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  • 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
  • A61K31/435—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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• • A—HUMAN NECESSITIES
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  • 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
  • A61K31/4245—Oxadiazoles
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
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  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the present application relates to novel substituted 1-[3-(heterocyclyl)benzyl]-1H-pyrazole derivatives, to processes for preparation thereof, to use thereof for treatment and/or prevention of diseases and to use thereof for production of medicaments for treatment and/or prevention of diseases, more particularly for treatment and/or prevention of hyperproliferative and angiogenic diseases and those diseases which arise from metabolic adaptation to hypoxic states.
• Such treatments can be effected in the form of monotherapy or else in combination with other medicaments or further therapeutic measures.
• Cancers are the consequence of uncontrolled cell growth of a wide variety of different tissues. In many cases the new cells penetrate into existing tissue (invasive growth), or they metastasize into remote organs. Cancers occur in a wide variety of different organs and often progress in a manner specific to the tissue.
• the term “cancer” as a generic term therefore describes a large group of defined diseases of different organs, tissue and cell types.
• tumours at early stages can be removed by surgical and radiotherapy measures. Metastasized tumours can generally only be treated palliatively by chemotherapeutics. The aim here is to achieve the optimum combination of an improvement in the quality of life and prolonging of life.
• Chemotherapies are often composed of combinations of cytotoxic medicaments.
• the majority of these substances have bonding to tubulin as their mechanism of action, or they are compounds which interact with the formation and processing of nucleic acids.
• these also include enzyme inhibitors which interfere with epigenetic DNA modification or cell cycle progression (e.g. histone deacetylase inhibitors, aurora kinase inhibitors). Since such therapies are toxic, there has recently been an increasing focus on targeted therapies in which specific processes in the cell are blocked without a high level of toxic stress. These especially include inhibitors of kinases which inhibit the phosphorylation of receptors and signal transmission molecules.
• imatinib which is used very successfully for treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST).
• CML chronic myeloid leukaemia
• GIST gastrointestinal stromal tumours
• substances which block EGFR kinase and HER2, such as erlotinib, and VEGFR kinase inhibitors, such as sorafenib and sunitinib which are used for kidney cell carcinomas, liver carcinomas and advanced stages of GIST.
• Bevacizumab inhibits the growth of blood vessels, which is an obstacle to rapid expansion of a tumour, since it requires connection to the blood vessel system for continuously functioning supply and disposal.
• hypoxia hypoxia
• HIF hypoxia-induced factor
• HIF oxygen-degradable domain
• the transcription factor HIF is formed by the regulated ⁇ -subunit and a constitutively present ⁇ -subunit (ARNT, aryl hydrocarbon receptor nuclear translocator).
• ARNT aryl hydrocarbon receptor nuclear translocator
• the HIF subunits are bHLH (basic helix loop helix) proteins which dimerize via their HLH and PAS (Per-Arnt-Sim) domains, which starts their transactivation activity (Jiang, Rue et al., 1996).
• WO 2004/089303-A2 describes diaryl-substituted pyrazoles as mGluR5 modulators for treatment of psychiatric disorders.
• WO 2010/072352-A1 and WO 2010/085584-A1 disclose 3-phenyl-5-(1H-pyrazol-4-yl)-1,2,4-oxadiazole derivatives as sphingosine-1-phosphate agonists for treatment of autoimmune and vascular disorders.
• WO 2005/030121-A2 and WO 2007/065010-A2 describe the usability of particular pyrazole derivatives for inhibition of the expression of HIF and HIF-regulated genes in tumour cells.
• WO 2008/141731-A2 discloses heteroaryl-substituted N-benzylpyrazoles as inhibitors of the HIF regulation pathway for treatment of cancers.
• many of these compounds do not have sufficient inhibitory activity or else, on the basis of their pharmacokinetic properties in animal models, are expected to have such a long half-life (>48 h) in the human body that significant substance accumulation is probable after repeated once-daily administration.
• this novel group of N-benzylpyrazole derivatives features a hydroxyl- or cyano-substituted heterocyclyl radical in the 3 position of the benzyl head group, which surprisingly leads to an improved profile of properties of the compounds.
• the present invention relates specifically to compounds of the formula (I)
• a particular embodiment of the present invention relates to compounds of the formula (I) in which
• the present invention also relates to particular prodrugs of compounds of the formula (I-A).
• prodrugs refers here to covalent derivatives of the compounds of the formula (I-A), which may themselves be biologically active or inactive, but are converted while present in the body, for example by a metabolic or hydrolytic route, to compounds of the formula (I-A).
• the present invention accordingly further provides compounds of the formula (I-PD)
• the compounds of the formula (I-PD) are prodrugs of the compounds of the formula (I-A) with a good solubility in aqueous or other physiologically compatible media; they additionally offer the possibility of salt formation with appropriate acids, which can lead to a further increase in solubility.
• the compounds of the formula (I-PD) and salts thereof are therefore especially suitable for intravenous administration forms or else for solid formulations with modified release characteristics. This could also open up additional therapeutic fields of use for these compounds.
• Inventive compounds are thus the compounds of the formulae (I), (I-A) and (I-PD) and the salts, solvates and solvates of the salts thereof, the compounds, encompassed by the formulae (I), (I-A) and (I-PD), of the formulae specified hereinafter and the salts, solvates and solvates of the salts thereof, and the compounds encompassed by the formulae (I), (I-A) and (I-PD) and specified hereinafter as working examples and the salts, solvates and solvates of the salts thereof, to the extent that the compounds encompassed by the formulae (I), (I-A) and (I-PD) and specified hereinafter are not already salts, solvates and solvates of the salts.
• the inventive compounds may exist in different stereoisomeric forms, i.e. in the form of configurational isomers or if appropriate also as conformational isomers (enantiomers and/or diastereomers, including those in the case of atropisomers).
• the present invention therefore encompasses the enantiomers or diastereomers and the respective mixtures thereof.
• the stereoisomerically homogeneous constituents can be isolated from such mixtures of enantiomers and/or diastereomers in a known manner; chromatography processes are preferably used for this purpose, especially HPLC chromatography on an achiral or chiral phase.
• the present invention encompasses all the tautomeric forms.
• the present invention also encompasses all suitable isotopic variants of the inventive compounds.
• An isotopic variant of an inventive compound is understood here to mean a compound in which at least one atom within the inventive compound has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature.
• isotopes which can be incorporated into an inventive compound are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C 15 N 17 O, 18 O, 32 P 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
• Particular isotopic variants of an inventive compound may be beneficial, for example, for the examination of the mechanism of action or of the active ingredient distribution in the body; due to comparatively easy preparability and detectability, especially compounds labelled with 3 H or 14 C isotopes are suitable for this purpose.
• the incorporation of isotopes, for example of deuterium can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example to an extension of the half-life in the body or to a reduction in the active dose required; such modifications of the inventive compounds may therefore in some cases also constitute a preferred embodiment of the present invention.
• Isotopic variants of the inventive compounds can be prepared by generally customary processes known to those skilled in the art, for example by the methods described below and the methods described in the working examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein.
• preferred salts are physiologically acceptable salts of the inventive compounds. Also encompassed are salts which are not themselves suitable for pharmaceutical applications but can be used, for example, for the isolation, purification or storage of the inventive compounds.
• Physiologically acceptable salts of the inventive compounds include especially the acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
• hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, mal
• solvates refer to those forms of the inventive compounds which, in solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water. Preferred solvates in the context of the present invention are hydrates.
• (C 1 -C 4 ) is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms.
• Preferred examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
• radicals which occur more than once are defined independently of one another.
• the radicals in the inventive compounds may be mono- or polysubstituted, unless specified otherwise. Substitution by one or two identical or different substituents is preferred. Particular preference is given to substitution by one substituent.
• the present invention further provides a process for preparing the compounds of the formula (I), characterized in that a compound of the formula (II)
• the coupling reaction (II)+(III) ⁇ (I) is performed with the aid of a transition metal catalyst.
• palladium(0) catalysts for example bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0) or tetrakis(triphenylphosphino)palladium(0), optionally in combination with additional phosphine ligands such as 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos) or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) [cf., for example, J.
• the coupling is generally performed with addition of a base.
• alkali metal carbonates, hydrogencarbonates, phosphates, hydrogenphosphates or tert-butoxides such as sodium carbonate, potassium carbonate, caesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, tripotassium phosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, sodium tert-butoxide or potassium tert-butoxide.
• Preference is given to using caesium carbonate or sodium tert-butoxide.
• reaction (II)+(III) ⁇ (I) is effected generally at standard pressure within a temperature range from +50° C. to +200° C., preferably at +100° C. to +150° C. However, performance at reduced or elevated pressure (e.g. from 0.5 to 5 bar) is also possible. It may be helpful to undertake the conversion with simultaneous microwave irradiation.
• the R 1 radical is hydroxyl
• these protecting groups can then be detached again by customary methods, for example by treatment with tetra-n-butylammonium fluoride.
• X is as defined above and Y is a leaving group, for example chlorine, bromine, iodine, mesylate, triflate or tosylate.
• the condensation reaction (IV)+(V) ⁇ (VI) is preferably performed with the aid of a carbodiimide such as N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC), in conjunction with 1-hydroxy-1H-benzotriazole (HOBt) as an active ester component, or with the aid of a phosgene derivative such as 1,1′-carbonyldiimidazole (CDI) in a high-boiling dipolar aprotic solvent, for example N,N-dimethylformamide or dimethyl sulphoxide.
• a carbodiimide such as N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC)
• HOBt 1-hydroxy-1H-benzotriazole
• CDI 1,1′-carbonyldiimidazole
• a high-boiling dipolar aprotic solvent for example N,N
• the initial coupling step in this reaction is effected generally within a temperature range from 0° C. to +50° C.; the cyclization to give the 1,2,4-oxadiazole is then accomplished by subsequently heating the reaction mixture to temperatures of +100° C. to +150° C.
• the reaction can be performed at standard, elevated or reduced pressure (e.g. from 0.5 to 5 bar); in general, standard pressure is employed.
• Suitable bases for the reaction (VI)+(VII) ⁇ (II) are customary inorganic or organic bases. These preferably include alkali metal hydroxides, for example lithium, sodium or potassium hydroxide, alkali metal alkoxides such as sodium or potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, or amides such as sodium amide, lithium or potassium bis(trimethylsilyl)amide or lithium diisopropylamide. Preference is given to using potassium tert-butoxide.
• an alkylation catalyst for example lithium bromide, sodium iodide, tetra-n-butylammonium bromide or benzyltriethylammonium chloride, may be advantageous.
• the reaction is effected generally within a temperature range from ⁇ 20° C. to +100° C., preferably at 0° C. to +60° C.
• the reaction can be performed at standard, elevated or reduced pressure (for example in the range from 0.5 to 5 bar); in general, standard pressure is employed.
• the present invention further provides a process for preparing the compounds of the formula (I-PD), characterized in that a compound of the formula (I-A)
• Activated forms of the compound (VIII) which are suitable for the introduction of the prodrug group R PD are, for example, corresponding chlorides or anhydrides, including mixed anhydrides, or else particular ester or amide derivatives.
• a free amino group present in the R PD radical is appropriately present here in temporarily protected form and is then released again at the end of the esterification reaction by familiar methods.
• Such protection used is preferably in the form of the tert-butoxycarbonyl group, which can be detached by treatment with a strong acid, such as hydrogen chloride or trifluoroacetic acid [cf., for example, M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis , Springer-Verlag, Berlin, 1984; M. Bodanszky, Principles of Peptide Synthesis , Springer-Verlag, Berlin, 1993; T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis , Wiley, New York, 1999].
• the inventive compounds have valuable pharmacological properties and can be used for prevention and treatment of diseases in humans and animals.
• inventive compounds are highly potent inhibitors of the HIF regulation pathway.
• inventive compounds have advantageous pharmacokinetic properties with regard to the distribution volume thereof and/or the clearance thereof, and the half-life derived therefrom, which makes them suitable for repeated once-daily administration.
• inventive compounds are especially suitable for treatment of hyperproliferative diseases in humans and in mammals in general.
• the compounds can inhibit, block, reduce or lower cell proliferation and cell division, and secondly increase apoptosis.
• the hyperproliferative diseases which can be treated using the inventive compounds include psoriasis, keloids, formation of scars and other proliferative diseases of the skin, benign diseases, such as benign prostate hyperplasia (BPH), and especially the group of tumour diseases.
• benign diseases such as benign prostate hyperplasia (BPH)
• BPH benign prostate hyperplasia
• tumour diseases include psoriasis, keloids, formation of scars and other proliferative diseases of the skin, benign diseases, such as benign prostate hyperplasia (BPH), and especially the group of tumour diseases.
• these are understood to mean especially the following diseases, but without any limitation thereto: mammary carcinomas and mammary tumours (ductal and lobular forms, also in situ), tumours of the respiratory tract (parvicellular and non-parvicellular carcinoma, bronchial carcinoma), cerebral tumours (e.g.
• tumours of the digestive organs oesophagus, stomach, gall bladder, small intestine, large intestine, rectum
• liver tumours including hepatocellular carcinoma, cholangiocellular carcinoma and mixed hepatocellular and cholangiocellular carcinoma
• tumours of the head and neck region larynx, hypopharynx, nasopharynx, oropharynx, lips and oral cavity
• skin tumours squamous epithelial carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer and nonmelanomatous skin cancer
• tumours of soft tissue including soft tissue sarcomas, osteosarcomas, malignant fibrous histiocytomas, lymphosarcomas and rhabdomyosarcoma
• tumours of the urinary tract tumours of the bladder, penis, kidney, renal pelvis and ureter
• tumours of the reproductive organs tumours of the endometrium, cervix, ovary, vagina, vulva and uterus in women and carcinomas of the prostate and testicles in men.
• treatment or “treat” is used in the conventional sense and means attending to, caring for and nursing a patient with the aim of combating, reducing, attenuating or alleviating a disease or health abnormality, and improving the living conditions impaired by this disease, as, for example, in the event of a cancer.
• the inventive compounds act as modulators of the HIF regulation pathway and are therefore also suitable for treatment of diseases associated with a harmful expression of the HIF transcription factor. This applies especially to the transcription factors HIF-1 ⁇ and HIF-2 ⁇ .
• harmful expression of HIF here means abnormal physiological presence of HIF protein. This can be caused by excessive synthesis of the protein (mRNA- or translation-related), by reduced degradation or by inadequate counter-regulation in the functioning of the transcription factor.
• HIF-1 ⁇ and HIF-2 ⁇ regulate more than 100 genes. This applies to proteins which play a role in angiogenesis and are therefore directly relevant to tumours, and also those which influence glucose, amino acid and lipid metabolism, and cell migration, metastasis and DNA repair, or improve the survival of tumour cells by suppressing apoptosis. Others act more indirectly via inhibition of the immune reaction and upregulation of angiogenic factors in inflammation cells. HIF also plays an important role in stem cells, and here especially tumour stem cells, which are reported to have elevated HIF levels. The inhibition of the HIF regulation pathway by the compounds of the present invention thus also has a therapeutic influence on tumour stem cells, which do not have a high proliferation rate and therefore are affected only inadequately by cytotoxic substances (cf. Semenza, 2007; Weidemann and Johnson, 2008).
• HIF inhibitors such as the compounds of the present invention
• HIF inhibitors are therapeutically beneficial in those contexts in which, for example, additional damage arises from adaptation of cells to hypoxic situations, since damaged cells can cause further damage if they do not function as intended.
• One example of this is the formation of epileptic foci in partly destroyed tissue following strokes.
• cardiovascular diseases if ischaemic processes occur in the heart or in the brain as a consequence of thromboembolic events, inflammations, wounds, intoxications or other causes.
• Inhibition of the HIF regulation pathway can therefore also be beneficial in the event of diseases such as heart failure, arrhythmia, myocardial infarction, apnoea-induced hypertension, pulmonary hypertension, transplant ischaemia, reperfusion damage, stroke and macular degeneration, and also for recovery of nerve function after traumatic damage or severance.
• diseases such as heart failure, arrhythmia, myocardial infarction, apnoea-induced hypertension, pulmonary hypertension, transplant ischaemia, reperfusion damage, stroke and macular degeneration, and also for recovery of nerve function after traumatic damage or severance.
• HIF is one of the factors which control the transition from an epithelial to a mesenchymal cell type, which is important especially for the lung and kidney
• inventive compounds can also be used to prevent or control fibroses of the lung and kidney associated with HIF.
• inflammatory joint diseases such as various forms of arthritis
• inflammatory intestinal diseases for example Crohn's disease.
• the compounds of the present invention can also be used for treatment of diseases associated with excessive or abnormal angiogenesis. These include diabetic retinopathy, ischaemic retinal vein occlusion and retinopathy in premature babies (cf. Aiello et al., 1994; Peer et al., 1995), age-related macular degeneration (AMD; cf. Lopez et al., 1996), neovascular glaucoma, psoriasis, retrolental fibroplasia, angiofibroma, inflammation, rheumatic arthritis (RA), restenosis, in-stent restenosis, and restenosis following vessel implantation.
• diseases associated with excessive or abnormal angiogenesis include diabetic retinopathy, ischaemic retinal vein occlusion and retinopathy in premature babies (cf. Aiello et al., 1994; Peer et al., 1995), age-related macular degeneration (AMD; cf. Lopez et al., 1996)
• Increased blood supply is additionally associated with cancerous, neoplastic tissue and leads here to accelerated tumour growth.
• the growth of new blood and lymph vessels facilitates the formation of metastases and hence the spread of the tumour.
• New lymph and blood vessels are also harmful to allografts in immunoprivileged tissues, such as the eye, which, for example, increases susceptibility to rejection reactions.
• Compounds of the present invention can therefore also be used for therapy of one of the aforementioned diseases, for example by inhibition of the growth of or a reduction in the number of blood vessels. This can be achieved via inhibition of endothelial cell proliferation or other mechanisms for preventing or attenuating the formation of vessels and via a reduction of neoplastic cells by apoptosis.
• HIF-1 ⁇ becomes enriched in the adipose tissue, resulting in an HIF-mediated shift in the catabolism in the direction of glycolysis, such that an increased amount of glucose as an energy carrier is consumed. This leads at the same time to reduced lipid metabolism and hence to storage of lipids in the tissue.
• inventive substances are therefore also suitable for treatment of HIF-1 ⁇ -mediated enrichment of lipids in the tissue, especially in the case of obesity.
• the present invention further provides for the use of the inventive compounds for treatment and/or prevention of disorders, especially the aforementioned disorders.
• the present invention further provides for the use of the inventive compounds for production of a medicament for treatment and/or prevention of disorders, especially the aforementioned disorders.
• the present invention furthermore provides the use of the inventive compounds in a method for treatment and/or prevention of disorders, especially the aforementioned disorders.
• the present invention further provides a method for treatment and/or prevention of disorders, especially the aforementioned disorders, using an effective amount of at least one of the inventive compounds.
• inventive compounds can be used alone or, if required, in combination with one or more other pharmacologically active substances, provided that this combination does not lead to undesirable and unacceptable side effects.
• the present invention therefore further provides medicaments comprising at least one of the inventive compounds and one or more further active ingredients, especially for treatment and/or prevention of the aforementioned disorders.
• the compounds of the present invention can be combined with known antihyperproliferative, cytostatic or cytotoxic substances for treatment of cancers.
• the combination of the inventive compounds with other substances commonly used for cancer therapy or else with radiotherapy is therefore particularly appropriate, since hypoxic regions of a tumour respond only weakly to the conventional therapies mentioned, whereas the compounds of the present invention display their activity there in particular.
• Suitable active ingredients for combinations include:
• the compounds of the present invention can be combined with antihyperproliferative agents, which may be, by way of example—though this list is not exclusive:
• inventive compounds can also be combined in a very promising manner with biological therapeutics, such as antibodies (for example avastin, rituxan, erbitux, herceptin) and recombinant proteins, which additively or synergistically enhance the effects of inhibition of the HIF signal pathway transmission.
• biological therapeutics such as antibodies (for example avastin, rituxan, erbitux, herceptin) and recombinant proteins, which additively or synergistically enhance the effects of inhibition of the HIF signal pathway transmission.
• Inhibitors of the HIF regulation pathway can also achieve positive effects in combination with other therapies directed against angiogenesis, for example with avastin, axitinib, recentin, regorafenib, sorafenib or sunitinib.
• Combinations with inhibitors of the proteasome and of mTOR and antihormones and steroidal metabolic enzyme inhibitors are particularly suitable because of their favourable profile of side effects.
• inventive compounds can also be used in conjunction with radiotherapy and/or surgical intervention.
• the present invention further provides medicaments which comprise at least one inventive compound, typically together with one or more inert, nontoxic, pharmaceutically suitable excipients, and the use thereof for the aforementioned purposes.
• inventive compounds may act systemically and/or locally.
• they can be administered in a suitable manner, for example by the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic route, or as an implant or stent.
• inventive compounds can be administered in administration forms suitable for these administration routes.
• Suitable administration forms for oral administration are those which work according to the prior art, which release the inventive compounds rapidly and/or in a modified manner and which contain the inventive compounds in crystalline and/or amorphized and/or dissolved form, for example tablets (uncoated or coated tablets, for example with gastric juice-resistant or retarded-dissolution or insoluble coatings which control the release of the inventive compound), tablets or films/oblates which disintegrate rapidly in the oral cavity, films/lyophilizates or capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
• tablets uncoated or coated tablets, for example with gastric juice-resistant or retarded-dissolution or insoluble coatings which control the release of the inventive compound
• tablets or films/oblates which disintegrate rapidly in the oral cavity
• films/lyophilizates or capsules for example hard or soft gelatin capsules
• sugar-coated tablets granules
• Parenteral administration can bypass an absorption step (e.g. intravenously, intraarterially, intracardially, intraspinally or intralumbally) or include an absorption (e.g. intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
• Administration forms suitable for parenteral administration include preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
• suitable examples are inhalable medicament forms (including powder inhalers, nebulizers), nasal drops, solutions or sprays, tablets, films/oblates or capsules for lingual, sublingual or buccal administration, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, sprinkling powders, implants or stents.
• Oral and parenteral administration are preferred, especially oral and intravenous administration.
• the inventive compounds can be converted to the administration forms mentioned. This can be done in a manner known per se, by mixing with inert, nontoxic, pharmaceutically suitable excipients.
• excipients include carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecylsulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants, for example ascorbic acid), dyes (e.g. inorganic pigments, for example iron oxides) and flavour and/or odour correctants.
• carriers for example microcrystalline cellulose, lactose, mannitol
• solvents e.g. liquid polyethylene glycols
• emulsifiers and dispersing or wetting agents for example sodium dodecy
• the dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to 20 mg/kg and most preferably 0.1 to 10 mg/kg of body weight.
• MS instrument type Micromass ZQ
• HPLC instrument type HP 1100 Series
• UV DAD column: Phenomenex Gemini 3 ⁇ , 30 mm ⁇ 3.00 mm
• eluent A 1 l of water+0.5 ml of 50% formic acid
• eluent B 1 l of acetonitrile+0.5 ml of 50% formic acid
• flow rate 0.0 min 1 ml/min ⁇ 2.5 min/3.0 min/4.5 min 2 ml/min
• UV detection 210 nm.
• MS instrument type Micromass ZQ
• HPLC instrument type Waters Alliance 2795
• eluent A 1 l of water+0.5 ml of 50% formic acid
• eluent B 1 l of acetonitrile+0.5 ml of 50% formic acid
• flow rate 2 ml/min
• UV detection 210 nm.
• Instrument Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9 ⁇ , 50 mm ⁇ 1 mm; eluent A: 1 l of water+0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile+0.5 ml of 50% formic acid; gradient: 0.0 min 90% A ⁇ 0.1 min 90% A ⁇ 1.5 min 10% A ⁇ 2.2 min 10% A; flow rate: 0.33 ml/min; oven: 50° C.; UV detection: 210 nm.
• MS instrument type Waters ZQ; HPLC instrument type: Agilent 1100 Series; UV DAD; column: Thermo Hypersil GOLD 3 ⁇ , 20 mm ⁇ 4 mm; eluent A: 1 l of water+0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile+0.5 ml of 50% formic acid; gradient: 0.0 min 100% A ⁇ 3.0 min 10% A ⁇ 4.0 min 10% A ⁇ 4.1 min 100% A (flow rate 2.5 ml/min); oven: 55° C.; flow rate: 2 ml/min; UV detection: 210 nm.
• MS instrument type Micromass ZQ
• HPLC instrument type HP 1100 Series
• UV DAD column: Phenomenex Gemini 3 ⁇ , 30 mm ⁇ 3.00 mm
• eluent A 1 l of water+0.5 ml of 50% formic acid
• eluent B 1 l of acetonitrile+0.5 ml of 50% formic acid
• flow rate 0.0 min 1 ml/min ⁇ 2.5 min/3.0 min/4.5 min 2 ml/min
• oven 50° C.
• UV detection 210 nm.
• Step 1 5-(5-Methyl-1H-pyrazol-3-yl)-3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazole
• Step 2 5-[1-(3-Bromobenzyl)-5-methyl-1H-pyrazol-3-yl]-3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazole
• activated zinc bromide on montmorillonite was prepared as follows: 7.0 g (31.1 mmol) of zinc bromide were initially charged in a 1 litre flask in 225 ml of methanol, and 28.2 g of K10 montmorillonite were added. Subsequently, the suspension was stirred at RT for 1 h. Then the mixture was concentrated to dryness on a rotary evaporator. The remaining fine powder was heated to bath temperature 200° C. in a sand bath under gentle vacuum (approx. 500 mbar) for 1 h and then allowed to cool under argon.
• the title compound was then prepared as follows: 49.63 g (267 mmol) of 1-phenyl-1-(trifluoromethyl)cyclopropane were initially charged in 1.25 litres of pentane, and the activated zinc bromide on montmorillonite obtained above was added. Then the reaction vessel was wrapped with aluminium foil on the outside, in order to reduce the incidence of light. 137 ml (2.67 mol) of bromine were slowly added dropwise while stirring. Subsequently, the reaction mixture was stirred in the dark at RT for 16 h. Then, while cooling with ice, 1 litre of saturated aqueous sodium sulphite solution was added dropwise.
• the resulting crude product was dissolved in 1.5 litres of ethyl acetate and the mixture was washed twice with 500 ml each time of saturated ammonium chloride solution and once with 500 ml of saturated sodium chloride solution. After drying the organic phase over anhydrous magnesium sulphate, the mixture was filtered and the filtrate was concentrated on a rotary evaporator.
• the oil obtained was purified by means of suction filtration through 175 g of silica gel with 40:1 cyclohexane/ethyl acetate as the eluent. After concentration of the product fractions and drying under high vacuum, 49.7 g (83% of theory) of the title compound were obtained.
• Step 3 N′-Hydroxy-4-[1-(trifluoromethyl)cyclopropyl]benzenecarboximide amide
• Step 4 5-(5-Methyl-1H-pyrazol-3-yl)-3- ⁇ 4-[1-(trifluoromethyl)cyclopropyl]phenyl ⁇ -1,2,4-oxadiazole
• the solid was filtered off with suction and washed with a little cold water.
• the still-moist crude product was recrystallized from a boiling mixture of 300 ml of ethanol and 350 ml of water. 11.03 g (83% of theory) of the title compound were obtained.
• Step 5 5-[1-(3-Bromobenzyl)-5-methyl-1H-pyrazol-3-yl]-3- ⁇ 4-[1-(trifluoromethyl)cyclopropyl]phenyl ⁇ -1,2,4-oxadiazole
• the crude product obtained was first purified by means of suction filtration through silica gel with 10:1 cyclohexane/ethyl acetate as the eluent.
• the product was further purified by stirring with a mixture of 50 ml of pentane and 2 ml of diethyl ether. After the solid had been filtered off with suction and dried, 1.34 g (88% of theory) of the title compound were obtained.
• a suspension of dichloro(dimethyl)titanium in a heptane/dichloromethane mixture was first prepared as follows: 100 ml (100 mmol) of a 1 M solution of titanium tetrachloride in dichloromethane were cooled to ⁇ 30° C., 100 ml (100 mmol) of a 1 M solution of dimethylzinc in heptane were added dropwise and the mixture was stirred at ⁇ 30° C. for a further 30 min. Subsequently, this suspension was cooled to ⁇ 40° C.
• Step 5 N′-Hydroxy-4-(1,1,1-trifluoro-2-methylpropan-2-yl)benzenecarboximide amide
• Step 6 5-(5-Methyl-1H-pyrazol-3-yl)-3-[4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl]-1,2,4-oxadiazole
• Step 7 5-[1-(3-Bromobenzyl)-5-methyl-1H-pyrazol-3-yl]-3-[4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl]-1,2,4-oxadiazole
• Step 3 5-(5-Methyl-1H-pyrazol-3-yl)-3-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1,2,4-oxadiazole
• Step 4 5-[1-(3-Bromobenzyl)-5-methyl-1H-pyrazol-3-yl]-3-[4-(tetrahydro-2H-pyran-4-yl)phenyl]-1,2,4-oxadiazole
• Example 1A/Step 2 250 mg (0.806 mmol) of the compound from Example 4A/Step 3 and 242 mg (0.967 mmol) of 3-bromobenzyl bromide were used to obtain 338 mg (87% of theory) of the title compound.
• the final purification of the product was effected here by extractive stirring from 10 ml of pentane/diisopropyl ether (5:1), to which a few drops of dichloromethane had been added.
• Step 3 4-(4-Fluorotetrahydro-2H-pyran-4-yl)-N′-hydroxybenzenecarboximide amide
• Example 4A/Step 2 By the process described in Example 4A/Step 2, 3.5 g (17.05 mmol) of the compound from Example 5A/Step 2 were used to obtain 3.57 g (88% of theory) of the title compound.
• the reaction time in this case was 2 h.
• Step 4 3-[4-(4-Fluorotetrahydro-2H-pyran-4-yl)phenyl]-5-(5-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole
• Step 5 5-[1-(3-Bromobenzyl)-5-methyl-1H-pyrazol-3-yl]-3-[4-(3-fluorooxetan-3-yl)phenyl]-1,2,4-oxadiazole
• Step 3 N′-Hydroxy-4-(1-methoxycyclobutyl)benzenecarboximide amide
• Step 4 3-[4-(1-Methoxycyclobutyl)phenyl]-5-(5-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazole
• Step 5 5-[1-(3-Bromobenzyl)-5-methyl-1H-pyrazol-3-yl]-3-[4-(1-methoxycyclobutyl)phenyl]-1,2,4-oxadiazole
• Step 1 tent-Butyl 3- ⁇ [tert-butyl(diphenyl)silyl]oxy ⁇ azetidine-1-carboxylate
• Step 1 tert-Butyl 4- ⁇ [tert-butyl(diphenyl)silyl]oxy ⁇ piperidine-1-carboxylate
• Example 8A/Step 2 Analogously to the process described in Example 8A/Step 2, 2.5 g (5.12 mmol, 90% purity) of the compound from Example 9A/Step 1 were used to obtain 1.45 g (83% of theory) of the title compound.
• the product was purified by means of MPLC (approx. 50 g of silica gel, eluent: ethyl acetate ⁇ 9:1 ethyl acetate/triethylamine)
• Step 1 N′-Hydroxy-4-[(trifluoromethyl)sulphanyl]benzenecarboximide amide
• the solid was filtered off with suction and washed with approx. 1 litre of cold water.
• the crude product was purified by recrystallization from a solvent mixture consisting of 500 ml each of acetonitrile and ethanol. After cooling, filtering and drying under high vacuum, a first portion of 94.2 g of the title compound was obtained. After concentration and another crystallization from 150 ml of ethanol, a further 6.2 g of the title compound were obtained. A total of 100.4 g (83% of theory) of the title compound was thus obtained.
• Step 3 5-[1-(3-Bromobenzyl)-5-methyl-1H-pyrazol-3-yl]-3- ⁇ 4-[(trifluoromethyl)sulphanyl]phenyl ⁇ -1,2,4-oxadiazole
• the crude product was purified by means of MPLC (silica gel, eluent: 1:1 cyclohexane/ethyl acetate) and subsequent extractive stirring in a mixture of 25 ml of pentane, 1 ml of diisopropyl ether and 125 ⁇ l of dichloromethane.
• MPLC sica gel, eluent: 1:1 cyclohexane/ethyl acetate
• the free base was obtained from the resulting formate salt of the title compound by percolation of a methanolic solution of the salt through a hydrogencarbonate cartridge (from Polymerlabs, Stratospheres SPE, PL-HCO 3 MP SPE, capacity 0.9 mmol).
• the final purification was effected by extractive stirring in a mixture of 3 ml of pentane and a few drops of diisopropyl ether.
• inventive compounds can be demonstrated by in vitro and in vivo studies, as known to the person skilled in the art.
• the usefulness of the inventive substances can be illustrated by way of example by in vitro (tumour) cell experiments and in vivo tumour models, as described below.
• the connection between inhibition of the HIF transcription activity and the inhibition of tumour growth has been demonstrated by numerous studies described in the literature (cf., for example Warburg, 1956; Semenza, 2007).
• HCT 116 cells were stably transfected with a plasmid which contained a luciferase reporter under the control of an HIF-responsive sequence. These cells were sown in microtitre plates [20 000 cells/cavity in RPMI 1640 medium with 10% foetal calf serum (FCS) and 100 ⁇ g/ml of hygromycin]. They were incubated overnight under standard conditions (5% CO 2 , 21% O 2 , 37° C., moistened). The following morning the cells were incubated with different concentrations of the test substances (0-10 ⁇ mol/l) in a hypoxia chamber (1% O 2 ). After 24 h, Bright Glo reagent (Promega, Wis., USA) was added in accordance with the manufacturer's instructions, and after 5 min the luminescence was measured. Cells which were incubated under normoxia served as background controls.
• FCS foetal calf serum
• Human bronchial carcinoma cells (H460 and A549) were incubated for 16 h with variable concentrations of the test substances (1 nM to 10 ⁇ M) under normoxic conditions and under partial oxygen pressure 1% (see HIF luciferase assay).
• the total RNA was isolated from the cells and transcribed into cDNA, and the mRNA expression of HIF target genes was analysed in real-time PCR. Active test substances already lower the mRNA expression of the HIF target genes compared with untreated cells under normoxic conditions, but in particular under hypoxic conditions.
• tumour cells were cultured in vitro and implanted subcutaneously, or tumour xenotransplant pieces were transplanted further subcutaneously.
• the animals were treated by oral, subcutaneous or intraperitoneal therapy after the tumour had been established.
• the activity of the test substances was analysed in monotherapy and in combination therapy with other pharmacological active substances.
• the tumour inhibitory potency of test substances on tumours of advanced size was characterized.
• the state of health of the animals was checked daily, and the treatments were performed in accordance with animal welfare regulations.
• tumour volume was calculated by the formula (L ⁇ B 2 )/2.
• tumour vessel architecture The influence of test substances on the tumour vessel architecture and the blood flow within the tumour was identified with the aid of computer microtomography and ultrasound microstudies on treated and untreated tumour-carrying mice.
• the pharmacokinetic parameters of the inventive compounds after intravenous or peroral administration can be determined as follows:
• the substance to be examined was administered to animals (for example mice or rats) intravenously as a solution (for example in corresponding plasma with a small addition of DMSO or in a PEG/ethanol/water mixture), and peroral administration was effected as a solution (for example in Solutol/ethanol/water or PEG/ethanol/water mixtures) or as a suspension (e.g. in tylose), in each case via a gavage.
• a solution for example in Solutol/ethanol/water or PEG/ethanol/water mixtures
• a suspension e.g. in tylose
• the pharmacokinetic parameters such as AUC (area under the concentration/time curve), C max , (maximum plasma concentration), t 1/2 (half life), V SS (distribution volume) and CL (clearance), and the absolute and relative bioavailability F and F rei (i.v./p.o. comparison or comparison of suspension to solution after p.o. administration), were calculated.
• the prodrug was administered either intravenously or perorally, as described above, and the concentrations both of the prodrug and of the active ingredient released were quantified in the processed plasma.
• the substance to be examined was administered perorally to rats, in each case in amounts between 1 and 3 mg/kg as a solution in Solutol/ethanol/water (40:10:50 or 40:20:40).
• test substance prodrug
• 0.6 mg of acetonitrile or acetonitrile/DMSO mixture was added.
• the sample vessel was placed into an ultrasound bath for approx. 10 seconds.
• 1.0 ml of the particular aqueous buffer solution was added (commercially available buffer solutions of pH 2, 4, 6.5, 8 and 10) and the sample was treated again in the ultrasound bath.
• 5 ⁇ l of the sample solution were analysed by HPLC every hour for its content of unchanged prodrug or active ingredient released therefrom by hydrolysis. Quantification was effected via the area percentages of the corresponding HPLC peaks.
• Example 1 Example 15 active pH prodrug ingredient 2 89 6 4 89 9 6.5 73 22 8 64 30 10 0 78
• test substance prodrug
• DMSO DMSO-dimethylsulfoxide
• sample vessel was placed into an ultrasound bath for approx. 10 seconds.
• 0.5 ml of rat plasma or human plasma at 37° C. was added to 0.5 ml of this solution.
• the sample was agitated and approx. 10 ⁇ l were taken for a first analysis (time t 0 ). Within the period up to 2 hours after commencement of incubation, 4-6 further aliquots were taken for quantification. The sample was kept at 37° C. over the test period. Characterization and quantification were effected by HPLC.
• the mixture of inventive compound, lactose and starch is granulated with a 5% solution (w/w) of the PVP in water. After drying, the granules are mixed with the magnesium stearate for 5 minutes. This mixture is pressed with a conventional tableting press (for tablet format see above).
• the guide value used for the pressing is a pressing force of 15 kN.
• a single dose of 100 mg of the inventive compound corresponds to 10 ml of oral suspension.
• Rhodigel is suspended in ethanol and the inventive compound is added to the suspension.
• the water is added while stirring.
• the mixture is stirred for approx. 6 h until swelling of the Rhodigel has ended.
• inventive compound 500 mg of the inventive compound, 2.5 g of polysorbate and 97 g of polyethylene glycol 400.
• a single dose of 100 mg of the inventive compound corresponds to 20 g of oral solution.
• the inventive compound is suspended in the mixture of polyethylene glycol and polysorbate while stirring. The stirring operation is continued until dissolution of the inventive compound is complete.
• the inventive compound is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g. isotonic saline, glucose solution 5% and/or PEG 400 solution 30%).
• a physiologically acceptable solvent e.g. isotonic saline, glucose solution 5% and/or PEG 400 solution 30%.
• the solution is subjected to sterile filtration and dispensed into sterile and pyrogen-free injection vessels.

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