WO2018122168A1 - Combinations of bub1 kinase and parp inhibitors - Google Patents

Combinations of bub1 kinase and parp inhibitors Download PDF

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Publication number
WO2018122168A1
WO2018122168A1 PCT/EP2017/084395 EP2017084395W WO2018122168A1 WO 2018122168 A1 WO2018122168 A1 WO 2018122168A1 EP 2017084395 W EP2017084395 W EP 2017084395W WO 2018122168 A1 WO2018122168 A1 WO 2018122168A1
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alkyl
methyl
indazol
amino
cycloalkyl
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PCT/EP2017/084395
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French (fr)
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Gerhard Siemeister
Sabine Zitzmann-Kolbe
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Bayer Pharma Aktiengesellschaft
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to combinations of at least two components, component A and component B, component A being an inhibitor of budding uninhibited by benzimidazoles 1 kinase (Bub1 ) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, and component B being an inhibitor of Poly(ADP-ribose) polymerase (PARP) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.
  • PARP Poly(ADP-ribose) polymerase
  • Another aspect of the present invention relates to the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, particularly for the treatment of cancer.
  • Another aspect of the present invention relates to the use of a PARP inhibitor as a sensitizer of cells to Bub1 inhibitors or vice versa.
  • Yet another aspect of the present invention relates to methods of treatment or prophylaxis of a cancer in a subject, comprising administering to said subject a therapeutically effective amount of a combination as described herein.
  • kits comprising a combination of:
  • component B as defined supra, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof ;
  • 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.
  • Cell cycle deregulation represents one of the classical hallmarks of cancer [Hanahan D and Weinberg RA, Cell 100, 57, 2000; Hanahan D and Weinberg RA, Cell 144, 646, 201 1 ] and consequently cell cycle arrest is the predominant mode of action of a lot of the cancer drugs on the market including " anti-mitotics ' such as taxanes and vinca alkaloids.
  • the concept of cell cycle checkpoint regulation offers a novel approach to cancer treatment: inactivation of cell cycle checkpoints is considered to drive tumor cells into cell divison despite DNA damage or unattached/misattached chromosomes resulting in a lethal degree of DNA damage or aneuploidy.
  • the spindle assembly checkpoint controls the accurate attachment of mircrotubules of the spindle device to the kinetochors (the attachment site for microtubules) of the duplicated chromosomes.
  • the SAC is active as long as unattached kinetochores are present and generates a wait-signal to give the dividing cell the time to ensure that each kinetochore is attached to a spindle pole, and to correct attachment errors [for recent review see Musacchio A, Curr. Biol. 25, R1002-R1018, 2015].
  • the SAC signal is initiated by multipolar-spindle 1 (Mpsl )-mediated phosphorlyation of Met-Glu-Leu-Thr (MELT) motifs on the kinetochore scaffold 1 (KNL-1 ) protein to generate docking sites for budding uninhibited by benzimidazole 1 (Bub1 )/Bub3 dimers.
  • Mpsl multipolar-spindle 1
  • MELT Met-Glu-Leu-Thr
  • Bub1 kinetochore scaffold 1
  • Bub3 dimers The N-terminal non-catalytic part of Bub1 represents a scaffold for the assembly of mitotic arrest deficient 1 (MAD1 )/MAD2, BubR1 and centromere protein E (CENP-E) proteins.
  • MCC diffusible mitotic checkpoint complex
  • APC/C ubiquitin ligase anaphase-promoting complex/cyclosome
  • Bub1 kinase phosphorylates histone H2A at Thr120 within the centromeric region of the duplicated chromosomes thereby creating binding sites for shugoshin proteins (Sgo) 1 and 2, which protect centromeric cohesin from premature degradation, and for the chromosomal passenger complex consisting of INCENP, survivin, borealin and Aurora B (AurB) [Kawashima et al. Science 327, 172, 2010; Watanabe Y, Cold Spring Harb. Symp. Quant. Biol. 75, 419, 2010]. Specific inhibition of Bub1 kinase activity results in reduced levels of Sgo1 and Sgo2 at mitotic centromeres.
  • AurB fails to concentrate at the centromeres and was instead found to be spread over the chromosome arms [Baron et al. eLife 5, e12187, 2016].
  • AurB activity localized at the centromeric region is essential for the resolution of microtubule - kinetochore attachment errors such as syntelic and merotelic attachments.
  • Dyslocatization of AurB due to Bub1 kinase inactivation strongly compromizes the cells ability to resolve attachment errors and results in an increased rate of chromosome aligment defects [Ricke et al. J. Cell Biol.
  • Bub1 kinase was reported to be involved in the DNA damage signaling pathway downstream of Ataxia-telangiectasia Mutated (ATM) kinase [Yang et al. DNA Repair 1 1 , 185, 2012] and in nonhomologous end-joining system of DNA double strand break repair [Jessulat et al. Mol. Cell. Biol. 35, 2448, 2015].
  • ATM Ataxia-telangiectasia Mutated
  • PARP enzyme Upon sensing of DNA damage PARP enzyme gets activated and attaches poly(ADP ribose) polymers to target proteins to recruit DNA repair enzymes. Inhibition of PARP has been shown to result in lethal DNA damage repair deficiency in BRCA-1/2 mutated cells [for recent review see: Ganguly et al. Biomark Cancer 8(suppl 1 ), 15, 2016].
  • the present invention provides combinations of at least two components, component A and component B, component A being an inhibitor of BUB1 -kinase or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, and component B being a PARP inhibitor or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.
  • the present invention relates to a kit comprising:
  • Component A a Bub1 kinase inhibitors as described herein, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof ;
  • Component B a PARP inhibitor as described herein, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof ; and, optionally, Component C : one or more further pharmaceutical agents ;
  • components A and B in any of the above- mentioned combinations are in the form of a pharmaceutical formulation/composition which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • the components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • the present invention covers the combinations as described herein for the treatment or prophylaxis of a disease. In accordance with another aspect, the present invention covers the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease.
  • the present invention covers methods of treatment or prophylaxis of a cancer in a subject, comprising administering to said subject a therapeutically effective amount of a combination as described herein.
  • Constituents which are optionally substituted as stated herein may be substituted, unless otherwise noted, one or more times, independently from one another at any possible position.
  • each definition is independent.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 V, W, Y and/or Z occur more than one time for any compound of formula (I) each definition of R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , V, W, Y and Z is independent.
  • a constituent be composed of more than one part, e.g.
  • Ci-C4-alkoxy-Ci-C4-alkyl- the position of a possible substituent can be at any of these parts at any suitable position.
  • a hyphen at the beginning or at the end of the constituent marks the point of attachment to the rest of the molecule. Should a ring be substituted the substitutent could be at any suitable position of the ring, also on a ring nitrogen atom if suitable.
  • the term "comprising" when used in the specification includes “consisting of”.
  • halogen atom halo- or Hal-
  • fluorine chlorine, bromine or iodine atom.
  • Ci-C6-alkyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2- methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1 , 1 - dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2- ethylbutyl, 1 -ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1 , 1 -
  • said group has 1 , 2, 3 or 4 carbon atoms ("Ci-C4-alkyl”), e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl”), e.g. a methyl, ethyl, n-propyl- or iso-propyl group.
  • Ci-C4-alkyl e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1 , 2 or 3 carbon atoms
  • Si-C3-alkyl e.g. a methyl, ethyl, n-propyl- or iso-propyl group.
  • Ci-C6-haloalkyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C6-alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F.
  • Said Ci-C6-haloalkyl group is, for example, -CF3, - CHF 2 , -CH2F, -CF2CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, or -CH(CH 2 F) 2 .
  • Ci-C6-alkoxy is to be understood as meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term “alkyl” is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof.
  • Particularly preferred is "Ci-C4-alkoxy” e.g.
  • Ci-C4-haloalkoxy is to be understood as meaning a linear or branched, saturated, monovalent Ci-C4-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F.
  • Said Ci-C4-haloalkoxy group is, for example, - OCF3, -OCHF2, -OCH2F, -OCF2CF3, or -OCH 2 CF 3 .
  • Ci-C6-hydroxyalkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C6-alkyl” is defined supra, and in which one or more hydrogen atoms is replaced by a hydroxy group, e.g. a hydroxy methyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 1 ,3-dihydroxypropan-2-yl, 3- hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1 -hydroxy-2-methyl-propyl group.
  • a hydroxy group e.g. a hydroxy methyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 1
  • Ci-C3-hydroxyalkyl e.g. a hydroxy methyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 1 ,3- dihydroxypropan-2-yl.
  • C2-C6-hydroxyalkyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group having 2, 3, 4, 5, or 6 carbon atoms, in which one or more hydrogen atoms is replaced by a hydroxy group, e.g. a 2-hydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 3-hydroxy-2-methyl-propyl, 2- hydroxy-2-methyl-propyl.
  • C2-C4-hydroxyalkyl more preferred is "C2- hydroxyalkyl", i.e. a 2-hydroxyethyl group.
  • C3-C6-cycloalkyl is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms ("C3-C6- cycloalkyl").
  • Said C3-C6-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
  • C3-C6-cycloalkyloxy is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon group of formula -O-cycloalkyl, in which the term “cycloalkyi” is defined supra, e.g. a. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group.
  • ⁇ - ⁇ - ⁇ as used throughout this text, e.g. in the context of the definition of "Ci- C6-alkyl”, “Ci-C6-haloalkyl”, “Ci-C6-hydroxyalkyl”, “Ci-C6-alkoxy”, is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C1-C6” is to be interpreted as any sub-range comprised therein, e.g.
  • C1-C6 C2-C5 , C3-C4 , C1-C2 , C1-C3 , C1-C4 , C1-C5 ; particularly C1-C2 , C1-C3 , C1-C4 , C1-C5, C1-C6; more particularly C1-C4 ; in the case of "Ci-C6-haloalkyl" or "Ci-C6-haloalkoxy" even more particularly C1-C2.
  • C2-C6 as used throughout this text, e.g.
  • C2- C6-hydroxyalkyl in the context of the definition of "C2- C6-hydroxyalkyl", is to be understood as meaning a hydroxyalkyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C2-C6” is to be interpreted as any sub-range comprised therein, e.g. C2-C6, C2-C5, C3-C4, particularly C2-C3, C2-C4, C2-C5, C2-C6.
  • C3-C6 as used throughout this text, e.g. in the context of the definition of "C3-C6-cycloalkyl”, is to be understood as meaning a cycloalkyi group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3-C6” is to be interpreted as any sub-range comprised therein, e.g. C3-C6 , C4-C5 , C3-C5 , C3-C4 , C4-C6, C5-C6 ; particularly
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • substituents of the compounds of the general formulae of the present invention is understood as meaning “one, two, three, four or five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or two”.
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2 ", is to be understood as meaning that at least one of V, W, Y and Z represents CR 2 , and the remaining, independently from each other, represent CH or CR 2 , as it is known to a skilled person.
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2 and the remaining represent CH; according to other embodiments of the invention, V, W, Y and Z independently of each other represent CH or CR 2 , wherein two of V, W, Y and Z, independently of each other, represent CR 2 and the remaining represent CH; still according to other embodiments of the invention, V, W, Y and Z independently of each other represent CH or CR 2 , wherein three of V, W, Y and Z, independently of each other, represent CR 2 and the remaining represents CH, for example.
  • the invention also includes all suitable isotopic variations of a compound (i.e. component A, B or C(when present)) used in the combination of the present invention.
  • An isotopic variation of a compound is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
  • isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 CI, 82 Br, 123 l, 124 l,
  • isotopic variations of a compound used in the combination of the present invention are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence is preferred in some circumstances.
  • isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds used in the combination of this invention optionally contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms is present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres.
  • asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • the compounds used in the combination of the present invention optionally contain sulphur atoms which are asymmetric, such as an asymmetric sulfoxide, of structure:
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable chiral HPLC columns are manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention includes all possible stereoisomers of the compounds used in the combination of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, or E- or Z-isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound used in the combination of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • the compounds used in the combination of the present invention may exist as tautomers.
  • the present invention includes all possible tautomers of the compounds used in the combination of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds used in the combination of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N-oxides.
  • the present invention also relates to useful forms of the compounds used in the combination as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
  • the compounds used in the combination of the present invention can exist as a hydrate, or as a solvate, wherein the compounds contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds used in the combination of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1 -19.
  • a suitable pharmaceutically acceptable salt of the compounds used in the combination of the present invention may be, for example, an acid-addition salt of a compound bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)- benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2- naphthoic, nicotinic, pamoic, pectinic, per
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1 -amino-2,3,4-butantriol.
  • basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides ; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate ; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyi halides like benzyl and phenethyl bromides and others.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate
  • diamyl sulfates long chain halides such as decyl, la
  • acid addition salts of the compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds used in the combination of the invention are prepared by reacting the compounds with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds used in the combination of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • the present text in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown.
  • in vivo hydrolysable ester is understood as meaning an in vivo hydrolysable ester of a compound used in the combination of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C1-C6 alkoxymethyl esters, e.g. methoxymethyl, C1-C6 alkanoyloxymethyl esters, e.g.
  • An in vivo hydrolysable ester of a compound used in the combination of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • the present invention covers all such esters.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds used in the combination of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • pharmacokinetic profile means one single parameter or a combination thereof including permeability, bioavailability, exposure, and pharmacodynamic parameters such as duration, or magnitude of pharmacological effect, as measured in a suitable experiment.
  • Compounds with improved pharmacokinetic profiles can, for example, be used in lower doses to achieve the same effect, may achieve a longer duration of action, or a may achieve a combination of both effects.
  • a "fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein component A and component B are present together in one unit dosage or in a single entity.
  • a "fixed combination” is a pharmaceutical composition wherein the said component A and the said component B are present in admixture for simultaneous administration, such as in a formulation.
  • Another example of a "fixed combination” is a pharmaceutical combination wherein the said component A and the said component B are present in one unit without being in admixture.
  • a non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said component A and the said component B (and optionally component C) are present in more than one unit.
  • a non-fixed combination or kit-of-parts is a combination wherein the said component A and the said component B (and optionally component C) are present separately, for example in different and separate pharmaceutical compositions.
  • the components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • embodiments disclosed herein are not meant to be understood as individual embodiments which would not relate to one another.
  • Features discussed with one embodiment or aspect of the invention are meant to be disclosed also in connection with other embodiments or aspects of the invention shown herein. If, in one case, a specific feature is not disclosed with one embodiment or aspect of the invention, but with another, the skilled person would understand that does not necessarily mean that said feature is not meant to be disclosed with said other embodiment or aspect of the invention. The skilled person would understand that it is the gist of this application to disclose said feature also for the other embodiment or spect of the invention, but that just for purposes of clarity and to keep the length of this specification manageable.
  • Component A can be selected from inhibitors of BUB1 -kinase or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof specifically or generically disclosed e.g. in the publications as mentioned above which are incorporated herein by reference.
  • Component A is selected from the group of Bub1 inhibitors generically or specifically disclosed in WO 2016/042084, which are incorporated by reference herein.
  • component A is an inhibitor of Bub1 of general formula (I),
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2,
  • V represents N, and W, Y and Z independently of each other represent CH or CR 2 , or,
  • V and Y represent N, and W and Z independently of each other represent CH or CR 2 ,
  • R 1 represents a group selected from:
  • Ci-C6-alkyl Ci-C6-haloalkyl, C3-C6-cycloalkyl,
  • R 2 represents, independently of each other, halogen or a group selected from: Ci-C 3 -alkyl, C 3 -C4-cycloalkyl, Ci-C 3 -haloalkyl, Ci-C 3 -alkoxy,
  • R 3 represents a group selected from:
  • said C2-C6-hydroxyalkyl groups being optionally substituted with one, two or three halogen atoms selected from:
  • R 5 and R 7 independently of each other represent hydrogen (glycine) or a group selected from:
  • -CH 3 (alanine), -C(H)(CH 3 ) 2 (valine), -(CH 2 ) 2 CH 3 (norvaline), -CH 2 C(H)(CH 3 ) 2 (leucine), - C(H)(CH 3 )CH 2 CH 3 (isoleucine), -(CH 2 ) 3 CH 3 (norleucine), -C(CH 3 ) 3 (2-ie/f-butylglycine), benzyl (phenylalanine), 4-hydroxybenzyl (tyrosine), -(CH 2 )3NH 2 (ornithine), -(CH 2 )4NH 2 (lysine), -(CH 2 ) 2 C(H)(OH)CH 2 NH 2 (hydroxylysine), -CH 2 OH (serine), -(CH 2 ) 2 OH (homoserine), -C(H)(OH)CH 3 (threonine), -(CH 2 ) 3
  • Ci-C3-alkyl Ci-C3-haloalkyl, C 2 -C3-hydroxyalkyl, C3-C4-cycloalkyl,
  • component A is an inhibitor of Bub1 of general formula (I) supra,
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2
  • V represents N, and W, Y and Z independently of each other represent CH or CR 2 ,
  • R 1 represents a group selected from:
  • Ci-C 4 -alkoxy Ci-C 4 -haloalkoxy, C 3 -C 4 -cycloalkyl, and
  • R 3 represents a group selected from:
  • said C2-C6-hydroxyalkyl groups being optionally substituted with one, two or three halogen atoms selected from:
  • R 5 and R 7 independently of each other represent hydrogen (glycine) or a group selected from:
  • -CHs (alanine), -C(H)(CH 3 ) 2 (valine), -(CH 2 ) 2 CH 3 (norvaline), -CH 2 C(H)(CH 3 )2 (leucine), - C(H)(CH 3 )CH 2 CH3 (isoleucine), -(CH 2 ) 3 CH 3 (norleucine), -C(CH 3 ) 3 (2-ie/f-butylglycine), benzyl (phenylalanine), 4-hydroxybenzyl (tyrosine), -(CH 2 ) 3 NH 2 (ornithine), -(CH 2 )4NH 2 (lysine), -(CH 2 ) 2 C(H)(OH)CH 2 NH 2 (hydroxylysine), -CH 2 OH (serine), -(CH 2 ) 2 OH (homoserine), -C(H)(OH)CH 3 (threonine), -(CH 2 )
  • R 8 represents hydrogen or a group selected from:
  • Ci-C 3 -alkyl Ci-C 3 -haloalkyl, C 2 -C 3 -hydroxyalkyl, C 3 -C 4 -cycloalkyl,
  • component A is an inhibitor of Bub1 of general formula (I) supra,
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2
  • V represents N, and W, Y and Z independently of each other represent CH or CR 2 ,
  • R 1 represents a group selected from:
  • R 2 represents, independently of each other, halogen or a group selected from: Ci-C3-alkyl, C3-C4-cycloalkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy,
  • Ci-C 4 -alkoxy Ci-C 4 -haloalkoxy, C3-C 4 -cycloalkyl, and
  • R 3 represents a group selected from:
  • said C2-C6-hydroxyalkyl group being optionally substituted with one, two or three halogen atoms selected from:
  • R 5 and R 7 independently of each other represent a group selected from:
  • R 8 represents hydrogen or a group selected from:
  • Ci-C3-alkyl Ci-C3-haloalkyl, C 2 -C3-hydroxyalkyl, C3-C 4 -cycloalkyl,
  • component A is an inhibitor of Bub1 of general formula (I) supra,
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W,
  • Y and Z represents CR 2
  • V represents N, and W, Y and Z independently of each other represent CH or CR 2 ,
  • R 1 represents a Ci-C3-alkyl group
  • R 3 represents a group selected from:
  • R 5 and R 7 independently of each other represent a group selected from:
  • component A is an inhibitor of Bub1 of general formula (I) supra,
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W, Y and Z represents CR 2
  • V represents N
  • W, Y and Z independently of each other represent CH or CR 2 ,
  • R 1 represents a methyl group
  • R 2 represents, independently of each other, fluorine, chlorine or a group selected from:
  • R 3 represents a group selected from:
  • R 5 represents -CH3 (alanine)
  • R 7 represents -(CH 2 )4NH 2 (lysine), or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
  • component A is an inhibitor of Bub1 of general formula (I) supra,
  • V, W, Y and Z independently of each other represent CH or CR 2 , wherein one of V, W,
  • Y and Z represents CR 2
  • V represents N
  • W, Y and Z independently of each other represent CH or CR 2
  • R 1 represents a methyl group
  • R 2 represents, independently of each other, fluorine, chlorine or a group selected from:
  • R 3 represents a -(Chb ⁇ OH group, or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
  • component A is a compound selected from the group consisting of :
  • component A is is 2- ⁇ 3,5-difluoro-4-[(3- ⁇ 5- methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl ⁇ -1 /-/-indazol-1 - yl)methyl]phenoxy ⁇ ethanol,
  • said component A is 2- ⁇ 3,5-difluoro-4-[(3- ⁇ 5-methoxy- 4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl ⁇ -1 /-/-indazol-1 -yl)methyl]phenoxy ⁇ ethanol or a pharmaceutically acceptable salt thereof.
  • component A is 2- ⁇ 3,5-difluoro-4-[(3- ⁇ 5- methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl ⁇ -1 /-/-indazol-1 - yl)methyl]phenoxy ⁇ ethanol.
  • component A is selected from the group of Bub1 inhibitors described generically or specifically in:
  • a combination of the present invention comprising Compound A1 as mentioned above and a PARP inhibitor is a preferred embodiment of the invention.
  • Another embodiment of the present invention covers a combination comprising the Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and a PARP inhibitor or a pharmaceutically acceptable salt thereof. Another embodiment of the present invention covers a combination comprising the
  • PARP inhibitor selected from the group consisting of:
  • Another embodiment of the present invention covers a combination comprising the Compound A1 or a pharmaceutically acceptable salt thereof and a PARP inhibitor selected from the group consisting of olaparib, rucaparib, talazoparib, and niraparib or a pharmaceutically acceptable salt thereof.
  • Component A may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. Preferably Component A is administered intravenously, intraperitoneally or orally.
  • Compound A1 is administered preferably orally.
  • Component B of the Combination Component B is a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.
  • component B is an inhibitor of PARP1 and/or PARP2.
  • component B is an inhibitor of PARP inhibitor selected from the group consisting of:
  • component B is a PARP inhibitor selected from the group consisting of:
  • olaparib rucaparib, talazoparib, and niraparib
  • PARP inhibitors according to the present invention are commercially available and/or can be prepared according to methods readily available to a skilled person. For example the following references, which are incorporated herein by reference, describe methods to prepare PARP inhibitors:
  • Component B preferably is administered by the more appropriate route within the knowledge of the skilled person.
  • Component B may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • Component B is olaparib, or a pharmaceutically acceptable salt, N-oxide, tautomer, solvate, hydrate or stereoisomer thereof.
  • Olaparib (AZD-2281 , trade name Lynparza) is a PARP inhibitor approved in the US and Europe.
  • olaparib is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
  • the recommended dose of Olaparib is 400 mg (eight 50 mg capsules) taken twice daily orally, for a total daily dose of 800 mg.
  • patients continue treatment until disease progression or unacceptable toxicity arises.
  • olaparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic) high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete response or partial response) to platinum-based chemotherapy.
  • the recommended dose of Olaparib is 400 mg (eight capsules) taken twice daily, equivalent to a total daily dose of 800 mg.
  • Patients should start treatment with olaparib no later than 8 weeks after completion of their final dose of the platinum- containing regimen.
  • BRCA susceptibility gene
  • Methods to determine BRCA mutation status are readily available to a skilled person (for example BRACAnalysis CDxTM from Myriad Genetic Laboratories).
  • the dosing and/or dosing regimen of olaparib may be adjusted according to patients's response, adverse events and or co-treatment with other drugs by the skilled person using methods readily available to him/her.
  • Component B is rucaparib, or a pharmaceutically acceptable salt, N-oxide, tautomer, solvate, hydrate or stereoisomer thereof.
  • Rucaparib (AG 014699, trade name Rubraca) is a PARP inhibitor approved in the US for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer. It has been/is being tested in clinical trials in patients with disorders such as:
  • rucaparib is taken orally, for example in tablet form.
  • tablets of rucaparib were administered orally at a dose of 600 mg, twice daily.
  • the FDA has granted accelerated approval to rucaparib for treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies.
  • the recommended dose and schedule for rucaparib is 600 mg (two 300 mg tablets) taken orally twice daily with or without food.
  • BRCA susceptibility gene
  • Methods to determine BRCA mutation status are readily available to a skilled person (for example BRACAnalysis CDxTM from Myriad Genetic Laboratories, or FoundationFocus CDxBRCA test from Foundation Medicine Inc., for example).
  • the dosing and/or dosing regimen of rucaparib may be adjusted according to patients's response, adverse events and or co-treatment with other drugs by the skilled person using methods readily available to him/her.
  • Component B is talazoparib, or a pharmaceutically acceptable salt, N-oxide, tautomer, solvate, hydrate or stereoisomer thereof.
  • Talazoparib (BMN-673) is a PARP inhibitor being investigated as a potential anti-cancer agent. It has been or is being tested in clinical trials in patients with disorders such as: - Deleterious BRCA1/2 Mutation-Associated Ovarian Cancer,
  • talazoparib is taken orally, for example in tablet or capsule form.
  • patients received 1 mg p.o. once daily on 28 day cycles.
  • patients received talazoparib oral capsules once daily (1 .0 mg/day) in 21 -day cycles.
  • BRCA susceptibility gene
  • Component B is niraparib, or a pharmaceutically acceptable salt, N-oxide, tautomer, solvate, hydrate or stereoisomer thereof.
  • Niraparib (MK-4827) is a PARP inhibitor being investigated as a potential anti-cancer agent. It has been or is being tested in clinical trials in patients with disorders such as:
  • niraparib is taken orally, for example in tablet or capsule form. In certain clinical studies, patients received 300 mg/day niraparib orally. Typically, patients should have confirmation of susceptibility gene (BRCA) mutation before talazoparib treatment is initiated. Methods to determine BRCA mutation status are readily available to a skilled person (for example BRACAnalysis CDxTM from Myriad Genetic Laboratories). The dosing and/or dosing regimen of niraparib may be adjusted according to patients's response, adverse events and or co-treatment with other drugs by the skilled person using methods readily available to him/her.
  • BRCA susceptibility gene
  • the present invention relates to a combination of any component A mentioned herein with any component B mentioned herein, optionally with any component C mentioned herein.
  • component A of the combination is the compound used in the experimental section (compound A1 ) and Component B is a PARP inhibitor used in the experimental section.
  • the present invention relates to a combination of a component A with a component B, optionally with a component C, as mentioned in the Examples Section herein.
  • the present invention relates to :
  • kit comprising:
  • component A one or more BUB1 -kinase inhibitors, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof ;
  • component B an inhibitor of PARP, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof; and, optionally, component C : one or more further pharmaceutical agents; in which optionally either or both of said components A and B in any of the above- mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
  • component C being at least one pharmaceutical agent includes the effective compound itself as well as its pharmaceutically acceptable salts, solvates, hydrates or stereoisomers as well as any composition or pharmaceutical formulation comprising such effective compound or its pharmaceutically acceptable salts, solvates, hydrates or stereoisomers. A list of such readily available agents is being provided further below.
  • the components may be administered together or independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
  • Component C being administered as the case may be.
  • Components of this invention can be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • binders such as acacia, corn starch or gelatin
  • disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn
  • Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present. Components of this invention can also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (1 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
  • the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs can be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
  • Components of this invention can also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the component in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1 -dioxolane-4- methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable
  • Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta- aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
  • suitable detergents include cationic detergents, for example dimethyl dial
  • compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile- lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 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 can be in the form of sterile injectable aqueous suspensions.
  • suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can be used in the preparation of injectables.
  • Components of the invention can also be administered in the form of suppositories for rectal administration of the drug. These components can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 1 1 , 1991 , incorporated herein by reference).
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art. It can be desirable or necessary to introduce a component of the present invention to the patient via a mechanical delivery device.
  • the construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art.
  • Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier.
  • One such implantable delivery system used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,01 1 ,472, issued April 30, 1991.
  • 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), 238-31 1 ; Strickley, R.G “Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1 " PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al, "Excipients and Their Use in Injectable Products” PDA Journal of Pharmaceutical Science & Technology 1997, 51 (4), 166-171 .
  • compositions for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CCI2F2 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); antim
  • 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
  • ointment bases examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment
  • penetration enhancers transdermal delivery
  • examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas
  • plasticizers examples include but are not limited to diethyl phthalate and glycerol
  • solvents examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid,
  • 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, 1 1 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
  • Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
  • the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • the compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof according to the combination as referred to above are components A.
  • the compounds according to the combination have valuable pharmaceutical properties, which make them commercially utilizable. In particular, they inhibit Bub1 kinase and are expected to be commercially applicable in the therapy of diseases (e.g. cancer).
  • component B is especially suitable to have effects on tumor diseases.
  • they inhibit PARP and are commercially applicable in the therapy of diseases (e.g. BRCA-mutated cancers).
  • the combinations of the present invention thus can be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g.
  • leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
  • One embodiment relates to the use of a combination according to the invention for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly breast-, prostate-, ovarian- or bladder cancer, glioblastoma (GBM), melanoma, or mantel cell lymphoma (MCL), and/or metastases thereof.
  • a cancer particularly breast-, prostate-, ovarian- or bladder cancer, glioblastoma (GBM), melanoma, or mantel cell lymphoma (MCL), and/or metastases thereof.
  • GBM glioblastoma
  • MCL mantel cell lymphoma
  • the invention relates to a method of treatment or prophylaxis of a cancer, particularly hepatocyte carcinoma, lung cancer, in particular breast-, prostate-, ovarian- or bladder cancer, GBM, melanoma, or MCL, and/or metastases thereof, in a subject, comprising administering to said subject a therapeutically effective amount of a combination according to the present invention.
  • a cancer particularly hepatocyte carcinoma, lung cancer, in particular breast-, prostate-, ovarian- or bladder cancer, GBM, melanoma, or MCL, and/or metastases thereof.
  • Preferred uses of the combinations of the invention are the treatment of breast-, prostate-, ovarian- or bladder cancer, GBM, melanoma, or MCL, and/or metastases thereof.
  • One preferred embodiment is the use of the combinations of the invention for the treatment of the disorders tested in the experimental section, for example, triple- negative breast cancer (TNBC), prostate cancer , melanoma and/or metastases thereof.
  • TNBC triple- negative breast cancer
  • prostate cancer melanoma and/or metastases thereof.
  • inappropriate within the context of the present invention, in particular in the context of "inappropriate cellular immune responses, or inappropriate cellular inflammatory responses", as used herein, is to be understood as preferably meaning a response which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases. Combinations of the present invention might be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
  • This invention includes a method comprising administering to a mammal in need thereof, including a human, an amount of a component A or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof , and an amount of component B of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; which is effective to treat the disorder.
  • Hyper-proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), as well as malignant neoplasia.
  • BPH benign prostate hyperplasia
  • malignant neoplasia treatable with the compounds according to the present invention include solid and hematological tumors. Solid tumors can be exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, anum, endocrine glands (e.g.
  • malignant neoplasias include inherited cancers exemplified by Retinoblastoma and Wilms tumor. In addition, malignant neoplasias include primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases").
  • Hematological tumors can be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non- Hodgkins disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of unknown primary site as well as AIDS related malignancies.
  • 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.
  • 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, eic, of a disease or disorder, such as a carcinoma.
  • Combinations of the present invention might also be used for treating disorders and diseases associated with excessive and/or abnormal angiogenesis.
  • Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism.
  • a number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal- vein occlusion, and retinopathy of prematurity [Aiello et al. New Engl. J. Med. 1994, 331 , 1480 ; Peer et al. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD ; see, Lopez et al. Invest. Opththalmol. Vis. Sci.
  • neovascular glaucoma neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc.
  • RA rheumatoid arthritis
  • restenosis in-stent restenosis
  • vascular graft restenosis etc.
  • the increased blood supply associated with cancerous and neoplastic tissue encourages growth, leading to rapid tumor enlargement and metastasis.
  • the growth of new blood and lymph vessels in a tumor provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer.
  • combinations of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation ; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
  • the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredients to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredients to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 30 mg/kg body weight per day.
  • the total amount of the active ingredients per dose will generally range from about 1 mg to about 500 mg per dose, and preferably from about 20 mg to about 200 mg per dose.
  • Clinically useful dosing schedules of a compound will range from one to three times a day dosing to once every four weeks dosing.
  • "drug holidays" in which a patient is not dosed with a drug for a certain period of time may be beneficial to the overall balance between pharmacological effect and tolerability.
  • a unit dosage may contain from about 0.5 mg to about 1500 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.
  • the PARP inhibitor can be administered to a patient at a dosage which can range from about 0.1 to about 300 mg/kg of total body weight. More specific dosages and dosage regimens are provided herein for several PARP inhibitors, such as for example for olaparib, rucaparib, talazoparib, and niraparib, and/or are known and/or can be readily determined by a skilled person using known techniques.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compounds employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a PARP inhibitor of the present invention or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, or a composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • Suitable dose(s), administration regime(s) and administration route(s) for PARP inhibitors include those defined in the Patient Information Leaflet or in Clinical Practice Guidelines in Oncology.
  • suitable dose(s), administration regime(s) and administration route(s) for PARP inhibitors may be readily determined by standard techniques known to the skilled person.
  • the dose(s), administration regime(s) and administration route(s) may have to be adapted according to, inter alia, the indication, the indication stage, the patient age and/or the patient gender, among other factors. Such adaptations can be readily determined by standard techniques known to the skilled person.
  • the administered dosage and/or administration regime may be modified, independently of each other or simultaneously, depending on any superior or unexpected results which may be obtained as routinely determined with this invention.
  • the PARP inhibitor can be administered to a patient orally, topically, parenterally, rectally, by inhalation, and by injection.
  • Administration by injection includes intravenous, intramuscular, subcutaneous, and parenterally as well as by infusion techniques.
  • the agents can be administered by any of the conventional routes of administration for these compounds.
  • the preferred route of administration for the hyper- proliferative/cytotoxic/cytostatic agents using this invention is typically by injection which is the same route of administration used for the agent alone. Any of the hyper- proliferative, cytotoxic or cytostatic agents can be administered in combination with an MKNK1 inhibitor of general formula (I) by any of the mentioned routes of administration.
  • the Bub1 inhibitor can be administered simultaneously with the PARP inhibitor. This can be performed by administering a single formulation which contains both the Bub1 inhibitor and the PARP inhibitor or by administering the Bub1 inihibitor and PARP inhibitor in independent formulations at the same time (concomittantly) to a patient.
  • the Bub1 inhibitor can be administered in tandem with the PARP inhibitor.
  • the Bub1 inihbitor can be administered prior to the PARP inhibitor.
  • the PARP inhibitor can be administered first followed by adminstration of the Bub1 inihibitor.
  • the choice of sequence administration of the Bub1 inihibitor relative to the PARP inhibitor may vary for different agents, and can be readily determined and, when needed, modified or adapted by the skilled person using techniques readily available in order, for example, to improve the therapeutic effect of the combination.
  • the PARP inhibitor can be administered using any regimen which is conventionally used for these agents.
  • the Bub1 inihibitor and the PARP inhibitor can be administered once or more times per day on the day(s) of administration.
  • the combinations of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth, more especially breast (for example TNBC), ovarian, prostate, and skin cancer.
  • breast for example TNBC
  • ovarian for example ovarian
  • prostate for example skin cancer.
  • Other preferred indications are those tumor types of all indications with BRCA1 and/or BRCA2 mutations.
  • breast for example TNBC
  • Other indications are tumours without STAG2 alterations (e.g. mutations) and/or ATM low or loss of expression.
  • Suitable methods to determine the genetic features (genetic profile) of a tumor are readily available to the skilled person, for example it can be determined using the methods/kits described herein, other known methods, and/or using commercially available methods/kits.
  • the combinations of component A and component B of this invention can be administered as the sole pharmaceutical agent or in combination with one or more further pharmaceutical agents C where the resulting combination of components A, B and C causes no unacceptable adverse effects.
  • 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:
  • Optional anti-hyper-proliferative agents which can be added as component C to the combination of components A and B of the present invention include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 1 1 th Edition of the Merck Index, (1996), which is hereby incorporated by reference.
  • anti-hyper-proliferative agents suitable for use as component C with the combination of components A and B of the present invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference.
  • 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:
  • (6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments, provide a longer time for tumor progression, and/or yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
  • the study was designed to determine the anti-proliferative effects of the combination treatment with a Bub1 kinase inhibitor and the PARP inhibitors olaparib, rucaparib, talazoparib, and niraparib on a panel of human tumor cell lines.
  • PARP inhibitors which are preferred component B of the present combination are described in the art and/or are available commercially, particularly the below depicted PARP inhibitors: a) Olaparib, 4-(3- ⁇ [4-(cyclopropylcarbonyl)piperazin-1 -yl]carbonyl ⁇ -4- fluorobenz l)phthalazin-1 (2H)-one
  • Tumor cells were propagated in a humidified 37°C incubator in their respective growth medium supplemented 10% fetal calf serum.
  • a compound A for analysis of combination effects between a compound A and a compound B, cells were plated in 384-well plates at the cell numbers per well as indicated in 2.1 (Study design).
  • IC50 values inhibiting concentration at 50% of maximal effect
  • DMSO vehicle
  • IC50 isobolograms were plotted with the actual concentrations of the two compounds on the x- and y-axis, and the combination index (CI) was calculated according to the median-effect model of Chou-Talalay [Chou T.C. Pharmacol. Rev. 58, 621 , 2006].
  • a CI of ⁇ 0.8 was defined as more than additive (synergistic) interaction, and a CI of >1 .2 was defined as antagonistic interaction.
  • CI50 interpretation code CI50 ⁇ 0.8, synergism; 0.8 ⁇ CI50 ⁇ 1 .2, additivity; Cl5o>1 .2, antagonism.
  • Table 1 summarizes the data for Compound A1 plus oiaparib.
  • Table 1 Calculated combination indices at IC50 (CI50) from proliferation assays of cell lines treated with combinations of Bub1 inhibitor Compound A1 and oiaparib. Mono- treatment IC50 values and the concentrations required in combination of the two test compounds to achieve the CI50 are shown. All concentrations are given in mol/L.
  • Table 2 summarizes the data for Compound A1 plus rucaparib.
  • Table 2 Calculated combination indices (CI) from proliferation assays of cell lines treated with combinations of Bub1 inhibitor Compound A1 and rucaparib. Mono- treatment I C50 values and the concentrations required in combination of the two test compounds to achieve the CI50 are shown. All concentrations are given in mol/L.
  • Table 3 summarizes the data for Compound A1 plus talazoparib.
  • Table 3 Calculated combination indices (CI) from proliferation assays of cell lines treated with combinations of Bub1 inhibitor Compound A1 and talazoparib. Mono- treatment I C50 values and the concentrations required in combination of the two test compounds to achieve the CI50 are shown. All concentrations are given in mol/L.
  • Table 4 summarizes the data for Compond A1 plus niraparib.
  • Table 4 Calculated combination indices (CI) from proliferation assays of cell lines treated with combinations of Bub1 inhibitor Compound A1 and niraparib. Mono- treatment I C50 values and the concentrations required in combination of the two test compounds to achieve the CI50 are shown. All concentrations are given in mol/L.
  • the MDA-MB-436 BRCA1 -mutated triple-negative breast cancer model was used for the human xenograft study to evaluate the efficacy of the Bub1 inhibitor plus Olaparib combination.
  • Animals were randomly assigned to experimental groups, twelve animals per group. At the initiation of the treatment, animals were tattooed and each cage was labeled with the cage number, study number and number of animals per cage.
  • MDA-MB-436 human breast cancer cells originally purchased from CLS Cell Lines Service (#300278), Eppelheim, Germany, were cultured as described according to the supplier ' s protocols. Cells were harvested for transplantation in a subconfluent (70%) state. Animals were injected with 1 x 10 6 MDA-MB-436 cells suspended in 25% Matrigel into the 4. mammary gland on day 0.
  • the oral application volumes were 10 ml/kg for mice, the intraperitoneal application volume was 10 ml/kg for mice.
  • the time interval between two applications per day was 6-7h.
  • Tumor response was assessed by determination of the tumor area (product of the longest diameter and its perpendicular) using a caliper.
  • the animal body weight was monitored as a measure for treatment-related toxicity. Measurement of tumor area and body weight were performed three times weekly.
  • Tumor growth inhibition is presented as T/C ratio (Treatment / Control) calculated with tumor areas when the vehicle control group had to be closed.
  • Relative tumor growth inhibition based on tumor area was calculated by the formula [(tumor area of treatment group at day x) - (tumor area of treatment group at day before first treatment)] / [(tumor area of vehicle group at day x) - (tumor area of vehicle group at day before first treatment)].
  • the animals treated with the combination of Compound A1 and Olaparib showed a strongly reduced tumor growth rate and mean relative tumor area at day 91 was 65% below the mean relative tumor area of the Olaparib treated tumors.
  • the difference in tumor areas between the Olaparib single agent treatment group and the combination treatment group were statistically significant (P ⁇ 0.001 ).
  • Bub1 kinase inhibitor compound A1 with PARP inhibitors olaparib, rucaparib, talazoparib, or niraparib in proliferation assays of human carcinoma cells showed the utility of the present invention.
  • the in vitro results showed predominantly more than additive (CI50 ⁇ 0.8) interaction.
  • Additive interations 0.8 ⁇ CI50 ⁇ 1 .2) and, and in one cell line an antagonistic interaction were observed (CI50 >1 .2) in cell lines whose characteristic genetic features notably decrease and/or eliminate the relevance (or role) of Bub1 in mitotsis of a cancer cell (thereby mechanistically not enabling the more than additive effect itself to manifest).
  • STAG2 mutated cell lines are more sensitive towards PARP inhibitors as compared to isogenic STAG2 wild-type cell lines and accumulate in the G2 phase of the cell cycle upon PARP inhibition [Bailey et al. Mol Cancer Ther. 13, 724, 2013].
  • deficiency of STAG2 function was described to result in derealization of Bub1 protein from the centromeric region of the chromosomes [Kleyman et al. J. Cell Sci.
  • Compound A1 was administered twice daily (2QD) p.o. at a dose of 50 mg/kg in the single agent treatment group and at 50 mg/kg in combination with olaparib, olaparib was administered once daily (1 QD) i.p. at a dose of 25 mg/kg.

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Abstract

The present invention relates to combinations of at least two components, component A and component B, component A being an inhibitor of Bub1 kinase, and component B being a PARP inhibitor. Another aspect of the present invention relates to the use of such combinations as described supra for the preparation of a medicament for the treatment or prophylaxis of a disease.

Description

COMBINATIONS OF BUB1 KINASE AND PARP INHIBITORS
The present invention relates to combinations of at least two components, component A and component B, component A being an inhibitor of budding uninhibited by benzimidazoles 1 kinase (Bub1 ) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, and component B being an inhibitor of Poly(ADP-ribose) polymerase (PARP) or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof. Another aspect of the present invention relates to the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, particularly for the treatment of cancer.
Another aspect of the present invention relates to the use of a PARP inhibitor as a sensitizer of cells to Bub1 inhibitors or vice versa.
Yet another aspect of the present invention relates to methods of treatment or prophylaxis of a cancer in a subject, comprising administering to said subject a therapeutically effective amount of a combination as described herein.
Further, the present invention relates to a kit comprising a combination of:
- one or more components A, as defined herein, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof ;
- a component B, as defined supra, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof ; and optionally
- one or more pharmaceutical agents C;
in which optionally either or both of said components A and B are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially.
BACKGROUND
Cell cycle deregulation represents one of the classical hallmarks of cancer [Hanahan D and Weinberg RA, Cell 100, 57, 2000; Hanahan D and Weinberg RA, Cell 144, 646, 201 1 ] and consequently cell cycle arrest is the predominant mode of action of a lot of the cancer drugs on the market including "anti-mitotics' such as taxanes and vinca alkaloids. The concept of cell cycle checkpoint regulation offers a novel approach to cancer treatment: inactivation of cell cycle checkpoints is considered to drive tumor cells into cell divison despite DNA damage or unattached/misattached chromosomes resulting in a lethal degree of DNA damage or aneuploidy.
The spindle assembly checkpoint (SAC, also known as spindle checkpoint or mitotic checkpoint) controls the accurate attachment of mircrotubules of the spindle device to the kinetochors (the attachment site for microtubules) of the duplicated chromosomes. The SAC is active as long as unattached kinetochores are present and generates a wait-signal to give the dividing cell the time to ensure that each kinetochore is attached to a spindle pole, and to correct attachment errors [for recent review see Musacchio A, Curr. Biol. 25, R1002-R1018, 2015].
The SAC signal is initiated by multipolar-spindle 1 (Mpsl )-mediated phosphorlyation of Met-Glu-Leu-Thr (MELT) motifs on the kinetochore scaffold 1 (KNL-1 ) protein to generate docking sites for budding uninhibited by benzimidazole 1 (Bub1 )/Bub3 dimers. The N-terminal non-catalytic part of Bub1 represents a scaffold for the assembly of mitotic arrest deficient 1 (MAD1 )/MAD2, BubR1 and centromere protein E (CENP-E) proteins. The inactive open from of MAD2 (o-MAD2) gets converted to the active closed conformation (c-MAD2) which binds cell-division cycle 20 homolog (CDC20) and BubR1 to form the diffusible mitotic checkpoint complex (MCC) which inhibits the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) and subsequently leads to mitotic arrest. Note that MCC generation requires Bub1 protein, however, it's kinase function is not involved.
Bub1 kinase phosphorylates histone H2A at Thr120 within the centromeric region of the duplicated chromosomes thereby creating binding sites for shugoshin proteins (Sgo) 1 and 2, which protect centromeric cohesin from premature degradation, and for the chromosomal passenger complex consisting of INCENP, survivin, borealin and Aurora B (AurB) [Kawashima et al. Science 327, 172, 2010; Watanabe Y, Cold Spring Harb. Symp. Quant. Biol. 75, 419, 2010]. Specific inhibition of Bub1 kinase activity results in reduced levels of Sgo1 and Sgo2 at mitotic centromeres. Furthermore, AurB fails to concentrate at the centromeres and was instead found to be spread over the chromosome arms [Baron et al. eLife 5, e12187, 2016]. AurB activity localized at the centromeric region is essential for the resolution of microtubule - kinetochore attachment errors such as syntelic and merotelic attachments. Dyslocatization of AurB due to Bub1 kinase inactivation strongly compromizes the cells ability to resolve attachment errors and results in an increased rate of chromosome aligment defects [Ricke et al. J. Cell Biol. 199, 931 , 2012], in particular in presence of attachment error inducing agents such as microtubule stabilizers paclitaxel or docetaxel. The recognition and repair of DNA damage is essential for normal cellular function and maintenance of genome stability. Bub1 kinase was reported to be involved in the DNA damage signaling pathway downstream of Ataxia-telangiectasia Mutated (ATM) kinase [Yang et al. DNA Repair 1 1 , 185, 2012] and in nonhomologous end-joining system of DNA double strand break repair [Jessulat et al. Mol. Cell. Biol. 35, 2448, 2015]. Upon sensing of DNA damage PARP enzyme gets activated and attaches poly(ADP ribose) polymers to target proteins to recruit DNA repair enzymes. Inhibition of PARP has been shown to result in lethal DNA damage repair deficiency in BRCA-1/2 mutated cells [for recent review see: Ganguly et al. Biomark Cancer 8(suppl 1 ), 15, 2016].
However, the state of the art neither discloses the combinations of the present invention comprising an inhibitor of Bub1 kinase and an inhibitor of PARP nor the use of a PARP inhibitor as a sensitizer of cells to Bub1 inhibitors or vice versa.
SUMMARY of the INVENTION
Surprisingly, it was observed that combinations of Bub1 kinase inhibitors or pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof, with PARP inhibitors or pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof, showed more that additive antiproliferative activity.
Therefore, in accordance with a first aspect, the present invention provides combinations of at least two components, component A and component B, component A being an inhibitor of BUB1 -kinase or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, and component B being a PARP inhibitor or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.
The combinations comprising at least two components, component A and component B, as decribed and defined herein, are also referred to as "combinations of the present invention".
Further, the present invention relates to a kit comprising:
- a combination of : Component A: a Bub1 kinase inhibitors as described herein, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof ;
Component B : a PARP inhibitor as described herein, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof ; and, optionally, Component C : one or more further pharmaceutical agents ;
in which optionally either or both of said components A and B in any of the above- mentioned combinations are in the form of a pharmaceutical formulation/composition which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The components may be administered independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
In accordance with another aspect, the present invention covers the combinations as described herein for the treatment or prophylaxis of a disease. In accordance with another aspect, the present invention covers the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease.
In accordance with another aspect, the present invention covers methods of treatment or prophylaxis of a cancer in a subject, comprising administering to said subject a therapeutically effective amount of a combination as described herein.
DETAILED DESCRIPTION OF THE INVENTION
A. Definitions
Constituents which are optionally substituted as stated herein, may be substituted, unless otherwise noted, one or more times, independently from one another at any possible position. When any variable occurs more than one time in any constituent, each definition is independent. For example, whenever R1, R2, R3, R4, R5, R7, R8 V, W, Y and/or Z occur more than one time for any compound of formula (I) each definition of R1, R2, R3, R4, R5, R7, R8, V, W, Y and Z is independent. Should a constituent be composed of more than one part, e.g. Ci-C4-alkoxy-Ci-C4-alkyl- , the position of a possible substituent can be at any of these parts at any suitable position. A hyphen at the beginning or at the end of the constituent marks the point of attachment to the rest of the molecule. Should a ring be substituted the substitutent could be at any suitable position of the ring, also on a ring nitrogen atom if suitable. The term "comprising" when used in the specification includes "consisting of".
If it is referred to "above or "supra", alone or in expressions such as "as mentioned above", "mentioned above", or "as defined supra", within the description it is referred to any of the disclosures made within the specification in any of the preceding pages.
If it is referred to "herein", alone or in expressions such as "as mentioned herein", "mentioned herein", or "as described herein" within the description it is referred to any of the disclosures made within the specification in any of the preceding or subsequent pages.
"suitable" within the sense of the invention means chemically possible to be made by methods within the knowledge of a skilled person.
The terms as mentioned in the present text have preferably the following meanings :
The term "halogen atom", "halo-" or "Hal-" is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.
The term "Ci-C6-alkyl" is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2- methylbutyl, 1 -methylbutyl, 1 -ethylpropyl, 1 ,2-dimethylpropyl, neo-pentyl, 1 , 1 - dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2- ethylbutyl, 1 -ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1 , 1 -dimethylbutyl, 2,3- dimethylbutyl, 1 ,3-dimethylbutyl, or 1 ,2-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1 , 2, 3 or 4 carbon atoms ("Ci-C4-alkyl"), e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, more particularly 1 , 2 or 3 carbon atoms ("Ci-C3-alkyl"), e.g. a methyl, ethyl, n-propyl- or iso-propyl group. The term "Ci-C6-haloalkyl" is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C6-alkyl" is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another. Particularly, said halogen atom is F. Said Ci-C6-haloalkyl group is, for example, -CF3, - CHF2, -CH2F, -CF2CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2CF3, or -CH(CH2F)2.
The term "Ci-C6-alkoxy" is to be understood as meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term "alkyl" is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof. Particularly preferred is "Ci-C4-alkoxy" e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy or sec-butoxyor an isomer thereof. More preferred is "Ci-alkoxy", i.e. methoxy.
The term "Ci-C4-haloalkoxy" is to be understood as meaning a linear or branched, saturated, monovalent Ci-C4-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F. Said Ci-C4-haloalkoxy group is, for example, - OCF3, -OCHF2, -OCH2F, -OCF2CF3, or -OCH2CF3.
The term "Ci-C6-hydroxyalkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C6-alkyl" is defined supra, and in which one or more hydrogen atoms is replaced by a hydroxy group, e.g. a hydroxy methyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 1 ,3-dihydroxypropan-2-yl, 3- hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1 -hydroxy-2-methyl-propyl group. Preferred is "Ci-C3-hydroxyalkyl", e.g. a hydroxy methyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 1 ,3- dihydroxypropan-2-yl.
The term "C2-C6-hydroxyalkyl" is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group having 2, 3, 4, 5, or 6 carbon atoms, in which one or more hydrogen atoms is replaced by a hydroxy group, e.g. a 2-hydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 3-hydroxy-2-methyl-propyl, 2- hydroxy-2-methyl-propyl. Preferred is "C2-C4-hydroxyalkyl", more preferred is "C2- hydroxyalkyl", i.e. a 2-hydroxyethyl group. The term "C3-C6-cycloalkyl" is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms ("C3-C6- cycloalkyl"). Said C3-C6-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
The term "C3-C6-cycloalkyloxy" is to be understood as meaning a saturated, monovalent, monocyclic hydrocarbon group of formula -O-cycloalkyl, in which the term "cycloalkyi" is defined supra, e.g. a. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy group.
The term "Ο-ι-Οβ", as used throughout this text, e.g. in the context of the definition of "Ci- C6-alkyl", "Ci-C6-haloalkyl", "Ci-C6-hydroxyalkyl", "Ci-C6-alkoxy", is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "C1-C6" is to be interpreted as any sub-range comprised therein, e.g. C1-C6 , C2-C5 , C3-C4 , C1-C2 , C1-C3 , C1-C4 , C1-C5 ; particularly C1-C2 , C1-C3 , C1-C4 , C1-C5, C1-C6; more particularly C1-C4 ; in the case of "Ci-C6-haloalkyl" or "Ci-C6-haloalkoxy" even more particularly C1-C2. The term "C2-C6", as used throughout this text, e.g. in the context of the definition of "C2- C6-hydroxyalkyl", is to be understood as meaning a hydroxyalkyl group having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term "C2-C6" is to be interpreted as any sub-range comprised therein, e.g. C2-C6, C2-C5, C3-C4, particularly C2-C3, C2-C4, C2-C5, C2-C6.
Further, as used herein, the term "C3-C6", as used throughout this text, e.g. in the context of the definition of "C3-C6-cycloalkyl", is to be understood as meaning a cycloalkyi group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term "C3-C6" is to be interpreted as any sub-range comprised therein, e.g. C3-C6 , C4-C5 , C3-C5 , C3-C4 , C4-C6, C5-C6 ; particularly
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.
Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system. As used herein, the term "one or more", e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning "one, two, three, four or five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or two". The term "V, W, Y and Z independently of each other represent CH or CR2, wherein one of V, W, Y and Z represents CR2", is to be understood as meaning that at least one of V, W, Y and Z represents CR2, and the remaining, independently from each other, represent CH or CR2, as it is known to a skilled person. For example, according to certain embodiments of the invention, V, W, Y and Z independently of each other represent CH or CR2, wherein one of V, W, Y and Z represents CR2 and the remaining represent CH; according to other embodiments of the invention, V, W, Y and Z independently of each other represent CH or CR2, wherein two of V, W, Y and Z, independently of each other, represent CR2 and the remaining represent CH; still according to other embodiments of the invention, V, W, Y and Z independently of each other represent CH or CR2, wherein three of V, W, Y and Z, independently of each other, represent CR2 and the remaining represents CH, for example.
The invention also includes all suitable isotopic variations of a compound (i.e. component A, B or C(when present)) used in the combination of the present invention. An isotopic variation of a compound is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into a compound used in the combination of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 11C, 13C, 14C, 15N, 170, 180, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36CI, 82Br, 123l, 124l, 129l and 1311, respectively. Certain isotopic variations of a compound used in the combination of the present invention, for example, those in which one or more radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence is preferred in some circumstances. Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.
By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds used in the combination of this invention optionally contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms is present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
The compounds used in the combination of the present invention optionally contain sulphur atoms which are asymmetric, such as an asymmetric sulfoxide, of structure:
II
0 , for example, in which * indicates atoms to which the rest of the molecule can be bound. Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention. Preferred compounds used in the combination are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds used in the combination of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.
The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
In order to limit different types of isomers from each other reference is made to lUPAC Rules Section E (Pure Appl Chem 45, 1 1 -30, 1976). The present invention includes all possible stereoisomers of the compounds used in the combination of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, or E- or Z-isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound used in the combination of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example. Further, the compounds used in the combination of the present invention may exist as tautomers.
The present invention includes all possible tautomers of the compounds used in the combination of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
Further, the compounds used in the combination of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.
The present invention also relates to useful forms of the compounds used in the combination as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
The compounds used in the combination of the present invention can exist as a hydrate, or as a solvate, wherein the compounds contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.
Further, the compounds used in the combination of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1 -19.
A suitable pharmaceutically acceptable salt of the compounds used in the combination of the present invention may be, for example, an acid-addition salt of a compound bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)- benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2- naphthoic, nicotinic, pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic, 2- hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic, methansulfonic, 2- naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.
Further, another suitably pharmaceutically acceptable salt of a compound used in the combination of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1 -amino-2,3,4-butantriol. Additionally, basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides ; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate ; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyi halides like benzyl and phenethyl bromides and others.
Those skilled in the art will further recognise that acid addition salts of the compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds used in the combination of the invention are prepared by reacting the compounds with the appropriate base via a variety of known methods.
The present invention includes all possible salts of the compounds used in the combination of the present invention as single salts, or as any mixture of said salts, in any ratio. In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown.
Unless specified otherwise, suffixes to chemical names or structural formulae such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCI", "x CF3COOH", "x Na+", for example, are to be understood as not a stoichiometric specification, but solely as a salt form.
This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates with (if defined) unknown stoichiometric composition.
As used herein, the term "in vivo hydrolysable ester" is understood as meaning an in vivo hydrolysable ester of a compound used in the combination of the present invention containing a carboxy or hydroxy group, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include for example alkyl, cycloalkyl and optionally substituted phenylalkyl, in particular benzyl esters, C1-C6 alkoxymethyl esters, e.g. methoxymethyl, C1-C6 alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters, C3-C8 cycloalkoxy-carbonyloxy-Ci-C6 alkyl esters, e.g. 1 -cyclohexylcarbonyloxyethyl ; 1 ,3-dioxolen-2-onylmethyl esters, e.g. 5-methyl-1 ,3- dioxolen-2-onylmethyl ; and Ci-C6-alkoxycarbonyloxyethyl esters, e.g. 1 - methoxycarbonyloxyethyl, and may be formed at any carboxy group in the compounds used in the combination of this invention.
An in vivo hydrolysable ester of a compound used in the combination of the present invention containing a hydroxy group includes inorganic esters such as phosphate esters and [alpha]-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of [alpha]-acyloxyalkyl ethers include acetoxymethoxy and 2,2- dimethylpropionyloxymethoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. The present invention covers all such esters. Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds used in the combination of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
In the context of the properties of the compounds used in the combination of the present invention the term "pharmacokinetic profile" means one single parameter or a combination thereof including permeability, bioavailability, exposure, and pharmacodynamic parameters such as duration, or magnitude of pharmacological effect, as measured in a suitable experiment. Compounds with improved pharmacokinetic profiles can, for example, be used in lower doses to achieve the same effect, may achieve a longer duration of action, or a may achieve a combination of both effects.
The term "combination" in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combination or kit-of- parts.
A "fixed combination" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein component A and component B are present together in one unit dosage or in a single entity. One example of a "fixed combination" is a pharmaceutical composition wherein the said component A and the said component B are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein the said component A and the said component B are present in one unit without being in admixture.
A non-fixed combination or "kit-of-parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said component A and the said component B (and optionally component C) are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the said component A and the said component B (and optionally component C) are present separately, for example in different and separate pharmaceutical compositions. The components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
Any such combination is covered by the present invention.
It is further to be understood that embodiments disclosed herein are not meant to be understood as individual embodiments which would not relate to one another. Features discussed with one embodiment or aspect of the invention are meant to be disclosed also in connection with other embodiments or aspects of the invention shown herein. If, in one case, a specific feature is not disclosed with one embodiment or aspect of the invention, but with another, the skilled person would understand that does not necessarily mean that said feature is not meant to be disclosed with said other embodiment or aspect of the invention. The skilled person would understand that it is the gist of this application to disclose said feature also for the other embodiment or spect of the invention, but that just for purposes of clarity and to keep the length of this specification manageable. It is further to be understood that the content of the prior art documents referred to herein is incorporated by reference, e.g., for enablement purposes, namely when e.g. a method is discussed details of which are described in said prior art document. This approach serves to keep the length of this specification manageable.
Component A of the Combination
Component A can be selected from inhibitors of BUB1 -kinase or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof specifically or generically disclosed e.g. in the publications as mentioned above which are incorporated herein by reference.
In an embodiment Component A is selected from the group of Bub1 inhibitors generically or specifically disclosed in WO 2016/042084, which are incorporated by reference herein.
In accordance with an embodiment, component A is an inhibitor of Bub1 of general formula (I),
Figure imgf000017_0001
(I),
in which,
V, W, Y and Z independently of each other represent CH or CR2, wherein one of V, W, Y and Z represents CR2,
or,
V represents N, and W, Y and Z independently of each other represent CH or CR2, or,
V and Y represent N, and W and Z independently of each other represent CH or CR2,
R1 represents a group selected from:
Ci-C6-alkyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl,
(Ci-C3-alkoxy)-(C2-C3-alkyl)-, and (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, R2 represents, independently of each other, halogen or a group selected from: Ci-C3-alkyl, C3-C4-cycloalkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy,
Ci-C3-haloalkoxy, -N(H)C(=0)-(Ci-C3-alkyl), -N(H)C(=0)H,
-N(H)C(=0)-(Ci-C3-hydroxyalkyl),
-N(H)C(=0)-(Ci-C3-alkyl)-(Ci-C3-alkoxy), -N(H)C(=0)-phenyl, -N(H)C(=0)-(C3-C4-cycloalkyl),
-N(H)C(=0)-(Ci-C3-alkyl)-(C3-C4-cycloalkyl), and -N(H)C(=0)N(H)R8,
said -N(H)C(=0)-phenyl being optionally substituted at the phenyl ring, one, two or three times, identically or differently, with a substituent selected from:
halogen, hydroxy, cyano, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, C3-C4-cycloalkyl, and
C3-C4-cycloalkyloxy, said -N(H)C(=0)-(C3-C4-cycloalkyl) being optionally substituted at the C3-C4-cycloalkyl ring with a substituent selected from:
fluorine, chlorine, trifluoromethyl, and methoxy, R3 represents a group selected from:
C2-C6-hydroxyalkyl, and R4,
said C2-C6-hydroxyalkyl groups being optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine,
R4 represents -(C2-C6-alkyl)-OC(=0)-C(H)(R5)-N(H)C(=0)-C(H)(R7)-NH2, in which C2-C6-alkyl is optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine,
R5 and R7 independently of each other represent hydrogen (glycine) or a group selected from:
-CH3 (alanine), -C(H)(CH3)2 (valine), -(CH2)2CH3 (norvaline), -CH2C(H)(CH3)2 (leucine), - C(H)(CH3)CH2CH3 (isoleucine), -(CH2)3CH3 (norleucine), -C(CH3)3 (2-ie/f-butylglycine), benzyl (phenylalanine), 4-hydroxybenzyl (tyrosine), -(CH2)3NH2 (ornithine), -(CH2)4NH2 (lysine), -(CH2)2C(H)(OH)CH2NH2 (hydroxylysine), -CH2OH (serine), -(CH2)2OH (homoserine), -C(H)(OH)CH3 (threonine), -(CH2)3N(H)C(=NH)NH2 (arginine), - (CH2)3N(H)C(=0)NH2 (citrulline), -CH2C(=0)NH2 (asparagine), -CH2C(=0)OH (aspartic acid), -(CH2)2C(=0)OH (glutamic acid), -(CH2)2C(=0)NH2 (glutamine), -CH2SH (cysteine), -(CH2)2SH (homocysteine), -(CH2)2SCH3 (methionine), -CH2SCH3 (S- methylcysteine), (1 /-/-imidazol-4-yl)methyl- (histidine), (1 /-/-indol-3-yl)methyl- (thryptophan), -CH2NH2 (2,3-diaminopropanoic acid), and -(CH2)2NH2 (2,4- diaminobutanoic acid), R8 represents hydrogen or a group selected from:
Ci-C3-alkyl, Ci-C3-haloalkyl, C2-C3-hydroxyalkyl, C3-C4-cycloalkyl,
(C3-C4-cycloalkyl)-(Ci-C3-alkyl)-, and (Ci-C3-alkoxy)-(C2-C3-alkyl)-, or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N- oxide, tautomer or stereoisomer. In accordance with another embodiment, component A is an inhibitor of Bub1 of general formula (I) supra,
wherein,
V, W, Y and Z independently of each other represent CH or CR2, wherein one of V, W, Y and Z represents CR2
or,
V represents N, and W, Y and Z independently of each other represent CH or CR2,
R1 represents a group selected from:
d-Cs-alkyl, Ci-C3-haloalkyl, C3-C4-cycloalkyl,
(Ci-C3-alkoxy)-(C2-C3-alkyl)-, and (C3-C4-cycloalkyl)-(Ci-C3-alkyl)-,
R2 represents, independently of each other, halogen or a group selected from: Ci-C3-alkyl, C3-C4-cycloalkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy, -N(H)C(=0)-(Ci-C3-alkyl), -N(H)C(=0)H,
-N(H)C(=0)-(Ci-C3-hydroxyalkyl),
-N(H)C(=0)-(Ci-C3-alkyl)-(Ci-C3-alkoxy), -N(H)C(=0)-phenyl, -N(H)C(=0)-(C3-C4-cycloalkyl),
-N(H)C(=0)-(Ci-C3-alkyl)-(C3-C4-cycloalkyl), and -N(H)C(=0)N(H)R8,
said -N(H)C(=0)-phenyl being optionally substituted at the phenyl ring, one, two or three times, identically or differently, with a substituent selected from:
halogen, hydroxy, cyano, Ci-C4-alkyl, Ci-C4-haloalkyl,
Ci-C4-alkoxy, Ci-C4-haloalkoxy, C3-C4-cycloalkyl, and
C3-C4-cycloalkyloxy,
said -N(H)C(=0)-(C3-C4-cycloalkyl) being optionally substituted at the C3-C4-cycloalkyl ring with a substituent selected from:
fluorine, chlorine, trifluoromethyl, and methoxy,
R3 represents a group selected from:
C2-C6-hydroxyalkyl, and R4,
said C2-C6-hydroxyalkyl groups being optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine, represents -(C2-C6-alkyl)-OC(=0)-C(H)(R5)-N(H)C(=0)-C(H)(R7)-NH2 in which C2-C6-alkyl is optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine, R5 and R7 independently of each other represent hydrogen (glycine) or a group selected from:
-CHs (alanine), -C(H)(CH3)2 (valine), -(CH2)2CH3 (norvaline), -CH2C(H)(CH3)2 (leucine), - C(H)(CH3)CH2CH3 (isoleucine), -(CH2)3CH3 (norleucine), -C(CH3)3 (2-ie/f-butylglycine), benzyl (phenylalanine), 4-hydroxybenzyl (tyrosine), -(CH2)3NH2 (ornithine), -(CH2)4NH2 (lysine), -(CH2)2C(H)(OH)CH2NH2 (hydroxylysine), -CH2OH (serine), -(CH2)2OH (homoserine), -C(H)(OH)CH3 (threonine), -(CH2)3N(H)C(=NH)NH2 (arginine), - (CH2)3N(H)C(=0)NH2 (citrulline), -CH2C(=0)NH2 (asparagine), -CH2C(=0)OH (aspartic acid), -(CH2)2C(=0)OH (glutamic acid), -(CH2)2C(=0)NH2 (glutamine), -CH2SH (cysteine), -(CH2)2SH (homocysteine), -(CH2)2SCH3 (methionine), -CH2SCH3 (S- methylcysteine), (1 /-/-imidazol-4-yl)methyl- (histidine), (1 /-/-indol-3-yl)methyl- (thryptophan), -CH2NH2 (2,3-diaminopropanoic acid), and -(CH2)2NH2 (2,4- diaminobutanoic acid),
R8 represents hydrogen or a group selected from:
Ci-C3-alkyl, Ci-C3-haloalkyl, C2-C3-hydroxyalkyl, C3-C4-cycloalkyl,
(C3-C4-cycloalkyl)-(Ci-C3-alkyl)-, and (Ci-C3-alkoxy)-(C2-C3-alkyl)-, or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
In accordance with a further embodiment, component A is an inhibitor of Bub1 of general formula (I) supra,
wherein,
V, W, Y and Z independently of each other represent CH or CR2, wherein one of V, W, Y and Z represents CR2
or,
V represents N, and W, Y and Z independently of each other represent CH or CR2,
R1 represents a group selected from:
Ci-C3-alkyl, Ci-C3-haloalkyl, and C3-C4-cycloalkyl, R2 represents, independently of each other, halogen or a group selected from: Ci-C3-alkyl, C3-C4-cycloalkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy,
Ci-C3-haloalkoxy, -N(H)C(=0)-(Ci-C3-alkyl), -N(H)C(=0)H,
-N(H)C(=0)-(Ci-C3-hydroxyalkyl),
-N(H)C(=0)-(Ci-C3-alkyl)-(Ci-C3-alkoxy), -N(H)C(=0)-phenyl, -N(H)C(=0)-(C3-C4-cycloalkyl),
-N(H)C(=0)-(Ci-C3-alkyl)-(C3-C4-cycloalkyl), and -N(H)C(=0)N(H)R8,
said -N(H)C(=0)-phenyl being optionally substituted at the phenyl ring, one, two or three times, identically or differently, with a substituent selected from:
halogen, hydroxy, cyano, Ci-C4-alkyl, Ci-C4-haloalkyl,
Ci-C4-alkoxy, Ci-C4-haloalkoxy, C3-C4-cycloalkyl, and
C3-C4-cycloalkyloxy,
said -N(H)C(=0)-(C3-C4-cycloalkyl) being optionally substituted at the C3-C4-cycloalkyl ring with a substituent selected from:
fluorine, chlorine, trifluoromethyl, and methoxy,
R3 represents a group selected from:
C2-C6-hydroxyalkyl, and R4,
said C2-C6-hydroxyalkyl group being optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine,
R4 represents -(C2-C6-alkyl)-OC(=0)-C(H)(R5)-N(H)C(=0)-C(H)(R7)-NH2, in which C2-C6-alkyl is optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine,
R5 and R7 independently of each other represent a group selected from:
-CH3 (alanine), -C(H)(CH3)2 (valine), -(CH2)2CH3 (norvaline), -(CH2)3NH2 (ornithine), - (CH2)4NH2 (lysine), and -(CH2)3N(H)C(=NH)NH2 (arginine),
R8 represents hydrogen or a group selected from:
Ci-C3-alkyl, Ci-C3-haloalkyl, C2-C3-hydroxyalkyl, C3-C4-cycloalkyl,
(C3-C4-cycloalkyl)-(Ci-C3-alkyl)-, and (Ci-C3-alkoxy)-(C2-C3-alkyl)-, or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
In accordance with another embodiment, component A is an inhibitor of Bub1 of general formula (I) supra,
wherein,
V, W, Y and Z independently of each other represent CH or CR2, wherein one of V, W,
Y and Z represents CR2
or,
V represents N, and W, Y and Z independently of each other represent CH or CR2,
R1 represents a Ci-C3-alkyl group, R2 represents, independently of each other, halogen or a group selected from: Ci-C3-alkyl, C3-C4-cycloalkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, and -N(H)C(=0)-(Ci-C3-alkyl),
R3 represents a group selected from:
C2-C6-hydroxyalkyl, and R4,
R4 represents -(C2-C6-alkyl)-OC(=0)-C(H)(R5)-N(H)C(=0)-C(H)(R7)-NH2,
R5 and R7 independently of each other represent a group selected from:
-CH3 (alanine), and -(CH2)4NH2 (lysine), or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
In accordance with another embodiment, component A is an inhibitor of Bub1 of general formula (I) supra,
wherein,
V, W, Y and Z independently of each other represent CH or CR2, wherein one of V, W, Y and Z represents CR2
or, V represents N, and W, Y and Z independently of each other represent CH or CR2,
R1 represents a methyl group, R2 represents, independently of each other, fluorine, chlorine or a group selected from:
methyl, cyclopropyl, difluoromethyl, methoxy, and -N(H)C(=0)-CH3,
R3 represents a group selected from:
-(CH2)2OH, and R4,
R4 represents -(CH2)2-OC(=0)-C(H)(R5)-N(H)C(=0)-C(H)(R7)-NH2,
R5 represents -CH3 (alanine),
R7 represents -(CH2)4NH2 (lysine), or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
In accordance with another embodiment, component A is an inhibitor of Bub1 of general formula (I) supra,
wherein, V, W, Y and Z independently of each other represent CH or CR2, wherein one of V, W,
Y and Z represents CR2
or,
V represents N, and W, Y and Z independently of each other represent CH or CR2, R1 represents a methyl group,
R2 represents, independently of each other, fluorine, chlorine or a group selected from:
methyl, cyclopropyl, difluoromethyl, methoxy, -N(H)C(=0)-CH3, -N(H)C(=0)-cyclopropyl, and -N(H)C(=0)N(H)-cyclopropyl, R3 represents a -(Chb^OH group, or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
In accordance with a further embodiment, component A is a compound selected from the group consisting of :
2-{4-[(3-{4-[(3-chloropyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 /-/-indazol-1 - yl)methyl]-3,5-difluorophenoxy}ethanol ,
2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(2-methylpyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethanol ,
2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethanol ,
/V-{4-[(2-{1 -[2,6-difluoro-4-(2-hydroxyethoxy)benzyl]-1 H-indazol-3-yl}-5- methoxypyrimidin-4-yl)amino]pyridin-2-yl}acetamide ,
2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methylpyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethanol ,
2-{3,5-difluoro-4-[(3-{4-[(3-fluoropyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethanol ,
2-(4-{[3-(4-{[2-(difluoromethyl)pyridin-4-yl]amino}-5-methoxypyrimidin-2-yl)-1 /-/-indazol- 1 -yl]methyl}-3,5-difluorophenoxy)ethanol ,
2-{4-[(3-{4-[(2,5-dimethylpyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 /-/-indazol-1 - yl)methyl]-3,5-difluorophenoxy}ethanol ,
2-{4-[(3-{4-[(3-cyclopropylpyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 /-/-indazol-1 - yl)methyl]-3,5-difluorophenoxy}ethanol ,
2-{1 -[2,6-difluoro-4-(2-hydroxyethoxy)benzyl]-1 /-/-indazol-3-yl}-4-[(2-methylpyrimidin-4- yl)amino]pyrimidin-5-ol
2-{3,5-difluoro-4-[(3-{4-[(2-fluoropyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 H- indazol-1 -yl)methyl]phenoxy}ethanol ,
2-{3,5-difluoro-4-[(3-{4-[(5-fluoro-2-methylpyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}- 1 H-indazol-1 -yl)methyl]phenoxy}ethanol ,
2-[3,5-difluoro-4-({3-[5-methoxy-4-(pyrimidin-4-ylamino)pyrimidin-2-yl]-1 H-indazol-1 - yl}methyl)phenoxy]ethanol
/V-{4-[(2-{1 -[2,6-difluoro-4-(2-hydroxyethoxy)benzyl]-1 H-indazol-3-yl}-5- methoxypyrimidin-4-yl)amino]-5-methylpyridin-2-yl}acetamide ,
2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(2-methylpyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethyl L-lysyl-L-alaninate, salt with trifluoroacetic acid , 2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(2-methylpyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethyl L-lysyl-L-alaninate ,
2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethyl L-lysyl-L-alaninate, salt with trifluoroacetic acid , 2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethyl L-lysyl-L-alaninate,
N-{4-[(2-{1 -[2,6-difluoro-4-(2-hydroxyethoxy)benzyl]-1 H-indazol-3-yl}-5-methoxy- pyrimidin-4-yl)amino]pyridin-2-yl}cyclopropanecarboxamide ,
1 -cyclopropyl-3-{4-[(2-{1 -[2,6-difluoro-4-(2-hydroxyethoxy)benzyl]-1 H-indazol-3-yl}-5- methoxypyrimidin-4-yl)amino]pyridin-2-yl}urea ,
2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methoxy-2-methylpyridin-4-yl)amino]pyrimidin-2- yl}-1 H-indazol-1 -yl)methyl]phenoxy}ethanol ,
2- {3,5-difluoro-4-[(3-{5-methoxy-4-[(5-methoxy-2-methylpyridin-4-yl)amino]pyrimidin-2- yl}-1 H-indazol-1 -yl)methyl]phenoxy}ethanol ,
3- {4-[(3-{4-[(2,5-dimethylpyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 H-indazol-1 - yl)methyl]-3,5-difluorophenoxy}propan-1 -ol ,
3-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl}-1 H- indazol-1 -yl)methyl]phenoxy}propan-1 -ol ,
3-{3,5-difluoro-4-[(3-{5-methoxy-4-[(2-methylpyrimidin-4-yl)amino]pyrimidin-2-yl}-1 H- indazol-1 -yl)methyl]phenoxy}propan-1 -ol ,
(2R)-3-{3,5-difluoro-4-[(3-{5-methoxy-4-[(2-methylpyrimidin-4-yl)amino]pyrimidin-2-yl}- 1 H-indazol-1 -yl)methyl]phenoxy}-2-methylpropan-1 -ol ,
(2R)-3-{4-[(3-{4-[(2,5-dimethylpyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 H-indazol- 1 -yl)methyl]-3,5-difluorophenoxy}-2-methylpropan-1 -ol ,
N-[4-({2-[1 -(2,6-difluoro-4-{[(2R)-3-hydroxy-2-methylpropyl]oxy}benzyl)-1 H-indazol-3- yl]-5-methoxypyrimidin-4-yl}amino)pyridin-2-yl]acetamide ,
(2R)-3-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl}- 1 H-indazol-1 -yl)methyl]phenoxy}-2-methylpropan-1 -ol ,
3-{3,5-difluoro-4-[(3-{5-methoxy-4-[(2-methylpyridin-4-yl)amino]pyrimidin-2-yl}-1 H- indazol-1 -yl)methyl]phenoxy}propan-1 -ol ,
2-{4-[(3-{4-[(2,6-dimethylpyrimidin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 H-indazol-1 - yl)methyl]-3,5-difluorophenoxy}ethanol ,
2-{3,5-difluoro-4-[(3-{4-[(2-fluoropyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 H- indazol-1 -yl)methyl]phenoxy}ethyl D-lysyl-L-alaninate, salt with trifluoroacetic acid , 2-{3,5-difluoro-4-[(3-{4-[(2-fluoropyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 H- indazol-1 -yl)methyl]phenoxy}ethyl D-lysyl-L-alaninate ,
2-{3,5-difluoro-4-[(3-{4-[(2-fluoropyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 H- indazol-1 -yl)methyl]phenoxy}ethyl L-lysyl-L-alaninate, salt with trifluoroacetic acid , and 2-{3,5-difluoro-4-[(3-{4-[(2-fluoropyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 H- indazol-1 -yl)methyl]phenoxy}ethyl L-lysyl-L-alaninate,
or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
In accordance with a preferred embodiment, component A is is 2-{3,5-difluoro-4-[(3-{5- methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/-indazol-1 - yl)methyl]phenoxy}ethanol,
or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
In a more preferred embodiment, said component A is 2-{3,5-difluoro-4-[(3-{5-methoxy- 4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/-indazol-1 -yl)methyl]phenoxy}ethanol or a pharmaceutically acceptable salt thereof. In an even more preferred embodiment, component A is 2-{3,5-difluoro-4-[(3-{5- methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/-indazol-1 - yl)methyl]phenoxy}ethanol.
In other embodiment, component A is selected from the group of Bub1 inhibitors described generically or specifically in:
WO2013/050438
WO 2013/092512
WO 2013/167698
WO 2014/147144
WO 2014/147203
WO 2014/147204
WO2014/202586
WO 2014/202590
WO 2014/202588
WO 2014/202584 WO 2015/193339
WO 2016/041925
WO 2016/042080
WO 2106/ 042081
WO 2016/120196 PCT/EP2015/063527
PCT/EP2016/068279, or
EP15200590.6
which are incorporated herein by reference in its entirety.
Compounds of formula (I) as described and defined herein can be prepared according to the preparation methods contained in WO 2016/042084 which is incorporated herein by reference in its entirety.
The BUB1 -inhibitors mentioned in the prior art as well as in the lists above have been disclosed for the treatment or prophylaxis of different diseases, especially cancer.
The specific compounds of the lists as disclosed above are preferred as being component A of the combination, most preferred are the compounds used in the experimental section.
The synergistic behavior of a combination of the present invention is demonstrated herein with a Bub1 inhibitor specifically disclosed as example 2-1 -3 in WO 2016/042084, referrred to as Compound A1 (or as Compd A1 ) below.
A combination of the present invention comprising Compound A1 as mentioned above and a PARP inhibitor is a preferred embodiment of the invention.
Another embodiment of the present invention covers a combination comprising the Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and a PARP inhibitor or a pharmaceutically acceptable salt thereof. Another embodiment of the present invention covers a combination comprising the
Compound A1 or a pharmaceutically acceptable salt thereof as mentioned above and a
PARP inhibitor selected from the group consisting of:
Niraparib (MK-4827),
Iniparib (BSI 201 ),
Talazoparib (BMN-673),
Olaparib (AZD-2281 ),
Rucaparib (AG014699, PF-01367338),
Veliparib (ABT-888),
CEP-8983,
CEP-9722,
E7016 (GPI21016),
AZD2461 ,
INO-1001 , and
BGB-290,
or a pharmaceutically acceptable salt, tautomer, N-oxide, solvate, hydrate or stereoisomer thereof.
Another embodiment of the present invention covers a combination comprising the Compound A1 or a pharmaceutically acceptable salt thereof and a PARP inhibitor selected from the group consisting of olaparib, rucaparib, talazoparib, and niraparib or a pharmaceutically acceptable salt thereof.
It is to be understood that the present invention relates also to any combination of the embodiments of component A described above.
Component A may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route. Preferably Component A is administered intravenously, intraperitoneally or orally.
Compound A1 is administered preferably orally.
Component B of the Combination Component B is a PARP inhibitor, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.
In accordance with another embodiment, component B is an inhibitor of PARP1 and/or PARP2.
In accordance with another embodiment, component B is an inhibitor of PARP inhibitor selected from the group consisting of:
Niraparib (MK-4827),
Iniparib (BSI 201 ),
Talazoparib (BMN-673),
Olaparib (AZD-2281 ),
Rucaparib (AG014699, PF-01367338),
Veliparib (ABT-888),
CEP-8983,
CEP-9722,
E7016 (GPI21016),
AZD2461 ,
INO-1001 , and
BGB-290,
or a pharmaceutically acceptable salt, N-oxide, tautomer, solvate, hydrate or stereoisomer thereof.
In accordance with a preferred embodiment, component B is a PARP inhibitor selected from the group consisting of:
olaparib, rucaparib, talazoparib, and niraparib,
or a pharmaceutically acceptable salt, N-oxide, tautomer, solvate, hydrate or stereoisomer thereof. PARP inhibitors according to the present invention are commercially available and/or can be prepared according to methods readily available to a skilled person. For example the following references, which are incorporated herein by reference, describe methods to prepare PARP inhibitors:
- olaparib, WO 2004/080976, WO 2008047082,
- rucaparib, WO 2000/042040, WO 2004/087713
- talazoparib, GB 2462361 , WO 201 1/130661 , WO 201 1/097602 - niraparib, WO 2008/084261 , WO 2009/087381
Component B preferably is administered by the more appropriate route within the knowledge of the skilled person.
Component B may be administered by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
According to certain embodiments of the present invention Component B is olaparib, or a pharmaceutically acceptable salt, N-oxide, tautomer, solvate, hydrate or stereoisomer thereof.
Olaparib (AZD-2281 , trade name Lynparza) is a PARP inhibitor approved in the US and Europe.
In the US, olaparib is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Typically, the recommended dose of Olaparib is 400 mg (eight 50 mg capsules) taken twice daily orally, for a total daily dose of 800 mg. Typically patients continue treatment until disease progression or unacceptable toxicity arises.
In Europe, olaparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic) high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete response or partial response) to platinum-based chemotherapy. Typically, The recommended dose of Olaparib is 400 mg (eight capsules) taken twice daily, equivalent to a total daily dose of 800 mg. Patients should start treatment with olaparib no later than 8 weeks after completion of their final dose of the platinum- containing regimen.
Typically, patients should have confirmation of susceptibility gene (BRCA) mutation before olaparib treatment is initiated, particularly patients with breast cancer. Methods to determine BRCA mutation status are readily available to a skilled person (for example BRACAnalysis CDx™ from Myriad Genetic Laboratories). The dosing and/or dosing regimen of olaparib may be adjusted according to patients's response, adverse events and or co-treatment with other drugs by the skilled person using methods readily available to him/her. According to certain embodiments of the present invention Component B is rucaparib, or a pharmaceutically acceptable salt, N-oxide, tautomer, solvate, hydrate or stereoisomer thereof. Rucaparib (AG 014699, trade name Rubraca) is a PARP inhibitor approved in the US for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer. It has been/is being tested in clinical trials in patients with disorders such as:
- metastatic breast and ovarian cancer with known BRCA1 or BRCA2 mutation, - maintenance after platinum-based chemotherapy for serous and endometrioid ovarian cancer,
- BRCA1/2 positive pancreatic cancer,
- relapsed, BRCA Mutant, High Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer.
- Metastatic Castration-resistant Prostate Cancer and Homologous Recombination Gene Deficiency.
Typically, rucaparib is taken orally, for example in tablet form. In Phase III clinical trials, tablets of rucaparib were administered orally at a dose of 600 mg, twice daily.
In the US, the FDA has granted accelerated approval to rucaparib for treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies. Typically, the recommended dose and schedule for rucaparib is 600 mg (two 300 mg tablets) taken orally twice daily with or without food.
Typically, patients should have confirmation of susceptibility gene (BRCA) mutation before rucaparib treatment is initiated. Methods to determine BRCA mutation status are readily available to a skilled person (for example BRACAnalysis CDx™ from Myriad Genetic Laboratories, or FoundationFocus CDxBRCA test from Foundation Medicine Inc., for example). The dosing and/or dosing regimen of rucaparib may be adjusted according to patients's response, adverse events and or co-treatment with other drugs by the skilled person using methods readily available to him/her.
According to certain embodiments of the present invention Component B is talazoparib, or a pharmaceutically acceptable salt, N-oxide, tautomer, solvate, hydrate or stereoisomer thereof.
Talazoparib (BMN-673) is a PARP inhibitor being investigated as a potential anti-cancer agent. It has been or is being tested in clinical trials in patients with disorders such as: - Deleterious BRCA1/2 Mutation-Associated Ovarian Cancer,
- Invasive Breast Cancer and a Deleterious BRCA Mutation,
- Advanced Cancer Patients With Somatic Alterations in BRCA1/2, Mutations/Deletions in PTEN or PTEN Loss, a Homologous Recombination Defect, Mutations/Deletions in Other BRCA Pathway Genes and Germline Mutation in BRCA1/2,
- BRCA1 and BRCA2 Wild-Type (i) Advanced Triple-Negative Breast Cancer and Homologous Recombination Deficiency, and (ii) Advanced HER2-Negative Breast Cancer With Either a Germline or Somatic Mutation in Homologous Recombination Pathway Genes,
- Relapsed Ovarian, Fallopian Tube, and Peritoneal Cancer (optionally in combination with temozolomide),
- Locally Advanced and/or Metastatic Breast Cancer with Germline BRCA Mutation,
- Untreated AML in Adults Unfit for Cytotoxic Chemotherapy or R/R AML in Combination Therapy with DNA Methyltransferase Inhibitor Decitabine,
- Breast Cancer in combination with Irinotecan.
Typically, talazoparib is taken orally, for example in tablet or capsule form. In certain clinical studies, patients received 1 mg p.o. once daily on 28 day cycles. In other clinical studies, patients received talazoparib oral capsules once daily (1 .0 mg/day) in 21 -day cycles.
Typically, patients should have confirmation of susceptibility gene (BRCA) mutation before talazoparib treatment is initiated. Methods to determine BRCA mutation status are readily available to a skilled person (for example BRACAnalysis CDx™ from Myriad Genetic Laboratories). The dosing and/or dosing regimen of talazoparib may be adjusted according to patients's response, adverse events and or co-treatment with other drugs by the skilled person using methods readily available to him/her.
According to certain embodiments of the present invention Component B is niraparib, or a pharmaceutically acceptable salt, N-oxide, tautomer, solvate, hydrate or stereoisomer thereof.
Niraparib (MK-4827) is a PARP inhibitor being investigated as a potential anti-cancer agent. It has been or is being tested in clinical trials in patients with disorders such as:
- Platinum Sensitive Ovarian Cancer,
- Advanced, BRCA1 -like, HER2-negative Breast Cancer Patients, - Advanced, Relapsed, High-Grade Serous Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer,
- Metastatic Castration-Resistant Prostate Cancer and DNA-Repair Anomalies,
- Advanced or Metastatic Triple-Negative Breast Cancer and Recurrent Ovarian Cancer in combination with Pembrolizumab.
- Platinum-sensitive Epithelial Ovarian Cancer in combination with bevacizumab.
- Homologous recombination deficiency(HRD)-Positive Advanced Ovarian Cancer. Typically, niraparib is taken orally, for example in tablet or capsule form. In certain clinical studies, patients received 300 mg/day niraparib orally. Typically, patients should have confirmation of susceptibility gene (BRCA) mutation before talazoparib treatment is initiated. Methods to determine BRCA mutation status are readily available to a skilled person (for example BRACAnalysis CDx™ from Myriad Genetic Laboratories). The dosing and/or dosing regimen of niraparib may be adjusted according to patients's response, adverse events and or co-treatment with other drugs by the skilled person using methods readily available to him/her.
In accordance with an embodiment, the present invention relates to a combination of any component A mentioned herein with any component B mentioned herein, optionally with any component C mentioned herein.
In one embodiment, component A of the combination is the compound used in the experimental section (compound A1 ) and Component B is a PARP inhibitor used in the experimental section. In a particular embodiment, the present invention relates to a combination of a component A with a component B, optionally with a component C, as mentioned in the Examples Section herein.
Further, the present invention relates to :
a kit comprising :
- a combination of :
component A: one or more BUB1 -kinase inhibitors, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof ;
component B : an inhibitor of PARP, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof; and, optionally, component C : one or more further pharmaceutical agents; in which optionally either or both of said components A and B in any of the above- mentioned combinations are in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially. The term "component C" being at least one pharmaceutical agent includes the effective compound itself as well as its pharmaceutically acceptable salts, solvates, hydrates or stereoisomers as well as any composition or pharmaceutical formulation comprising such effective compound or its pharmaceutically acceptable salts, solvates, hydrates or stereoisomers. A list of such readily available agents is being provided further below.
The components may be administered together or independently of one another by the oral, intravenous, topical, local installations, intraperitoneal or nasal route.
Component C being administered as the case may be.
Components of this invention can be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present. Components of this invention can also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
Syrups and elixirs can be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
Components of this invention can also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the component in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1 -dioxolane-4- methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants. Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, for example, alkyl-beta- aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures. The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile- lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 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 can be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.
The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables. Components of the invention can also be administered in the form of suppositories for rectal administration of the drug. These components can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol.
Another formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 1 1 , 1991 , incorporated herein by reference). Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art. It can be desirable or necessary to introduce a component of the present invention to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,01 1 ,472, issued April 30, 1991. The compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al, "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-31 1 ; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1 " PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. 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
Figure imgf000038_0001
air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene- butadiene copolymers); buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate) carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection) chelating agents (examples include but are not limited to edetate disodium and edetic acid) colorants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (examples include but are not limited to bentonite); emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate); encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil);
ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas) plasticizers (examples include but are not limited to diethyl phthalate and glycerol); solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)); surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate); suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples include but are not limited to magnesium stearate and talc); tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch); tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate); tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross- linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch); tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc); tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet/capsule opaquants (examples include but are not limited to titanium dioxide); tablet polishing agents (examples include but are not limited to carnuba wax and white wax); thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin); tonicity agents (examples include but are not limited to dextrose and sodium chloride); viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth); and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate). Pharmaceutical compositions according to the present invention can be illustrated as follows:
Sterile IV Solution: A 5 mg/mL solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over about 60 minutes. 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, 1 1 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
Immediate Release Tablets/Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
Commercial utility
Component A
The compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof according to the combination as referred to above are components A. The compounds according to the combination have valuable pharmaceutical properties, which make them commercially utilizable. In particular, they inhibit Bub1 kinase and are expected to be commercially applicable in the therapy of diseases (e.g. cancer).
Component B
Due to the mechanism as discussed in the introductory section component B is especially suitable to have effects on tumor diseases. In particular, they inhibit PARP and are commercially applicable in the therapy of diseases (e.g. BRCA-mutated cancers).
Combination
The combinations of the present invention thus can be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
One embodiment relates to the use of a combination according to the invention for the preparation of a medicament for the treatment or prophylaxis of a cancer, particularly breast-, prostate-, ovarian- or bladder cancer, glioblastoma (GBM), melanoma, or mantel cell lymphoma (MCL), and/or metastases thereof.
In one embodiment the invention relates to a method of treatment or prophylaxis of a cancer, particularly hepatocyte carcinoma, lung cancer, in particular breast-, prostate-, ovarian- or bladder cancer, GBM, melanoma, or MCL, and/or metastases thereof, in a subject, comprising administering to said subject a therapeutically effective amount of a combination according to the present invention.
Preferred uses of the combinations of the invention are the treatment of breast-, prostate-, ovarian- or bladder cancer, GBM, melanoma, or MCL, and/or metastases thereof. One preferred embodiment is the use of the combinations of the invention for the treatment of the disorders tested in the experimental section, for example, triple- negative breast cancer (TNBC), prostate cancer , melanoma and/or metastases thereof.
The term "inappropriate" within the context of the present invention, in particular in the context of "inappropriate cellular immune responses, or inappropriate cellular inflammatory responses", as used herein, is to be understood as preferably meaning a response which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases. Combinations of the present invention might be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
This invention includes a method comprising administering to a mammal in need thereof, including a human, an amount of a component A or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof , and an amount of component B of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; which is effective to treat the disorder.
Hyper-proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), as well as malignant neoplasia. Examples of malignant neoplasia treatable with the compounds according to the present invention include solid and hematological tumors. Solid tumors can be exemplified by tumors of the breast, bladder, bone, brain, central and peripheral nervous system, colon, anum, endocrine glands (e.g. thyroid and adrenal cortex), esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva. Malignant neoplasias include inherited cancers exemplified by Retinoblastoma and Wilms tumor. In addition, malignant neoplasias include primary tumors in said organs and corresponding secondary tumors in distant organs ("tumor metastases"). Hematological tumors can be exemplified by aggressive and indolent forms of leukemia and lymphoma, namely non- Hodgkins disease, chronic and acute myeloid leukemia (CML / AML), acute lymphoblastic leukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma. Also included are myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, and cancers of unknown primary site as well as AIDS related malignancies.
Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
Examples of cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
Examples of brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus. Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
Examples of liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma. Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell. Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
The term "treating" or "treatment" as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, eic, of a disease or disorder, such as a carcinoma. Combinations of the present invention might also be used for treating disorders and diseases associated with excessive and/or abnormal angiogenesis.
Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal- vein occlusion, and retinopathy of prematurity [Aiello et al. New Engl. J. Med. 1994, 331 , 1480 ; Peer et al. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD ; see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855], neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumor enlargement and metastasis. Moreover, the growth of new blood and lymph vessels in a tumor provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer. Thus, combinations of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation ; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.
Dose and administration
Component A
Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of hyper-proliferative disorders and angiogenic disorders, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions, the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredients to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated. The total amount of the active ingredients to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 30 mg/kg body weight per day. The total amount of the active ingredients per dose will generally range from about 1 mg to about 500 mg per dose, and preferably from about 20 mg to about 200 mg per dose. Clinically useful dosing schedules of a compound will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
Component B
The PARP inhibitor can be administered to a patient at a dosage which can range from about 0.1 to about 300 mg/kg of total body weight. More specific dosages and dosage regimens are provided herein for several PARP inhibitors, such as for example for olaparib, rucaparib, talazoparib, and niraparib, and/or are known and/or can be readily determined by a skilled person using known techniques.
The specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compounds employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a PARP inhibitor of the present invention or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, or a composition thereof can be ascertained by those skilled in the art using conventional treatment tests. Suitable dose(s), administration regime(s) and administration route(s) for PARP inhibitors include those defined in the Patient Information Leaflet or in Clinical Practice Guidelines in Oncology. Alternatively, suitable dose(s), administration regime(s) and administration route(s) for PARP inhibitors may be readily determined by standard techniques known to the skilled person.
The dose(s), administration regime(s) and administration route(s) may have to be adapted according to, inter alia, the indication, the indication stage, the patient age and/or the patient gender, among other factors. Such adaptations can be readily determined by standard techniques known to the skilled person.
For both the Bub1 inhibitors and the PARP inhibitors of the present invention the administered dosage and/or administration regime may be modified, independently of each other or simultaneously, depending on any superior or unexpected results which may be obtained as routinely determined with this invention.
The PARP inhibitor can be administered to a patient orally, topically, parenterally, rectally, by inhalation, and by injection. Administration by injection includes intravenous, intramuscular, subcutaneous, and parenterally as well as by infusion techniques. The agents can be administered by any of the conventional routes of administration for these compounds. The preferred route of administration for the hyper- proliferative/cytotoxic/cytostatic agents using this invention is typically by injection which is the same route of administration used for the agent alone. Any of the hyper- proliferative, cytotoxic or cytostatic agents can be administered in combination with an MKNK1 inhibitor of general formula (I) by any of the mentioned routes of administration.
For administering the Bub1 inhibitor and the PARP inhibitor, by any of the routes of administration herein discussed, the Bub1 inhibitor can be administered simultaneously with the PARP inhibitor. This can be performed by administering a single formulation which contains both the Bub1 inhibitor and the PARP inhibitor or by administering the Bub1 inihibitor and PARP inhibitor in independent formulations at the same time (concomittantly) to a patient.
Alternatively, the Bub1 inhibitor can be administered in tandem with the PARP inhibitor. The Bub1 inihbitor can be administered prior to the PARP inhibitor. Also, the PARP inhibitor can be administered first followed by adminstration of the Bub1 inihibitor. The choice of sequence administration of the Bub1 inihibitor relative to the PARP inhibitor may vary for different agents, and can be readily determined and, when needed, modified or adapted by the skilled person using techniques readily available in order, for example, to improve the therapeutic effect of the combination. Also, the PARP inhibitor can be administered using any regimen which is conventionally used for these agents.
In another regimen of administration, the Bub1 inihibitor and the PARP inhibitor can be administered once or more times per day on the day(s) of administration.
Any of the routes and regimens of administration may be modified depending on any superior or unexpected results which may be obtained as routinely determined with this invention.
Combinations of the present invention
The combinations of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth, more especially breast (for example TNBC), ovarian, prostate, and skin cancer. Other preferred indications are those tumor types of all indications with BRCA1 and/or BRCA2 mutations. Also preferred indications are breast (for example TNBC), ovarian, prostate, and skin cancer with BRCA1 and/or BRCA2 mutations. Other indications are tumours without STAG2 alterations (e.g. mutations) and/or ATM low or loss of expression.
Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art, for example using the methods described herein in the Experimental section.
Suitable methods to determine the genetic features (genetic profile) of a tumor are readily available to the skilled person, for example it can be determined using the methods/kits described herein, other known methods, and/or using commercially available methods/kits.
The combinations of component A and component B of this invention can be administered as the sole pharmaceutical agent or in combination with one or more further pharmaceutical agents C where the resulting combination of components A, B and C causes no unacceptable adverse effects. For example, the combinations of components A and B of this invention can be combined with component C, i.e. one or more further pharmaceutical agents, such as known anti-angiogenesis, anti-hyper- proliferative, antiinflammatory, analgesic, immunoregulatory, diuretic, antiarrhytmic, anti-hypercholsterolemia, anti-dyslipidemia, anti-diabetic or antiviral agents, and the like, as well as with admixtures and combinations thereof.
Component C, can be one or more pharmaceutical agents such as:
131 1-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basiliximab, belotecan, bendamustine, besilesomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, calcium folinate, calcium levofolinate, capecitabine, capromab, carbamazepine carboplatin, carboquone, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, cobimetinib, copanlisib , crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dianhydrogalactitol, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nelarabine, neridronic acid, netupitant/palonosetron, nivolumab, pentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaratumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palbociclib, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, roniciclib , samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.
Optional anti-hyper-proliferative agents which can be added as component C to the combination of components A and B of the present invention include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 1 1 th Edition of the Merck Index, (1996), which is hereby incorporated by reference.
Other anti-hyper-proliferative agents suitable for use as component C with the combination of components A and B of the present invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated by reference.
Generally, the use of cytotoxic and/or cytostatic agents as component C in combination with a combination of components A and B of the present invention will serve to:
(1 ) yield better efficacy in reducing the growth of a tumor and/or metastasis or even eliminate the tumor and/ or metastasis as compared to administration of either agent alone,
(2) provide for the administration of lesser amounts of the administered chemo- therapeutic 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, provide for a higher response rate among treated patients,
(6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments, provide a longer time for tumor progression, and/or yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
EXPERIMENTAL SECTION
The study was designed to determine the anti-proliferative effects of the combination treatment with a Bub1 kinase inhibitor and the PARP inhibitors olaparib, rucaparib, talazoparib, and niraparib on a panel of human tumor cell lines.
1. Preparation of Bub1 and PARP inhibitors
The schemes and procedures described in the art as cited in the present application disclose general synthetic routes and specific procedures to arrive at the Bub1 inhibitor compounds which are preferred components A of the present combination. Specifically, compound A1 , 2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methoxypyridin-4- yl)amino]pyrimidin-2-yl}-1 H-indazol-1 -yl)methyl]phenoxy}ethanol can be prepared according to the methods described in WO2016/042084, particularly using the method
Figure imgf000056_0001
Compound A1 ;
Similarly, the PARP inhibitors which are preferred component B of the present combination are described in the art and/or are available commercially, particularly the below depicted PARP inhibitors: a) Olaparib, 4-(3-{[4-(cyclopropylcarbonyl)piperazin-1 -yl]carbonyl}-4- fluorobenz l)phthalazin-1 (2H)-one
Figure imgf000056_0002
b) Rucaparib, 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1 ,3,4,5-tetrahydro-6H- aze ino[5,4,3-cd]indol-6-one phosphate
Figure imgf000057_0001
c) Talazoparib, (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1 -methyl-1 H-1 ,2,4-triazol-5-yl)- 2!7!8!9-tetrahydro-3H-pyrido[4!3,2-de]phthalazin-3-one
Figure imgf000057_0002
d Niraparib, 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide hydrochloride
Figure imgf000057_0003
2. Biological in vitro Experiments:
2.1 Test system
Figure imgf000057_0004
2.2 Study design
Figure imgf000058_0001
2.3 Methods and parameters
Tumor cells were propagated in a humidified 37°C incubator in their respective growth medium supplemented 10% fetal calf serum. For analysis of combination effects between a compound A and a compound B, cells were plated in 384-well plates at the cell numbers per well as indicated in 2.1 (Study design). After 24h, cells were treated with a Bub1 inhibitor (component A) and with one of the PARP inhibitors (component B) olaparib, rucaparib, talazoparib, or niraparib for single compound treatments (final concentrations see 2.2 (Study design)), and in nine different fixed-ratio combinations of compound A (D1 ) and compound B (D2) (0.9xD1 +0.1 xD2, 0.8xD1 +0.2xD2, 0.7xD1 +0.3xD2, 0.6xD1 +0.4xD2, 0.5xD1 +0.5xD2, 0.4xD1 +0.6xD2, 0.3xD1 +0.7xD2, 0.2xD1 +0.8xD2, 0.1 xD1 +0.9xD2). Cell viability was assessed after 96 hour exposure with the Cell Titre-Glo Luminescent Cell Viability Assay (Promega). 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 measurement readings taken immediately before compound exposure (=0%). IC50 isobolograms were plotted with the actual concentrations of the two compounds on the x- and y-axis, and the combination index (CI) was calculated according to the median-effect model of Chou-Talalay [Chou T.C. Pharmacol. Rev. 58, 621 , 2006]. A CI of <0.8 was defined as more than additive (synergistic) interaction, and a CI of >1 .2 was defined as antagonistic interaction.
2.4 Results
Calculated combination indices (CI50) at IC50 for Bub1 inhibitor plus PARP inhibitor are summarized in tables 1 to 4, along with the mono-treatment IC50 values and the concentrations required in combination to achieve the CI50.
CI50 interpretation code: CI50 <0.8, synergism; 0.8< CI50≤1 .2, additivity; Cl5o>1 .2, antagonism.
In case of synergism lowest CI50 along with corresponding compound concentrations is presented, in case of antagonism, highest CI50 is given.
2.4.1 Combination of compound A1 with oiaparib
Table 1 summarizes the data for Compound A1 plus oiaparib.
Table 1 : Calculated combination indices at IC50 (CI50) from proliferation assays of cell lines treated with combinations of Bub1 inhibitor Compound A1 and oiaparib. Mono- treatment IC50 values and the concentrations required in combination of the two test compounds to achieve the CI50 are shown. All concentrations are given in mol/L.
Figure imgf000059_0001
BRCA2 mt, 9.2E-07 1 .7E-05 2.6E-07 3.1 E-06 0.62
Prostate 22RV1
ATR mt 1 .4E-06 9.1 E-06 5.1 E-07 1 .5E-06 0.45
Ovary IGR-OV-1 hypermutated 2.9E-06 6.4E-06 additive
Glioblastoma STAG2 mt 2.2E-06 4.2E-06
H4 additive (GBM)
42-MG-BA STAG2 mt 2.9E-06 1 .6E-05 additive
Melanoma LOX IMVI STAG2 del 2.0E-06 1 .7E-05 8.0E-07 3.6E-06 0.63
Ewing STAG2mt
SK-ES-1 2.3E-06 4.4E-06 1 .8E-06 3.6E-06 1 .58 sarcoma
Mantel cell ATM low 1 .3E-06 1 .5E-06
GRANTA- lymphoma expression additive
519
(MCL)
Bladder UM-UC-3 STAG2 mt 3.4E-06 2.7E-05 additive
2.4.2 Combination of compound A1 with rucaparib
Table 2 summarizes the data for Compound A1 plus rucaparib.
Table 2: Calculated combination indices (CI) from proliferation assays of cell lines treated with combinations of Bub1 inhibitor Compound A1 and rucaparib. Mono- treatment I C50 values and the concentrations required in combination of the two test compounds to achieve the CI50 are shown. All concentrations are given in mol/L.
Figure imgf000060_0001
2.4.3 Combination of compound A1 with talazoparib
Table 3 summarizes the data for Compound A1 plus talazoparib.
Table 3: Calculated combination indices (CI) from proliferation assays of cell lines treated with combinations of Bub1 inhibitor Compound A1 and talazoparib. Mono- treatment I C50 values and the concentrations required in combination of the two test compounds to achieve the CI50 are shown. All concentrations are given in mol/L.
Figure imgf000061_0001
2.4.4 Combination of compound A1 with niraparib
Table 4 summarizes the data for Compond A1 plus niraparib.
Table 4: Calculated combination indices (CI) from proliferation assays of cell lines treated with combinations of Bub1 inhibitor Compound A1 and niraparib. Mono- treatment I C50 values and the concentrations required in combination of the two test compounds to achieve the CI50 are shown. All concentrations are given in mol/L.
Figure imgf000061_0002
3. Biological in vivo Experiments:
The MDA-MB-436 BRCA1 -mutated triple-negative breast cancer model was used for the human xenograft study to evaluate the efficacy of the Bub1 inhibitor plus Olaparib combination.
3.1 Test system, study design and methods
Experiments were initiated after an acclimatization period of at least 7 days. Animals were kept in a 12 hours light/dark cycle, food and water was available ad libitum and housing temperature was 23 °C. All animal experiments were conducted in accordance with the German animal welfare law and approved by local authorities. Study design
Animals were randomly assigned to experimental groups, twelve animals per group. At the initiation of the treatment, animals were tattooed and each cage was labeled with the cage number, study number and number of animals per cage.
Figure imgf000062_0001
Methods and parameters
MDA-MB-436 human breast cancer cells originally purchased from CLS Cell Lines Service (#300278), Eppelheim, Germany, were cultured as described according to the supplier's protocols. Cells were harvested for transplantation in a subconfluent (70%) state. Animals were injected with 1 x 106 MDA-MB-436 cells suspended in 25% Matrigel into the 4. mammary gland on day 0.
When tumors reached a predetermined size in mice of approx. 35 mm2 animals were randomized into treatment and control groups (n=12 animals/group) and treatment with Compound A1 , Olaparib, or combination started. The oral application volumes were 10 ml/kg for mice, the intraperitoneal application volume was 10 ml/kg for mice. The time interval between two applications per day was 6-7h. Tumor response was assessed by determination of the tumor area (product of the longest diameter and its perpendicular) using a caliper. The animal body weight was monitored as a measure for treatment-related toxicity. Measurement of tumor area and body weight were performed three times weekly.
Animals were sacrificed when showing signs of toxicity (>20% body weight loss) or when tumors reached a size of approximately 150 mm2.
Tumor growth inhibition is presented as T/C ratio (Treatment / Control) calculated with tumor areas when the vehicle control group had to be closed. Relative tumor growth inhibition based on tumor area (relative T/C) was calculated by the formula [(tumor area of treatment group at day x) - (tumor area of treatment group at day before first treatment)] / [(tumor area of vehicle group at day x) - (tumor area of vehicle group at day before first treatment)].
Statistical analysis
Statistical analysis was assessed using SigmaStat software. A T-test and a One Way Analysis of Variance (ANOVA) were performed. When P values <0.05 it is designated statistically significant difference.
3.2 Results Treatment for all groups started at a tumor size of approx. 35 mm2, at day 27 after tumor cell inoculation. Groups 1 and 2 were treated until day 69 when they had to be terminated for animal welfare reasons. Treatment of groups 3 and 4 was continued until day 91 when they were terminated.
At day 69 when the vehicle group had to be terminated due to tumor size, Compound A1 (group 2) showed only marginal single agent efficacy (relative T/Carea 0.82), whereas Olaparib (group 2) was moderately efficacious (relative T/Carea 0.47). Surprisingly, the the combination of Compound A1 and Olaparib was highly efficacious (relative T/Carea 0.22). The mean tumor areas of all treatment groups were statistically different from the vehicle group (p<0.05). Olaparib-treated tumors showed a continuous growth even under continued Olaparib treatment and reached a size that required termination of the study at day 91 . Surprisingly, the animals treated with the combination of Compound A1 and Olaparib showed a strongly reduced tumor growth rate and mean relative tumor area at day 91 was 65% below the mean relative tumor area of the Olaparib treated tumors. The difference in tumor areas between the Olaparib single agent treatment group and the combination treatment group were statistically significant (P<0.001 ).
4. Conclusions:
In summary, in the present studies the combination of Bub1 kinase inhibitor compound A1 with PARP inhibitors olaparib, rucaparib, talazoparib, or niraparib in proliferation assays of human carcinoma cells showed the utility of the present invention. The in vitro results showed predominantly more than additive (CI50 <0.8) interaction. Additive interations (0.8< CI50≤1 .2) and, and in one cell line an antagonistic interaction were observed (CI50 >1 .2) in cell lines whose characteristic genetic features notably decrease and/or eliminate the relevance (or role) of Bub1 in mitotsis of a cancer cell (thereby mechanistically not enabling the more than additive effect itself to manifest). For example, cell lines which were reported to have mutations in the STAG2 gene [Solomon et al. BMB Rep. 47, 299, 2014] showed an additive or antagonistic effects upon combination treatment with a Bub1 kinase inhibitor and a PARP inhibitor. STAG2 mutated cell lines are more sensitive towards PARP inhibitors as compared to isogenic STAG2 wild-type cell lines and accumulate in the G2 phase of the cell cycle upon PARP inhibition [Bailey et al. Mol Cancer Ther. 13, 724, 2013]. Furthermore, deficiency of STAG2 function was described to result in derealization of Bub1 protein from the centromeric region of the chromosomes [Kleyman et al. J. Cell Sci. 127, 4225, 2014]. Accumulation of PARP inhibitor treated STAG2 deficient cells in G2 phase, in which Bub1 kinase is dispensible, and derealization of Bub1 protein most probably causes the missing sensitizing effect of Bub1 kinase inhibition on PARP inhibitor treatment. Activating phosphorylation of Bub1 on Ser314 by ATM kinase has been reported [Yang et al. Mol. Cell, 44, 597, 201 1]. In the case of GRANTA-519 cells, low levels of ATM protein expression [Williamson et al. Mol. Cancer Ther. 9, 347, 2010] may hamper proper activation of Bub1 kinase and increase sensitivity against PARPi mono- treatment limiting the sensitizing effect of Bub1 kinase inhibition on PARPi treatment.
The in vivo study in the MDA-MB-436 BRCA1 -mutated triple-negative human breast cancer model xenografted orthotopically onto NOD-SCID mice clearly demonstrated the more than additive anti-tumor efficacy of the combination of a Bub1 kinase inhibitor with a PARP inhibitor as compared to the respective single agent efficacies. Surprisingly, combining an Bub1 kinase inhibitor with an PARP inhibitor strongly deminished the outgrowth of the tumors under continued treatment as compared to PARP inhibitor single agent treatment.
These results demonstrate that combination of Bub1 kinase inhibitors with PARP inhibitors can result in more than additive anti-proliferative (synergistic) efficacy in tumor cells and in vivo tumor models and warrant further clinical evaluation of this promising combination therapy for the treatment of cancer.
Description of the Figures
Figure 1
Time course of MDA-MB-436 BRCA1 -mutated triple-negative breast cancer xenograft model on NOD-SCID mice and body weight change (%). Treatment with Compound A1 , olaparib, or the combination of Compound A1 and olaparib started at a tumor size of approx. 35 mm2, at day 27 after tumor cell inoculation. Groups 1 and 2 were treated until day 69 when they had to be terminated for animal welfare reasons. Treatment of groups 3 and 4 was continued until day 91 when they were terminated.
Compound A1 was administered twice daily (2QD) p.o. at a dose of 50 mg/kg in the single agent treatment group and at 50 mg/kg in combination with olaparib, olaparib was administered once daily (1 QD) i.p. at a dose of 25 mg/kg.

Claims

1. A combination of at least two components, component A and component B, comprising a component A being an inhibitor of Bub1 , or a pharmaceutically acceptable salt, tautomer, N-oxide, solvate, hydrate or stereoisomer thereof, and component B being an inhibitor of PARP, or a pharmaceutically acceptable salt, tautomer, N-oxide, solvate, hydrate or stereoisomer thereof.
2. The combination according to claim 1 , comprising a component A being an inhibitor of Bub1 of general formula (I),
Figure imgf000066_0001
in which,
V, W, Y and Z independently of each other represent CH or CR2, wherein one of V, W,
V and Z represents CR2,
or,
V represents N, and W, Y and Z independently of each other represent CH or CR2, or,
V and Y represent N, and W and Z independently of each other represent CH or CR2,
R1 represents a group selected from:
Ci-C6-alkyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl,
(Ci-C3-alkoxy)-(C2-C3-alkyl)-, and (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, R2 represents, independently of each other, halogen or a group selected from: Ci-C3-alkyl, C3-C4-cycloalkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy,
Ci-C3-haloalkoxy, -N(H)C(=0)-(Ci-C3-alkyl), -N(H)C(=0)H, -N(H)C(=0)-(Ci-C3-hydroxyalkyl),
-N(H)C(=0)-(Ci-C3-alkyl)-(Ci-C3-alkoxy), -N(H)C(=0)-phenyl, -N(H)C(=0)-(C3-C4-cycloalkyl),
-N(H)C(=0)-(Ci-C3-alkyl)-(C3-C4-cycloalkyl), and -N(H)C(=0)N(H)R8,
said -N(H)C(=0)-phenyl being optionally substituted at the phenyl ring, one, two or three times, identically or differently, with a substituent selected from:
halogen, hydroxy, cyano, Ci-C4-alkyl, Ci-C4-haloalkyl,
Ci-C4-alkoxy, Ci-C4-haloalkoxy, C3-C4-cycloalkyl, and
C3-C4-cycloalkyloxy,
said -N(H)C(=0)-(C3-C4-cycloalkyl) being optionally substituted at the C3-C4-cycloalkyl ring with a substituent selected from:
fluorine, chlorine, trifluoromethyl, and methoxy,
R3 represents a group selected from:
C2-C6-hydroxyalkyl, and R4,
said C2-C6-hydroxyalkyl groups being optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine, R4 represents -(C2-C6-alkyl)-OC(=0)-C(H)(R5)-N(H)C(=0)-C(H)(R7)-NH2, in which C2-C6-alkyl is optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine, R5 and R7 independently of each other represent hydrogen (glycine) or a group selected from:
-CH3 (alanine), -C(H)(CH3)2 (valine), -(CH2)2CH3 (norvaline), -CH2C(H)(CH3)2 (leucine), - C(H)(CH3)CH2CH3 (isoleucine), -(CH2)3CH3 (norleucine), -C(CH3)3 (2-ie/f-butylglycine), benzyl (phenylalanine), 4-hydroxybenzyl (tyrosine), -(CH2)3NH2 (ornithine), -(CH2)4NH2 (lysine), -(CH2)2C(H)(OH)CH2NH2 (hydroxylysine), -CH2OH (serine), -(CH2)2OH (homoserine), -C(H)(OH)CH3 (threonine), -(CH2)3N(H)C(=NH)NH2 (arginine), - (CH2)3N(H)C(=0)NH2 (citrulline), -CH2C(=0)NH2 (asparagine), -CH2C(=0)OH (aspartic acid), -(CH2)2C(=0)OH (glutamic acid), -(CH2)2C(=0)NH2 (glutamine), -CH2SH (cysteine), -(CH2)2SH (homocysteine), -(CH2)2SCH3 (methionine), -CH2SCH3 (S- methylcysteine), (1 /-/-imidazol-4-yl)methyl- (histidine), (1 H-indol-3-yl)methyl- (thryptophan), -CH2NH2 (2,3-diaminopropanoic acid), and -(CH2)2NH2 (2,4- diaminobutanoic acid),
R8 represents hydrogen or a group selected from:
Ci-C3-alkyl, Ci-C3-haloalkyl, C2-C3-hydroxyalkyl, C3-C4-cycloalkyl,
(C3-C4-cycloalkyl)-(Ci-C3-alkyl)-, and (Ci-C3-alkoxy)-(C2-C3-alkyl)-, or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
3. The combination according to claim 2, wherein,
V, W, Y and Z independently of each other represent CH or CR2, wherein one of V, W,
Y and Z represents CR2
or,
V represents N, and W, Y and Z independently of each other represent CH or CR2, R1 represents a group selected from:
d-Cs-alkyl, Ci-C3-haloalkyl, C3-C4-cycloalkyl,
(Ci-C3-alkoxy)-(C2-C3-alkyl)-, and (C3-C4-cycloalkyl)-(Ci-C3-alkyl)-,
R2 represents, independently of each other, halogen or a group selected from: Ci-C3-alkyl, C3-C4-cycloalkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy,
Ci-C3-haloalkoxy, -N(H)C(=0)-(Ci-C3-alkyl), -N(H)C(=0)H,
-N(H)C(=0)-(Ci-C3-hydroxyalkyl),
-N(H)C(=0)-(Ci-C3-alkyl)-(Ci-C3-alkoxy), -N(H)C(=0)-phenyl, -N(H)C(=0)-(C3-C4-cycloalkyl),
-N(H)C(=0)-(Ci-C3-alkyl)-(C3-C4-cycloalkyl), and -N(H)C(=0)N(H)R8,
said -N(H)C(=0)-phenyl being optionally substituted at the phenyl ring, one, two or three times, identically or differently, with a substituent selected from:
halogen, hydroxy, cyano, Ci-C4-alkyl, Ci-C4-haloalkyl,
Ci-C4-alkoxy, Ci-C4-haloalkoxy, C3-C4-cycloalkyl, and C3-C4-cycloalkyloxy, said -N(H)C(=0)-(C3-C4-cycloalkyl) being optionally substituted at the C3-C4-cycloalkyl ring with a substituent selected from:
fluorine, chlorine, trifluoromethyl, and methoxy, R3 represents a group selected from:
C2-C6-hydroxyalkyl, and R4,
said C2-C6-hydroxyalkyl groups being optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine,
R4 represents -(C2-C6-alkyl)-OC(=0)-C(H)(R5)-N(H)C(=0)-C(H)(R7)-NH2, in which C2-C6-alkyl is optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine,
R5 and R7 independently of each other represent hydrogen (glycine) or a group selected from:
-CH3 (alanine), -C(H)(CH3)2 (valine), -(CH2)2CH3 (norvaline), -CH2C(H)(CH3)2 (leucine), - C(H)(CH3)CH2CH3 (isoleucine), -(CH2)3CH3 (norleucine), -C(CH3)3 (2-ie/f-butylglycine), benzyl (phenylalanine), 4-hydroxybenzyl (tyrosine), -(Chb^Nhb (ornithine), -(Chb^Nhb (lysine), -(CH2)2C(H)(OH)CH2NH2 (hydroxylysine), -CH2OH (serine), -(CH2)2OH (homoserine), -C(H)(OH)CH3 (threonine), -(CH2)3N(H)C(=NH)NH2 (arginine), - (CH2)3N(H)C(=0)NH2 (citrulline), -CH2C(=0)NH2 (asparagine), -CH2C(=0)OH (aspartic acid), -(CH2)2C(=0)OH (glutamic acid), -(CH2)2C(=0)NH2 (glutamine), -CH2SH (cysteine), -(CH2)2SH (homocysteine), -(CH2)2SCH3 (methionine), -CH2SCH3 (S- methylcysteine), (1 /-/-imidazol-4-yl)methyl- (histidine), (1 /-/-indol-3-yl)methyl- (thryptophan), -CH2NH2 (2,3-diaminopropanoic acid), and -(Chb^Nhb (2,4- diaminobutanoic acid), R8 represents hydrogen or a group selected from:
Ci-C3-alkyl, Ci-C3-haloalkyl, C2-C3-hydroxyalkyl, C3-C4-cycloalkyl,
(C3-C4-cycloalkyl)-(Ci-C3-alkyl)-, and (Ci-C3-alkoxy)-(C2-C3-alkyl)-, or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
4. The combination according to any one of claims 1 to 3, wherein,
V, W, Y and Z independently of each other represent CH or CR2, wherein one of V, W, Y and Z represents CR2
or,
V represents N, and W, Y and Z independently of each other represent CH or CR2,
R1 represents a group selected from:
d-Cs-alkyl, Ci-C3-haloalkyl, and C3-C4-cycloalkyl,
R2 represents, independently of each other, halogen or a group selected from: Ci-C3-alkyl, C3-C4-cycloalkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy,
Ci-C3-haloalkoxy, -N(H)C(=0)-(Ci-C3-alkyl), -N(H)C(=0)H, -N(H)C(=0)-(Ci-C3-hydroxyalkyl),
-N(H)C(=0)-(Ci-C3-alkyl)-(Ci-C3-alkoxy), -N(H)C(=0)-phenyl, -N(H)C(=0)-(C3-C4-cycloalkyl),
-N(H)C(=0)-(Ci-C3-alkyl)-(C3-C4-cycloalkyl), and -N(H)C(=0)N(H)R8,
said -N(H)C(=0)-phenyl being optionally substituted at the phenyl ring, one, two or three times, identically or differently, with a substituent selected from:
halogen, hydroxy, cyano, Ci-C4-alkyl, Ci-C4-haloalkyl,
Ci-C4-alkoxy, Ci-C4-haloalkoxy, C3-C4-cycloalkyl, and
C3-C4-cycloalkyloxy,
said -N(H)C(=0)-(C3-C4-cycloalkyl) being optionally substituted at the C3-C4-cycloalkyl ring with a substituent selected from:
fluorine, chlorine, trifluoromethyl, and methoxy,
R3 represents a group selected from:
C2-C6-hydroxyalkyl, and R4,
said C2-C6-hydroxyalkyl group being optionally substituted with one, two or three halogen atoms selected from:
fluorine, and chlorine,
R4 represents -(C2-C6-alkyl)-OC(=0)-C(H)(R5)-N(H)C(=0)-C(H)(R7)-NH2, in which C2-C6-alkyl is optionally substituted with one, two or three halogen atoms selected from: fluorine, and chlorine,
R5 and R7 independently of each other represent a group selected from:
-CH3 (alanine), -C(H)(CH3)2 (valine), -(CH2)2CH3 (norvaline), -(CH2)3NH2 (ornithine), - (CH2)4NH2 (lysine), and -(CH2)3N(H)C(=NH)NH2 (arginine),
R8 represents hydrogen or a group selected from:
Ci-C3-alkyl, Ci-C3-haloalkyl, C2-C3-hydroxyalkyl, C3-C4-cycloalkyl,
(C3-C4-cycloalkyl)-(Ci-C3-alkyl)-, and (Ci-C3-alkoxy)-(C2-C3-alkyl)-, or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
5. The combination according to any one of claims 1 to 4, wherein,
V, W, Y and Z independently of each other represent CH or CR2, wherein one of V, W,
Y and Z represents CR2
or,
V represents N, and W, Y and Z independently of each other represent CH or CR2, R1 represents a Ci-C3-alkyl group,
R2 represents, independently of each other, halogen or a group selected from: Ci-C3-alkyl, C3-C4-cycloalkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, and -N(H)C(=0)-(Ci-C3-alkyl),
R3 represents a group selected from:
C2-C6-hydroxyalkyl, and R4,
R4 represents -(C2-C6-alkyl)-OC(=0)-C(H)(R5)-N(H)C(=0)-C(H)(R7)-NH2,
R5 and R7 independently of each other represent a group selected from:
-CH3 (alanine), and -(CH2)4NH2 (lysine), or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
6. The combination according to any one of claims 1 to 5, wherein,
V, W, Y and Z independently of each other represent CH or CR2, wherein one of V, W,
Y and Z represents CR2
or,
V represents N, and W, Y and Z independently of each other represent CH or CR2, R1 represents a methyl group,
R2 represents, independently of each other, fluorine, chlorine or a group selected from:
methyl, cyclopropyl, difluoromethyl, methoxy, and -N(H)C(=0)-CH3,
R3 represents a group selected from:
-(CH2)2OH, and R4,
R4 represents -(CH2)2-OC(=0)-C(H)(R5)-N(H)C(=0)-C(H)(R7)-NH2,
R5 represents -CH3 (alanine), R7 represents -(CH2)4NH2 (lysine), or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
7. The combination according to any one of claims 1 to 6, wherein,
V, W, Y and Z independently of each other represent CH or CR2, wherein one of V, W,
Y and Z represents CR2
or,
Y represents N, and W, Y and Z independently of each other represent CH or CR2, R1 represents a methyl group,
R2 represents, independently of each other, fluorine, chlorine or a group selected from:
methyl, cyclopropyl, difluoromethyl, methoxy, -N(H)C(=0)-CH3, -N(H)C(=0)-cyclopropyl, and -N(H)C(=0)N(H)-cyclopropyl,
R3 represents a -(Chb^OH group, or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
8. The combination according to any one of claims 1 to 7, wherein the component A is a compound selected from the group consisting of :
2-{4-[(3-{4-[(3-chloropyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 /-/-indazol-1 - yl)methyl]-3,5-difluorophenoxy}ethanol ,
2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(2-methylpyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethanol ,
2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethanol ,
/V-{4-[(2-{1 -[2,6-difluoro-4-(2-hydroxyethoxy)benzyl]-1 H-indazol-3-yl}-5- methoxypyrimidin-4-yl)amino]pyridin-2-yl}acetamide ,
2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methylpyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethanol ,
2-{3,5-difluoro-4-[(3-{4-[(3-fluoropyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethanol ,
2-(4-{[3-(4-{[2-(difluoromethyl)pyridin-4-yl]amino}-5-methoxypyrimidin-2-yl)-1 /-/-indazol- 1 -yl]methyl}-3,5-difluorophenoxy)ethanol ,
2-{4-[(3-{4-[(2,5-dimethylpyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 /-/-indazol-1 - yl)methyl]-3,5-difluorophenoxy}ethanol ,
2-{4-[(3-{4-[(3-cyclopropylpyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 /-/-indazol-1 - yl)methyl]-3,5-difluorophenoxy}ethanol ,
2-{1 -[2,6-difluoro-4-(2-hydroxyethoxy)benzyl]-1 /-/-indazol-3-yl}-4-[(2-methylpyrimidin-4- yl)amino]pyrimidin-5-ol 2-{3,5-difluoro-4-[(3-{4-[(2-fluoropyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 H- indazol-1 -yl)methyl]phenoxy}ethanol ,
2-{3,5-difluoro-4-[(3-{4-[(5-fluoro-2-methylpyridin-4-yl)amino]-5-methoxypyrimidin-2-yl^ 1 H-indazol-1 -yl)methyl]phenoxy}ethanol ,
2-[3,5-difluoro-4-({3-[5-methoxy-4-(pyrimidin-4-ylamino)pyrimidin-2-yl]-1 H-indazol-1 - yl}methyl)phenoxy]ethanol
/V-{4-[(2-{1 -[2,6-difluoro-4-(2-hydroxyethoxy)benzyl]-1 H-indazol-3-yl}-5- methoxypyrimidin-4-yl)amino]-5-methylpyridin-2-yl}acetamide ,
2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(2-methylpyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethyl L-lysyl-L-alaninate, salt with trifluoroacetic acid , 2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(2-methylpyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethyl L-lysyl-L-alaninate ,
2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethyl L-lysyl-L-alaninate, salt with trifluoroacetic acid , 2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethyl L-lysyl-L-alaninate,
N-{4-[(2-{1 -[2,6-difluoro-4-(2-hydroxyethoxy)benzyl]-1 H-indazol-3-yl}-5-methoxy- pyrimidin-4-yl)amino]pyridin-2-yl}cyclopropanecarboxamide ,
1 -cyclopropyl-3-{4-[(2-{1 -[2,6-difluoro-4-(2-hydroxyethoxy)benzyl]-1 H-indazol-3-yl}-5- methoxypyrimidin-4-yl)amino]pyridin-2-yl}urea ,
2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methoxy-2-methylpyridin-4-yl)amino]pyrimidin-2- yl}-1 H-indazol-1 -yl)methyl]phenoxy}ethanol ,
2- {3,5-difluoro-4-[(3-{5-methoxy-4-[(5-methoxy-2-methylpyridin-4-yl)amino]pyrimidin-2- yl}-1 H-indazol-1 -yl)methyl]phenoxy}ethanol ,
3- {4-[(3-{4-[(2,5-dimethylpyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 H-indazol-1 - yl)methyl]-3,5-difluorophenoxy}propan-1 -ol ,
3-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl}-1 H- indazol-1 -yl)methyl]phenoxy}propan-1 -ol ,
3-{3,5-difluoro-4-[(3-{5-methoxy-4-[(2-methylpyrimidin-4-yl)amino]pyrimidin-2-yl}-1 H- indazol-1 -yl)methyl]phenoxy}propan-1 -ol ,
(2R)-3-{3,5-difluoro-4-[(3-{5-methoxy-4-[(2-methylpyrimidin-4-yl)amino]pyrimidin-2-yl}- 1 H-indazol-1 -yl)methyl]phenoxy}-2-methylpropan-1 -ol ,
(2R)-3-{4-[(3-{4-[(2,5-dimethylpyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 H-indazol- 1 -yl)methyl]-3,5-difluorophenoxy}-2-methylpropan-1 -ol ,
N-[4-({2-[1 -(2,6-difluoro-4-{[(2R)-3-hydroxy-2-methylpropyl]oxy}benzyl)-1 H-indazol-3- yl]-5-methoxypyrimidin-4-yl}amino)pyridin-2-yl]acetamide , (2R)-3-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrim
1 H-indazol-1 -yl)methyl]phenoxy}-2-methylpropan-1 -ol ,
3-{3,5-difluoro-4-[(3-{5-methoxy-4-[(2-methylpyridin-4-yl)amino]pyrimidin-2 H- indazol-1 -yl)methyl]phenoxy}propan-1 -ol ,
2-{4-[(3-{4-[(2,6-dimethylpyrimidin-4-yl)amino]-5-methoxypyrimidin-2-y H-indazol-1 - yl)methyl]-3,5-difluorophenoxy}ethanol ,
2-{3,5-difluoro-4-[(3-{4-[(2-fluoropyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 H- indazol-1 -yl)methyl]phenoxy}ethyl D-lysyl-L-alaninate, salt with trifluoroacetic acid , 2-{3,5-difluoro-4-[(3-{4-[(2-fluoropyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 H- indazol-1 -yl)methyl]phenoxy}ethyl D-lysyl-L-alaninate ,
2-{3,5-difluoro-4-[(3-{4-[(2-fluoropyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 H- indazol-1 -yl)methyl]phenoxy}ethyl L-lysyl-L-alaninate, salt with trifluoroacetic acid , and 2-{3,5-difluoro-4-[(3-{4-[(2-fluoropyridin-4-yl)amino]-5-methoxypyrimidin-2-yl}-1 H- indazol-1 -yl)methyl]phenoxy}ethyl L-lysyl-L-alaninate, or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
9. The combination according to any one of claims 1 to 8, wherein the component A is 2-{3,5-difluoro-4-[(3-{5-methoxy-4-[(3-methoxypyridin-4-yl)amino]pyrimidin-2-yl}-1 /-/- indazol-1 -yl)methyl]phenoxy}ethanol,
or an N-oxide, a pharmaceutically acceptable salt, a solvate, a hydrate, a tautomer or a stereoisomer of said compound, or a pharmaceutically acceptable salt of said N-oxide, tautomer or stereoisomer.
10. The combination according to any one of claims 1 to 9, wherein the component B is an inhibitor of PARP1 and/or PARP2.
11. The combination according to any one of claims 1 to 10, wherein the component B is a compound selected from the group consisting of :
Niraparib (MK-4827),
Iniparib (BSI 201 ),
Talazoparib (BMN-673),
Olaparib (AZD-2281 ), Rucaparib (AG014699, PF-01367338),
Veliparib (ABT-888),
CEP-8983,
CEP-9722,
E7016 (GPI21016),
AZD2461 ,
INO-1001 , and
BGB-290,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a pharmaceutically acceptable salt, or a mixture of same.
12. The combination according to any one of claims 1 to 1 1 , wherein the component B is a compound selected from the group consisting of :
olaparib, rucaparib, talazoparib, and niraparib, or a pharmaceutically acceptable salt thereof.
13. Use of a combination according to any one of claims 1 to 12 for the preparation of a medicament for the treatment or prophylaxis of a cancer and/or metastases thereof.
14. Use according to claim 13, wherein the cancer is breast- (for example TNBC), prostate-, ovarian- or bladder cancer, GBM, melanoma, or MCL, and/or metastases thereof.
15. Use according to claim 13 or 14, wherein the cancer and/or metastases thereof have a BRCA1 and/or a BRCA2 mutation.
16. Use according to any one of claims 13 to 15, wherein the cancer and/or metastases thereof do not have a STAG2 mutation and/or ATM low or loss of expression.
17. A kit comprising a combination of :
one or more components A as defined in any one of the claims 1 to 9;
one or more components B as defined in any one of claims 1 , 10, 1 1 or 12;
and, optionally, one or more further pharmaceutical agents C;
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.
18. A pharmaceutical composition comprising a combination according to claims 1 to 12 together with a pharmaceutically acceptable ingredient.
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