is hydrogen, (Ci-C -alkyl, (Ci-C4)-alkylcarbonyl, (C3-C6)-cycloalkyl or 4- to 6- membered heterocycloalkyl, wherein
(i) said (Ci-C4)-alkyl is optionally substituted with hydroxy, amino, amino- carbonyl, mono-(Ci-C4)-alkylaminocarbonyl or di-(Ci-C4)-alkylamino- carbonyl, and
(ii) said (C3-C6)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci-C4)-alkyl, hydroxy and amino, and (iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci- C -alkyl, hydroxy, oxo and amino,
R11 is hydrogen or (Ci-C -alkyl,
R12 is hydrogen, (Ci-C4)-alkyl, (C3-Ce)-cycloalkyl or 4- to 6-membered heterocyclo alkyl, wherein
(/) said (Ci-C -alkyl is optionally substituted with hydroxy, amino, amino- carbonyl, mono-(Ci-C4)-alkylaminocarbonyl or di-(Ci-C4)-alkylamino- carbonyl, and
(ii) said (C3-Ce)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci-C4)-alkyl, hydroxy and amino, and
(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci- C4)-alkyl, hydroxy, oxo and amino, or
R9 and R10, or R11 and R12, respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 7-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R13), O, S and S(0)2, and which may be substituted on ring carbon atoms with up to three substituents independently selected from the group consisting of fluoro, (Ci-C4)-alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
R13 is hydrogen, (Ci-C4)-alkyl, (C3-C6)-cycloalkyl, formyl or (Ci-C4)-alkyl- carbonyl, and
R15 is (Ci-C -alkyl, with the proviso that G1 is not chloro when G2 is chloro or cyano, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof; said compounds are published as compounds of general formula I in International patent application PCT/EP2012/074977, filed on December 12, 2012, published as WO 2013/087578 A1 on June 20, 2013, which is incorporated herein by reference in its entirety. In WO 2013/087578 Al, said compounds of general formula I are described on pp. 5 et seq., they may be synthesized according to the methods given therein on pp. 19 et seq., and are exemplified as specific compound Examples 1 to 127 on pp. 109 to 205 therein.
Said component A may be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independnently of one another by the oral, subcutaneous, intravenous, topical, local, intraperitoneal or nasal route.
The definitions used in relation to the structure (A) in this text are as follows:
(Ci-CA- Alkyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. There may be mentioned by way of example and preferably: methyl, ethyl, «-propyl, isopropyl, «-butyl, /50-butyl, sec-butyl, and /c/7-butyl.
(Ci-CA-Alkoxy in the context of the invention represents a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. There may be mentioned by way of example and preferably: methoxy, ethoxy, «-propoxy, isopropoxy, «-butoxy, /so-butoxy, sec-butoxy, and /c/T-butoxy. in the context of the invention represents an amino group with a
Figure imgf000020_0001
straight-chain or branched alkyl substituent which contains 1 to 4 carbon atoms. There may be mentioned by way of example and preferably: methylamino, ethylamino, «-propylamino, iso- propylamino, «-butylamino, and tert-butylamino.
Di-(Ci -C4Valkylamino in the context of the invention represents an amino group with two identical or different straight- chain or branched alkyl substituents which each contain 1 to 4 carbon atoms. There may be mentioned by way of example and preferably: A/A-dimethylamino, A/A-diethylamino, /V-ethyl-iV-methylamino, /V-methyl-/V-«-propylamino, A-isopropyl-A- methylamino, /V-isopropyl-/V-«-propylamino, A/A-diisopropylamino, /V-«-butyl-/V-methylamino, and /V-tert-butyl-iV-methylamino. (Ci -Cfl-Alkylcarbonyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms which is bonded to the rest of the molecule via a carbonyl group [-C(=0)-]. There may be mentioned by way of example and preferably: acetyl, propionyl, w-butyryl, Ao-butyryl, w-pentanoyl, and pivaloyl. (Ci -C^-Alkoxycarbonyl in the context of the invention represents a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms which is bonded to the rest of the molecule via a carbonyl group [-C(=0)-]. There may be mentioned by way of example and preferably: methoxy- carbonyl, ethoxycarbonyl, w-propoxycarbonyl, isopropoxycarbonyl, w-butoxycarbonyl, and tert- butoxy carbonyl. Mono-(Ci -C4')-alkylaminocarbonyl in the context of the invention represents an amino group which is bonded to the rest of the molecule via a carbonyl group [-C(=0)-] and which has a straight-chain or branched alkyl substituent having 1 to 4 carbon atoms. There may be mentioned by way of example and preferably: methylaminocarbonyl, ethylaminocarbonyl, n- propylaminocarbonyl, isopropylaminocarbonyl, w-butylaminocarbonyl, and tert-butylamino- carbonyl.
Di-(Ci -C4')-alkylaminocarbonyl in the context of the invention represents an amino group which is bonded to the rest of the molecule via a carbonyl group [-C(=0)-] and which has two identical or different straight-chain or branched alkyl substituents having in each case 1 to 4 carbon atoms. There may be mentioned by way of example and preferably: AZ/V-dimethylaminocarbonyl, A/iV-diethylaminocarbonyl, /V-ethyl-/V-methylaminocarbonyl, /V-methyl-/V-«-propylaminocarbo- nyl, /V-isopropyl-/V-methylaminocarbonyl, LZ/V-diisopropylaminocarbonyl, /V-«-butyl-/V-methyl- aminocarbonyl, and /V-tert-butyl-/V-methylaminocarbonyl. Cvcloalkyl in the context of the invention represents a monocyclic, saturated carbocycle
Figure imgf000021_0001
having 3 to 6 ring carbon atoms. There may be mentioned by way of example: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Preferred are cyclopropyl and cyclobutyl.
4- to 7-membered heterocvcloalkyl and 4- to 6-membered heterocvcloalkyl in the context of the invention represent a monocyclic, saturated heterocycle with 4 to 7 or, respectively, 4 to 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O, S and S(0)2, and which can be bonded via a ring carbon atom or via a ring nitrogen atom (if present). 4- to 6-membered heterocycloalkyl containing one ring nitrogen atom and optionally one further ring heteroatom from the series N, O or S(0)2 is preferred. 5- or 6-membered hetero cvcloalkyl containing one ring nitrogen atom and optionally one further ring heteroatom from the series N or O is particularly preferred. There may be mentioned by way of example: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, thiolanyl, 1,1- dioxidothiolanyl, 1 ,2-oxazolidinyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1 ,4-dioxanyl, 1,2-oxazinanyl, morpho- linyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl, azepanyl, 1 ,4-diazepanyl, and 1,4- oxazepanyl. Preferred are azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, 1,2-oxa- zolidinyl, 1,3-oxazolidinyl, piperidinyl, piperazinyl, 1,2-oxazinanyl, morpholinyl, and thio morpholinyl. Particularly preferred are pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.
5-membered aza-heteroaryl in the context of the invention represents an aromatic heterocyclic radical (heteroaromatic) having 5 ring atoms in total, which contains at least one ring nitrogen atom and optionally one or two further ring heteroatoms from the series N, O and/or S, and which is bonded via a ring carbon atom or optionally via a ring nitrogen atom (when allowed by valency). 5-membered aza-heteroaryl containing one ring nitrogen atom and one or two further ring heteroatoms from the series N and/or O is preferred. There may be mentioned by way of example: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl. Preferred are pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and oxa- diazolyl.
An oxo substituent in the context of the invention represents an oxygen atom, which is bonded to a carbon atom via a double bond. For all the radicals which occur several times, the meaning thereof is independent of each other. If radicals in the compounds according to the invention are substituted, the radicals can be mono- or polysubstituted, unless specified otherwise. Substitution by one or by two or three identical or different substituents is preferred. Substitution by one or by two identical or different substituents is particularly preferred. In accordance with another embodiment of the above-mentioned aspects of the present invention, said combinations are of: component A : which is one or more a 6,7-disubstituted 5-(l-benzothiophen-2- yl)pyrrolo[2,l-f][l,2,4]-triazin-4-amine compounds of general formula (I), supra, which is selected from the list consisting of : Example 1
4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]-
[1.2.4] triazin-7 -yljmethyl } piperazin-2 -one
Example 2
4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]-
[1.2.4]triazin-7-yl]methyl}piperazin-2-one dihydrochloride
Example 3
(3R)-3 -( { [4-Amino-6-(methoxymethyl)-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one dihydrochloride Example 4
(3R)-3 -( { [4-Amino-6-(methoxymethyl)-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one
Example 5
4-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]- [l,2,4]triazin-7-yl]methyl}piperazin-2-one
Example 6
4- { [4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)pyrrolo- [2, 1 -f] [1 ,2,4]triazin-7-yl]methyl}piperazin-2-one dihydrochloride Example 7
(3R)-3 -( { [4-Amino-6-(ethoxymethyl)-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one dihydrochloride
Example 8
(3R)-3 -( { [4-Amino-6-(ethoxymethyl)-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one
Example 9
Ai-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]-
[1.2.4]triazin-7-yl]methyl}glycinamide dihydrochloride Example 10
6-(Ethoxymethyl)-5-(7-methoxy-5-methyl- 1 -benzothiophen-2 -yl)-7-(morpholin-4-ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-4-amine
Example 11
1 -(4- { [4-Amino-6-(ethoxymethyl)-5 -(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo [2, 1 -f] -
[1.2.4] triazin-7 -yljmethyl } piperazin- 1 -yl)ethanone dihydrochloride
Example 12
[4-Amino-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)-7-(piperazin- 1 -ylmethyl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-6-yl]methanol bis(formiate) Example 13
4- { [4- Amino-6-(hydroxymethyl)-5 -(7-methoxy-5 -methyl- 1 -benzothiophen-2 -yl)pyrrolo [2 , 1 -f] -
[1.2.4] triazin-7 -yljmethyl } piperazin-2 -one
Example 14
7-{[(55)-3-Amino-3-methylpyrrolidin-l-yl]methyl}-6-(methoxymethyl)-5-(7-methoxy-5-methyl- l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]triazin-4-amine trihydrochloride
Example 15
7-{[(35)-3-Amino-3-methylpyrrolidin-l-yl]methyl}-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-l- benzothiophen-2-yl)pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-4-amine
Example 16
1 -(4- {[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l -benzothiophen-2 -yl)pyrrolo-
[2,1 -f] [1 ,2,4]triazin-7-yl]methyl}piperazin-l -yl)ethanone dihydrochloride
Example 17
6-(Methoxymethyl)-5-(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)- pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-4-amine formiate Example 18
6-(Ethoxymethyl)-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-4-amine Example 19
6-(Ethoxymethyl)-5 -(7 -methoxy-5-methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-4-amine dihydrochloride
Example 20
1 -(4- { [4-Amino-6-(ethoxymethyl)-5 -(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo [2, 1 -f] -
[l,2,4]triazin-7-yl]methyl}piperazin-l-yl)ethanone
Example 21
4-({4-Amino-6-[(2-hydroxyethoxy)methyl]-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)- pyrrolo[2,l-f][l,2,4]triazin-7-yl}methyl)piperazin-2-one formiate Example 22
2- { [4-Amino-5-(7-methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)pyrrolo- [2, 1 -f] [ 1 ,2,4]triazin-6-yl]methoxy } ethanol dihydrochloride
Example 23
6-(Butoxymethyl)-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)-7-(piperazin- 1 -ylmethyl)- pyrrolo[2,l-f][l,2,4]triazin-4-amine formiate
Example 24
5-(7-Methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)-6-(propoxymethyl)- pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-4-amine bis(formiate)
Example 25
6-[(Cyclopropylmethoxy)methyl]-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l- ylmethyl)pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-4-amine bis(formiate)
Example 26
6-[(Cyclobutyloxy)methyl]-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-yl- methyl)pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-4-amine Example 27
6-(Isopropoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)- pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-4-amine formiate Example 28
6- [(2 -Methoxy ethoxy )methyl] -5 -(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-y l)-7 -(piperazin- 1 -yl- methyl)pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-4-amine formiate
Example 29
5-(7-Methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)-6-[(2,2,2-trifhioro- ethoxy)methyl]pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine formiate
Example 30
6- [(2 -Aminoethoxy)methyl] -5 -(7-methoxy-5 -methyl- 1 -benzothiophen-2-y l)-7 -(piperazin- 1 -yl- methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydrochloride Example 31
Methyl {[4-amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-6-yl]methoxy}acetate
Example 32
{ [4-Amino-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)pyrrolo- [2,l-f][l,2,4]triazin-6-yl]methoxy}acetic acid
Example 33
2- { [4-Amino-5-(7-methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)pyrrolo- [2, 1 -f] [ 1 ,2,4]triazin-6-yl]methoxy} acetamide
Example 34
2-( {7- [(4-Acetylpiperazin- 1 -yl)methyl]-4-amino-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)- pyrrolo[2, 1 -f] [1 ,2,4]triazin-6-yl}methoxy)acetamide
Example 35
5-(7-Methoxy-5-methyl-l-benzothiophen-2-yl)-6-(phenoxymethyl)-7-(piperazin-l-ylmethyl)- pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-4-amine bis(formiate) Example 36
5 -(7 -Methoxy-5 -methyl- 1 -benzothiophen-2-y l)-6- [(methylamino)methyl] -7 -(piperazin- 1 -yl- methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydrochloride Example 37
6-[(Dimethylamino)methyl]-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-yl- methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydro chloride
Example 38
6-[(Ethylamino)methyl]-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-yl- methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydrochloride
Example 39
2-({[4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)pyrrolo- [2 , 1 -f] [ 1 ,2 ,4]triazin-6-yl]methyl } amino)ethanol trihydrochloride Example 40
rac- 1 - { [4-Amino-5 -(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)-7-(piperazin- 1 -ylmethyl)- pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-6-yl]methyl}piperidin-3 -ol trihydrochloride
Example 41
1 - { [4-Amino-5-(7-methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)pyrrolo- [2,l-f][l,2,4]triazin-6-yl]methyl}piperidin-4-ol trihydrochloride
Example 42
rac- 1 - { [4-Amino-5 -(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)-7-(piperazin- 1 -ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-6-yl]methyl}pyrrolidin-3-ol trihydrochloride
Example 43
6- [(Diethylamino)methyl] -5-(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -yl- methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydrochloride
Example 44
6-[(Cyclobutylamino)methyl]-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)-7-(piperazin- 1 -yl- methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydrochloride Example 45
5-(7-Methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)-6-(pyrrolidin-l-yl- methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydrochloride Example 46
6-[(Cyclopropylamino)methyl]-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)-7-(piperazin- 1 -yl- methyl)pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-4-amine trihydrochloride
Example 47
6- { [(Cy clopropylmethyl)amino]methyl} -5 -(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)-7-
(piperazin- 1 -ylmethyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydrochloride
Example 48
/V-{[4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-6-yl]methyl} glycine trihydrochloride Example 49
4- { [4-Amino-5-(7-methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-6-yl]methyl}piperazin-2-one trihydrochloride
Example 50
[4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo- [2,l-f][l,2,4]triazin-6-yl]methanol
Example 51
(3S)- 3-( { [4-Amino-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-6-yl]methyl}amino)pyrrolidin-2-one
Example 52
4-{[4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo-
[2,l-f][l,2,4]triazin-6-yl]methyl}piperazin-2-one
Example 53
rac- 1 -( { [4-Amino-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-6-yl]methyl}amino)propan-2-ol
Example 54
l-({[4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-6-yl]methyl}amino)-2-methylpropan-2-ol Example 55
1 -(4- { [4-Amino-6-(hydroxymethyl)-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-7-yl]methyl}piperazin-l -yl)ethanone
Example 56
( /?)-3-[({7-[(4-Acetylpiperazin-l-yl)methyl]-4-amino-5-(7-methoxy-5-methyl-l-benzothiophen- 2-yl)pyrrolo[2,l -f] [1 ,2,4]triazin-6-yl}methyl)amino]pyrrolidin-2-one
Example 57
l-(4-{[4-Amino-6-{[(2-hydroxy-2-methylpropyl)amino]methyl}-5-(7-methoxy-5-methyl-l- benzothiophen-2-yl)pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-7-yl]methyl [piperazin- 1 -yl)ethanone Example 58
4-({4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-6-[(3-oxopiperazin-l-yl)methyl]- pyrrolo[2,l-f][l,2,4]triazin-7-yl}methyl)piperazine-l-carbaldehyde formiate
Example 59
4-( { 7- [(4-Acetylpiperazin- 1 -yl)methyl] -4-amino-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2 -yl)- pyrrolo[2,l-f][l,2,4]triazin-6-yl}methyl)piperazin-2-one
Example 60
Methyl 4-amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylcarbonyl)- pyrrolo[2,l -f] [1 ,2,4]triazine-6-carboxylate bis(formiate)
Example 61
5-(7-Methoxy-5-methyl-l -benzothiophen-2-yl)-6-(l ,3-oxazol-5-yl)-7-(piperazin-l -ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-4-amine trihydrochloride
Example 62
6-(Aminomethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l -ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-4-amine trihydrochloride Example 63
A- {[4-Amino-5-(7-methoxy-5-methyl-l -benzothiophen-2 -yl)-7-(piperazin-l-ylmethyl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-6-yl]methyl}acetamide bis(trifluoroacetate) Example 64
A- {[4-Amino-5-(7-methoxy-5-methyl-l -benzothiophen-2 -yl)-7-(piperazin-l-ylmethyl)pyrrolo- [2,l-f][l,2,4]triazin-6-yl]methyl}acetamide dihydrochloride
Example 65
/V-({4-Amino-7-[(4-formylpiperazin-l-yl)methyl]-5-(7-methoxy-5-methyl-l-benzothiophen- 2-yl)pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-6-yl}methyl)acetamide formiate
Example 66
N-({ 7- [(4-Acety lpiperazin- 1 -yl)methyl] -4-amino-5 -(7-methoxy-5 -methyl- 1 -benzothiophen-2 -yl)- pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-6-yl}methyl)acetamide Example 67
A-( {4-Amino-5-(7-methoxy-5-methyl-l -benzothiophen-2 -yl)-7-[(3-oxopiperazin-l -yl)methyl]- pyrrolo[2,l -f] [ 1 ,2,4]triazin-6-yl}methyl)acetamide
Example 68
4-Amino-6-(hydroxymethyl)-5-(7-methoxy-5-methyl-l -benzothiophen-2 -yl)pyrrolo[2,l-f]- [l,2,4]triazine-7-carbonitrile
Example 69
4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]- [1,2 ,4] triazine-7 -carbonitrile
Example 70
4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl- 1 -benzothiophen-2 -yl)pyrrolo[2, 1 -f] [1 ,2,4]- triazine-7-carbonitrile
Example 71
4-Amino-5-(7 -methoxy-5 -methyl- 1 -benzothiophen-2 -yl)-6- [(3 -oxopiperazin- 1 -yl)methyl]- pyrrolo[2,l -f] [1 ,2,4]triazine-7-carbonitrile Example 72
N,N'- { [4-Amino-5 -(7-m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo [2, 1 -f] [ 1 ,2,4]triazine- 6,7-diyl]bis(methylene)}diacetamide Example 73
2-[4-Amino-6-(hydroxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]- [1,2 ,4] triazin-7-yl]propan-2 -ol
Example 74
4-{[4-Amino-7-(2-hydroxypropan-2-yl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo- [2, 1 -f] [1 ,2,4]triazin-6-yl]methyl}piperazin-2-one
Example 75
[4-Amino-5-(7-methoxy-5-methyl-l -benzothiophen-2-yl)-7-methylpyrrolo[2,l -f] [1 ,2,4]triazin- 6-yl]methanol Example 76
4-{[4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-methylpyrrolo[2,l-f][l,2,4]- triazin-6-yl]methyl } piperazin-2 -one
Example 77
l-({[4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-methylpyrrolo[2,l- f] [ 1 ,2,4]triazin-6-yl]methyl}amino)-2-methylpropan-2-ol formiate
Example 78
1 -( {[4-Amino-5-(7-methoxy-5-methyl-l -benzothiophen-2-yl)-7-methylpyrrolo[2,l-f] [1,2,4]- triazin-6-yl]methyl}amino)-2-methylpropan-2-ol
Example 79
[4-Amino-7-chloro-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]triazin- 6-yl]methanol
Example 80
4-{[4-Amino-7-chloro-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l- f][l,2,4]triazin-6-yl]methyl}piperazin-2-one Example 81
1 -( { [4-Amino-7-chloro-5-(7-methoxy-5-methyl-l -benzothiophen-2-yl)pyrrolo[2, 1 -f] [ 1 ,2,4]- triazin-6-yl]methyl}amino)-2-methylpropan-2-ol formiate Example 82
1 -( { [4-Amino-7-chloro-5-(7-methoxy-5-methyl-l -benzothiophen-2-yl)pyrrolo[2, 1 -f] [ 1 ,2,4]- triazin-6-yl]methyl}amino)-2-methylpropan-2-ol
Example 83
7-Chloro-6-(ethoxymethyl)-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)pyrrolo[2, 1 -f] [1 ,2,4]- triazin-4-amine
Example 84
5-(7-Methoxy-5-methyl-l-benzothiophen-2-yl)-6-methyl-7-(piperazin-l-ylmethyl)pyrrolo[2,l-f]-
[1.2.4]triazin-4-amine formiate Example 85
6-Chloro-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)pyrrolo[2,l-f]-
[1.2.4]triazin-4-amine trihydrochloride
Example 86
[4-Amino-6-(ethoxymethyl)-5 -(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo [2, 1 -f] [ 1 ,2,4] - triazin-7-yl]methanol
Example 87
1 - { [4-Amino-6-(ethoxymethyl)-5-(7 -methoxy-5-methyl- 1 -benzothiophen-2-yl)pyrrolo[2, 1 -f] - [ 1 ,2 ,4] triazin-7-yl]methyl } imidazolidin-2-one
Example 88
4- {[4-Amino-5-(7-methoxy- 1 -benzothiophen-2-yl)-6-(methoxymethyl)pyrrolo[2, 1 -f] [ 1 ,2,4]- triazin-7 -yl]methyl } piperazin-2 -one
Example 89
4- { [4-Amino-6-(methoxymethyl)-5-(5-methyl-l -benzothiophen-2-yl)pyrrolo[2, 1 -f] [ 1 ,2,4]triazin- 7 -yl]methyl } piperazin-2-one Example 90
l-[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]-
[1.2.4] triazin-7-yl] ethanol Example 91
[4-Amino-6-(ethoxymethyl)-5 -(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo [2, 1 -f] [ 1 ,2,4] - triazin-7 -yl] (cy clopropyl)methanol
Example 92
(35)-3-( {[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l -benzothiophen-2-yl)pyrrolo-
[2,1 -f] [1 ,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one
Example 93
(35)-3-({[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Example 106
4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-/V-[(. /?)-2-oxo- pyrrolidin-3-yl]pyrrolo[2,l -f] [1 ,2,4]triazine-7-carboxamide Example 107
4-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]- [ 1 ,2 ,4] triazin-7 -yl] carbonyl } piperazin-2 -one
Figure imgf000037_0002
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Example 124
4-{[4-Amino-5-(5,7-dimethoxy-l-benzothiophen-2-yl)-6-(methoxymethyl)pyrrolo[2,l-f][l,2,4]- triazin-7 -yljmethyl } piperazin-2 -one Example 125
4- { [4- Amino-7 -(hydro xymethyl)-5 -(7-methoxy-5 -methyl- 1 -benzothiophen-2 -yl)pyrrolo [2 , 1 -f] - [1,2 ,4] triazin-6-yl]methyl } piperazin-2 -one
Example 126
4-{[4-Amino-7-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]- [l,2,4]triazin-6-yl]methyl}piperazin-2-one
Example 127
4-{[4-Amino-7-(ethoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]- [1,2 ,4] triazin-6-yl]methyl } piperazin-2 -one
In a particularly preferred embodiment, compound A is rogaratinib (shown supra as structure II).
In accordance with another embodiment of the above-mentioned aspects of the present invention, said combinations are of: component B: a compound selected from the list consisting of Ulixertinib, Trametinib, BAY‘672 , AZD8055, Lapatinib, Erlotinib, Apitolisib, Dactolisib, Cabozantinib, and BAY-474 or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof, as described and defined herein. Pharmaceutical formulations of components A and B of the combinations of the present invention
As mentioned supra, the components A or B may, independently from one another, be in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independently of one another by the oral, subcutaneous, intravenous, topical, local, intraperitoneal or nasal route.
Said compositions can be utilized to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes combinations in which components A and B, independently of one another, are pharmaceutical formulations compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a said component. A pharmaceutically acceptable carrier is preferably a carrier that is relatively non toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of component, and/or combination. A pharmaceutically effective amount of a combination is preferably that amount which produces a result or exerts an influence on the particular condition being treated. The combinations of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.
For oral administration, the combinations can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and com starch. In another embodiment, the combinations of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, com starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, com 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.
The pharmaceutical compositions of this invention may 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 from 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 may 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 may 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.
The combinations of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound 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-l,l-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, com 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 quartemary 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 15% 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 may 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 may 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.
A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions 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 11, 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 may be desirable or necessary to introduce the pharmaceutical composition 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. 5,011,472, 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 1998, 52(5), 238-311; 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. et 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, com 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, com 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, com 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 camuba 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.
Lyophilized 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 100 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, 11 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.
Method of treating cancer Within the context of the present invention, the term“cancer” includes, but is not limited to, cancers of the endometrium, breast, lung, brain, reproductive organs, digestive tract, urinary tract, liver, eye, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include multiple myeloma, lymphomas, sarcomas, and leukemias. Examples of endometrial cancer include, but not limited to type I EC
(estrogen-dependent and/or progesterone-dependent with endometrioid histology) and type II EC, or endometriosis (hormone-independent poorly differentiated endometrioid, clear cell and serous carcinomas).
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. The present invention relates to a method for using the combinations of the present invention, in the treatment or prophylaxis of a cancer, particularly bladder cancer. The combinations of the present invention can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis, in the treatment or prophylaxis of cancer, in particular bladder cancer. This method comprises administering to a mammal in need thereof, including a human, an amount of a combination of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; etc. which is effective for the treatment or prophylaxis of cancer, in particular bladder cancer.
The term“treating” or“treatment” as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
Dose and administration
Based upon standard laboratory techniques known to evaluate compounds useful for the treatment or prophylaxis of cancer, in particular bladder cancer, head & neck cancer, liver cancer, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the combinations of this invention can readily be determined for treatment of the indication. The amount of the active ingredient to be administered in the treatment of the condition can vary widely according to such considerations as the particular combination and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1,500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific combination employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a combination of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
Therapies using combinations of component A as described supra„ component B as described supra„ and component C : one or more further pharmaceutical agents.
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 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 1311-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, 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, Iasocholine, 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, temoporfm, 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, vinfhmine, 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 (when component B is not itself paclitaxel), 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-1B inhibitor, a DPP-IV inhibitor, a 11-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 11th 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 ah, publ. by McGraw- Hill, pages 1225-1287, (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 or even eliminate the tumor as compared to administration of either agent alone,
(2) provide for the administration of lesser amounts of the administered chemotherapeutic agents,
(3) provide for a chemotherapeutic treatment that is well tolerated in the patient with fewer deleterious pharmacological complications than observed with single agent chemotherapies and certain other combined therapies,
(4) provide for treating a broader spectrum of different cancer types in mammals, especially humans,
(5) provide for a higher response rate among treated patients,
(6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments,
(7) provide a longer time for tumor progression, and/or
(8) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects. EXAMPLES
The following abbreviations are used in the Examples:
• Component A : o “rogaratinib,” or“compound A” means Example 1 of WO 2013/087578 A1 i.e. a compound of structure :
Figure imgf000061_0001
(which is an example of component A as described and defined herein).
• Component B : o a compound selected from the list consisting of Ulixertinib, Trametinib, BAY
‘672 , AZD8055, Lapatinib, Erlotinib, Apitolisib, Dactolisib, Cabozantinib, and BAY-474 or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof, as described and defined herein
, i.e. a compound of structure :
(which is an example of component B as described and defined herein).
Materials and methods: Generation of rogaratinib-resistant UBC cell lines: JMSU-1 (FGFR1 -driven) and RT-112 (FGFR3 -driven) UBC cells were cultured with varying concentrations of rogaratinib over several weeks to months in order to generate several biologically independent rogaratinib-resistant sublines:
For generation of RT - 112 ROGA 1 and RT - 112 ROGA2 , RT - 112 cells were initially treated with
60mM rogaratinib for 4 weeks and allowed to recover for 6 weeks. Then, RT-112 ROGA1 was kept at 1 mM rogaratinib for 15 weeks, after which rogaratinib concentration was increased to 1.5mM for 2 weeks and RT-112 ROGA2 was treated with 0.3mM rogaratinib for 10 weeks, then with O.όmM for 6 weeks and with 1 mM for two weeks.. In both cell lines resistance was observed after 27 weeks in total. To generate RT-112 ROGA3, RT-112 cells were initially treated with 20mM rogaratinib for 4 weeks, allowed to recover for one week, kept with 20mM rogaratinib for 6 weeks, then at 1 mM rogaratinib for 14 weeks and at 1 5mM rogaratinib for 2 weeks before resistance was observed (27 weeks in total). RT-112 ROGA4 and RT-112 ROGA5 were generated by initially treating RT-112 cells with 15nM rogaratinib (IC50 for proliferation inhibition in RT-112 cells) or with 60nM (IC80) rogaratinib and concentrations were increased incrementally over a period of 25 weeks to 1 mM or 0.5 mM rogaratinib, respectively.
JMSU-1 cells were treated either for 5 weeks with rogaratinib concentrations corresponding to IC80 (80nM) resulting in JMSU-1 ROGA1 or to IC50 (30nM) resulting in JMSU-1 ROGA2 and JMSU-1 ROGA4, or for 10 weeks with rogaratinib concentrations corresponding to IC10 (5nM) resulting in JMSU-1 ROGA3.
Response to rogaratinib was determined in a standard proliferation assay. Cells were seeded at optimal density to reach 80% confluency by the end of the assay, and treated with a range of rogaratinib concentrations for 72h. Cell mass was determined using crystal violet staining.
Proliferation inhibition by rogaratinib was calculated as described below. Cells were considered rogaratinib-resistant when rogaratinib-induced proliferation arrest was <50% at ImM.
In vitro combination assessment: The effects of combinations of the present invention were evaluated using combination index isobologram analysis for in vitro assessment. The efficacy parameters were the effects in a 72-hour growth assay. Briefly, cells were plated at the indicated cell density in 384-well plates in 30 pL respective medium with 10% FCS and incubated in a humidified 37°C incubator. After 24 hours, baseline cell growth respective viability was measured in a control plate using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega), while the cells in parallel plates were treated by adding 5 pL of experimental media containing:
• either A alone (concentration range 1.0E-05 M to 8.6E-12 M or 3E-05 to 8.6E-11), or
· B alone (concentration range 1.0E-05 M to 8.6E-12 M or 3E-05 to 8.6E-11), or
• the combination of A (as component A) plus B (as component B) at nine different fixed-ratio combinations (0.9xA+0.1xB, 0.8xA+0.2xB, 0.7xA+0.3xB, 0.6xA+0.4xB, 0.5xA+0.5xB, 0.4xA+0.6xB, 0.3xA+0.7xB, 0.2xA+0.8xB, 0.1xA+0.9xB). Test compounds were added to the wells using a Tecan-HP Digital Dispenser. CellTiter-Glo® Luminescent Cell Viability Assay was conducted at 72 hours after compound exposure. Data were analyzed for effects on proliferation and on viability. IC50 values (inhibitory concentration at 50% of maximal effect) were determined by means of a 4 parameter fit on measurement data which were normalized to vehicle (DMSO) treated cells (=100%) and either the signal obtained in wells with medium but without cells (viability) or measurement readings of the control plate taken immediately before compound exposure (proliferation) (=0%). IC50 isobolograms were plotted with the actual concentrations of the two compounds on the x- and y-axis, and the combination index (Cl) was calculated according to the median-effect model of Chou-Talalay (Ref. 1). A Cl of <0.8 was defined as more than additive (or synergistic) interaction, and a Cl of >1.2 was defined as antagonistic interaction. In cases where 50% inhibition of maximal effect was not reached in monotherapy treatment, the highest compound concentration applied (IE-05 M or 3E-05 M) was used to calculate the combination index.
In vivo combination assessment: The in vivo efficacy was evaluated at maximal tolerated dose (MTD) or sub-MTD dose in tumor xenograft models in NMRI nude mice. Tumor cells were cultivated according to suppliers’ recommendation in media containing 10% FCS. Cells were harvested for transplantation in a subconfluent (70%) state and were subcutaneously injected in 100 mΐ RPMI-1640 containing 50% matrigel (see Table 2). When tumors were approximately the size of 50-mm2, the animals were randomized to treatment and control groups, and treatment was started. Treatment of each animal was based on individual body weight. The optimal formulation, application route and schedule were used for each compound (see Table 3). Oral administration (p.o.) was carried out via gavage. All application volumes were 10 ml/kg. Tumors were measured using a caliper at least twice a week. The animal body weight was monitored at least twice a week as a measure for treatment-related toxicity. AT/AC ratios (Treatment / Control) were calculated on the differences in mean tumor volumes between start of treatment and the last day at which data is available for all groups ([volumefmai - volumeday o]treated/[volumefmai - volumeday o]controi). Statistical analysis was performed on Log-transformed tumor volume using one way ANOVA, with Turkey’s multiple testing correction. P-values of the respective comparisons are indicated as follows: p < 0.05 = *, p < 0.01 = * *, p < 0.001 = ** *, p < 0.0001 = *** *.
The invention is demonstrated in the following examples which are not meant to limit the invention in any way:
Table 1. Molecular features of cell line models used
Figure imgf000064_0001
Figure imgf000064_0002
Table 2. Tumor models used for assessment of compound A (FGFRi rogaratinib) and compound B in bladder tumor models in vivo.
Figure imgf000064_0003
Table 3: Formulations, route and schedule of compounds for in vivo experiments.
Figure imgf000065_0001
Example 1. Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) and a MAPK pathway inhibitor compound B consisting of either a ERK1/2 inhibitor
(ulixertinib) or a MEK1/2 inhibitor (trametinib or BAY‘672) in rogaratinib-resistant urothelial bladder tumor models.
As indicated in table 1, FGFR receptors are often overexpressed or mutated in UBC leading to increased pathway activity which often results in increased MAPK (ERK1/2) signaling. Long term treatment of the FGFR3-driven RT-112 cell line with the FGFR inhibitor rogaratinib led to the 5 rogaratinib-resistant sublines RT-112 ROGA1-5. The antiproliferative activity of compound A (rogaratinib) was evaluated in combination with compound B consisting of either the ERK1/2 inhibitor ulixertinib or one of the two MEK1/2 inhibitors trametinib or BAY‘672 and compared to the single agent activity in human cell lines derived from urothelial bladder cancers and rogaratinib-resistant cell lines derived thereof using the CellTiter-Glo® Luminescent Cell Viability Assay as described in the Materials and Methods section. Surprisingly, combining compound A (rogaratinib) and ERK1/2 inhibitor compound B for treating rogaratinib-resistant UBC cells results in synergistic inhibition of proliferation compared to single agent treatment as demonstrated in figure 1. Furthermore, combining compound A (rogaratinib) and MEK1/2 inhibitor compound B for treating UBC cells results in synergistic inhibition of proliferation compared to single agent treatment as demonstrated in figures 2 and 3. Data are summarized in tables 4 - 6. The combination benefit of compound A (rogaratinib) and MEK1/2 inhibitor compound B (trametinib) could also be observed in vivo in 2 urothelial bladder cancer cell line- derived xenograft models in figures 4 and 5.
Table 4. Calculated combination indices at IC50 (CI50) from proliferation analysis of bladder cancer cell lines treated with combinations of compound A (rogaratinib) and ERK1/2 inhibitor compound B (ulixertinib). In case of synergism lowest CI50 along with corresponding compound concentrations is presented.
Figure imgf000066_0001
Table 5. Calculated combination indices at IC50 (CI50) from proliferation analysis of bladder cancer cell lines treated with combinations of compound A (rogaratinib) and MEK1/2 inhibitor compound B (trametinib). In case of synergism lowest CI50 along with corresponding compound concentrations is presented.
Figure imgf000066_0002
Table 6. Calculated combination indices at IC50 (CI50) from proliferation analysis of bladder cancer cell line JMSU-1 treated with combinations of compound A (rogaratinib) and MEK1/2 inhibitor compound B (BAY‘672). In case of synergism lowest CI50 along with corresponding compound concentrations is presented.
Figure imgf000066_0003
Figure 1. Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with ERK1/2 inhibitor compound B (ulixertinib) in UBC RT-112 cells and rogaratinib-resistant RT- 112 cell-derived sublines. The combination of pan-FGFR inhibitor compound A (rogaratinib) and ERK1/2 inhibitor compound B (ulixertinib) was tested and compared to the single agent activity in RT-112 cells and rogaratinib-resistant cell lines RT-112 ROGA1, RT-112 ROGA3, RT-112 ROGA4 and RT-112 ROGA5 using the CellTiter-Glo® Luminescent Cell Viability Assay. The combination treatment shows synergistic effects on proliferation for almost all concentration combinations used.
Figure 2. Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with MEK1/2 inhibitor compound B (trametinib) in RT-112 and JMSU-1 cells. The combination of pan-FGFR inhibitor compound A (rogaratinib) and MEK1/2 inhibitor compound B (trametinib) was tested and compared to the single agent activity in RT-112 and JMSU-1 UBC cells using the CellTiter-Glo® Luminescent Cell Viability Assay. The combination treatment shows synergistic effects on proliferation in both cell lines for all concentration combinations used.
Figure 3. Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with MEK1/2 inhibitor compound B (BAY‘672) in RT-112 and JMSU-1 cells. The combination of pan-FGFR inhibitor compound A (rogaratinib) and MEK1/2 inhibitor compound B (BAY‘672) was tested and compared to the single agent activity in RT-112 and JMSU-1 cells using the CellTiter-Glo® Luminescent Cell Viability Assay. In RT-112 and JMSU-1 cells no activating MAPK pathway mutations are known. The combination treatment shows synergistic effects on proliferation in both cell lines for almost all concentration combinations used.
Figure 4. Beneficial combination of FGFR inhibitor compound A (rogaratinib) and MEK inhibitor compound B (trametinib) in RT112 bladder cancer xenograft model, implanted subcutaneously in nude mice. The combination of FGFR inhibitor compound A and MEK inhibitor compound B was tested and compared to the single agent activity in the urothelial bladder cancer model RT112 for which in vitro synergism was observed (see Figure 2). Treatment was initiated at a tumor size of 163 mm3. RT112-tumor bearing mice were treated once daily with 75 mg/kg (filled squares) of compound A (rogaratinib) or with 0.25 mg/kg of compound B (trametinib (closed triangles)) or with a combination of compound A and compound B at the respective doses (open squares). Figure 4 displays tumor growth as mean tumor volume over time (upper panel), and the body weight loss relative to maximum body weight (lower panel). A maximal body weight loss of 3.1%, 4.3%, and 5.0% was observed compared to maximal body weight in both monotherapies and combination therapy, respectively.
At day 6, the last time point at which data is available for all groups, treatment of FGFR inhibitor A (rogaratinib, 75 mg/kg QD) was active with a AT/AC of 40% (Table 7). The MEK inhibitor compound B at 0.25 mg/kg showed a AT/AC of 51%. Combination of compound A with compound B yielded a tumor growth inhibition with AT/AC = 22%. At the end of the experiment, combination treatment resulted in significantly higher anti-tumor efficacy than any of the single agent treatments. In conclusion, rogaratinib and trametinib showed single agent activity and the combination of rogaratinib with trametinib led to significant treatment benefit compared to rogaratinib and trametinib monotherapy.
Figure 5. Beneficial combination of FGFR inhibitor compound A (rogaratinib) and MEK inhibitor compound B (trametinib) in JMSU1 bladder cancer xenograft model, implanted subcutaneously in nude mice. The combination of FGFR inhibitor compound A and MEK inhibitor compound B was tested and compared to the single agent activity in the urothelial bladder cancer model JMSU1 for which in vitro synergism was observed (see Figure 2). Treatment was initiated at a tumor size of 131 mm3. JMSUl-tumor bearing mice were treated once daily with 75 mg/kg (filled squares) of compound A (rogaratinib) or with 0.25 mg/kg of compound B (trametinib (closed triangles)) or with a combination of compound A and compound B at the respective doses (open triangles). Figure 5 displays tumor growth as mean tumor volume over time (upper panel), and the relative body weight (lower panel). A maximal body weight loss of 1.0%, 4.4%, and 7.8% was observed compared to maximum body weight in both monotherapies and combination therapy, respectively.
At day 9, the time point for termination of the vehicle group, treatment of FGFR inhibitor compound A (rogaratinib, 75mg/kg) was active with a AT/AC of -10% (Table 7). MEK inhibitor compound B at 0.25mg/kg was inactive with AT/AC of 63% . Combination of compound A with compound B led to tumor regression with -52% AT/AC. The addition of compound B (0.25 mg/kg) to 75 mg/kg of compound A led to a statistically significant decrease in tumor volume as compared to the respective monotherapy of compound A or B (p < 0.05 and <0.0001, respectively).
In conclusion, at termination of the respective treatment groups, rogaratinib inhibited tumor growth as single agent while trametinib alone was inactive. Surprisingly, the combination of rogaratinib with trametinib led to strong tumor regression and therefore showed a clear treatment benefit compared to the respective monotherapy.
Table 7: DT/AC in % for the combination or respective monotherapies of compound A (rogaratinib) and compound B (trametinib).
Figure imgf000068_0001
Figure imgf000069_0001
Example 2. Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) and a PI3K/AKT/mTOR pathway inhibitor compound B consisting of either a PI3K inhibitor (apitolisib or dactolisib) or a mTOR inhibitor (AZD8055) in rogaratinib-resistant urothelial bladder tumor models.
As indicated in table 1, FGFR receptors are often overexpressed or mutated in UBC leading to increased pathway activity which often results in increased MAPK (ERK1/2) signalling or in activation of the PDK/AKT/mTOR pathway. The antiproliferative activity of compound A (rogaratinib) was evaluated in combination with compound B consisting of either a PI3K inhibitor (apitolisib or dactolisib) or a mTOR inhibitor (AZD8055) and compared to the single agent activity in human cell lines derived from urothelial bladder cancers using the CellTiter- Glo® Luminescent Cell Viability Assay as described in the Materials and Methods section. Surprisingly, combining compound A (rogaratinib) and either PI3K inhibitor (apitolisib or dactolisib) or mTOR inhibitor (AZD8055) compound B for treating UBC cells results in synergistic inhibition of proliferation compared to single agent treatment as demonstrated in figures 6-8. Data are summarized in tables 8-10.
Table 8. Calculated combination indices at IC50 (CI50) from proliferation analysis of bladder cancer cell lines treated with combinations of compound A (rogaratinib) and PI3K inhibitor compound B (apitolisib). In case of synergism lowest CI50 along with corresponding compound concentrations is presented.
Figure imgf000069_0002
Table 9. Calculated combination indices at IC50 (CI50) from proliferation analysis of bladder cancer cell lines treated with combinations of compound A (rogaratinib) and PI3K inhibitor compound B (dactolisib). In case of synergism lowest CI50 along with corresponding compound concentrations is presented.
Figure imgf000070_0002
Table 10. Calculated combination indices at IC50 (CI50) from proliferation analysis of bladder cancer cell lines treated with combinations of compound A (rogaratinib) and mTOR inhibitor compound B (AZD8055). In case of synergism lowest CI50 along with corresponding compound concentrations is presented.
Figure imgf000070_0001
Figure 6. Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with PI3K inhibitor compound B (apitolisib) in JMSU-1 cells. The combination of pan-FGFR inhibitor compound A (rogaratinib) and PI3K inhibitor compound B (apitolisib) was tested and compared to the single agent activity in JMSU-1 and rogaratinib-resistant JMSU-1 ROGA1 UBC cells using the CellTiter-Glo® Luminescent Cell Viability Assay. The combination treatment shows synergistic effects on proliferation in both cell lines for all concentration combinations used.
Figure 7. Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with PI3K inhibitor compound B (dactolisib) in JMSU-1 cells. The combination of pan-FGFR inhibitor compound A (rogaratinib) and PI3K inhibitor compound B (dactolisib) was tested and compared to the single agent activity in JMSU-1 UBC cells using the CellTiter-Glo® Luminescent Cell Viability Assay. The combination treatment shows synergistic effects on proliferation for all concentration combinations used.
Figure 8. Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with mTOR inhibitor compound B (AZD8055) in RT-112 and JMSU-1 cells. The combination of pan-FGFR inhibitor compound A (rogaratinib) and mTOR inhibitor compound B (AZD8055) was tested and compared to the single agent activity in RT-112 and JMSU-1 UBC cells using the CellTiter- Glo® Luminescent Cell Viability Assay. The combination treatment shows synergistic effects on proliferation in both cell lines for almost all concentration combinations used. Example 3. Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) and an EGFR receptor tyrosine kinase inhibitor compound B (lapatinib or erlotinib) in urothelial bladder tumor models. As indicated in table 1, FGFR receptors are often overexpressed or mutated in UBC leading to increased pathway activity which often results in increased MAPK (ERK1/2) signalling. Long term treatment of the FGFR3-driven RT-112 cell line with the FGFR inhibitor rogaratinib led to the 5 rogaratinib-resistant sublines RT-112 ROGA1-5. Generation of rogaratinib resistance in the RT-112 cell line did not lead to increased phosphorylation levels of either EGFR or HER2 as determined by R&D human phospho-RTK profiler arrays. The antiproliferative activity of compound A (rogaratinib) was evaluated in combination with compound B consisting of either the dual ERBB 1 (EGFR) and ERBB2 (HER2) receptor tyrosine kinase inhibitor lapatinib or the ERBB1 (EGFR) receptor tyrosine kinase inhibitor erlotinib and compared to the single agent activity in human cell lines derived from urothelial bladder cancers using the CellTiter-Glo® Luminescent Cell Viability Assay as described in the Materials and Methods section.
Surprisingly, combining compound A (rogaratinib) and inhibitor compound B (lapatinib or erlotinib) for treating RT-112 UBC cells and rogaratinib-resistant sublines derived thereof results in synergistic inhibition of proliferation compared to single agent treatment as demonstrated in figures 9-10. Data are summarized in tables 11 and 12. The combination benefit of compound A (rogaratinib) and compound B (lapatinib) could also be observed in vivo in the RT112 urothelial bladder cancer cell line -derived xenograft model in figure 11.
Table 11. Calculated combination indices at IC50 (CI50) from proliferation analysis of bladder cancer cell lines treated with combinations of compound A (rogaratinib) and dual ERBB1
(EGFR) and ERBB2 (HER2) receptor tyrosine kinase inhibitor compound B (lapatinib). In case of synergism lowest CI50 along with corresponding compound concentrations is presented.
Figure imgf000071_0001
Figure imgf000072_0001
Table 12. Calculated combination indices at IC50 (CI50) from proliferation analysis of bladder cancer cell lines treated with combinations of compound A (rogaratinib) and ERBB 1 (EGFR) receptor tyrosine kinase inhibitor compound B (erlotinib). In case of synergism lowest CI50 along with corresponding compound concentrations is presented.
Figure imgf000072_0002
Figure 9. Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with dual ERBB 1 (EGFR) and ERBB2 (HER2) receptor tyrosine kinase inhibitor compound B (lapatinib) in RT-112 UBC cells. The combination of pan-FGFR inhibitor compound A (rogaratinib) and dual EGFR/HER2 inhibitor compound B (lapatinib) was tested and compared to the single agent activity in UBC RT-112 cells and rogaratinib-resistant sublines RT-112 ROGA1, RT-112 ROGA2, RT-112 ROGA3, RT-112 ROGA4, and RT-112 ROGA5 derived thereof using the CellTiter-Glo® Luminescent Cell Viability Assay. The combination treatment shows synergistic effects on proliferation in all cell lines tested for all concentration combinations used.
Figure 10. Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with ERBB1 (EGFR) receptor tyrosine kinase inhibitor compound B (erlotinib) in UBC RT-112 cells and rogaratinib-resistant RT-112 cell-derived sublines. The combination of pan-FGFR inhibitor compound A (rogaratinib) and EGFR inhibitor compound B (erlotinib) was tested and compared to the single agent activity in UBC RT-112 cells and rogaratinib-resistant cell lines RT-112 ROGA1, RT-112 ROGA2, RT-112 ROGA3, RT-112 ROGA4 and RT-112 ROGA5 using the CellTiter-Glo® Luminescent Cell Viability Assay. The combination treatment shows synergistic effects on proliferation in all cell lines tested for all concentration combinations used. Figure 11. Beneficial combination of FGFR inhibitor compound A (rogaratinib) and dual EGFR/HER2 inhibitor compound B (lapatinib) in the RT112 bladder cancer xenograft model, implanted subcutaneously in nude mice. The combination of FGFR inhibitor compound A and EGFR/HER2 inhibitor compound B was tested and compared to the single agent activity in the urothelial bladder cancer model RT112 for which in vitro synergism was observed (see Figure 9). Treatment was initiated at a tumor size of 163 mm3. RT112-tumor bearing mice were treated twice daily with 54 mg/kg (filled squares) of compound A (rogaratinib) or once daily with 75 mg/kg of compound B (lapatinib (closed triangles)) or in combination of compound A and compound B at the respective doses and schedules (open triangles). Figure 11 displays tumor growth as mean tumor volume over time (upper panel), and the relative body weight (lower panel). A maximal body weight loss of 2.5%, 1.6% and 5.0% was observed compared to starting body weight with both monotherapies and combination therapy, respectively.
At day 6, the last time point for which data is available for all groups, treatment of FGFR inhibitor compound A (rogaratinib, 54 mg/kg) was active with a AT/AC of 30%. EGFR inhibitor compound B at 75 mg/kg was inactive with AT/AC of 69%. Combination of compound A with compound B yielded a tumor growth inhibition with 19% AT/AC. The addition of compound B to compound A further reduced tumor growth compare to compound A alone and led to a statistically significant decrease in tumor volume as compared to the monotherapy of compound B. In conclusion, at termination of the respective treatment groups, the combination of rogaratinib with lapatinib showed treatment benefit compared to the respective monotherapy.
Example 4. Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) and a HGFR (MET) inhibitor compound B (cabozantinib or BAY-474) in urothelial bladder tumor models.
As indicated in table 1, FGFR receptors are often overexpressed or mutated in UBC leading to increased pathway activity which often results in increased MAPK (ERK1/2) signalling. Long term treatment of the FGFR1 -overexpressing JMSU-1 cell line with the FGFR inhibitor rogaratinib led to the 4 rogaratinib-resistant sublines JMSU-1 ROGA1-4 which showed increased activation of a variety of non-FGFR receptor tyrosine kinases. The antiproliferative activity of compound A (rogaratinib) was evaluated in combination with compound B consisting either of the HGFR / VEGFR2 inhibitor capozantinib or the HGFR selective inhibitor BAY-474 and compared to the single agent activity in human UBC cell line JMSU-1 and rogaratinib-resistant sublines derived thereof using the CellTiter-Glo® Luminescent Cell Viability Assay as described in the Materials and Methods section. Surprisingly, combining compound A (rogaratinib) and compound B consisting of either non-selective HGFR inhibitor capozantinib or of HGFR selective BAY-474 for treating JMSU-1 UBC cells and rogaratinib-resistant sublines derived thereof results in synergistic inhibition of proliferation and viability compared to single agent treatment as demonstrated in figures 12 and 13. Data are summarized in tables 13 and 14.
Table 13. Calculated combination indices at IC50 (CI50) from proliferation and viability analysis of bladder cancer cell lines treated with combinations of compound A (rogaratinib) and receptor tyrosine kinase inhibitor compound B (capozantinib). In case of synergism lowest CI50 along with corresponding compound concentrations is presented.
Figure imgf000074_0001
Table 14. Calculated combination indices at IC50 (CI50) from proliferation analysis of bladder cancer cell lines treated with combinations of compound A (rogaratinib) and HGFR (MET) inhibitor compound B (BAY-474). In case of synergism lowest CI50 along with corresponding compound concentrations is presented.
Figure imgf000074_0002
Figure 12. Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with HGFR non-selective receptor tyrosine kinase inhibitor compound B (capozantinib) in rogaratinib-resistant UBC cells. The combination of pan-FGFR inhibitor compound A
(rogaratinib) and HGFR non-selective inhibitor compound B (capozantinib) was tested and compared to the single agent activity in JMSU-1 UBC cell-derived rogaratinib-resistant JMSU-1 ROGA1 and JMSU-1 ROGA3 sublines using the CellTiter-Glo® Luminescent Cell Viability Assay. The combination treatment shows synergistic effects on proliferation in both cell lines tested for all concentration combinations used.
Figure 13. Synergistic combination of pan-FGFR inhibitor compound A (rogaratinib) with HGFR-selective receptor tyrosine kinase inhibitor compound B (BAY-474) in rogaratinib- resistant UBC cells. The combination of pan-FGFR inhibitor compound A (rogaratinib) and HGFR-selective inhibitor compound B (BAY-474) was tested and compared to the single agent activity in JMSU-1 UBC cell derived rogaratinib-resistant JMSU-1 ROGA1 and JMSU-1 ROGA3 sublines using the CellTiter-Glo® Luminescent Cell Viability Assay. The combination treatment shows synergistic effects on proliferation in both cell lines for all concentration combinations used.
Figure 14. Beneficial combination of FGFR inhibitor compound A (rogaratinib) and MET inhibitor compound B (BAY-474) in the JMSU1 bladder cancer xenograft model, implanted subcutaneously in nude mice. The combination of FGFR inhibitor compound A and MET inhibitor compound B was tested and compared to the single agent activity in the urothelial bladder cancer model JMSU1 for which in vitro synergism was observed (see Figure 13). Treatment was initiated at a tumor size of 131 mm3. JMSUl-tumor bearing mice were treated twice daily either with 54 mg/kg (filled squares) of compound A (rogaratinib) or with 20 mg/kg of compound B (BAY-474 (closed triangles)) or in combination of compound A and compound B at the respective doses (open triangles). Figure 14 displays tumor growth as mean tumor volume over time (upper panel), and the body weight loss relative to maximum body weight (lower panel). A maximal body weight loss of 7.1%%, 2.3% and 10.8% was observed compared to maximum body weight in both monotherapies and combination therapy, respectively.
At day 9, the timepoint for termination of the vehicle group, treatment with MET inhibitor compound B (BAY-474) was inactive 118% AT/AC. FGFR inhibitor compound A at 54 mg/kg was active and caused tumor regression with AT/AC of -56%. Combination of compound A with compound B yielded comparable tumor regression with -52% AT/AC. Treatment was pursued for compound A in monotherapy and for the combination group for additional eighteen days. In the combination group 72% (5 of 7) of evaluable tumors showed complete responses compared to 53% (14 of 26) of evaluable tumors treated with rogaratinib compound A alone.
In conclusion, the MET inhibitor compound B was inactive in the JMSU1 xenograft model while rogaratinib compound A alone induced tumor regression including 53% complete responses. The combination benefit is corroborated by the observation that addition of the MET inhibitor compound B to compound A showed better tumor control resulting in a higher fraction of complete responses in the combination group compared to the monotherapy group. The synergistic in vitro effects of the combination of compound A (rogaratinib) with compound B (MET inhibitor) found for the rogaratinib-resistant cell lines JMSU-1 ROGA1 and JMSU-1 ROGA3 as shown in Figures 12 and 13, together with the observation in Figure 14, suggest that rogaratinib-resistant bladder tumors may respond to a compound inhibiting the receptor tyrosine kinase MET and show decreased growth when treated with a combination of compound A (rogaratinib) and a MET inhibitor.

Claims

1. A combination of :
component A : one or more 6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]- triazin-4-amine compounds of general formula (I) :
Figure imgf000077_0001
wherein
R is hydrogen, chloro, methyl or methoxy, R is hydrogen or methoxy, with the proviso that at least one of R1 and R2 is other than hydrogen,
G represents chloro, (Ci-C -alkyl, (Ci-C -alkoxy carbonyl, 5-membered aza-heteroaryl, or the group -CH2-OR3, -CH2-NR4R5 or -C(=0)-NR4R6, wherein
R3 is hydrogen, (Ci-C -alkyl, (C3-Ce)-cycloalkyl or phenyl, wherein
(i) said (Ci-C -alkyl is optionally substituted with hydroxy, (Ci-C -alkoxy, hydroxycarbonyl, (Ci-C4)-alkoxy carbonyl, amino, aminocarbonyl, mono- (Ci-C4)-alkylaminocarbonyl, di-(Ci-C4)-alkylaminocarbonyl, (C3-Ce)-cyclo- alkyl or up to three fluoro atoms, and (ii) said (C3-Ce)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci-C -alkyl, hydroxy and amino, and
(iii) said phenyl is optionally substituted with one or two substituents indepen dently selected from the group consisting of fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoromethoxy, (Ci-C -alkyl and (Ci-C4)-alkoxy,
R4 is hydrogen or (Ci-C -alkyl,
R5 is hydrogen, (Ci-C -alkyl, (Ci-C -alkylcarbonyl, (C3-C6)-cycloalkyl or 4- to 6- membered heterocycloalkyl, wherein
(i) said (Ci-C -alkyl is optionally substituted with hydroxy, (Ci-C -alkoxy, hydroxycarbonyl, (Ci-C4)-alkoxy carbonyl, aminocarbonyl, mono-(Ci-C4)- alkylaminocarbonyl, di-(Ci-C4)-alkylaminocarbonyl or (C3-Ce)-cycloalkyl, and
(ii) said (C3-C6)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci-C4)-alkyl, hydroxy and amino, and
(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci- C4)-alkyl, hydroxy, oxo and amino,
R6 is hydrogen, (Ci-C4)-alkyl, (C3-Ce)-cycloalkyl or 4- to 6-membered heterocyclo alkyl, wherein
(i) said (Ci-C4)-alkyl is optionally substituted with hydroxy, (Ci-C4)-alkoxy, hydroxycarbonyl, (Ci-C4)-alkoxy carbonyl, amino, aminocarbonyl, mono- (Ci-C4)-alkylaminocarbonyl, di-(Ci-C4)-alkylaminocarbonyl or (C3-C6)- cycloalkyl, and (ii) said (C3-Ce)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci-C -alkyl, hydroxy and amino, and (iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci- C -alkyl, hydroxy, oxo and amino, or
R4 and R5, or R4 and R6, respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 7-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R7) and O, and which may be substituted on ring carbon atoms with one or two substituents independently selected from the group consisting of (C1-C4)- alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
R7 is hydrogen, (Ci-C4)-alkyl, formyl or (Ci-C -alkylcarbonyl, and
G2 represents chloro, cyano, (Ci-C -alkyl, or the group -CR8AR8B-OH, -CH2- NR9R10, -C(=0)-NRnR12 or -CH2-OR15, wherein
R8A and R8B are independently selected from the group consisting of hydrogen, (C1-C4)- alkyl, cyclopropyl and cyclobutyl,
R9 is hydrogen or (Ci-C4)-alkyl,
R10 is hydrogen, (Ci-C4)-alkyl, (Ci-C4)-alkylcarbonyl, (C3-C6)-cycloalkyl or 4- to 6- membered heterocycloalkyl, wherein
(/) said (Ci-C4)-alkyl is optionally substituted with hydroxy, amino, amino carbonyl, mono-(Ci-C4)-alkylaminocarbonyl or di-(Ci-C4)-alkylamino- carbonyl, and (ii) said (C3-Ce)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci-C -alkyl, hydroxy and amino, and
(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci- C -alkyl, hydroxy, oxo and amino,
R11 is hydrogen or (Ci-C -alkyl,
R12 is hydrogen, (Ci-C -alkyl, (C3-Ce)-cycloalkyl or 4- to 6-membered heterocyclo alkyl, wherein
(i) said (Ci-C -alkyl is optionally substituted with hydroxy, amino, amino- carbonyl, mono-(Ci-C4)-alkylaminocarbonyl or di-(Ci-C4)-alkylamino- carbonyl, and
(ii) said (C3-Ce)-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci-C4)-alkyl, hydroxy and amino, and
(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (Ci- C4)-alkyl, hydroxy, oxo and amino, or
R9 and R10, or R11 and R12, respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 7-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R13), O, S and S(0)2, and which may be substituted on ring carbon atoms with up to three substituents independently selected from the group consisting of fluoro, (Ci-C4)-alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein R13 is hydrogen, (Ci-C4)-alkyl, (C3-Ce)-cycloalkyl, formyl or (Ci-C -alkyl- carbonyl, and
R15 is (Ci-C4)-alkyl, with the proviso that G1 is not chloro when G2 is chloro or cyano, or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;
and
component B: a compound of the class selected from the list consisting of PI3K inhibitors, MAPK inhibitors, RAS inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, and RTK (e.g. MET, EGFR, HGFR, VEGFR, KDR) inhibitors.
2. The combination according to claim 1, wherein : said component A is one or more 6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l- f][l,2,4]-triazin-4-amine compounds according to claim 1, which are selected from the list consisting of specific compound Examples 1 to 127 on pp. 109 to 215 of PCT/EP2012/074977, published as WO 2013/087578 A1 on June 20, 2013,
or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ;
optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
3. The combination according to any one of claims 1 to 2, wherein : said component A is one or more 6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l- f][l,2,4]-triazin-4-amine compounds of general formula (B) according to claim 1, which is selected from the list consisting of :
Example 1
4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]-
[1.2.4] triazin-7 -yljmethyl } piperazin-2 -one
Example 2
4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]-
[1.2.4]triazin-7-yl]methyl}piperazin-2-one dihydrochloride
Example 3 (3R)- 3 -( { [4-Amino-6-(methoxymethyl)-5-(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one dihydrochloride
Example 4
(3R)-3 -( { [4-Amino-6-(methoxymethyl)-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one
Example 5
4-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]-
[1.2.4] triazin-7 -yljmethyl } piperazin-2 -one
Example 6
4- { [4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)pyrrolo-
[2, 1 -f] [1 ,2,4]triazin-7-yl]methyl}piperazin-2-one dihydrochloride
Example 7
(3R)-3 -( { [4-Amino-6-(ethoxymethyl)-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one dihydrochloride
Example 8
(3R)-3 -( { [4-Amino-6-(ethoxymethyl)-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one
Example 9
Ai-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]- [l,2,4]triazin-7-yl]methyl}glycinamide dihydrochloride
Example 10
6-(Ethoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-4-amine
Example 11
1 -(4- { [4-Amino-6-(ethoxymethyl)-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo [2, 1 -f] -
[1.2.4] triazin-7 -yljmethyl } piperazin- 1 -yl)ethanone dihydrochloride
Example 12
[4-Amino-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)-7-(piperazin- 1 -ylmethyl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-6-yl]methanol bis(formiate)
Example 13
4- { [4- Amino-6-(hydroxymethyl)-5 -(7-methoxy-5 -methyl- 1 -benzothiophen-2 -yl)pyrrolo [2 , 1 -f] -
[1.2.4] triazin-7 -yljmethyl } piperazin-2 -one
Example 14
7-{[(35)-3-Amino-3-methylpyrrolidin-l-yl]methyl}-6-(methoxymethyl)-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-4-amine trihydrochloride Example 15
7-{[(35)-3-Amino-3-methylpyrrolidin-l-yl]methyl}-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-l- benzothiophen-2-yl)pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-4-amine
Example 16
l-(4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-7-yl]methyl}piperazin-l -yl)ethanone dihydrochloride
Example 17
6-(Methoxymethyl)-5-(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)- pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-4-amine formiate
Example 18
6-(Ethoxymethyl)-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-4-amine
Example 19
6-(Ethoxymethyl)-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-4-amine dihydrochloride
Example 20
1 -(4- { [4-Amino-6-(ethoxymethyl)-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo [2,1-fj-
[l,2,4]triazin-7-yl]methyl}piperazin-l-yl)ethanone
Example 21
4-({4-Amino-6-[(2-hydroxyethoxy)methyl]-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)- pyrrolo[2,l-f][l,2,4]triazin-7-yl}methyl)piperazin-2-one formiate
Example 22
2- { [4-Amino-5-(7-methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)pyrrolo- [2, 1 -f] [ 1 ,2,4]triazin-6-yl]methoxy } ethanol dihydrochloride
Example 23
6-(Butoxymethyl)-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)-7-(piperazin- 1 -ylmethyl)- pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-4-amine formiate
Example 24
5-(7-Methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)-6-(propoxymethyl)- pyrrolo[2,l-f][l,2,4]triazin-4-amine bis(formiate)
Example 25
6-[(Cyclopropylmethoxy)methyl]-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l- ylmethyl)pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-4-amine bis(formiate)
Example 26 6-[(Cyclobutyloxy)methyl]-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-yl- methyl)pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-4-amine
Example 27
6-(Isopropoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)- pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-4-amine formiate
Example 28
6- [(2 -Methoxy ethoxy )methyl] -5 -(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-y l)-7 -(piperazin- 1 -yl- methyl)pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-4-amine formiate
Example 29
5-(7-Methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)-6-[(2,2,2-trifhioro- ethoxy)methyl]pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine formiate
Example 30
6- [(2 -Aminoethoxy)methyl] -5 -(7-methoxy-5 -methyl- 1 -benzothiophen-2-y l)-7 -(piperazin- 1 -yl- methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydrochloride
Example 31
Methyl {[4-amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-6-yl]methoxy}acetate
Example 32
{ [4-Amino-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)pyrrolo- [2,l-f][l,2,4]triazin-6-yl]methoxy}acetic acid
Example 33
2- { [4-Amino-5-(7-methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)pyrrolo- [2, 1 -f] [ 1 ,2,4]triazin-6-yl]methoxy} acetamide
Example 34
2-( {7- [(4-Acetylpiperazin- 1 -yl)methyl]-4-amino-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)- pyrrolo[2, 1 -f] [1 ,2,4]triazin-6-yl}methoxy)acetamide
Example 35
5-(7-Methoxy-5-methyl-l-benzothiophen-2-yl)-6-(phenoxymethyl)-7-(piperazin-l-ylmethyl)- pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-4-amine bis(formiate)
Example 36
5 -(7 -Methoxy-5 -methyl- 1 -benzothiophen-2-y l)-6- [(methylamino)methyl] -7 -(piperazin- 1 -yl- methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydrochloride
Example 37
6-[(Dimethylamino)methyl]-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-yl- methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydrochloride Example 38
6-[(Ethylamino)methyl]-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-yl- methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydro chloride
Example 39
2-({[4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)pyrrolo- [2,l-f][l,2,4]triazin-6-yl]methyl}amino)ethanol trihydrochloride
Example 40
rac- 1 - { [4-Amino-5 -(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)-7-(piperazin- 1 -ylmethyl)- pyrrolo [2, 1 -f] [ 1 ,2,4]triazin-6-yl]methyl}piperidin-3 -ol trihydrochloride
Example 41
1 - { [4-Amino-5-(7-methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)pyrrolo- [2,1 -f] [ 1 ,2,4]triazin-6-yl]methyl}piperidin-4-ol trihydrochloride
Example 42
rac- 1 - { [4-Amino-5 -(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)-7-(piperazin- 1 -ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-6-yl]methyl}pyrrolidin-3-ol trihydrochloride
Example 43
6- [(Diethylamino)methyl] -5-(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -yl- methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydrochloride
Example 44
6-[(Cyclobutylamino)methyl]-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-yl- methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydrochloride
Example 45
5-(7-Methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)-6-(pyrrolidin-l-yl- methyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydrochloride
Example 46
6-[(Cyclopropylamino)methyl]-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)-7-(piperazin- 1 -yl- methyl)pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-4-amine trihydrochloride
Example 47
6- { [(Cy clopropylmethyl)amino]methyl} -5 -(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)-7- (piperazin- 1 -ylmethyl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine trihydrochloride
Example 48
/V-{[4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-6-yl]methyl} glycine trihydrochloride
Example 49 4- { [4-Amino-5-(7-methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7 -(piperazin- 1 -ylmethyl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-6-yl]methyl}piperazin-2-one trihydrochloride
Example 50
[4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo- [2, 1 -f] [1 ,2,4]triazin-6-yl]methanol
Example 51
(3S)- 3-( { [4-Amino-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-6-yl]methyl}amino)pyrrolidin-2-one
Example 52
4-{[4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo- [2,l-f][l,2,4]triazin-6-yl]methyl}piperazin-2-one
Example 53
rac- 1 -( { [4-Amino-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-6-yl]methyl}amino)propan-2-ol
Example 54
1-({[4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(morpholin-4-ylmethyl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-6-yl]methyl}amino)-2-methylpropan-2-ol
Example 55
1 -(4- { [4-Amino-6-(hydroxymethyl)-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-7-yl]methyl}piperazin-l -yl)ethanone
Example 56
(37?)-3-[({7-[(4-Acetylpiperazin-l-yl)methyl]-4-amino-5-(7-methoxy-5-methyl-l-benzothiophen-
2-yl)pyrrolo[2,l -f] [1 ,2,4]triazin-6-yl}methyl)amino]pyrrolidin-2-one
Example 57
l-(4-{[4-Amino-6-{[(2-hydroxy-2-methylpropyl)amino]methyl}-5-(7-methoxy-5-methyl-l- benzothiophen-2-yl)pyrrolo [2, 1 -f] [ 1 , 2, 4]triazin-7-yl]methyl [piperazin- 1 -yl)ethanone
Example 58
4-({4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-6-[(3-oxopiperazin-l-yl)methyl]- pyrrolo[2,l-f][l,2,4]triazin-7-yl}methyl)piperazine-l-carbaldehyde formiate
Example 59
4-( { 7- [(4-Acetylpiperazin- 1 -yl)methyl] -4-amino-5 -(7 -methoxy-5 -methyl- 1 -benzothiophen-2 -yl)- pyrrolo[2,l -f] [1 ,2,4]triazin-6-yl}methyl)piperazin-2-one
Example 60
Methyl 4-amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylcarbonyl)- pyrrolo[2,l -f] [1 ,2,4]triazine-6-carboxylate bis(formiate) Example 61
5-(7-Methoxy-5 -methyl- 1 -benzothiophen-2-yl)-6-( 1 ,3 -oxazol-5-yl)-7-(piperazin- 1 -ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-4-amine trihydrochloride
Example 62
6-(Aminomethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l -ylmethyl)- pyrrolo[2,l -f] [1 ,2,4]triazin-4-amine trihydrochloride
Example 63
A- {[4-Amino-5-(7-methoxy-5-methyl-l -benzothiophen-2 -yl)-7-(piperazin-l-ylmethyl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-6-yl]methyl}acetamide bis(trifhioroacetate)
Example 64
A- {[4-Amino-5-(7-methoxy-5-methyl-l -benzothiophen-2 -yl)-7-(piperazin-l-ylmethyl)pyrrolo- [2,l-f][l,2,4]triazin-6-yl]methyl}acetamide dihydrochloride
Example 65
A-({4-Amino-7-[(4-formylpiperazin-l-yl)methyl]-5-(7-methoxy-5-methyl-l-benzothiophen- 2-yl)pyrrolo[2,l-f][l,2,4]triazin-6-yl}methyl)acetamide formiate
Example 66
A-( { 7- [(4-Acety lpiperazin- 1 -yl)methyl] -4-amino-5 -(7-methoxy-5 -methyl- 1 -benzothiophen-2 -yl)- pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-6-yl}methyl)acetamide
Example 67
A-( {4-Amino-5-(7-methoxy-5-methyl-l -benzothiophen-2 -yl)-7-[(3-oxopiperazin-l -yl)methyl]- pyrrolo[2,l -f] [ 1 ,2,4]triazin-6-yl}methyl)acetamide
Example 68
4-Amino-6-(hydroxymethyl)-5-(7-methoxy-5-methyl-l -benzothiophen-2 -yl)pyrrolo[2,l-f]- [1,2 ,4] triazine-7 -carbonitrile
Example 69
4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]- [1,2 ,4] triazine-7 -carbonitrile
Example 70
4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl- 1 -benzothiophen-2 -yl)pyrrolo[2, 1 -f] [1 ,2,4]- triazine-7-carbonitrile
Example 71
4-Amino-5-(7 -methoxy-5 -methyl- 1 -benzothiophen-2 -yl)-6- [(3 -oxopiperazin- 1 -yl)methyl]- pyrrolo[2,l -f] [1 ,2,4]triazine-7-carbonitrile
Example 72 N,N'- { [4-Amino-5 -(7-m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo [2, 1 -f] [ 1 ,2,4]triazine-
6,7-diyl]bis(methylene)}diacetamide
Example 73
2-[4-Amino-6-(hydroxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]- [l,2,4]triazin-7-yl]propan-2-ol
Example 74
4-{[4-Amino-7-(2-hydroxypropan-2-yl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo- [2, 1 -f] [1 ,2,4]triazin-6-yl]methyl}piperazin-2-one
Example 75
[4-Amino-5-(7-methoxy-5-methyl-l -benzothiophen-2-yl)-7-methylpyrrolo[2,l -f] [1 ,2,4]triazin-
6-yl]methanol
Example 76
4-{[4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-methylpyrrolo[2,l-f][l,2,4]- triazin-6-yl]methyl } piperazin-2 -one
Example 77
l-({[4-Amino-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-methylpyrrolo[2,l- f] [ 1 ,2,4]triazin-6-yl]methyl}amino)-2-methylpropan-2-ol formiate
Example 78
1 -( {[4-Amino-5-(7-methoxy-5-methyl-l -benzothiophen-2-yl)-7-methylpyrrolo[2,l-f] [1,2,4]- triazin-6-yl]methyl}amino)-2-methylpropan-2-ol
Example 79
[4-Amino-7-chloro-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]triazin-
6-yl]methanol
Example 80
4-{[4-Amino-7-chloro-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l- f][l,2,4]triazin-6-yl]methyl}piperazin-2-one
Example 81
1 -( { [4-Amino-7-chloro-5-(7-methoxy-5-methyl-l -benzothiophen-2-yl)pyrrolo[2, 1 -f] [ 1 ,2,4]- triazin-6-yl]methyl}amino)-2-methylpropan-2-ol formiate
Example 82
1 -( { [4-Amino-7-chloro-5-(7-methoxy-5-methyl-l -benzothiophen-2-yl)pyrrolo[2, 1 -f] [ 1 ,2,4]- triazin-6-yl]methyl}amino)-2-methylpropan-2-ol
Example 83
7-Chloro-6-(ethoxymethyl)-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)pyrrolo[2, 1 -f] [1 ,2,4]- triazin-4-amine Example 84
5-(7-Methoxy-5-methyl-l-benzothiophen-2-yl)-6-methyl-7-(piperazin-l-ylmethyl)pyrrolo[2,l-f]-
[1.2.4]triazin-4-amine formiate
Example 85
6-Chloro-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-7-(piperazin-l-ylmethyl)pyrrolo[2,l-f]-
[1.2.4]triazin-4-amine trihydrochloride
Example 86
[4-Amino-6-(ethoxymethyl)-5 -(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo [2, 1 -f] [ 1 ,2,4] - triazin-7 -yljmethanol
Example 87
1 - { [4-Amino-6-(ethoxymethyl)-5-(7 -methoxy-5-methyl- 1 -benzothiophen-2-yl)pyrrolo[2, 1 -f] - [ 1 ,2 ,4] triazin-7-yl]methyl } imidazolidin-2-one
Example 88
4- {[4-Amino-5-(7-methoxy- 1 -benzothiophen-2-yl)-6-(methoxymethyl)pyrrolo[2, 1 -f] [ 1 ,2,4]- triazin-7-yl]methyl}piperazin-2-one
Example 89
4- { [4-Amino-6-(methoxymethyl)-5-(5-methyl-l -benzothiophen-2-yl)pyrrolo[2, 1 -f] [ 1 ,2,4]triazin- 7 -yl]methyl } piperazin-2-one
Example 90
l-[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]-
[1.2.4] triazin-7-yl] ethanol
Example 91
[4-Amino-6-(ethoxymethyl)-5 -(7 -m ethoxy-5 -methyl- 1 -benzothiophen-2-yl)pyrrolo [2, 1 -f] [ 1 ,2,4] - triazin-7 -yl] (cy clopropyl)methanol
Example 92
(55)-3-({[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one
Example 93
(35)-3-({[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo- [2,1 -f] [1 ,2,4]triazin-7-yl]methyl}amino)pyrrolidin-2-one
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Example 106
4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)-/V-[(. /?)-2-oxo- pyrrolidin-3-yl]pyrrolo[2,l -f] [1 ,2,4]triazine-7-carboxamide
Example 107
4-{[4-Amino-6-(ethoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]- [ 1 ,2 ,4] triazin-7 -yl] carbonyl } piperazin-2 -one
Figure imgf000093_0002
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Example 124
4-{[4-Amino-5-(5,7-dimethoxy-l-benzothiophen-2-yl)-6-(methoxymethyl)pyrrolo[2,l-f][l,2,4]- triazin-7 -yljmethyl } piperazin-2 -one
Example 125
4- { [4- Amino-7 -(hydro xymethyl)-5 -(7-methoxy-5 -methyl- 1 -benzothiophen-2 -yl)pyrrolo [2 , 1 -f] - [1,2 ,4] triazin-6-yl]methyl } piperazin-2 -one
Example 126
4-{[4-Amino-7-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]- [l,2,4]triazin-6-yl]methyl}piperazin-2-one
Example 127
4-{[4-Amino-7-(ethoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]- [1,2 ,4] triazin-6-yl]methyl } piperazin-2 -one or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof ;
optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
4. The combination according to any one of claims 1 to 3, wherein said component A is 4-{[4- Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl- 1 -benzothiophen-2-yl)pyrrolo[2, 1 -f] [ 1 ,2,4]- triazin-7 -yljmethyl } piperazin-2 -one . 5. The combination according to any one of claims 1 to 4, wherein said component B is a compound selected from the list consisting of Ulixertinib, Trametinib, BAY‘672 , AZD8055, Lapatinib, Erlotinib, Apitolisib, Dactolisib, Cabozantinib, and BAY-474 or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof, as described and defined herein, optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially
for use in treating bladder cancer.
6. The combination according to any one of claims 1 to 5, wherein said component A is 4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]- [l,2,4]triazin-7-yl]methyl}piperazin-2-one and said component B is Ulixertinib.
7. The combination according to any one of claims 1 to 5, wherein said component A is 4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]-
[l,2,4]triazin-7-yl]methyl}piperazin-2-one and said component B is Trametinib.
8. The combination according to any one of claims 1 to 5, wherein said component A is 4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]-
[l,2,4]triazin-7-yl]methyl}piperazin-2-one and said component B is BAY 1076672. 9. The combination according to any one of claims 1 to 5, wherein said component A is
4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]-
[l,2,4]triazin-7-yl]methyl}piperazin-2-one and said component B is AZD8055.
10. The combination according to any one of claims 1 to 5, wherein said component A is 4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]-
[l,2,4]triazin-7-yl]methyl}piperazin-2-one and said component B is Lapatinib.
11. The combination according to any one of claims 1 to 5, wherein said component A is 4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]- [l,2,4]triazin-7-yl]methyl}piperazin-2-one and said component B is Erlotinib.
12. The combination according to any one of claims 1 to 5, wherein said component A is 4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]-
[l,2,4]triazin-7-yl]methyl}piperazin-2-one and said component B is Cabozantinib.
13. The combination according to any one of claims 1 to 5, wherein said component A is 4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]-
[l,2,4]triazin-7-yl]methyl}piperazin-2-one and said component B is BAY-474. 14. Use of a combination according to any one of claims 1 to 13 for the preparation of a medicament for the treatment or prophylaxis of bladder cancer.
15. A method of treatment or prophylaxis of bladder cancer in a subject, comprising administering to said subject a therapeutically effective amount of a combination according to any one of claims 1 to 13.
16. A kit comprising a combination of :
component A : one or more 6,7-disubstituted 5-(l-benzothiophen-2-yl)pyrrolo[2,l-f][l,2,4]- triazin-4-amine compounds of general formula (B), or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof, according to any one of claims 1 to 9 ; and
component B: a compound selected from the list consisting of Ulixertinib, Trametinib, BAY‘672 , AZD8055, Lapatinib, Erlotinib, Apitolisib, Dactolisib, Cabozantinib, and BAY-474 or physiologically acceptable salts, solvates, hydrates or stereoisomers thereof, according to any one of claims 1 to 13,
in which optionally both or either 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,
for use in treating bladder cancer. 17. The combination according to any one of claims 1 to 5, wherein said component A is
4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]-
[l,2,4]triazin-7-yl]methyl}piperazin-2-one and said component B is Apitolisib.
18. The combination according to any one of claims 1 to 5, wherein said component A is 4-{[4-Amino-6-(methoxymethyl)-5-(7-methoxy-5-methyl-l-benzothiophen-2-yl)pyrrolo[2,l-f]- [l,2,4]triazin-7-yl]methyl}piperazin-2-one and said component B is Dactolisib.
PCT/EP2019/057087 2018-03-23 2019-03-21 Combinations of rogaratinib WO2019180141A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP18163722.4 2018-03-23
EP18163722 2018-03-23

Publications (1)

Publication Number Publication Date
WO2019180141A1 true WO2019180141A1 (en) 2019-09-26

Family

ID=61768110

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2019/057087 WO2019180141A1 (en) 2018-03-23 2019-03-21 Combinations of rogaratinib

Country Status (1)

Country Link
WO (1) WO2019180141A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10870657B2 (en) 2015-12-22 2020-12-22 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US10933054B2 (en) 2017-06-21 2021-03-02 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
WO2021133509A1 (en) * 2019-12-27 2021-07-01 Angex Pharmaceutical, Inc. Heterocyclic compounds as mtor inhibitors

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5011472A (en) 1988-09-06 1991-04-30 Brown University Research Foundation Implantable delivery system for biological factors
US5023252A (en) 1985-12-04 1991-06-11 Conrex Pharmaceutical Corporation Transdermal and trans-membrane delivery of drugs
WO2005030140A2 (en) 2003-09-26 2005-04-07 Exelixis, Inc. C-met modulators and methods of use
WO2005121142A1 (en) 2004-06-11 2005-12-22 Japan Tobacco Inc. 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2h-pyrido’2,3-d! pyrimidine derivatives and related compounds for the treatment of cancer
US20060014768A1 (en) 2004-06-11 2006-01-19 Japan Tobacco Inc. Pyrimidine compound and medical use thereof
WO2007138612A2 (en) 2006-05-25 2007-12-06 Vittal Mallya Scientific Research Foundation A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4- yl]-(3-ethynylphenyl)amine hydrochloride
EP1888578A2 (en) 2005-05-20 2008-02-20 Novartis AG Imidazoquinolines as lipid kinase inhibitors
US7354939B2 (en) 2004-05-14 2008-04-08 Vertex Pharmaceuticals Incorporated Pyrrole inhibitors of ERK protein kinase, synthesis thereof and intermediates thereto
WO2008071451A1 (en) 2006-12-14 2008-06-19 Bayer Schering Pharma Aktiengesellschaft Dihydropyridine derivatives useful as protein kinase inhibitors
EP2303875A2 (en) 2008-06-20 2011-04-06 AstraZeneca AB Compositions with and process for methylmorpholin-subsituted pyrido[2,3-d]pyrimidines
WO2013087578A1 (en) 2011-12-15 2013-06-20 Bayer Pharma Aktiengesellschaft Disubstituted benzothienyl-pyrrolotriazines and their use as fgfr kinase inhibitors
US8563719B2 (en) 2010-03-23 2013-10-22 Scinopharm Taiwan, Ltd. Process and intermediates for preparing lapatinib
US8710221B2 (en) 2010-03-23 2014-04-29 Scinopharm Taiwan, Ltd. Process and intermediates for preparing lapatinib
US8895729B2 (en) 2012-10-10 2014-11-25 Genentech, Inc. Process for making thienopyrimidine compounds

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5023252A (en) 1985-12-04 1991-06-11 Conrex Pharmaceutical Corporation Transdermal and trans-membrane delivery of drugs
US5011472A (en) 1988-09-06 1991-04-30 Brown University Research Foundation Implantable delivery system for biological factors
WO2005030140A2 (en) 2003-09-26 2005-04-07 Exelixis, Inc. C-met modulators and methods of use
US7354939B2 (en) 2004-05-14 2008-04-08 Vertex Pharmaceuticals Incorporated Pyrrole inhibitors of ERK protein kinase, synthesis thereof and intermediates thereto
WO2005121142A1 (en) 2004-06-11 2005-12-22 Japan Tobacco Inc. 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2h-pyrido’2,3-d! pyrimidine derivatives and related compounds for the treatment of cancer
US20060014768A1 (en) 2004-06-11 2006-01-19 Japan Tobacco Inc. Pyrimidine compound and medical use thereof
EP1888578A2 (en) 2005-05-20 2008-02-20 Novartis AG Imidazoquinolines as lipid kinase inhibitors
WO2007138612A2 (en) 2006-05-25 2007-12-06 Vittal Mallya Scientific Research Foundation A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4- yl]-(3-ethynylphenyl)amine hydrochloride
WO2008071451A1 (en) 2006-12-14 2008-06-19 Bayer Schering Pharma Aktiengesellschaft Dihydropyridine derivatives useful as protein kinase inhibitors
EP2303875A2 (en) 2008-06-20 2011-04-06 AstraZeneca AB Compositions with and process for methylmorpholin-subsituted pyrido[2,3-d]pyrimidines
US8563719B2 (en) 2010-03-23 2013-10-22 Scinopharm Taiwan, Ltd. Process and intermediates for preparing lapatinib
US8710221B2 (en) 2010-03-23 2014-04-29 Scinopharm Taiwan, Ltd. Process and intermediates for preparing lapatinib
WO2013087578A1 (en) 2011-12-15 2013-06-20 Bayer Pharma Aktiengesellschaft Disubstituted benzothienyl-pyrrolotriazines and their use as fgfr kinase inhibitors
US8895729B2 (en) 2012-10-10 2014-11-25 Genentech, Inc. Process for making thienopyrimidine compounds

Non-Patent Citations (21)

* Cited by examiner, † Cited by third party
Title
"Goodman and Gilman's The Pharmacological Basis of Therapeutics", 1996, MCGRAW-HILL, pages: 1225 - 1287
"Merck Index", 1996
BERGERS; HANAHAN, NAT. REV. CANCER, vol. 8, 2008, pages 592 - 603
CHRESTA ET AL., CANCER RES., vol. 70, 2010, pages 288
FORBES ET AL., NUCLEIC ACIDS RES., vol. 43, 2015, pages D805 - D811
GERMANN ET AL., MOL. CANCER THER., vol. 16, 2017, pages 2351 - 2363
GROENENDIJK; BERNARDS, MOL. ONCOL., vol. 8, 2014, pages 1067 - 1083
HARTUNG, I. ET AL.: "Optimization of allosteric MEK inhibitors. Part 2: Taming the sulfamide group balances compound distribution", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 26, 2016, pages 186 - 193, XP029336531, DOI: doi:10.1016/j.bmcl.2015.11.004
ITOH; ORNITZ, J. BIOCHEM., vol. 149, no. 2, 2011, pages 121 - 130
KORC; FRIESEL, CURR. CANCER DRUGS TARGETS, vol. 5, 2009, pages 639 - 651
LAKE ET AL., CELL. MOL. LIFE SCI., vol. 73, 2016, pages 4397 - 4413
MAIRA ET AL., MOL. CANCER THER., vol. 7, 2008, pages 1851
NEMA, S. ET AL.: "Excipients and Their Use in Injectable Products", PDA JOURNAL OF PHARMACEUTICAL SCIENCE & TECHNOLOGY, vol. 51, no. 4, 1997, pages 166 - 171
POLANSKA ET AL., DEVELOPMENTAL DYNAMICS, vol. 238, no. 2, 2009, pages 277 - 293
POWELL, M.F. ET AL.: "Compendium of Excipients for Parenteral Formulations", PDA JOURNAL OF PHARMACEUTICAL SCIENCE & TECHNOLOGY, vol. 52, no. 5, 1998, pages 238 - 311, XP009119027
RAUCH ET AL., CURR. OPIN. CHEM. BIOL., vol. 41, 2016, pages 151 - 158
STRICKLEY, R.G: "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1", PDA JOURNAL OF PHARMACEUTICAL SCIENCE & TECHNOLOGY, vol. 53, no. 6, 1999, pages 324 - 349
SWINNEY; ANTHONY, NATURE REV. DRUG DISC., vol. 10, no. 7, 2011, pages 507 - 519
WALLIN ET AL., MOL.CANCER THER., vol. 10, 2011, pages 2426
WESCHE ET AL., BIOCHEM. J., vol. 437, no. 2, 2011, pages 199 - 213
ZOPF D. ET AL., POSTER PRESENTED AT THE 22ND EORTC-NCI-AACR SYMPOSIUM, 16 November 2010 (2010-11-16)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10870657B2 (en) 2015-12-22 2020-12-22 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US11560390B2 (en) 2015-12-22 2023-01-24 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US10933054B2 (en) 2017-06-21 2021-03-02 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US10940139B2 (en) 2017-06-21 2021-03-09 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11000515B2 (en) 2017-06-21 2021-05-11 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11026930B1 (en) 2017-06-21 2021-06-08 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11213515B1 (en) 2017-06-21 2022-01-04 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11541041B1 (en) 2017-06-21 2023-01-03 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, Rasopathies, and fibrotic disease
WO2021133509A1 (en) * 2019-12-27 2021-07-01 Angex Pharmaceutical, Inc. Heterocyclic compounds as mtor inhibitors

Similar Documents

Publication Publication Date Title
EP3268490B1 (en) Substituted 2,3-dihydroimidazo[1,2-c]quinazoline-containing combinations
WO2018122168A1 (en) Combinations of bub1 kinase and parp inhibitors
JP2018512403A (en) Use of substituted 2,3-dihydroimidazo [1,2-c] quinazolines
EP3219329A1 (en) Combinations of copanlisib
AU2018248586A1 (en) Anticancer combination therapy
WO2017134000A1 (en) Copanlisib biomarkers
AU2018241944A1 (en) Anticancer combination therapy
WO2019180141A1 (en) Combinations of rogaratinib
US11660301B2 (en) Combination of ATR kinase inhibitors with PARP inhibitors
WO2018206547A1 (en) Combination of bub1 and atr inhibitors
US10925880B2 (en) Combination of PI3K-inhibitors
US20210369724A1 (en) Combination of atr kinase inhibitors with 2,3-dihydroimidazo[1,2-c]quinazoline compounds
WO2019105734A1 (en) Combinations of copanlisib
WO2018215282A1 (en) Combination of bub1 and pi3k inhibitors
WO2018158175A1 (en) Combination of bub1 inhibitors
EP3585437B1 (en) Combinations of copanlisib with anti-pd-1 antibody
US11185549B2 (en) Combination of a PI3K-inhibitor with an androgen receptor antagonist
WO2020164997A1 (en) Combination of pi3k-inhibitors
WO2021260443A1 (en) Combinations of 2,3-dihydroimidazo[1,2-c]quinazolines

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19712194

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19712194

Country of ref document: EP

Kind code of ref document: A1