WO2016202756A1 - Composés 2-(1h-pyrazol-1-yl)-1h-benzimidazole substitués - Google Patents

Composés 2-(1h-pyrazol-1-yl)-1h-benzimidazole substitués Download PDF

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WO2016202756A1
WO2016202756A1 PCT/EP2016/063541 EP2016063541W WO2016202756A1 WO 2016202756 A1 WO2016202756 A1 WO 2016202756A1 EP 2016063541 W EP2016063541 W EP 2016063541W WO 2016202756 A1 WO2016202756 A1 WO 2016202756A1
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represent
fluorine
hydrogen atom
chlorine atom
compound
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PCT/EP2016/063541
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Kai Thede
Ludwig Zorn
Patrick STEIGEMANN
Sylvia Grünewald
Carolyn ALGIRE
Roland Neuhaus
Sven Christian
Judith GÜNTHER
Marcus Koppitz
Wolfgang Schwede
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Bayer Pharma Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to substituted 2-(lH-pyrazol-l-yl)-lH-benzimidazole compounds of general formula (I) as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.
  • Cancer is the leading cause of death in developed countries and the second leading cause of death in developing countries. Deaths from cancer worldwide are projected to continue rising, with an estimated 12 million deaths in 2030. While substantial progress has been made in developing effective therapies, there is a strong need for additional therapeutic modalities that target cancer and related diseases.
  • cancer disease arises after a selection process for cells with acquired functional capabilities to enhance survival and/or resistance towards apoptosis and a limitless proliferative potential.
  • Due to lagging (neo-) vascularization unrestrained growth of cancer cells leads to tumor regions with suboptimal nutrient and oxygen supply.
  • oxygen and nutrient concentrations decrease and cancer cells react by expression of hypoxia and low-nutrition responsive pathways to promote cell survival in an unfavorable metabolic microenvironment.
  • cancer cells in undervascularized tumor regions are considered more resistant to radiation and cytostatic chemotherapy and to contribute to repopulation of the tumor after therapy (Minchinton IA, Tannock IF. Drug penetration in solid tumours.
  • the objective of the present invention is to provide compounds which can be used for cancer therapy, in particular compounds that target cancer cells including cancer stem(-like) cells in hypoxic or nutrient-deprived tumor regions or which underwent metabolic adjustments to an unfavorable environment.
  • WO03/037274 discloses inter alia lH-pyrazole-4-carboxamides as sodium channel inhibitors.
  • WO01/19798 discloses inter alia l-heteroaryl-lH-pyrazol-4-yl-carboxamides and 1-aryl-lH- pyrazol-4-yl-carboxamides having activity against mammalian factor Xa.
  • WO2012/080729 disclosed inter alia lH-pyrazole-4-carboxamides as casein kinase 1 delta inhibitors.
  • US5342851 discloses inter alia l-(l,3-thiazol-2-yl)-lH-pyrazole-4-carboxamides as platelet aggregation inhibitors.
  • WO2004/056815 discloses pyrazole-derivatives as factor Xa inhibitors.
  • WO2004/099154 and US2005/0020564 disclose pyrazole-amides and -sulfonamides compounds as sodium channel modulators.
  • WO2009/137338 discloses pyrazole compounds as CC 1 antagonists.
  • WO2013/070659 discloses inter alia pyrazole derivatives as modulators of opioid receptors.
  • WO2010/111059 discloses inter alia lH-pyrazole-4-carboxamides as P2X3 receptor antagonists.
  • said compounds of the present invention have surprising and advantageous properties.
  • said compounds of the present invention are suitable to treat cancer.
  • the compounds of the present invention have surprisingly been found to effectively reduce tumor cell viability in nutrient deprived regions.
  • said compounds of the present invention have been found to effectively kill cancer cells in inner tumor spheroid regions.
  • Said compounds of the present invention may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, undesirable cellular immune responses, or undesirable cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, undesirable cellular immune responses, or undesirable cellular inflammatory responses, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas including angioimmunoblastic T-cell lymphomas, head and neck tumours including brain tumours and brain metastases (e.g.
  • tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours including cholangiocarcinoma, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas including chondrosarcomas, and/or metastases thereof.
  • the present invention covers compounds of general formula (I) :
  • R 2 represents a fluorine or a chlorine atom or a group selected from :
  • R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom
  • R 3 represents a fluorine or a chlorine atom or a group selected from :
  • R 2 , R 4 , R 5 and R 6 each represent a hydrogen atom
  • R 4 represents a fluorine or a chlorine atom or a group selected from :
  • R 2 , R 3 , R 5 and R 6 each represent a hydrogen atom
  • R 2 and R 3 each represent, independently of each other, a fluorine or a chlorine atom or a group selected from :
  • R 4 , R 5 and R 6 each represent a hydrogen atom
  • R 2 and R 4 each represent, independently of each other, a fluorine or a chlorine atom or a group selected from :
  • R 3 , R 5 and R 6 each represent a hydrogen atom
  • R 2 and R 5 each represent, independently of each other, a fluorine or a chlorine atom or a group selected from :
  • R 3 , R 4 and R 6 each represent a hydrogen atom
  • R 2 and R 6 each represent, independently of each other, a fluorine or a chlorine atom or a group selected from :
  • R 3 , R 4 and R 5 each represent a hydrogen atom
  • R 4 each represent, independently of each other, a fluorine or a chlorine atom or a group selected from :
  • R 2 , R 5 and R 6 each represent a hydrogen atom
  • R 3 and R 5 each represent, independently of each other, a fluorine or a chlorine atom or a group selected from :
  • R 2 , R 4 and R 6 each represent a hydrogen atom
  • R 2 , R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom; or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • substituted means that one or more hydrogens on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
  • the compounds of general formula (I) may exist as isotopic variants.
  • the invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).
  • Isotopic variant of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • Isotopic variant of the compound of general formula (I) is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), n 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, 125 l, 129 l and 131 l, respectively.
  • isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), n 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,
  • the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium ("deuterium- containing compounds of general formula (I)").
  • Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3 H or 14 C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability.
  • Positron emitting isotopes such as 18 F or n C may be incorporated into a compound of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications.
  • Deuterium-containing and 13 C-containing compounds of general formula (I) can be used in mass spectrometry analyses (H. J. Leis et al., Curr. Org. Chem., 1998, 2, 131) in the context of preclinical or clinical studies.
  • Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent.
  • a reagent for an isotopic variant of said reagent preferably for a deuterium-containing reagent.
  • deuterium from D2O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954; Esaki et al., Chem. Eur. J., 2007, 13, 4052).
  • Deuterium gas is also a useful reagent for incorporating deuterium into molecules.
  • deuterium-containing compound of general formula (I) is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%.
  • the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
  • the selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [A. Streitwieser et al., J. Am. Chem. Soc, 1963, 85, 2759; C. L. Perrin, et al., J. Am. Chem. Soc, 2007, 129, 4490], basicity [C. L. Perrin, et al., J. Am. Chem. Soc, 2003, 125, 15008; C. L. Perrin in Advances in Physical Organic Chemistry, 44, 144; C. L. Perrin et al., J. Am. Chem.
  • deuterium-containing compound of general formula (I) can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I).
  • deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. es.Toxicol., 2013, 26, 410; Uetrecht et al., Chemical Research in Toxicology, 2008, 21, 9, 1862; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102).
  • Kassahun et al., WO2012/112363 are examples for this deuterium effect. Still other cases have been reported in which reduced rates of metabolism result in an increase in exposure of the drug without changing the rate of systemic clearance (e.g. Rofecoxib: F. Schneider et al., Arzneim. Forsch. Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads.
  • a compound of general formula (I) may have multiple potential sites of attack for metabolism.
  • deuterium-containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected.
  • the deuterium atom(s) of deuterium- containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P 4 so.
  • the present invention concerns a deuterium-containing compound of general formula (I) having 1, 2, 3 or 4 deuterium atoms, particularly with 1, 2 or 3 deuterium atoms.
  • the present invention concerns a deuterium-containing compound of general formula (I), comprising one or more CD3 groups.
  • 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 of this invention optionally contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired.
  • Asymmetric carbon atoms are present in the ( ) 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.
  • Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • 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.
  • 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 H PLC 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 of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • the compounds 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 as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds.
  • 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 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.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention 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
  • 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, l-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, aralkyl 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 claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds 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 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, C 1 -C6 alkoxymethyl esters, e.g. methoxymethyl, C 1 -C6 alkanoyloxymethyl esters, e.g.
  • An in vivo hydrolysable ester of a compound 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 of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 2 represents a fluorine or a chlorine atom or a group selected from :
  • R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom
  • R 2 , R 4 , R 5 and R 6 each represent a hydrogen atom
  • R 2 , R 3 , R 5 and R 6 each represent a hydrogen atom
  • R 2 and R 3 each represent, independently of each other, a fluorine or a chlorine atom ;
  • R 4 , R 5 and R 6 each represent a hydrogen atom
  • R 2 and R 4 each represent, independently of each other, a fluorine or a chlorine atom
  • R 3 , R 5 and R 6 each represent a hydrogen atom
  • R 2 and R 5 each represent, independently of each other, a fluorine or a chlorine atom
  • R 3 , R 4 and R 6 each represent a hydrogen atom
  • R 2 and R 6 each represent, independently of each other, a fluorine or a chlorine atom
  • R 3 , R 4 and R 5 each represent a hydrogen atom
  • R 3 and R 4 each represent, independently of each other, a fluorine or a chlorine atom
  • R 2 , R 5 and R 6 each represent a hydrogen atom
  • R 3 and R 5 each represent, independently of each other, a fluorine or a chlorine atom
  • R 2 , R 4 and R 6 each represent a hydrogen atom
  • R 2 , R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 2 represents a fluorine or a chlorine atom or a group selected from :
  • R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom
  • R 3 represents a fluorine or a chlorine atom
  • R 2 , R 4 , R 5 and R 6 each represent a hydrogen atom
  • R 4 represents a fluorine or a chlorine atom
  • R 2 , R 3 , R 5 and R 6 each represent a hydrogen atom
  • R 2 and R 3 each represent, independently of each other, a fluorine or a chlorine atom
  • R 4 , R 5 and R 6 each represent a hydrogen atom;
  • R 2 and R 5 each represent, independently of each other, a fluorine or a chlorine atom;
  • R 3 , R 4 and R 6 each represent a hydrogen atom
  • R 2 and R 6 each represent, independently of each other, a fluorine or a chlorine atom
  • R 3 , R 4 and R 5 each represent a hydrogen atom
  • R 3 and R 4 each represent, independently of each other, a fluorine or a chlorine atom
  • R 2 , R 5 and R 6 each represent a hydrogen atom
  • R 3 and R 5 each represent, independently of each other, a fluorine or a chlorine atom
  • R 2 , R 4 and R 6 each represent a hydrogen atom
  • R 2 , R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 2 represents a fluorine or a chlorine atom or a group selected from
  • R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom
  • R 3 represents a fluorine or a chlorine atom
  • R 2 , R 4 , R 5 and R 6 each represent a hydrogen atom
  • R 4 represents a fluorine or a chlorine atom
  • R 2 , R 3 , R 5 and R 6 each represent a hydrogen atom
  • R 2 and R 3 each represent a fluorine or a chlorine atom
  • R 4 , R 5 and R 6 each represent a hydrogen atom
  • R 2 and R 5 each represent a fluorine or a chlorine atom
  • R 3 , R 4 and R 6 each represent a hydrogen atom
  • R 2 and R 6 each represent a fluorine or a chlorine atom
  • R 3 , R 4 and R 5 each represent a hydrogen atom
  • R 3 and R 4 each represent a fluorine or a chlorine atom
  • R 2 , R 5 and R 6 each represent a hydrogen atom
  • R 3 and R 5 each represent, independently of each other, a fluorine or a chlorine atom
  • R 2 , R 4 and R 6 each represent a hydrogen atom
  • R 2 , R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 2 represents a fluorine or a chlorine atom or a group selected from cyano, methyl, difluoromethyl, methoxy and difluoromethoxy; and R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 2 represents a fluorine or a chlorine atom or a group selected from difluoromethyl, methoxy and difluoromethoxy; and R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which : R 3 represents a fluorine or a chlorine atom or a group selected from cyano and methyl; and R 2 , R 4 , R 5 and R 6 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 3 represents a fluorine or a chlorine atom
  • R 2 , R 4 , R 5 and R 6 each represent a hydrogen atom
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 4 represents a fluorine or a chlorine atom or a group selected from cyano and methyl; and R 2 , R 3 , R 5 and R 6 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 4 represents a fluorine or a chlorine atom
  • R 2 , R 3 , R 5 and R 6 each represent a hydrogen atom
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 2 and R 3 each represent, independently of each other, a fluorine or a chlorine atom or a group selected from cyano and methyl; and R 4 , R 5 and R 6 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 2 and R 3 each represent, independently of each other, a fluorine or a chlorine atom ; and R 4 , R 5 and R 6 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 2 and R 4 each represent, independently of each other, a fluorine or a chlorine atom or a group selected from cyano and methyl; and R 3 , R 5 and R 6 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 2 and R 4 each represent, independently of each other, a fluorine or a chlorine atom; and R 3 , R 5 and R 6 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 2 and R 5 each represent, independently of each other, a fluorine or a chlorine atom or a group selected from cyano and methyl; and R 3 , R 4 and R 6 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 2 and R 5 each represent, independently of each other, a fluorine or a chlorine atom; and R 3 , R 4 and R 6 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 2 and R 6 each represent, independently of each other, a fluorine or a chlorine atom or a group selected from cyano and methyl; and R 3 , R 4 and R 5 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 2 and R 6 each represent, independently of each other, a fluorine or a chlorine atom; and R 3 , R 4 and R 5 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 3 and R 4 each represent, independently of each other, a fluorine or a chlorine atom or a group selected from cyano and methyl; and R 2 , R 5 and R 6 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 3 and R 4 each represent, independently of each other, a fluorine or a chlorine atom; and R 2 , R 5 and R 6 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 3 and R 5 each represent, independently of each other, a fluorine or a chlorine atom or a group selected from cyano and methyl; and R 2 , R 4 and R 6 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 3 and R 5 each represent, independently of each other, a fluorine or a chlorine atom; and R 2 , R 4 and R 6 each represent a hydrogen atom.
  • the present invention relates to compounds of general formula (I), supra, in which :
  • R 2 , R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom.
  • the present invention covers compounds of general formula (I) which are disclosed in the Example section of this text, infra.
  • the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.
  • the present invention covers intermediate compounds which are useful for the preparation of the compounds of general formula (I), supra.
  • the present invention covers the use of the intermediate compound (V) :
  • the present invention covers the use of the intermediate compound (VII) :
  • the present invention covers the use of the intermediate compounds of general formula (VI) :
  • the present invention relates to compounds of general formula (I), as decribed supra, or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for use in the treatment or prophylaxis of a disease.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of general formula (I), as decribed supra, or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, and a pharmaceutically acceptable diluent or carrier.
  • the pharmaceutical combination comprises:
  • one or more second active ingredients selected from chemotherapeutic anti-cancer agents (see below).
  • the present invention relates to use of a compound of general formula (I), as described supra, or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of a disease.
  • the present invention relates to use of a compound of general formula (I), as described supra, or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the preparation of a medicament for the prophylaxis or treatment of a disease.
  • the disease as mentioned before is in particular a disease of uncontrolled cell growth, proliferation and/or survival, an undesirable cellular immune response, or an undesirable cellular inflammatory response, particularly in which the disease of uncontrolled cell growth, proliferation and/or survival, undesirable cellular immune response, or undesirable cellular inflammatory response is a haematological tumour, a solid tumour 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.
  • 1 H-NM data are listed in the form of 1 H-NMR peaklists. For each signal peak the ⁇ value in ppm is given, followed by the signal intensity, reported in round brackets. The ⁇ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: ⁇ (intensityi), 62 (intens ⁇ ), ... , ⁇ , (intensity,), ... , ⁇ ⁇ (intensity n ).
  • a 1 H-NMR peaklist is similar to a classical 1 H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical 1 H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of target compounds (also the subject of the invention), and/or peaks of impurities.
  • the peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compounds (e.g., with a purity of >90%).
  • Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify the reproduction of our manufacturing process on the basis of "by-product fingerprints".
  • An expert who calculates the peaks of the target compounds by known methods can isolate the peaks of target compounds as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical 1 H- NMR interpretation.
  • Scheme 1 outlines the preparation of compounds of the formula (I), in which 2 , R 3 , R 4 , R 5 and R 6 are as defined supra, starting from 2-hydrazinyl-lH-benzimidazole (III), which can be converted into the ethyl pyrazole-carboxylate (IV) by treatment with ethyl 2-formyl-3- oxopropanoate.
  • 2-Hydrazinyl-lH-benzimidazole (III) is well known to the person skilled in the art (CAS Registry Number 15108-18-6) and is commercially available.
  • Said ethyl pyrazole- carboxylate (IV) can be subsequently converted into pyrazole-carboxylic acid (V), e.g.
  • Said pyrazole-carboxylic acid or its respective salts of the formula (V) can be subsequently converted into compounds of the general formula (I). This can be accomplished directly by reacting a compound of the formula (V) or a salt thereof, such as for example a salt with hydrochloric acid, with an amine of the general formula (VI) or a salt thereof, such as for example a salt with hydrochloric acid, in an amide coupling reaction, for example in the presence of a tertiary aliphatic amine, such as ⁇ , ⁇ -diisopropylethylamine, and propane phosphonic acid anhydride (also known as T3P), in a suitable solvent such as ⁇ , ⁇ -dimethylformamide.
  • Amines of the general formula (VI) are well known to the person skilled in the art, and are often commercially available.
  • the amide coupling reaction can be performed by reaction of compound of the general formula (VI) or a salt thereof, such as for example a salt with hydrochloric acid with an acid chloride of general formula (VII) or a salt thereof, such as for example a salt with hydrochloric acid.
  • Methods for the preparation of acid chlorides from carboxylic acid are well known to the person skilled in the art.
  • the present invention also relates to a method of preparing a compound of general formula (I) as defined supra, said method comprising the step of allowing a compound of formula (V) :
  • R 3 , R 4 , R 5 and R 6 are as defined for the compounds of general formula (I) supra, or a salt thereof, such as for example a salt with hydrochloric acid, in the presence of a tertiary aliphatic amine, such as ⁇ , ⁇ -diisopropylethylamine, and propane phosphonic acid anhydride, thereby giving a compound of general formula (I) :
  • R , R , R , R and R are as defined supra.
  • the present invention also relates to a method of preparing a compound of general formula (I) as defined supra, said method comprising the step of allowing a compound of formula (VII) :
  • All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.
  • the compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be digested using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g.
  • the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
  • a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the persion skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc.) of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
  • Instrument Waters Autopurificationsystem SQD; column: Waters XBrigde C18 5 ⁇ 100x30mm; water + 0.1% vol. formic acid (99%) / acetonitrile gradient; temperature: room temperature; injection: 2500 ⁇ ; DAD scan: 210-400 nm.
  • Method 2 Instrument: Waters Acquity UPLC-MS SQD; column: Acquity UPLC BEH C18 1.7 50x2. lmm; Eluent A: water + 0.1% vol. formic acid (99%), Eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; rate 0.8 mL/min; temperature: 60 °C; DAD scan: 210-400 nm; ELSD.
  • the compound of intermediate 2 (122 mg, 535 ⁇ ) was provided in DMF (1.5 mL). N,N- diisopropylethylamine (280 ⁇ , 1.6 mmol), propane phosphonic acid anhydride (T3P, 470 ⁇ , 50% in DMF, 800 ⁇ ) and l-(3-chloro-5-fluorophenyl)methanamine (128 mg, 802 ⁇ ) were added, and the mixture was stirred at room temperature for 4 days. After concentration, the remaining material was triturated with ethanol and water and the mixture was stirred for 15 minutes. The precipitate was collected by filtration, and was dried under reduced pressure. 156 mg (76% of theory) of the title compound were obtained.
  • the compound of intermediate 2 (2.00 g, 8.76 mmol) was provided in DMF (30 mL). N,N- diisopropylethylamine (4.6 mL, 26 mmol), l-(3-fluorophenyl)methanamine (1.65 g, 13.1 mmol) and propane phosphonic acid anhydride (T3P, 7.7 mL, 50% in DMF, 13 mmol) were added, and the mixture was stirred at room temperature over night. The mixture was poured into a mixture of water and ethanol (150 mL, 4:1) and was stirred for 15 minutes. The precipitate was collected by filtration, was washed with water and was dried under reduced pressure at 50 °C.
  • the compound of intermediate 2 (110 mg, 443 ⁇ ) was provided in DMF (1.3 mL). l-[2- (Difluoromethyl)phenyl]methanamine (105 mg, 665 ⁇ ), propane phosphonic acid anhydride (T3P, 520 ⁇ , 50% in DMF, 890 ⁇ ) and N,N-diisopropylethylamine (310 ⁇ , 1.8 mmol) were added, and the mixture was stirred at room temperature over night. After filtration, purification by HPLC (column: chromatorex C18, mobile phase: acetonitrile/water + 0.1% formic acid) yielded 105 mg (64% of theory) of the title compound.
  • HPLC columnumn: chromatorex C18, mobile phase: acetonitrile/water + 0.1% formic acid
  • the compound of intermediate 2 (100 mg, 438 ⁇ ) was provided in DMF (2 mL). N,N- diisopropylethylamine (230 ⁇ , 1.3 mmol), l-(2,3-difluorophenyl)methanamine (94.1 mg, 657 ⁇ ) and propane phosphonic acid anhydride (T3P, 380 ⁇ , 50% in DMF, 660 ⁇ ) were added, and the mixture was stirred at room temperature over night. After filtration, purification by HPLC (method 3) yielded 44.2 mg (28% of theory) of the title compound.
  • the compound of intermediate 2 (100 mg, 438 ⁇ ) was provided in DMF (2 mL). N,N- diisopropylethyla mine (230 ⁇ , 1.3 mmol), l-(3,4-difluorophenyl)methanamine (94.1 mg, 657 ⁇ ) and propane phosphonic acid anhydride (T3P, 380 ⁇ , 50% in DMF, 660 ⁇ ) were added, and the mixture was stirred at room temperature over night. After filtration, purification by HPLC (method 3) yielded 34.4 mg (22% of theory) of the title compound.
  • the compound of intermediate 2 (100 mg, 438 ⁇ ) was provided in DMF (2 mL). N,N- diisopropylethylamine (230 ⁇ , 1.3 mmol), l-(2,6-difluorophenyl)methanamine (94.1 mg, 657 ⁇ ) and propane phosphonic acid anhydride (T3P, 380 ⁇ , 50% in DMF, 660 ⁇ ) were added, and the mixture was stirred at room temperature over night. After filtration, purification by HPLC (method 3) yielded 34.5 mg (22% of theory) of the title compound.
  • the compound of intermediate 2 (100 mg, 438 ⁇ ) was provided in DMF (2 mL). N,N- diisopropylethylamine (230 ⁇ , 1.3 mmol), 1-phenylmethanamine (70.4 mg, 657 ⁇ ) and propane phosphonic acid anhydride (T3P, 380 ⁇ , 50% in DMF, 660 ⁇ ) were added, and the mixture was stirred at room temperature over night. After filtration, purification by HPLC (1. method 3, 2. method 1) yielded 37.3 mg (27% of theory) of the title compound.
  • the compound of intermediate 2 (100 mg, 438 ⁇ ) was provided in DMF (2 mL). N,N- diisopropylethyla mine (230 ⁇ , 1.3 mmol), l-(2-fluorophenyl)methanamine (82.3 mg, 657 ⁇ ) and propane phosphonic acid anhydride (T3P, 380 ⁇ , 50% in DMF, 660 ⁇ ) were added, and the mixture was stirred at room temperature over night. After filtration, purification by HPLC (method 3) yielded 47.2 mg (32% of theory) of the title compound.
  • the compound of intermediate 2 (100 mg, 438 ⁇ ) was provided in DMF (2 mL). N,N- diisopropylethyla mine (230 ⁇ , 1.3 mmol), l-(4-fluorophenyl)methanamine (82.3 mg, 657 ⁇ ) and propane phosphonic acid anhydride (T3P, 380 ⁇ , 50% in DMF, 660 ⁇ ) were added, and the mixture was stirred at room temperature over night. After filtration, purification by HPLC (method 3) yielded 29.1 mg (20% of theory) of the title compound.
  • the compound of intermediate 2 (100 mg, 438 ⁇ ) was provided in DMF (2 mL). N,N- diisopropylethyla mine (230 ⁇ , 1.3 mmol), l-(4-chlorophenyl)methanamine (93.1 mg, 657 ⁇ ) and propane phosphonic acid anhydride (T3P, 380 ⁇ , 50% in DMF, 660 ⁇ ) were added, and the mixture was stirred at room temperature over night. After filtration, purification by HPLC (1. method 3, 2. method 1) yielded 25.8 mg (17% of theory) of the title compound.
  • the compound of intermediate 2 (100 mg, 438 ⁇ ) was provided in DMF (2 mL). N,N- diisopropylethylamine (230 ⁇ , 1.3 mmol), l-(2-chlorophenyl)methanamine (93.1 mg, 657 ⁇ ) and propane phosphonic acid anhydride (T3P, 380 ⁇ , 50% in DMF, 660 ⁇ ) were added, and the mixture was stirred at room temperature over night. After filtration, purification by HPLC (method 3) yielded 33.4 mg (21% of theory) of the title compound.
  • the compound of intermediate 2 (100 mg, 438 ⁇ ) was provided in DMF (2 mL). N,N- diisopropylethylamine (230 ⁇ , 1.3 mmol), l-[2-(difluoromethoxy)phenyl]methanamine (114 mg, 657 ⁇ ) and propane phosphonic acid anhydride (T3P, 380 ⁇ , 50% in DMF, 660 ⁇ ) were added, and the mixture was stirred at room temperature over night. The mixture was triturated with ethanol and water and was stirred for 15 minutes. The precipitate was collected by filtration, and was dried under reduced pressure at 50 °C. Purification by HPLC (method 1) yielded 42.0 mg (25% of theory) of the title compound.
  • the compound of intermediate 2 (100 mg, 438 ⁇ ) was provided in DMF (2 mL). N,N- diisopropylethylamine (230 ⁇ , 1.3 mmol), l-(2-methoxyphenyl)methanamine (90.2 mg, 657 ⁇ ) and propane phosphonic acid anhydride (T3P, 380 ⁇ , 50% in DMF, 660 ⁇ ) were added, and the mixture was stirred at room temperature over night. The mixture was triturated with ethanol and water and was stirred for 15 minutes. The precipitate was collected by filtration, and was dried under reduced pressure at 50 °C. 107 mg (65% of theory) of the title compound were obtained.
  • the compounds of formula (I) of the present invention can be converted to any salt as described herein, by any method which is known to the person skilled in the art.
  • any salt of a compound of formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
  • compositions of the compounds of the invention are provided.
  • compositions containing one or more compounds of the present invention can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof.
  • a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention.
  • a pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
  • a pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts an influence on the particular condition being treated.
  • the compounds of the present invention can be administered with pharmaceutically- acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.
  • the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
  • the solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatine type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
  • the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatine, 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, colouring agents, and flavouring agents such as peppermint, oil of wintergreen, or cherry flavouring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • binders such as acacia, corn starch or gelatine
  • disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid
  • Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavouring and colouring agents described above, may also be present.
  • the pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
  • Suitable emulsifying agents may be (1) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
  • the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate ; one or more colouring agents ; one or more flavouring agents ; and one or more sweetening agents such as sucrose or saccharin.
  • Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavouring and colouring agents.
  • the compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-l,l-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant
  • Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates ; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates ; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers ; and amphoteric detergents, for example, alkyl-beta- aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.
  • suitable detergents include cationic detergents, for example
  • 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 minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • compositions may be in the form of sterile injectable aqueous suspensions.
  • suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia ; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions.
  • sterile fixed oils are conventionally employed as solvents or suspending media.
  • any bland, fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can be used in the preparation of injectables.
  • composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are, for example, cocoa butter and polyethylene glycol.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 11, 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.
  • a mechanical delivery device It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device.
  • the construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art.
  • Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier.
  • One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body is described in US Patent No. 5,011,472, issued April 30, 1991.
  • compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired.
  • Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al., "Compendium of Excipients for Parenteral Formulations” PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311 ; Strickley, .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, F2CIC-CCI F2
  • 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
  • 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 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
  • flavourants examples 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 limited to bentonite
  • emulsifying agents include but are not limited to
  • 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 min.
  • Lyophilised powder for IV administration A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lyophilised 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 min.
  • Intramuscular suspension The following solution or suspension can be prepared, for intramuscular injection:
  • Hard Shell Capsules A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
  • Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
  • Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
  • Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
  • the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • a "fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity.
  • a "fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient 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 first active ingredient and the said second active ingredient 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 first active ingredient and the said second active ingredient are present in more than one unit.
  • a non-fixed combination or kit-of-parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately.
  • the components of the non-fixed combination or kit-of-parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • the compounds of this invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects.
  • the present invention relates also to such combinations.
  • the compounds of this invention can be combined with known chemotherapeutic agents or anti-cancer agents, e.g. anti-hyper-proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
  • Other indication agents include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, antimetabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, toposisomerase inhibitors, biological response modifiers, or anti-hormones.
  • chemotherapeutic anti-cancer agents includes but is not limited to
  • the compounds of the invention may also be administered in combination with protein therapeutics.
  • protein therapeutics suitable for the treatment of cancer or other angiogenic disorders and for use with the compositions of the invention include, but are not limited to, an interferon (e.g., interferon .alpha., .beta., or .gamma.) supraagonistic monoclonal antibodies, Tuebingen, T P-1 protein vaccine, Colostrinin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1, bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab, rhMBL, MFE-CP1 + ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35,
  • Monoclonal antibodies useful as the protein therapeutic include, but are not limited to, muromonab-CD3, abciximab, edrecolomab, daclizumab, gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab, efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.
  • a compound of general formula (I) as defined herein can optionally be administered in combination with one or more of the following: A Y-162, ARRY-300, ARRY-704, AS-703026, AZD-5363, AZD-8055, BEZ-235, BGT-226, BKM-120, BYL-719, CAL-101, CC-223, CH-5132799, deforolimus, E-6201, enzastaurin , GDC-0032, GDC-0068, GDC-0623, GDC-0941, GDC-0973, GDC-0980, GSK-2110183, GSK-2126458, GSK-2141795, MK-2206, novolimus, OSI-027, perifosine, PF-04691502, PF-05212384, PX-866, rapamycin, RG-7167, RO-4987655, RO- 5126766, selumetinib, TAK-733, trametinib,
  • cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to: (1) yield better efficacy in reducing the growth of a tumor or even eliminate the tumor as compared to administration of either agent alone,
  • a compound of the present invention may be used to sensitize a cell to radiation. That is, treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the invention.
  • the cell is treated with at least one compound of the invention.
  • the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the invention in combination with conventional radiation therapy.
  • the present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated with one or more compounds of the invention prior to the treatment of the cell to cause or induce cell death.
  • the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
  • a cell is killed by treating the cell with at least one DNA damaging agent. That is, after treating a cell with one or more compounds of the invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell.
  • DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g., cisplatinum), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.
  • a cell is killed by treating the cell with at least one method to cause or induce DNA damage.
  • methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage.
  • a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell.
  • a compound of the invention is administered to a cell prior to the radiation or other induction of DNA damage in the cell.
  • a compound of the invention is administered to a cell concomitantly with the radiation or other induction of DNA damage in the cell.
  • a compound of the invention is administered to a cell immediately after radiation or other induction of DNA damage in the cell has begun.
  • the cell is in vitro.
  • the cell is in vivo.
  • the compounds of the present invention have surprisingly been found to effectively reduce tumor cell viability in nutrient deprived regions.
  • said compounds of the present invention have been found to effectively kill cancer cells in inner tumor spheroid regions and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, undesirable cellular immune responses, or undesirable cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, undesirable cellular immune responses, or undesirable cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, undesirable cellular immune responses, or undesirable cellular inflammatory responses are affected by reduction of tumor cell viability in nutrient deprived regions, 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.
  • the present invention covers a compound of general formula (I), or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease, as mentioned supra.
  • Another particular aspect of the present invention is therefore the use of a compound of general formula (I), described supra, or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of a disease.
  • Another particular aspect of the present invention is therefore the use of a compound of general formula (I) described supra for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease.
  • the diseases referred to in the two preceding paragraphs are diseases of uncontrolled cell growth, proliferation and/or survival, undesirable cellular immune responses, or undesirable cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, undesirable cellular immune responses, or undesirable 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.
  • undesirable within the context of the present invention, in particular in the context of "undesirable cellular immune responses, or undesirable cellular inflammatory responses", as used herein, is to be understood as 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.
  • the use is in the treatment or prophylaxis of diseases, wherein the diseases are haemotological tumours, solid tumours and/or metastases thereof.
  • the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat mammalian hyper-proliferative disorders.
  • Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; etc. which is effective to treat the disorder.
  • Hyperproliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • BPH benign prostate hyperplasia
  • solid tumours such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases.
  • Those disorders also include lymphomas, sarcomas, and leukaemias.
  • 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, anaplastic astrocytoma, diffuse astrocytoma, glioblastoma, oligodendroglioma, secondary glioblastoma multiforme as well as neuroectodermal and pineal tumour.
  • Tumours of the male reproductive organs include, but are not limited to prostate and testicular cancer.
  • Tumours 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.
  • Tumours of the digestive tract include, but are not limited to anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
  • Tumours of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
  • Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
  • liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
  • Head-and-neck cancers include, but are not limited to laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.
  • Lymphomas include, but are not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.
  • treating or “treatment” as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
  • the present invention also provides methods of treating disorders and diseases associated with excessive and/or abnormal angiogenesis.
  • Undesirable 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 ( A), restenosis, in-stent restenosis, vascular graft restenosis, etc.
  • A 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 tumour enlargement and metastasis.
  • the growth of new blood and lymph vessels in a tumour provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer.
  • compounds 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 ingredient 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 ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • "drug holidays" in which a patient is not dosed with a drug for a certain period of time may be beneficial to the overall balance between pharmacological effect and tolerability.
  • a unit dosage may contain from about 0.5 mg to about 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 will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
  • the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
  • the diseases of said method are haematological tumours, solid tumour and/or metastases thereof.
  • the compounds 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.
  • the average value also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested
  • the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.
  • Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.
  • MCTS multicellular tumor spheroids
  • the tumor spheroid assay enables the identification of compounds that induce cell death in inner, nutrient-deprived tumor spheroid core regions, while not affecting well-supplied outer regions with direct access to the culture media, thereby excluding general cytotoxic compounds.
  • general tumor spheroids were generated for high-content screening by seeding single cell suspensions of cancer cells into agarose-coated multiwell (e.g. 96 well or 384 well plates) plates (Friedrich J. Spheroid-based drug screen: considerations and practical approach. Nat. Protoc.
  • a heated (e.g. by Microwave) 1.5% w/v agarose e.g. Agarose NA, Sigma-Aldrich GE17-0554- 01
  • DMEM e.g. Life Technologies 11880-028
  • FBS fetal bovine serum
  • the multidrop and dispensing cassette was heated by infrared lamps.
  • a trypsinized (e.g. TrypLE from Life Technologies 12604-013) single cell suspension (of e.g. T47D (ATCC: HTB-133), MCF7 (ATCC: HTB-22), DLD-1 (ATCC: CCL-221), H460 (ATCC: HTB-177)) was seeded into agarose-coated (1.5% w/v) 384-well clear bottom plates in 40 ⁇ PMI1640 or suitable cell culture medium (e.g. Life Technologies, 11875-093) containing 10% (v/v) FBS (e.g.
  • test compounds were added from a 3x stock solution by hand or liquid handling robots (e.g. CyBi-Well with 384-Well pipetting head) in 20 ⁇ suitable cell culture medium (e.g. Life Technologies, 11875-093) containing 10% (v/v) FBS (e.g. PAA Laboratories A15-151) supplemented with 1% Penicillin/Streptomycin (e.g. Sigma-Aldrich P0781) (and 0.01 ⁇ g/mL insulin for T47D cells (e.g.
  • Life Technologies 12585-014 either in single concentration, typically reaching 10 ⁇ endconcentration on the spheroids from a 10 mM Stock solution with DMSO levels never exceeding 1%, or as dilution typically covering a range of 10 ⁇ to 0.51 nM final concentration on the spheroids and subsequently incubated for three days under standard cell culture conditions at 37 °C and 5% CO2 in humidified incubators.
  • spheroids Prior to imaging, spheroids were stained for 6 h by adding Hoechst 33342 (final 2 ⁇ g/mL from a 1 mg/mL stock solution, e.g. Life Technologies H-1399) as counterstain for all nuclei and 0.5 ⁇ Sytox Green ( as stain for dead cells (e.g.
  • Suitable cell culture medium e.g. Life Technologies, 11875-093
  • suitable cell culture medium e.g. Life Technologies, 11875-093
  • FBS e.g. PAA Laboratories A15-151
  • Penicillin/Streptomycin e.g. Sigma-Aldrich P0781
  • 0.01 ⁇ g/mL insulin for T47D cells e.g. Life Technologies 12585-014
  • liquid dispensers e.g. Multidrop Combi, Type 836 and standard tube dispensing cassettes, Thermo Scientific.
  • the plates were imaged on automated microscopes at the appropriate wavelengths and filter conditions for Hoechst and Sytox green staining (e.g. Opera confocal spinning disc, Hoechst excitation: 405 nm, emission: 450 nm; Sytox green excitation 488 nm, emission 540-575 nm).
  • Hoechst and Sytox green staining e.g. Opera confocal spinning disc, Hoechst excitation: 405 nm, emission: 450 nm; Sytox green excitation 488 nm, emission 540-575 nm.

Abstract

La présente invention concerne des composés 2-(pyrazol-1-yl)-benzimidazole substitués de formule générale (I) : dans laquelleR2, R3, R4, R5 et R6 ont la signification indiquée dans la description, des procédés de préparation desdits composés, des composés intermédiaires utiles pour préparer lesdits composés, des compositions pharmaceutiques et des combinaisons comprenant lesdits composés et l'utilisation desdits composés pour fabriquer une composition pharmaceutique pour le traitement ou la prophylaxie d'une maladie, en particulier les néoplasmes, en tant que seul agent ou en combinaison avec d'autres principes actifs.
PCT/EP2016/063541 2015-06-18 2016-06-14 Composés 2-(1h-pyrazol-1-yl)-1h-benzimidazole substitués WO2016202756A1 (fr)

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