WO2011141325A1 - Hydroxyalkylbenzyle-pyrazoles et leur utilisation pour le traitement de maladies hyperprolifératives et angiogéniques - Google Patents

Hydroxyalkylbenzyle-pyrazoles et leur utilisation pour le traitement de maladies hyperprolifératives et angiogéniques Download PDF

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WO2011141325A1
WO2011141325A1 PCT/EP2011/057019 EP2011057019W WO2011141325A1 WO 2011141325 A1 WO2011141325 A1 WO 2011141325A1 EP 2011057019 W EP2011057019 W EP 2011057019W WO 2011141325 A1 WO2011141325 A1 WO 2011141325A1
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mmol
compound
methyl
phenyl
theory
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PCT/EP2011/057019
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German (de)
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Michael Härter
Hartmut Beck
Frank SÜSSMEIER
Susanne Greschat
Peter Ellinghaus
Kerstin BERHÖRSTER
Karl-Heinz Thierauch
Joachim Schuhmacher
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Bayer Pharma Aktiengesellschaft
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Priority to AU2011252222A priority Critical patent/AU2011252222A1/en
Priority to KR1020127032070A priority patent/KR20130108998A/ko
Priority to CA2798374A priority patent/CA2798374A1/fr
Priority to CN2011800338366A priority patent/CN103003266A/zh
Priority to RU2012152800/04A priority patent/RU2012152800A/ru
Priority to MX2012012905A priority patent/MX2012012905A/es
Application filed by Bayer Pharma Aktiengesellschaft filed Critical Bayer Pharma Aktiengesellschaft
Priority to EP11716947A priority patent/EP2569309A1/fr
Priority to JP2013509504A priority patent/JP2013530139A/ja
Priority to BR112012028652A priority patent/BR112012028652A2/pt
Publication of WO2011141325A1 publication Critical patent/WO2011141325A1/fr
Priority to IL222850A priority patent/IL222850A0/en
Priority to ZA2012/09298A priority patent/ZA201209298B/en

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    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • 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 1- [3- (hydroxyalkyl) benzyl] -lH-pyrazole derivatives, processes for their preparation, their use for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or prevention of diseases, in particular for the treatment and / or prevention of hyperproliferative and angiogenic diseases as well as those diseases which arise through a metabolic adaptation to hypoxic conditions.
  • Such treatments may be monotherapy or in combination with other medicines or other therapeutic measures.
  • Cancers are the result of uncontrolled cell growth of various tissues. In many cases, the new cells invade existing tissues (invasive growth) or they metastasize to distant organs. Cancers occur in various organs and often have tissue-specific disease courses. Therefore, the term cancer as a generic term describes a large group of defined diseases of various organs, tissues and cell types.
  • early stage tumors may be removed by surgical and radiotherapeutic measures.
  • metastatic tumors can only be treated palliatively by chemotherapeutic agents.
  • the goal here is to achieve the optimal combination of improving the quality of life and extending the lifetime.
  • Chemotherapies often consist of combinations of cytotoxic drugs. The majority of these substances have a binding mechanism to tubulin, or they are compounds that interact with the formation and processing of nucleic acids. More recently, these include enzyme inhibitors that interfere with epigenetic DNA modification or cell cycle progression (eg, histone deacetylase inhibitors, Aurora kinase inhibitors). Since such therapies are toxic, more and more recently, targeted therapies are being used in which specific processes in the cell are blocked, without any high toxic load occurs. These include in particular inhibitors of kinases which inhibit the phosphorylation of receptors and signal transduction molecules. An example of this is imatinib, which is used very successfully for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST).
  • CML chronic myeloid leukemia
  • GIST gastrointestinal stromal tumors
  • EGFR kinase and HER2 blocking substances such as erlotinib and VEGFR kinase inhibitors such as sorafenib and sunitinib, which are used in renal cell carcinoma, liver carcinoma and advanced stages of GIST.
  • Bevacizumab inhibits blood vessel growth, which hinders the rapid expansion of a tumor because it requires a connection to the blood vessel system for a continuously functioning supply and disposal.
  • hypoxia hypoxia
  • FIH factor inhibiting HIF
  • HIF can be degraded via the proteasome apparatus via the Hippel Lindau protein (part of a ubiquitin E3 ligase complex) (Maxwell, Wiesener et al., 1999). In the absence of oxygen, breakdown is avoided, the protein is up-regulated and leads to the transcription or blockade of the transcription of numerous (more than 100) other proteins (Semenza and Wang, 1992, Wang and Semenza, 1995).
  • the transcription factor HIF is formed by the regulated a- and constitutively present aryl hydrocarbon receptor nuclear translocator (ARNT).
  • ARNT aryl hydrocarbon receptor nuclear translocator
  • the HIF subunits are bHLH (basic helix loop helix) proteins that dimerize via their HLH and PAS (per-Arnt-Sim) domain, which starts their transactivating activity (Jiang, Rue et al., 1996 ).
  • HIF ⁇ ⁇ protein In the major tumor entities, overexpression of the HIF ⁇ ⁇ protein is correlated with increasing blood vessel density and increased VEGF expression (Hirota and Semenza, 2006). At the same time, the glucose metabolism is changed towards glycolysis, and the Krebs cycle is reduced in favor of the production of cell building blocks. This also implies a change in the fat metabolism. Such changes seem to ensure the survival of the tumors. On the other hand, if the activity of HIF is inhibited, then it would be possible to suppress the development of tumors.
  • WO 2004/089303-A2 describes di-aiyl-substituted pyrazoles as mGluR5 modulators for the treatment of psychiatric disorders.
  • WO-2010/072352-A1 and WO 2010/085584-A1 disclose 3-phenyl-5- (1H-pyrazol-4-yl) -1,4,4-oxadiazole derivatives as sulfinosin-1 - phosphate agonists for the treatment of autoimmune and vascular diseases.
  • WO 2005/030121 -A2 and WO 2007/065010-A2 describe the usefulness of certain pyrazole derivatives for inhibiting the expression of HIF and HIF-regulated genes in tumor cells.
  • heteroaryl-substituted N-benzylpyrazoles are disclosed as inhibitors of the HIF-regulation pathway for the treatment of coxious diseases.
  • many of these compounds have insufficient inhibitory activity or, because of their pharmacokinetic properties in animal models, allow such a long half-life (> 48 h) in the human body that significant substance accumulation after repeated daily dosing is likely is.
  • this new group of N-benzylpyrazole derivatives is characterized by a hydroxyalkyl substituent in the 3-position of the benzyl head group, which surprisingly leads to an improved property profile of the compounds.
  • the present invention relates to compounds of the general formula (I)
  • R 1A and R 1B independently of one another are hydrogen, deuterium, methyl, hydroxymethyl or trifluoromethyl or are linked to one another and, together with the carbon atom to which they are bonded, are a cyclopropan-1, 1-diyl, cyclobutane-1,1-diyl Form oxetane-3,3-diyl or tetrahydro-2H-pyran-4,4-diyl ring,
  • R 2A and R 2B are independently hydrogen, deuterium, methyl or trifluoromethyl, and
  • R 3A and R 3B independently of one another denote hydrogen, fluorine, methyl, hydroxymethyl or trifluoromethyl or and together with the carbon atom to which they are attached, a cyclopropane-l, l -diyl, cyclobutane-l, l -diyl, oxetane-3,3-diyl or tetrahydro-2H-pyran-4 To form 4-diyl ring,
  • R 4 is trifluoromethoxy, trifluoromethylsulfanyl, trifluoromethylsulfonyl, pentafluorosulfanyl, trimethylsilyl or a group of the formula stands in which
  • R 5A and R 5B independently of one another are hydrogen, fluorine, methyl, ethyl, propyl or isopropyl or are linked to one another and, together with the carbon atom to which they are attached, are a cyclopropane-1,1-diyl-, cyclobutane form l, l -diyl, cyclopentane-l, 1-diyl, cyclohexane-l, l -diyl, oxetane-3,3-diyl or tetrahydro-2H-pyran-4,4-diyl ring, and
  • R 6 is hydrogen, fluorine, methyl, trifluoromethyl, methoxymethyl or ethoxymethyl
  • R 7 is hydrogen, fluorine or methyl, and their salts, solvates and solvates of the salts.
  • A is a group of the formula stands in which
  • R 2A and R 2B are both hydrogen or deuterium, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfanyl, pentafluorosulfanyl, trimethylsilyl or a group of the formula stands in which
  • R 5A and R 5B are both methyl or linked together and together with the carbon atom to which they are attached form a cyclopropane-1,1-diyl or tetrahydro-2H-pyran-4,4-diyl ring, and
  • R 6 is fluorine, methyl or trifluoromethyl
  • R 7 is hydrogen or fluorine, and their salts, solvates and solvates of the salts.
  • Particularly preferred in the context of the present invention are compounds of the formula (I) in which
  • A is a group of the formula
  • R 4 represents trifluoromethoxy, trifluoromethylsulfanyl or a group of the formula stands in which
  • R 7 is hydrogen, and their salts, solvates and solvates of the salts.
  • the present invention also encompasses certain prodrugs of the compounds of formula (I).
  • prodrugs hereby denotes covalent derivatives of the compounds of the formula (I) which themselves may be biologically active or inactive, but are converted during their residence time in the body by, for example, metabolic or hydrolytic routes to compounds of the formula (I).
  • Another object of the present invention are accordingly compounds of the formula (I-PD)
  • R is a prodrug group of the formula wherein
  • R and R independently of one another are hydrogen or methyl, and their salts, solvates and solvates of the salts.
  • R 8 is methyl, isopropyl, isobutyl or sec-butyl, and ilire salts, solvates and solvates of the salts.
  • the compounds of formula (I-PD) are prodrugs of the compounds of formula (I) having good solubility in aqueous or other physiologically acceptable media; They also offer the possibility of salt formation with corresponding bases or acids, which can lead to a further increase in solubility.
  • the compounds of the formula (I-PD) and their salts are therefore particularly suitable for intravenous administration. As a result, other therapeutic applications for these compounds could be developed.
  • Compounds according to the invention are thus the compounds of the formulas (I) and (I-PD) and their salts, solvates and solvates of the salts, the compounds of the formulas (I) and (I-PD) of the formulas below and their salts, Solvates and solvates of the salts and those of the formulas (I) and (I-PD), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as in the of the formulas (I) and (I -PD), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including sol at atropisomers).
  • the present invention therefore includes the enantiomers and diastereoisomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase. If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood here to mean a compound in which at least one atom within the compound according to the invention is exposed to another atom of the same atomic number but with a different atomic mass than the atomic mass, which usually or predominantly occurs in nature. exchanges.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 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 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • isotopic variants of a compound of the invention such as, in particular, those in which one or more radioactive isotopes are incorporated, may be useful, for example, for the study of the mechanism of action or drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes in particular are suitable for this purpose.
  • isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by generally customary processes known to the person skilled in the art, for example by the methods described below and the rules reproduced in the exemplary embodiments by using corresponding isotopic modifications of the respective reagents and / or starting compounds.
  • Salts which are preferred in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms, as exemplified and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, Triethanolamine, dicyclohexylamine, dimethylanine ethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and am
  • Solvates in the context of the invention are those fins of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • C 1 -C 4 -alkyl is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms, by way of example and by preference: methyl, ethyl, n-propyl, isopropyl, - butyl, isobutyl, sec-butyl, tert-butyl. butyl.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. Substitution with one or two or three identical or different substituents is preferred. Particularly preferred is the substitution with one or two identical or different substituents. Very particular preference is given to the substitution with a substituent.
  • Another object of the present invention is a process for the preparation of the compounds of formulas (I) and (I-PD), characterized in that initially a N'-hydroxyamidine of the formula (II)
  • X is a leaving group such as chlorine, bromine, iodine, mesylate, triflate or tosylate, and
  • R 10 is hydrogen or a conventional hydroxy protecting group such as acetyl, tetrahydropyranyl, trimethylsilyl, triisopropylsilyl, tert. Butyldimethylsilyl or tert. Butyl (diphenyl) silyl, to give a compound of formula (VI) in which A, R 4 , R 7 and R 10 each have the meanings given above, then, if present, the hydroxy protective group R 10 is split off by customary methods and the resulting compound of the formula (I)
  • R PD , R 4 and R 7 in each case have the abovementioned meanings, and converting the compounds of the formula (I) or (I-PD) thus obtained, if appropriate, into their enantiomers and / or diastereomers and / or with the corresponding (i) solvents and / or (ii) bases or acids in their solvates, salts and / or solvates of the salts.
  • the condensation reaction (II) + (III) -> (IV) is preferably carried out with the aid of a carbodiimide, such as N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDC), in conjunction with 1-hydroxy-1H-benzotriazole ( HOBt) as the active ester component, or with the aid of a phosgene derivative such as ⁇ , ⁇ -carbonyldiimidazole (CDI) in a high-boiling dipolar aprotic solvent such as N, N-dimethylformamide or dimethyl sulfoxide.
  • a carbodiimide such as N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide (EDC)
  • HOBt 1-hydroxy-1H-benzotriazole
  • CDI phosgene derivative
  • a high-boiling dipolar aprotic solvent such as N, N
  • the initial coupling step in this reaction is generally carried out in a temperature range from 0 ° C to + 50 ° C; the cyclization to the 1,2,4-oxadiazole is then accomplished by subsequent heating of the reaction mixture to temperatures of + 100 ° C to + 150 ° C.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar); usually one works at normal pressure.
  • Inert solvents for process step (IV) + (V) -> (VI) are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4 - Dioxane, 1, 2-dimethoxyethane or bis (2-methoxyethyl) ether, hydrocarbons such as benzene, toluene, xylene, pentane, hexane, cyclohexane or petroleum fractions, or dipolar aprotic solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, NN Dimethylformamide (DMF), N, N-dimethylacetamide
  • Suitable bases for the reaction (IV) + (V) - »(VI) are customary inorganic or organic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali alcoholates such as sodium or potassium, sodium or potassium ethoxide or sodium or potassium feri.-butoxide, alkali metal hydrides such as sodium or potassium hydride, or amides such as Sodium amide, lithium or potassium bis (trimethylsilyl) amide or Lithiumdiisopro- pylamid.
  • alkali metal hydroxides such as lithium, sodium or potassium hydroxide
  • alkali alcoholates such as sodium or potassium, sodium or potassium ethoxide or sodium or potassium feri.-butoxide
  • alkali metal hydrides such as sodium or potassium hydride
  • amides such as Sodium amide, lithium or potassium bis (trimethylsilyl) amide or Lithiumdiisopro- pylamid.
  • potassium tert-butoxide is used.
  • an alkylation catalyst such as, for example, lithium bromide, sodium or potassium iodide, tetra-n-butylammonium bromide or benzyltriethylammonium chloride, is advantageous.
  • the reaction is generally carried out in a temperature range from -20 ° C to + 100 ° C, preferably at 0 ° C to + 60 ° C.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar); usually one works at normal pressure.
  • Conventional methods for the removal of a hydroxy-protecting group R 10 include, for example, in ester derivatives, the basic or acidic hydrolysis or the reaction with organometallics (such as In the case of tetrahydropyranyl ethers, the acid hydrolysis and in the case of silyl ethers likewise the hydrolysis or the treatment with fluorides (such as, for example, potassium or tetra-n-butylammonium fluoride) [cf. eg TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999].
  • organometallics such as In the case of tetrahydropyranyl ethers, the acid hydrolysis and in the case of silyl ethers likewise the hydrolysis or the treatment with fluorides (such as, for example, potassium or tetra-n-butylammonium fluoride) [cf. eg TW Greene and PGM Wuts, Protective Groups in
  • Activated forms of the compound (VII) which are suitable for the introduction of the prodrug group R PD [transformation (I) (I-PD)] are, for example, corresponding chlorides or anhydrides, including mixed anhydrides, or else certain ester or amide derivatives.
  • R PD further existing hydroxyl or amino groups are expediently present in temporarily protected form and are then released at the end of the reaction sequence by conventional methods.
  • a protective group for a hydroxy function benzyl is preferably used in this process step, which is removed again by hydrogenolysis, and as the amino protective group is tert-butoxycarbonyl which can be cleaved off by treatment with a strong acid such as hydrogen chloride or trifluoroacetic acid [see.
  • Z generally represents a substituent or a functional group with the aid of which the above-defined hydroxyalkyl group HO-A- can be introduced or built up by subsequent chemical transformations to give a compound of the formula (IX) in which R 4 , R 7 and Z have the meanings given above, and then converted by taking place by literature methods transformations of the group Z into compounds of formula (I).
  • the reaction (IV) + (VIII) -> ⁇ (IX) is carried out under similar reaction conditions with respect to solvent, base and temperature, as described above in process step (IV) + (V) -> (VI).
  • substituents or functional groups Z in formula (VIII) by means of which the hydroxyalkyl group HO-A- defined above can be introduced or built up are, on the one hand, halides such as bromide or iodide and, on the other hand, a carbonyl group-containing group Radicals such as alkoxycarbonyl, alkoxycarbonylalkyl, hydroxycarbonyl, hydroxycarbonylalkyl, formyl, alkylcarbonyl or alkylcarbonylalkyl.
  • the subject transformations are carried out by known methods known to those skilled in the art and include, for example, reactions such as reduction with complex metal hydrides, 1,2-addition of organometallic compounds (eg Grignard compounds) to carbonyl compounds, hydroxylation, C-alkylation and C-acylation as well as the introduction and removal of temporary protective groups [see also the following Reaction Schemes 1 -7 and the preparation of the embodiments described in detail in the Experimental Part].
  • reactions such as reduction with complex metal hydrides, 1,2-addition of organometallic compounds (eg Grignard compounds) to carbonyl compounds, hydroxylation, C-alkylation and C-acylation
  • organometallic compounds eg Grignard compounds
  • the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
  • the compounds of the present invention are highly potent inhibitors of the HIF regulatory pathway.
  • the compounds of the present invention have beneficial pharmacokinetic properties in terms of their volume of distribution and / or clearance and the half-life derived therefrom, making them suitable for repeated once daily dosing.
  • the compounds according to the invention are particularly suitable for the treatment of hyperproliferative disorders in humans and in mammals in general.
  • the compounds can inhibit, block, reduce or decrease cell proliferation and cell division and, on the other hand, enhance apoptosis.
  • the hyperproliferative diseases for the treatment of which the compounds according to the invention can be used include, among others, psoriasis, keloids, scarring and other proliferative diseases of the skin, benign diseases such as benign prostatic hyperplasia (BPH), and in particular the group of tumor diseases.
  • benign diseases such as benign prostatic hyperplasia (BPH)
  • BPH benign prostatic hyperplasia
  • breast carcinomas and breast tumors are under the in particular the following diseases: breast carcinomas and breast tumors (ductal and lobular forms, also in situ), respiratory tumors (small cell and non-small cell carcinoma, bronchial carcinoma), brain tumors (eg of the brainstem and hypothalamus , Astrocytoma, medulloblastoma, ependymoma as well as neuro-ectodermal and pineal tumors), tumors of the digestive organs (esophagus, stomach, gall bladder, small intestine, large intestine, rectum), liver tumors (including hepatocellular carcinoma, cholangiocarcinoma and mixed hepatocellular cholangiocarcinoma), tumors of the head and neck area (larynx, hypopharynx, nasopharynx, oropharynx, lips and oral cavity), skin tumors (squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer
  • proliferative blood diseases in solid form and as circulating blood cells such as lymphomas, leukemias and myeloproliferative disorders, for example acute myeloid, acute lymphoblastic, chronic lymphocytic, chronic myelogenous and hairy cell leukemia, as well as AIDS-correlated lymphomas, Hodgkin's lymphomas, Non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma and lymphoma in the central nervous system.
  • lymphomas such as lymphomas, leukemias and myeloproliferative disorders, for example acute myeloid, acute lymphoblastic, chronic lymphocytic, chronic myelogenous and hairy cell leukemia, as well as AIDS-correlated lymphomas, Hodgkin's lymphomas, Non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma and lymphoma in the central nervous
  • HIF human immunodeficiency virus
  • treatment or “treating” is used conventionally within the context of this invention and means the care, care and supervision of a patient with the aim of combating, reducing, alleviating or alleviating a disease or health deviation and improving living conditions that are affected by this disease, such as cancer.
  • the compounds according to the invention act as modulators of the HIF regulation pathway and are therefore also suitable for the treatment of diseases which are associated with a detrimental expression of the HIF transcription factor. This concerns in particular the transcription factors HIF-1 ⁇ and HIF-2a.
  • harmful expression of HIF means a non-normal physiological presence of HIF protein. This may be due to excessive synthesis of the protein (mRNA- or translation-related), by reduced degradation or by insufficient counterregulation in the function of the transcription factor.
  • HIF- ⁇ and HIF-2a regulate more than 100 genes. This concerns proteins that play a role in angiogenesis and are therefore directly tumor-relevant, as well as those that influence the glucose, amino acid and lipid metabolism as well as cell migration, metastasis and DNA repair or by suppression of apoptosis survival improve the tumor cells. Others act more indirectly via inhibition of the immune response and upregulation of angiogenic factors in inflammatory cells. HIF also plays an important role in the stem cells, in particular the tumor stem cells, which are reported to have elevated HIF levels. Inhibition of the HIF-regulation pathway by the compounds of the present invention thus also therapeutically influences tumor stem cells which do not have a high proliferation rate and therefore are only insufficiently affected by cytotoxic substances (see Semenza, 2007, Weidemann and Johnson, 2008).
  • HIF inhibitors - such as the compounds of the present invention - are therapeutically useful in those contexts in which, for example, adaptation of cells to hypoxic situations causes additional damage, as damaged cells, if not functioning properly, can cause further damage.
  • An example of this is the formation of epileptic foci in partially destroyed tissue after strokes.
  • cardiovascular disease when ischemic processes occur in the heart or brain as a result of thromboembolic events, inflammation, wounding, intoxication or other causes. These can lead to damage such as a locally slowed down action potential, which in turn can cause arrhythmias or chronic heart failure.
  • transient form e.g. Through apnea, it may under certain circumstances come to an essential increase in blood pressure, which can lead to known sequelae such as stroke and myocardial infarction.
  • the inhibition of the HIF-regulation pathway as achieved by the compounds according to the invention can therefore also be used in diseases such as cardiac insufficiency, arrhythmia, myocardial infarction, apnea-induced hypertension, pulmonary hypertension, transplantation ischemia, reperfusion damage, stroke and macular degeneration as well as for the recovery of the nerve function be helpful after traumatic injury or severance.
  • diseases such as cardiac insufficiency, arrhythmia, myocardial infarction, apnea-induced hypertension, pulmonary hypertension, transplantation ischemia, reperfusion damage, stroke and macular degeneration as well as for the recovery of the nerve function be helpful after traumatic injury or severance.
  • HIF is one of the factors controlling the transition from an epithelial to a mesenchymal cell type, which is particularly important to the lung and kidney
  • the compounds of the present invention can also be used to augment HIF-associated lung and kidney fibroses prevent or curb.
  • Chugwash polycythemia is mediated by HIF-2a activity during erythropoiesis in, among other places, the spleen.
  • the compounds according to the invention as inhibitors of the HIF regulatory pathway, are therefore also suitable for suppressing the excessive formation of erythrocytes here and thus for alleviating the effects of this disease.
  • the compounds of the present invention may also be used to treat diseases associated with excessive or abnormal angiogenesis. These include diabetic retinopathy, ischemic retinal vein occlusion and retinopathy in preterm birth (see Aiello et al., 1994, Peer et al., 1995), age-related macular degeneration (AMD, Lopez et al., 1996), neovascular glaucoma, psoriasis , retrolental fibroplasia, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, / ⁇ .yfeni-restenosis and restenosis after vascular implantation.
  • diseases associated with excessive or abnormal angiogenesis include diabetic retinopathy, ischemic retinal vein occlusion and retinopathy in preterm birth (see Aiello et al., 1994, Peer et al., 1995), age-related macular degeneration (AMD, Lopez et al., 1996),
  • Increased blood supply is also associated with cancerous neoplastic tissue, leading to accelerated tumor growth.
  • the growth of new blood and lymph vessels facilitates the formation of metastases and thus the spread of the tumor.
  • New lymphoid and blood vessels are also detrimental to allografts in immune-privileged tissues, such as the eye, which, for example, increases susceptibility to rejection.
  • Compounds of the present invention can therefore also be used to treat any of the aforementioned diseases, e.g. by inhibiting growth or reducing the number of blood vessels. This can be achieved via inhibition of endothelial cell proliferation or other mechanisms to prevent or attenuate vascularization and via reduction of neoplastic cells by apoptosis.
  • HIF- ⁇ ⁇ In obesity, HIF- ⁇ ⁇ accumulates in the adipose tissue and thus leads to a HIF-mediated shift in the energy metabolism in the direction of glycolysis, so that more and more glucose is consumed as an energy carrier. At the same time this leads to a reduced fat metabolism and thus to an accumulation of fats in the tissue.
  • the substances according to the invention Therefore, they are also suitable for the treatment of HIF- ⁇ -mediated accumulation of fats in tissue especially in obesity.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention in a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • the compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects.
  • Another object of the present invention are therefore pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases.
  • the compounds of the present invention can be combined with known anti-hyperproliferative, cytostatic or cytotoxic substances for the treatment of cancers.
  • the combination of the compounds according to the invention with other substances which are commonly used for cancer therapy or else with radiation therapy is therefore particularly indicated since hypoxic regions of a tumor respond only slightly to the said conventional therapies, whereas the compounds of the present invention in particular exert their activity there.
  • Suitable combination active ingredients are:
  • the compounds of the present invention may be combined with anti-hyperproliferative agents, which may be by way of example, without being exhaustive:
  • the compounds of the present invention can also be combined with biological therapeutics such as antibodies (eg, Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins, which additively or synergistically enhance the effects of inhibiting HIF signaling pathway transfer.
  • Inhibitors of the HIF-regulatory pathway such as the compounds of the present invention, may also produce positive effects in combination with other angiogenesis-targeted therapies, such as Avastin, axitinib, recentin, regorafenib, sorafenib, or sunitinib.
  • Combinations with proteasome and mTOR inhibitors as well as antihormones and steroidal metabolic enzyme inhibitors are particularly suitable because of their favorable side effect profile.
  • the combination of compounds of the present invention with other cytostatic or cytotoxic agents may have the following aims: • improved efficacy in slowing down the growth of a tumor, reducing its size or even eliminating it completely compared to treatment with a single drug;
  • the compounds of the invention may also be used in conjunction with radiotherapy and / or surgical intervention.
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention), tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates, capsules (for example hard or soft), gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention
  • tablets or films / wafers rapidly breaking down in the oral cavity
  • films / lyophilisates capsules (for example hard or soft), gelatin capsules), dragees, granules, pellets, powders, emulsion
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicines including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (eg plasters)
  • milk pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients e.g., microcrystalline cellulose, lactose, mannitol
  • solvents e.g, liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents e.g., sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders e.g., polyvinylpyrrolidone
  • synthetic and natural polymers e.g.
  • Albumin e.g antioxidants such as ascorbic acid
  • dyes eg inorganic pigments such as iron oxides
  • Device type MS Micromass ZQ
  • Device type HPLC HP 1100 Series
  • UV DAD Column: Phenomenex Gemini 3 ⁇ 30 mm x 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 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.
  • Device type MS Micromass ZQ
  • Device type HPLC Waters Alliance 2795; Column: Phenomenex syn ergi 2.5 ⁇ MAX-RP 100A Mercury 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% strength 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 -» 3.0 min 5% A -> 4.0 min 5% A - »4.01 min 90% A; Flow: 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.
  • Method 4 (LC / MS):
  • Device Type MS Waters ZQ
  • Device Type HPLC Agilent 1100 Series
  • UV DAD Column: Thermo Hypersil GOLD 3 ⁇ 20mm x 4mm
  • Eluent A 1 l of water + 0.5 ml of 50% strength formic acid
  • eluent B 1 l of acetonitrile + 0.5 ml of 50% formic acid
  • Flow 2 ml / min
  • UV detection 210 nm.
  • Device type MS Micromass ZQ
  • Device type HPLC HP 1100 Series
  • UV DAD Column: Phenomenex Gemini 3 ⁇ 30 mm x 3.00 mm
  • Eluent A 1 l of water + 0.5 ml of 50% strength formic acid
  • eluent B 1 l of acetonitrile + 0.5 ml of 50% formic acid
  • Flow 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.
  • Instrument Micromass GCT, GC 6890; Column: Restek RTX-35, 15 m ⁇ 200 ⁇ x 0.33 ⁇ ; constant flow with helium: 0.88 ml / min; Oven: 70 ° C; Inlet: 250 ° C; Gradient: 70 ° C, 30 ° C / min -> 310 ° C (hold for 3 min).
  • a suspension of dichloro (dimethyl) titanium in a heptane / dichloromethane mixture was prepared as follows: 100 ml (100 mmol) of a 1 M solution of titanium tetrachloride in dichloromethane was cooled to -30 ° C., 100 ml (100 mmol) was added dropwise. a 1 M solution of dimethylzinc in heptane and stirred for 30 min at -30 ° C after.
  • this suspension was cooled to -40 ° C and a solution of 10 g (39.5 mmol) l- (4-bromophenyl) -2,2,2-trifluoro -ethanone added in 50 ml of dichloromethane.
  • the mixture was stirred for 5 min at -40 ° C, then allowed to come the temperature to RT and stirred for a further 2 h at RT.
  • 50 ml of water were slowly added dropwise and then diluted with a further 300 ml of water.
  • Step 4 4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzenecarbonitrile
  • Step 5 N'-Hydroxy-4- (1,1,1-trifluoro-2-methylpropan-2-yl) berizolcarboxiinidamide
  • Step 2 4- (2-fluoropropan-2-yl) -N'-hydroxybenzenecarboximidamide
  • Step 2 4- (3-Fluorooxetan-3-yl) benzenecarbonitrile
  • Step 3 4- (3-Fluorooxetan-3-yl) -N'-hydroxybenzenecarboximidamide
  • Step 1 4- (4-Hydroxytetrahydro-2H-pyran-4-yl) benzenecarbonitrile
  • Step 3 4- (4-fluorotetrahydro-2H-pyran-4-yl) -N'-hydroxybenzenecarboximidamide
  • Step 2 4- (1-fluorocyclobutyl) benzenecarbonitrile
  • Step 3 4- (1-Fluorocyclobutyl) -N'-hydroxybenzenecarboximidamide
  • Step 1 4- (Tetrahydro-2H-pyran-4-yl) benzonitrile
  • Step 1 Ethyl 1 - (4-bromophenyl) cyclobutanecarboxylate
  • Step 3 1 Bromo-4- [1- (methoxymethyl) cyclobutyl] benzene
  • a solution of 7.0 g (29.0 mmol) of the compound from Example 14A / step 2 in 120 ml of anhydrous DMF was admixed at about 5 ° C. with 1.28 g (31.9 mmol) of a 60% suspension of sodium hydride in mineral oil. After stirring at this temperature for 1 h, 2.2 ml (34.8 mmol) of methyl iodide were added. The reaction mixture was allowed to warm to rt and stirring continued for 15 h. Subsequently, the reaction mixture was concentrated on a rotary evaporator to a volume of about 20 ml. About 500 ml of water were added and the mixture extracted three times with about 200 ml of diethyl ether.
  • Step 5 N'-hydroxy-4- [1- (methoxymethyl) cyclobutyl] benzenecarboximidamide
  • Activated zinc bromide on montmorillonite was initially prepared as follows: 7.0 g (31.1 mmol) of zinc bromide were placed in 225 ml of methanol in a 1 liter flask and 28.2 g of montmorillonite K10 were added. Subsequently, the suspension was stirred for 1 h at RT. It was then evaporated to dryness on a rotary evaporator. The remaining fine powder was heated under low vacuum (about 500 mbar) for 1 hour in a sand bath to 200 ° C bath temperature 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 liters of pentane and montmorillonite was added to the activated zinc bromide obtained above. Then, the reaction vessel was externally packed with aluminum foil to reduce the incidence of light. 137 ml (2.67 mol) of bromine were slowly added dropwise with stirring. The reaction mixture was then stirred at RT for 16 h in the dark. Then, under ice-cooling, 1 liter of saturated aqueous sodium sulfite solution was dropwise added thereto. The solids were filtered off with suction and washed twice with pentane.
  • the resulting crude product was dissolved in 1.5 liters of ethyl acetate and washed twice with 500 ml of saturated ammonium chloride solution and once with 500 ml of saturated sodium chloride solution. After drying the organic phase over anhydrous magnesium sulfate was filtered and the filtrate was concentrated on a rotary evaporator. The resulting oil was purified by suction filtration over 175 g silica gel with cyclohexane / ethyl acetate 40: 1 as eluent. After evaporation of the product fractions and drying in a high vacuum, 49.7 g (83% of theory) of the title compound were obtained.
  • Step 3 N'-hydroxy-4- [1- (trifluoromethyl) cyclopropyl] benzenecarboximidamide
  • Step 2 4- [1- (ethoxymethyl) cyclobutyl] benzonitrile
  • Step 1 Ethyl 1 - (4-bromophenyl) cyclopentanecarboxylate
  • Step 3 1 Bromo-4- [1- (methoxymethyl) cyclopentyl] benzene
  • Step 4 4- [1 - (Methoxymethyl) cyclopentyl] benzonitrile
  • Step 1 Ethyl (4-bromo-2-fluorophenyl) acetate
  • Step 4 4-Bromo-2-fluoro-1- [(methoxymethyl) cyclobutyl] benzene
  • Step 6 3-Fluoro-N'-hydroxy-4- [1- (methoxymethyl) cyclobutyl] benzenecarboximidamide
  • Step 2 1 - (4-Bromo-2-fluorophenyl) -2,2,2-trifluoro-ethanone
  • Step 3 2- (4-Bromo-2-fluorophenyl) -1,1,1-trifluoropropan-2-ol
  • a suspension of dichloro (dimethyl) titanium in a heptane / dichloromethane mixture was prepared as follows: 160 mL (160 mmol) of a 1M solution of titanium tetrachloride in dichloromethane was cooled to -30 ° C, then 160 mL (160 mL) was added dropwise mmol) of a 1 M solution of dimethylzinc in heptane and the mixture was stirred for 30 minutes at -30 ° C after. The suspension was then cooled to -40 ° C. and a solution of 19.4 g (65.9 mmol, purity 92%) of the compound from Example 21 A / Step 2 in 80 ml of dichloromethane was added.
  • Step 4 2- (4-Bromo-2-fluorophenyl) -1,1,1-trifluo-2-propanolanilane sulfonate
  • Step 5 4-Bromo-2-fluoro-1 - (1,1-trifluoro-2-methylpropan-2-yl) benzene
  • Step 6 3-Fluoro-4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzonitrile
  • Step 7 3-Fluoro-N'-hydroxy-4- (1,1,1-trifluoro-2-methylpipan-2-yl) benzenecarboximidamide
  • Example 22A Analogously to the process described under Example 22A (Method A), 3.15 g (25.0 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 4.91 g (25.0 mmol) of the compound from Example 2A were admixed with 5.0 g (68% of theory). Th.) Of the title compound.
  • the product was precipitated by stirring the reaction mixture into ice water, filtered off, washed with water and dried under high vacuum after completion of the reaction.
  • Example 22A Analogously to the process described under Example 22A (Method A), from 2.52 g (20.0 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 4.63 g (20.0 mmol, 90% purity) of the compound from Example 9A 4.67 g ( 78% of theory) of the title compound.
  • the product was precipitated by stirring the reaction mixture into ice water, filtered off, washed with water and dried under high vacuum after completion of the reaction.
  • Example 22A Analogously to the process described under Example 22A (Method A), 2.0 g (15.9 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 3.78 g (15.9 mmol) of the compound from Example 16A were added to 3.15 g (92% purity, 56% of theory) of the title compound.
  • the product in this case was not obtained via a chromatographic purification but by washing the crude product with water and pentane and then drying in vacuo.
  • Example 22A Analogously to the process described under Example 22A (Method A), from 600 mg (4.76 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 1.12 g (4.76 mmol) of the compound from Example 8A 485 mg (31% of theory) of the title compound.
  • the crude product in this case was not purified by chromatography but by crystallization from ethanol.
  • Example 22A Analogously to the process described under Example 22A (Method A), from 6.66 g (52.8 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 11.54 g (52.8 mmol) of the compound from Example 6A 9.02 g (55%) of theory , Th.) Of the title compound.
  • the crude product in this case was not purified by chromatography but by crystallization from ethanol.
  • Example 22A Analogously to the process described under Example 22A (Method A), 1.58 g (12.5 mmol) of 5-methyl-1H-pyrazole-3-carboxylic acid and 3.28 g (12.5 mmol) of the compound from Example 7A were mixed with 2.87 g (65% of theory). Th.) Of the title compound.
  • the product was precipitated by stirring the reaction mixture into ice water, filtered off, washed with water and dried under high vacuum after completion of the reaction.
  • Step 1 1 - [3 - ( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) phenyl] cyclopropanol
  • Step 2 1 - [3 - ( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) phenyl] cyclopropylacetate
  • Step 4 1- (3- ⁇ [(Methylsulfonyl) oxy] methyl ⁇ phenyl) cyclopropylacetate
  • Step 1 1 - (3-Bromophenyl) -2-methylpropan-2-ol
  • Step 3 1 - [3 - (Hydroxymethyl) phenyl] -2-methylpropan-2-ol
  • a solution of 1.07 g (6.00 mmol) of the compound from Example 48A / Step 2 in 30 mL of anhydrous THF was added dropwise at 0 ° C with 6.0 mL (6.0 mmol) of lithium aluminum hydride solution (1.0 M in THF). After the end of the addition, the mixture was stirred at RT for a further 1 h. Then, carefully added 1-2 ml of saturated aqueous ammonium chloride solution and then about 30 ml of ethyl acetate. As much anhydrous magnesium sulfate was added as needed to completely take up the aqueous phase. After filtration, the filtrate was subjected to rotation freed of steamer solvent and the residue dried under high vacuum. There were obtained 1.09 g (100% of theory) of the title compound.
  • Step 1 Methyl 1 - (3-Bromophenyl) cyclopropanecarboxylate
  • Step 3 ⁇ [1- (3-Bromophenyl) cyclopropyl] methoxy ⁇ (triisopropyl) silane
  • Step 5 [3 - (1 - ⁇ [(Triisopropylsilyl) oxy] methyl ⁇ cyclopropyl) phenyl] methanol
  • Example 50A / Step 2 Analogously to the process described under Example 50A / Step 2, 3.50 g (13.7 mmol) of the compound from Example 50A / Step 1 were reacted with lithium aluminum deuteride (instead of lithium aluminum hydride) to give 1.39 g (44% of theory) of the title compound.
  • Step 2 ( ⁇ [1- (3-Bromophenyl) cyclopropyl] -1,1-dideuteromethyl ⁇ oxy) (triisopropyl) silane
  • Step 3 3 - (1 - ⁇ [(Triisopropylsilyl) oxy] dideuteromethyl ⁇ cyclopropyl) benzaldehyde
  • Example 56A Analogously to the process described under Example 56A, from 150 mg (0.443 mmol) of the compound from Example 32A and methyl 3-bromomethylbenzoate, 43 mg (19% of theory) of the title compound were obtained. In addition, 85 mg (41% of theory) of the corresponding benzoic acid were isolated.
  • Example 65A Methyl 3 - [(3 - ⁇ 3 - [4- (1-fluorocyclobutyl) phenyl] -1,2,4-oxadiazol-5-yl ⁇ -5-methyl-1H-pyrazol-1-yl) - methyljbenzoat
  • Example 67A Analogously to the process described in Example 67A, from 211 mg (0.71 mmol) of the compound from Example 26A and 232 mg (0.78 mmol, purity 95%) of the compound from Example 47A, 231 mg (90% pure, 60% of theory) were obtained. ) of the title compound.
  • the chromatographic purification of the product was carried out here with cyclohexane / ethyl acetate 4: 1 as the eluent.
  • Example 67A Analogously to the process described under Example 67A, from 238 mg (0.71 mmol) of the compound from Example 23A and 232 mg (0.78 mmol, purity 95%) of the compound from Example 47A, 286 mg (88% purity, 68% of theory). ) of the title compound.
  • the chromatographic purification of the product was carried out here with cyclohexane / ethyl acetate 3: 1 as the eluent.
  • Example 66A Analogously to the process described under Example 66A, from 190 mg (0.71 mmol) of the compound from Example 41A and 232 mg (0.78 mmol, purity 95%) of the compound from Example 47A 359 mg (69% purity, 76% of theory) .) Of the title compound.
  • Example 66A Analogously to the method described under Example 66A, from 237 mg (0.71 mmol) of the compound from Example 30A and 232 mg (0.78 mmol, purity 95%) of the compound from Example 47A, 408 mg (70% purity, 77% of theory). ) of the title compound.
  • Example 73A 1- ⁇ 3 - [(5-Methyl-3- ⁇ 3- [4- (pentafluoro- 6- sulfanyl) phenyl], 2,4-oxadiazol-5-yl ⁇ -1H-pyrazol-1-yl) - methyl] phenyl ⁇ cyclopropylacetate
  • Example 66A Analogously to the process described under Example 66A, from 275 mg (0.71 mmol) of the compound from Example 38A and 232 mg (0.78 mmol, purity 95%) of the compound from Example 47A, 423 mg (75% purity, 75% of theory) were obtained. ) of the title compound.
  • the reaction time in this case was 4 h at RT.
  • Example 66A Analogously to the process described under Example 66A, from 223 mg (0.78 mmol) of the compound from Example 24A and 255 mg (0.86 mmol, purity 95%) of the compound from Example 47A, 406 mg (75% purity, 82% of theory) were obtained. ) of the title compound.
  • the reaction time in this case was 4 h at RT.
  • Example 76A 1- ⁇ 3 - [(3- ⁇ 3- [4- (4-fluorotetrahydro-2H-pyran-4-yl) -phenyl] -l, 2,4-oxadiazol-5-yl ⁇ -5-methyl- 1H-pyrazol-1-yl) methyl] phenyl 1 ⁇ cyclopropylacetate
  • Example 66A Analogously to the method described under Example 66A, from 256 mg (0.78 mmol) of the compound from Example 27A and 255 mg (0.86 mmol, purity 95%) of the compound from Example 47A 415 mg (65% purity, 67% of theory) of th .) Of the title compound.
  • the reaction time in this case was 16 h at RT.
  • Example 66A Analogously to the process described under Example 66A, from 254 mg (0.78 mmol) of the compound from Example 36A and 255 mg (0.86 mmol, purity 95%) of the compound from Example 47A 396 mg (72% purity, 70% of theory) were obtained. ) of the title compound.
  • the reaction time in this case was 4 h at RT.
  • Example 66A Analogously to the process described under Example 66A, from 200 mg (0.54 mmol, purity 95%) of the compound from Example 45A and 176 mg (0.59 mmol, purity 96%) of the compound from Example I 47A, 192 mg (69% purity, 46% of theory) of the title compound.
  • the reaction time in this case was 4 h at RT.
  • Example 54A Analogously to the process described under Example 54A (Method A), 0.50 g (1.49 mmol) of the compound from Example 23A and 0.50 g (1.93 mmol) of ethyl [3- (bromomethyl) phenyl] acetate [Lit .: SR Kasibhatla et al, J. Med. Chem. 2000, 43 (8), 1508-1518] to 0.47 g (62% of theory) of the title compound. The product was isolated here by preparative HPLC (Method 17).
  • the crude product was purified by suction filtration over about 2 kg of silica gel (0.06-0.2 mm particle size) with a cyclohexane / ethyl acetate gradient [9: 1 (5 liter) - " ⁇ 8: 2 (4 liters) -> ⁇ 7: (3 4 liters) -> ⁇ 6: 4 (4 liters) -> 1: 1 (4 liters)] as eluent. There were obtained 33.8 g (48% of T, 87% purity) of the title compound.
  • Example 87A Ethyl 2-methyl-2- ⁇ 3 - [(5-methyl-3- ⁇ 3- [4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2 , 4-oxadiazol-5-yl ⁇ -1H-pyrazol-1-yl) methyl] phenyl ⁇ propanoate
  • Example 85A Analogously to the procedure described under Example 85A, 0.50 g (1.49 mmol) of the compound from Example 23A and 0.55 g (1.93 mmol) of the compound from Example 49A were reacted to give 0.49 g (59% of theory) of the title compound.
  • the product was purified by preparative HPLC according to Method 17.
  • Example 85 A Analogously to the process described under Example 85 A, 0.14 g (0.44 mmol) of the compound from Example 22A and 0.15 g (0.53 mmol) of the compound from Example 49A were reacted to give 0.14 g (60% of theory) of the title compound.
  • the product was purified by preparative HPLC according to Method 17.
  • the mixture was first stirred at -40 ° C for a further 10 minutes before the cold bath was removed and stirring was continued for 16 hours at RT. Then 50 ml of water were added and the mixture was extracted three times with approx. 25 ml of ethyl acetate each time. The combined organic extracts were washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and finally freed from the solvent on a rotary evaporator. The residue was purified by MPLC (silica gel, eluent: cyclohexane / ethyl acetate 5: 1 ⁇ 1: 1).
  • Example 95A 1- ⁇ 3 - [(3- ⁇ 3- [3-Fluoro-4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl ⁇ -5-methyl-1H-pyrazole-1 yl) methyl] phenyl ⁇ cyclopropylacetate

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Abstract

La présente invention concerne des nouveaux dérivés de 1-[3-(hydroxyalkyl)benzyl]-1H-pyrazole, leur procédé de fabrication, leur utilisation pour le traitement et/ou la prévention de maladies ainsi que leur utilisation pour la fabrication de médicaments pour le traitement et/ou la prévention de maladies, en particulier pour le traitement et/ou la prévention de maladies hyperprolifératives et angiogéniques telles que ces maladies qui sont provoquées par une adaptation métabolique à des états hypoxiques. De tels traitements peuvent avoir lieu en tant que monothérapie ou aussi en combinaison avec d'autres médicaments ou d'autres mesures thérapeutiques.
PCT/EP2011/057019 2010-05-08 2011-05-03 Hydroxyalkylbenzyle-pyrazoles et leur utilisation pour le traitement de maladies hyperprolifératives et angiogéniques WO2011141325A1 (fr)

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WO2014031928A3 (fr) * 2012-08-24 2014-05-22 Philip Jones Modulateurs hétérocycliques de l'activité du facteur hif utilisés pour le traitement de maladies
US9018380B2 (en) 2012-08-24 2015-04-28 Boar of Regents, The University of Texas System Heterocyclic modulators of HIF activity for treatment of disease
US9115120B2 (en) 2012-08-24 2015-08-25 Board Of Regents, The University Of Texas Systems Heterocyclic modulators of HIF activity for treatment of disease
US9663504B2 (en) 2014-02-25 2017-05-30 Board Of Regents, The University Of Texas System Salts of heterocyclic modulators of HIF activity for treatment of disease

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CN107235873B (zh) * 2017-07-04 2018-11-06 中节能万润股份有限公司 一种美司钠的制备方法

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WO2014031928A3 (fr) * 2012-08-24 2014-05-22 Philip Jones Modulateurs hétérocycliques de l'activité du facteur hif utilisés pour le traitement de maladies
US9018380B2 (en) 2012-08-24 2015-04-28 Boar of Regents, The University of Texas System Heterocyclic modulators of HIF activity for treatment of disease
US9115120B2 (en) 2012-08-24 2015-08-25 Board Of Regents, The University Of Texas Systems Heterocyclic modulators of HIF activity for treatment of disease
US9481692B2 (en) 2012-08-24 2016-11-01 Board Of Regents, The University Of Texas System Heterocyclic modulators of HIF activity for treatment of disease
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US11001594B2 (en) 2012-08-24 2021-05-11 Board Of Regents, The University Of Texas System Heterocyclic modulators of HIF activity for treatment of disease
US9663504B2 (en) 2014-02-25 2017-05-30 Board Of Regents, The University Of Texas System Salts of heterocyclic modulators of HIF activity for treatment of disease
US10363248B2 (en) 2014-02-25 2019-07-30 Board Of Regents, The University Of Texas System Salts of heterocyclic modulators of HIF activity for treatment of disease
US10888554B2 (en) 2014-02-25 2021-01-12 Board Of Regents, The University Of Texas System Salts of heterocyclic modulators of HIF activity for treatment of disease

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