EP2768826A1 - Substituierte oxadiazolylpyridinone und - pyridazinone als hif - hemmer - Google Patents

Substituierte oxadiazolylpyridinone und - pyridazinone als hif - hemmer

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Publication number
EP2768826A1
EP2768826A1 EP12772952.3A EP12772952A EP2768826A1 EP 2768826 A1 EP2768826 A1 EP 2768826A1 EP 12772952 A EP12772952 A EP 12772952A EP 2768826 A1 EP2768826 A1 EP 2768826A1
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EP
European Patent Office
Prior art keywords
mmol
alkyl
compound
substituted
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12772952.3A
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German (de)
English (en)
French (fr)
Inventor
Michael Härter
Hartmut Beck
Peter Ellinghaus
Kerstin Unterschemmann
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Bayer Intellectual Property GmbH
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Bayer Intellectual Property GmbH
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Priority to EP12772952.3A priority Critical patent/EP2768826A1/de
Publication of EP2768826A1 publication Critical patent/EP2768826A1/de
Withdrawn legal-status Critical Current

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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
    • C07D413/14—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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

Definitions

  • the present application relates to novel substituted 5- (l, 2,4-oxadiazol-5-yl) pyridin-2-ones and 6- (l, 2,4-oxadiazol-5-yl) pyridazin-3-ones, processes to their manufacture, their use for the treatment and / or prevention of diseases, and their use in 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 and of those diseases caused by a metabolic Adaptation to hypoxic conditions arise.
  • 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
  • Tumors of early stages 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, they are increasing in recent times Targeted therapies that block specific processes in the cell without causing high levels of toxic exposure.
  • These include in particular inhibitors of kinases which inhibit the phosphorylation of receptors and signal transduction molecules.
  • imatinib is used very successfully for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST).
  • 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 or advanced stages of GIST.
  • Bevacizumab inhibits blood vessel growth, which hinders the rapid expansion of a tumor, as 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 ).
  • HIFla protein In the major tumor entities, overexpression of the HIFla 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.
  • the object of the present invention was thus to provide novel compounds which act as potent inhibitors of the transactivating effect of the transcription factor HIF and as such can be used for the treatment and / or prevention of diseases, in particular of hyperproliferative and angiogenic diseases such as cancer and tumor 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, and in WO 2008/141731 -A2, WO 2010 / 054762- A1, WO 2010/054763-A1 and WO 2010/054764-A1 disclose heteroaryl-substituted pyrazole derivatives as inhibitors of the HIF regulation pathway for the treatment of cancers.
  • WO 03/068230-A1 and WO 2005/018557-A2 describe substituted pyridinones for the treatment of diseases which are mediated by activities of p38 MAP kinase and / or tumor necrosis factor (TNF).
  • TNF tumor necrosis factor
  • the present invention relates to compounds of the general formula (I) in which either (z) A for CR A and
  • D is CH or N or (ii)
  • R A is chlorine, cyano, nitro, amino, (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy or mono- (C 1 -C 4 ) -alkylamino, where (Ci -C4) alkyl, (Ci-C4) alkoxy and mono- (Ci-C4) -alkylamino may be substituted with hydroxyl or up to three times with fluorine, and
  • (C 3 -C 6 ) -cycloalkyl is substituted by hydroxy, hydroxy- (C 1 -C 4 ) -alkyl or (C 1 -C 4 ) -alkylcarbonyl-oxy, and in which
  • R 1 and R 2 are linked together and together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle containing another heteroatom from the series N (R 5 ), O, S or S (0 ) 2 and which may contain up to twice, the same or different, a residue selected from
  • Fluorine, cyano, (Ci-C4) alkyl, hydroxy, methoxy and ethoxy may be substituted, wherein (Ci-C 4 ) alkyl in turn may be substituted with hydroxyl or up to three times with fluorine, and wherein
  • R 5 is (C 1 -C 4 ) -alkyl which may be substituted up to three times by fluorine, or (C 3 -C 6) -cycloalkyl, (C 1 -C 4 ) -alkylcarbonyl or (C 1 -C 4 ) -alkoxycarbonyl, and R 3 and R 4 independently of one another denote hydrogen or (C 1 -C 4 ) -alkyl which is hydroxyl,
  • Methoxy, ethoxy or phenyl or may be substituted up to three times by fluorine, or
  • R 3 and R 4 are linked together and have the meanings of R 1 and R 2 , Y is CH or N,
  • Z is C-R TM or N, in which
  • R m is hydrogen, fluorine, chlorine, methyl or trifluoromethyl
  • R p is halogen, cyano, pentafluorothio, tri (C 1 -C 4 ) -alkylsilyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio, C 6 ) -alkylsulfonyl, (C 3 -C 6 ) -cycloalkyl or 4- to 6-membered
  • Heterocyclyl is where (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkoxy, (C 1 -C 6 ) -alkylthio and (C 1 -C 6 ) -alkylsulfonyl, in turn, having a radical selected from the series hydroxy, methoxy and ethoxy, and may be substituted up to sixfold with fluorine and (C3-C6) -cycloalkyl and 4- to 6-membered heterocyclyl in turn up to two times, identically or differently, with a radical selected from the group fluorine, (Ci-C i) alkyl , Trifluoromethyl, hydroxy, methoxy and ethoxy, and their salts, solvates and solvates of the salts, with the exception of the compounds 1- (4-chlorobenzyl) -5- [3- (4-methylphenyl) -1, 2 , 4-oxadiazol-5-yl]
  • Another object of the present invention is the use of a compound selected from the group consisting of
  • Compounds according to the invention or compounds which can be used according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds of the formulas below and their salts encompassed by formula (I) , Solvates and solvates of the salts and the compounds of formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), mentioned below are not already salts, Solvates and solvates of the salts.
  • the compounds according to the invention may exist in different stereoisomeric forms, ie in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in the case of 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.
  • 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 to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • 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 used 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 according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, formic Citric acid, fumaric acid, maleic acid and benzoic acid.
  • 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 1 to 16 carbon atoms, for example and preferably ethylamine, diethylamine, triethylamine, N, N-diisopropylethylamine, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, diethylaminoethanol, procaine, dicyclohexylamine, dibenzylamine, N-methylmorpholine, N-methylpiperidine, arginine, lysine and 1,2-ethylenediamine.
  • 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
  • solvates are those forms 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.
  • N-oxides of pyridyl rings and tertiary cyclic amine moieties contained in compounds of this invention are also encompassed by the present invention.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically).
  • substituents have the following meaning: (Ci-C fi VAlkyl (Ca-CfiVAlkyl fd-C ⁇ alkyl and (C ⁇ alkyl, in the context of the invention a straight-chain or branched alkyl radical having from 1 to 6, 2 to 6, 1 to 4 or 2 to 4 carbon atoms Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl.
  • Hydroxy- (C 1 -C 4 -alkyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms which carries a hydroxy group as substituent within the chain or terminally, by way of example and by preference: hydroxymethyl, 1-hydroxyethyl , 2-hydroxyethyl, 1-hydroxy-1-methylethyl, 1, 1-dimethyl-2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy-2-methylpropyl, 2-hydroxy-1-methylpropyl , 2-hydroxy-2-methylpropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl and 4-hydroxybutyl.
  • Tri- (C 1 -C 4 -alkylsilyl in the context of the invention is a silyl group having three identical or different straight-chain or branched alkyl substituents, each of which has 1 to 4 carbon atoms, by way of example and preferably: trimethylsilyl, tert-butyl dimethylsilyl and triisopropylsilyl.
  • Mono- (C 1 -C 4 -alkylamino in the context of the invention represents an amino group having a straight-chain or branched alkyl substituent which has from 1 to 4 carbon atoms, by way of example and by preference: methylamino, ethylamino, n-propylamino, isopropylamino, n- Butylamino, isobutylamino, ec -butylamino and tert -butylamino.
  • (C 1 -C 6 -alkylthio, (C 2 -C 6 -alkylthio and (C 2 -C 4 -alkylthio in the context of the invention are a straight-chain or branched alkylthio radical (also called alkylsulfanyl radical) having 1 to 6, 2 to 6 Examples of these are preferably: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, .yec.-butylthio, tert-butylthio, n-pentylthio, 2-pentylthio, 3 or Pentylthio, neopentylthio, n-hexylthio, 2-hexylthio and 3-hexylthio.
  • alkylthio radical also called alkylsulfanyl radical
  • (C 1 -C 4 -alkylcarbonyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms which has a carbonyl group [-C (0O) -] with the radical linked to the molecule.
  • Examples which may be mentioned by way of example include: acetyl, propionyl, n-butyryl, isobutyryl, n-pentanoyl and pivaloyl.
  • (C 1 -C 4 -Alkylcarbonyloxy in the context of the invention represents an oxy radical having a straight-chain or branched alkylcarbonyl substituent which has 1 to 4 carbon atoms in the alkyl radical and is linked to the O atom via the carbonyl group, by way of example and preferably: acetoxy Propionoxy, n-butyroxy, isobutyroxy, n-pentanoyloxy and pivaloyloxy.
  • C CeVAlkoxy, and (C 2 -C 4 -alkoxy in the context of the invention represent a straight-chain or branched alkoxy radical having 1 to 6, 2 to 6, 1 to 4 or 2 to 4 carbon atoms by way of example and preferably: methoxy, ethoxy, n-propoxy , Isopropoxy, n-butoxy, isobutoxy, ec-butoxy, tert -butoxy, -pentoxy, 2-pentoxy, 3-pentoxy, neopentoxy, n-hexoxy, 2-hexoxy and 3-hexoxy.
  • Examples which may be mentioned by preference include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and tert-butoxycarbonyl.
  • (C 3 -C 6 -cycloalkyl in the context of the invention is a monocyclic, saturated cycloalkyl group having 3 to 6 ring carbon atoms, by way of example and by preference: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, 4- to 6-membered heterocyclyl in the definition of the radical R p is a monocyclic, saturated heterocycle having a total of 4 to 6 ring atoms which contains one or two ring heteroatoms from the series N, O, S and / or S (O) 2 and is bonded via a ring heteroatom
  • a 4- or 5-membered heterocyclyl having a ring heteroatom from the series N or O and 6-membered heterocyclyl having one or two ring heteroatoms is selected from the group consisting of carbon atoms and optionally a ring nitrogen atom N and / or O.
  • azetidinyl oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, 1,1-dioxothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,3-thiazolide inyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl and 1,1-dioxothiomorpholinyl.
  • a 4- to 6-membered heterocycle in the definition of the radicals R 1 and R 2 is a monocyclic, saturated heterocycle having a total of 4 to 6 ring atoms, which is a ring nitrogen atom via which it is linked to the rest of the molecule, and in addition may contain a second ring heteroatom from the series N, O, S or S (0) 2 .
  • Examples include: azetidin-1-yl, pyrrolidin-1-yl, pyrazolidin-1-yl, 1, 2-oxazolidin-2-yl, l, 3-oxazolidin-3-yl, l, 3-thiazolidine-3 yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl and 1, 1-dioxideothiomorpholin- 4-yl. Preference is given to azetidin-1-yl, pyrrolidin-1-yl, 1, 2-oxazolidin-2-yl, piperidin-1-yl, piperazin-1-yl and morpholin-4-yl.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine, fluorine or bromine, more preferably fluorine or chlorine.
  • 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 identical or different substituents is preferred. Particularly preferred is the substitution with a substituent.
  • A is CR A and D is CH or N or (ii)
  • R 1 and R 2 are linked together and together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain another heteroatom from the series N (R 5 ) or O and which may be up to may be substituted twice, identically or differently, with a radical selected from the group consisting of fluorine, cyano, (C 1 -C 4) -alkyl, hydroxy, methoxy and ethoxy, where (C 1 -C 4) -alkyl in turn with hydroxy or up to three times with Fluorine may be substituted, and wherein
  • R 5 is (C 1 -C 4) -alkyl which may be substituted up to three times by fluorine, or (C 3 -C 6) -cycloalkyl, (C 1 -C 4) -alkylcarbonyl or (C 1 -C 4) -alkoxycarbonyl, and
  • R 3 and R 4 independently of one another represent hydrogen or (C 1 -C 4 ) -alkyl which may be substituted by hydroxyl, methoxy or ethoxy or up to three times by fluorine, or
  • R 3 and R 4 are linked together and have the meanings of R 1 and R 2 , Y is CH or N,
  • Z is C-R TM or N, in which
  • R m is hydrogen or fluorine
  • (C3-C6) -cycloalkyl and 4- to 6-membered heterocyclyl in turn up to twice, identically or differently, substituted by a radical selected from the group fluorine, (Ci-C i) alkyl, trifluoromethyl, hydroxy, methoxy and ethoxy their salts, solvates and solvates of salts.
  • a particular embodiment of the present invention comprises compounds of the formula (I) in which
  • R A is chlorine, cyano or (C 1 -C 12) -alkyl which may be substituted by hydroxyl or up to three times by fluorine,
  • R P is pentafluorothio, trimethylsilyl, trifluoromethyl, (C 2 -C 6 ) -alkyl, trifluoromethoxy, (C 2 -C 6 ) -alkoxy, trifluoromethylthio, (C 2 -C 6 ) -alkylthio or (C 3 -C 6 ) -cycloalkyl, where ( C 2 -C 6) -alkyl, (C 2 -C 6) -alkoxy and (C 2 -C 6) -alkylthio may in turn be substituted by one radical selected from the series hydroxy and methoxy and up to sixfold by fluorine and
  • (C3-C6) -cycloalkyl may be substituted by a radical selected from the group fluorine, methyl, trifluoromethyl, hydroxy and methoxy, and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • R A is amino or mono- (C 1 -C 4) -alkylamino which may be substituted by hydroxyl or up to three times by fluorine, and
  • D is N, and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which A is CH or N and
  • Cyclopropyl and cyclobutyl with hydroxy, hydroxy (Ci-C4) alkyl or acetoxy are substituted, and wherein R 1 and R 2 are linked together and together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain another heteroatom from the series N (R 5 ) or O and which may be up to may be substituted twice, the same or different, with a radical selected from the group fluorine, cyano, methyl, hydroxy and methoxy, wherein
  • R 5 is (Ci-C i) -alkyl, which may be substituted up to three times by fluorine, or cyclopropyl, cyclobutyl or acetyl, and
  • R 3 and R 4 independently of one another represent hydrogen or (C 1 -C 4 ) -alkyl which may be substituted by hydroxyl, methoxy or up to three times by fluorine, or
  • R 3 and R 4 are linked together and have the meanings of R 1 and R 2 , and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • R p is pentafluorothio, trimethylsilyl, trifluoromethyl, (C 2 -C 6 ) -alkyl, trifluoromethoxy, (C 2 -C 6 ) -alkoxy, trifluoromethylthio, (C 2 -C 6 ) -alkylthio or (C 3 -C 6 ) -cycloalkyl, where ( C 2 -C 6) -alkyl, (C 2 -C 6) -alkoxy and (C 2 -C 6) -alkylthio may in turn be substituted by one radical selected from the series hydroxy and methoxy and up to six times by fluorine, and
  • (C3-C6) -cycloalkyl may be substituted by a radical selected from the group fluorine, methyl, trifluoromethyl, hydroxy and methoxy, and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • Y is N
  • R p represents pentafluorothio, trimethylsilyl, trifluoromethyl, (C2-C6) alkyl, trifluoromethoxy, (C2-COE) - alkoxy, trifluoromethylthio, (C2-C 6) -alkylthio or (C 3 -C 6) -Cycloalkyl, wherein (C2-C6) alkyl, (C2-Ce) alkoxy and (C2-C6) alkylthio in turn may be substituted by a radical selected from the series hydroxy and methoxy and up to six times with fluorine, and
  • (C3-C6) -cycloalkyl may be substituted by a radical selected from the group fluorine, methyl, trifluoromethyl, hydroxy and methoxy, and their salts, solvates and solvates of the salts.
  • Another particular embodiment of the present invention comprises compounds of the formula (I) in which
  • R P is pentafluorothio, trimethylsilyl, trifluoromethyl, (C 2 -C 6 ) -alkyl, trifluoromethoxy, (C 2 -C 6 ) -alkoxy, trifluoromethylthio, (C 2 -C 6 ) -alkylthio or (C 3 -C 6 ) -cycloalkyl, where ( C 2 -C 6) -alkyl, (C 2 -C 6) -alkoxy and (C 2 -C 6) -alkylthio may in turn be substituted by one radical selected from the series hydroxy and methoxy and up to six times by fluorine, and
  • (C3-C6) -cycloalkyl may be substituted by a radical selected from the group fluorine, methyl, trifluoromethyl, hydroxy and methoxy, 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 either (z)
  • D is CH or N or (ii)
  • A is CH or N and D is CR D in which R A is (C 1 -C 4 ) -alkyl, amino or mono- (C 1 -C 4 ) -alkylamino, where (C 1 -C 4 ) -alkyl and mono- (C 1 -C 4 ) -alkyl Ci-C4) -alkylamino may be substituted with hydroxyl or up to three times with fluorine, and
  • Cyclopropyl and cyclobutyl are substituted with hydroxy, hydroxymethyl or acetoxy, and wherein
  • R 1 and R 2 are linked together and, together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocycle which may contain another heteroatom from the series N (R 5 ) or O and which a radical selected from the group cyano, methyl, hydroxy and methoxy may be substituted, wherein
  • R 5 is (Ci-C i) -alkyl, which may be substituted up to three times by fluorine, or cyclopropyl, cyclobutyl or acetyl, and
  • R 3 and R 4 independently of one another represent hydrogen or (C 1 -C 12) -alkyl which may be substituted by hydroxyl, or
  • R 3 and R 4 are linked together and have the meanings of R 1 and R 2 , Y is CH or N,
  • Z is C-R TM or N, in which
  • R m is hydrogen or fluorine
  • R p is pentafluorothio, trimethylsilyl, (C 2 -C 4) -alkyl, trifluoromethoxy, (C 2 -C 4) -alkoxy, trifluoromethylthio, (C 2 -C 4) -alkylthio, cyclopropyl or cyclobutyl, where (C 2 -C 4) -alkyl , (C 2 -C 4) -alkoxy and (C 2 -C 4) -alkylthio may be substituted by hydroxy or methoxy or up to three times by fluorine, and
  • Cyclopropyl and cyclobutyl may be substituted by a radical selected from the group fluorine, methyl, tri-fluoromethyl, hydroxy and methoxy, and their salts, solvates and solvates of the salts.
  • D is CH or N or (ii)
  • R D is CR D , wherein R A is methyl, amino, methylamino or ethylamino, and
  • R 1 and R 2 are linked together and together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycle which may contain another heteroatom from the series N (R 5 ) or O and which may have a Rest selected from the series cyano, methyl and hydroxy may be substituted, wherein
  • R 5 represents methyl, ethyl, 2,2,2-trifluoroethyl, cyclopropyl or acetyl
  • R and R independently of one another represent hydrogen or methyl or
  • R 3 and R 4 are linked together and have the meanings of R 1 and R 2 ,
  • Y is CH or N
  • R p is trifluoromethoxy, trifluoromethylthio, 1,1,1-trifluoro-2-methylpropan-2-yl or 1- (trifluoromethyl) cyclopropan-1-yl, and also their salts, solvates and solvates of the salts.
  • the present invention further provides a process for the preparation of the compounds of the formula (I) according to the invention, which comprises reacting a pyridinone or pyridazinone carboxylic acid of the formula (II)
  • X is a common leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, to give a compound of the formula (IV)
  • X represents a customary leaving group such as, for example, chlorine, bromine, iodine, mesylate, triflate or tosylate, to give the compound of the formula (I) according to the invention
  • A, D, R p , Y and Z have the abovementioned meanings, alkylating and optionally separating the compounds of the formula (I) thus obtained into their enantiomers and / or diastereomers and / or with the corresponding (i) solvents and / or or (ii) converting bases or acids into their solvates, salts and / or solvates of the salts.
  • Inert solvents for process steps (II) + (III) - > ⁇ (IV) and (VI) + (III) - > ⁇ (I) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, 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, Ethylbenzene, pentane, hexane, cyclohexane or petroleum fractions, or dipolar aprotic solvents such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (D
  • Suitable bases for process steps (II) + (III) - > ⁇ (IV) and (VI) + (III) - > ⁇ (I) are customary inorganic or organic bases. These include in particular alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali alcoholates such as sodium or potassium, sodium or potassium or sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, or alkali amides such as sodium amide, lithium diisopropylamide or lithium, sodium or potassium bis (trimethylsilyl) amide.
  • an alkylation catalyst such as lithium bromide, sodium or potassium iodide, tetra-n-butylammonium bromide or benzyltriethylammonium chloride, is advantageous.
  • the reactions are generally carried out in a temperature range from -20 ° C to + 120 ° C, preferably at 0 ° C to + 70 ° C.
  • the reactions can be carried out at normal, at elevated or at reduced pressure (for example from 0.5 to 5 bar); usually one works at normal pressure.
  • Suitable condensing agents in process steps (IV) + (V) - > ⁇ (I) and (II) + (V) -> ⁇ (VI) are carbodiimides such as NN'-diethyl, NN'-dipropyl, N , N'-diisopropyl, N, N-dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as NN'-carbonyldiimidazole (CDI) or isobutyl chloroformate, 1, 2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl
  • the condensations (IV) + (V) - > ⁇ (I) and (II) + (V) - > ⁇ (VI) are preferably carried out in a high-boiling dipolar aprotic solvent such as N, N-dimethylformamide or dimethylsulfoxide ,
  • the initial coupling step in these reactions is generally carried out in a temperature range from 0 ° C to + 50 ° C; the cyclization to 1,2,4-oxadiazole is then accomplished by subsequent heating of the reaction mixture to temperatures of + 100 ° C to + 150 ° C.
  • the reactions can be carried out at normal, at elevated or at reduced pressure (for example from 0.5 to 5 bar); usually one works at normal pressure.
  • transformations are carried out by conventional methods known to those skilled in the art and include, for example, reactions such as nucleophilic or electrophilic substitution reactions, transition metal-mediated coupling reactions (eg Ullmann or Buchwald-Hartwig reaction), addition reactions of organometallics (eg Grignard compounds or lithium organyls) to carbo - nylENSen, oxidation and reduction reactions, hydrogenation, alkylation, acylation, amination, the formation of nitriles, carboxylic acid esters and carboxylic acid amides, the ester cleavage and hydrolysis and the introduction and removal of temporary protecting groups.
  • reactions such as nucleophilic or electrophilic substitution reactions, transition metal-mediated coupling reactions (eg Ullmann or Buchwald-Hartwig reaction), addition reactions of organometallics (eg Grignard compounds or lithium organyls) to carbo - nylENSen, oxidation and reduction reactions, hydrogenation, alkylation, acylation, amination, the formation of
  • compounds of the formula (I) according to the invention can also be prepared by initially substituting other functional groups outside the scope of R A in the starting compounds of the process variants described above instead of the substituents R A , R D and / or R p , R D or R P , which are then converted by subsequent, familiar to those skilled transformations (as exemplified in the previous paragraph) into the respective substituents R A , R D and R p .
  • R A , R D and / or R p serving functional groups are radicals such as nitro, hydroxy, chlorine, bromine, methanesulfonate (mesylate), trifluoromethanesulfonate (triflate), formyl, alkylcarbonyl, hydroxy carbonyl and Alkoxycarbonyl [cf. also the production of the exemplary embodiments and their precursors described in detail in the following Experimental Part].
  • 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.
  • treatment includes controlling, inhibiting, delaying, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury, or a disease health disorder, the development, progression or progression of such conditions and / or the symptoms of such conditions.
  • therapy is understood to be synonymous with the term “treatment”.
  • prevention means the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, an unfolding or Progression of such conditions and / or to experience, suffer, or have the symptoms of such conditions.
  • the treatment or prevention of a disease, ailment, a disease, an injury or a health disorder can be partial or complete in this context.
  • the compounds according to the invention are highly potent inhibitors of the HIF regulation pathway.
  • the compounds according to the invention have an advantageous pharmacokinetic profile which makes them suitable for oral administration.
  • 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.
  • hyperproliferative diseases for the treatment of which the compounds according to the invention can be used include psoriasis, keloids, scarring and other proliferative diseases of the skin, benign disorders such as benign prostatic hyperplasia (BPH), and in particular the group of cancer and tumor diseases.
  • BPH benign prostatic hyperplasia
  • breast carcinomas and breast tumors include, but are not limited to, 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 brain stem and hypothalamus, astrocytoma, medulloblastoma, epidymymy and 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 and non
  • proliferative blood diseases in solid form and as circulating blood cells such as lymphomas, leukemias and myeloproliferative diseases, for example acute myeloid, acute lymphoblastic, chronic lymphocytic, chronic myelogenous and hairy cell leukemia, as well as AIDS-correlated lymphomas, Hodgkin's lymphoma, 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 diseases, for example acute myeloid, acute lymphoblastic, chronic lymphocytic, chronic myelogenous and hairy cell leukemia, as well as AIDS-correlated lymphomas, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma and lymphoma in the
  • 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.
  • the term "harmful expression of HIF” herein means a non-normal physiological presence of HIF protein. This may be due to excessive synthesis of the protein (due to mRNA or translation), reduced degradation or insufficient counterregulation in the function of the transcription factor.
  • HIF- ⁇ ⁇ and HIF-2a regulate more than 100 genes. This concerns proteins which play a role in angiogenesis and are therefore directly tumor-relevant, and also those which 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 cause damage like a locally slowed down Action potential, which in turn can cause arrhythmias or chronic heart failure.
  • 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.
  • HIF is one of the factors controlling the transition from an epithelial to a mesenchymal cell type, which is particularly important for the lung and kidney
  • the compounds of the invention can also be used to access HIF-associated lung and kidney fibroses prevent or curb.
  • inflammatory joint diseases such as various forms of arthritis
  • inflammatory bowel diseases such as, for example, Crohn's disease.
  • Chugwash polycythemia is mediated by HIF-2a activity during erythropoiesis in, among others, the spleen.
  • the compounds according to the invention as inhibitors of the HIF regulation 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, in-stent 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), neovascular gla
  • the present invention can also be used to treat any of the aforementioned diseases, for example 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 directs cellular processes in ⁇ -cells, liver and muscle cells and adipose tissue fat cells; HIF also has an influence on the control of body weight and plays a role, especially in type II diabetes (see Girgis et al., 2012).
  • the compounds according to the invention are therefore also suitable for the treatment of diabetes, the metabolic syndrome and pathological obesity (obesity).
  • Another object of the present invention is thus 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 counter The present invention therefore relates to medicaments containing at least one of the compounds according to the invention and one or more further active compounds, in particular for the treatment and / or prevention of the abovementioned disorders.
  • 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, but not exhaustive: aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, bleomycin, busulfan, camptothecin, carboplatin , Carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, 2 ', 2'-difluorodoxycytidine, docetaxel, doxorubicin (adriamycin), epirubicin, epothilone and its derivatives, erythro-hydroxynonyladenine, ethinyl estradiol, etoposide , Fludarabine phosphate, 5-fluorodeoxyuridine,
  • the compounds of the invention may also be combined with biological therapeutics such as antibodies (e.g., Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins which additively or synergistically enhance the effects of inhibiting HIF signaling pathway transfer.
  • biological therapeutics such as antibodies (e.g., 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 can also provide positive effects in combination with other anti-angiogenic therapies, such as Avastin, axitinib, recentin, regorafenib, sorafenib, or sunitinib.
  • Combinations with proteasome and mTOR inhibitors as well as with antihormones and steroidal metabolic enzyme inhibitors are also particularly suitable because of their favorable side effect profile.
  • the combination of compounds of the present invention with other cytostatic or cytotoxic agents can achieve the following objectives: improved efficacy in slowing down the growth of a tumor, reducing its size, or even its total elimination relative to one Single agent treatment;
  • 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- contain 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.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release 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 e.g. Soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • 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
  • Instrument Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 ⁇ , 50 mm x 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% strength formic acid; Gradient: 0.0 min 90% A - » ⁇ 0.1 min 90% A -» ⁇ 1.5 min 10% A -> 2.2 min 10% A; Flow: 0.33 ml / min; Temperature: 50 ° C; UV detection: 210 nm.
  • Device type MS Micromass Quattro Micro
  • Device type HPLC Agilent Series 1 100
  • 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% strength formic acid
  • Gradient: 0.0 min 100%) A -> ⁇ 3.0 min 10%
  • Temperature 50 ° C
  • Flow 2 ml / min
  • UV detection 210 nm.
  • Device type MS Micromass ZQ
  • Device type HPLC HP 1 100 series
  • UV DAD Column: Phenomenex Gemini 3 ⁇ , 30 mm x 3 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% strength formic acid
  • Flow 0.0 min 1 ml / min-> 2.5 min / 3.0 min / 4.5 min 2 ml / min
  • Temperature 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, 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% strength Formic acid, eluent B: 1 liter acetonitrile + 0.5 ml 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; Temperature: 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).
  • the coupling patterns of 'H-NMR signals are based on the optical appearance of the signals concerned and do not necessarily correspond a strict, physically correct interpretation.
  • the indication of the chemical shift refers to the center of the relevant signal; with wide multiplets, an interval is specified.
  • 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 1 1 - (3-Bromophenyl) -2-methylpropan-2-ol
  • Step 3 1 - [3 - (Hydroxymethyl) phenyl] -2-methylpropan-2-ol
  • Step 4 3 - (2-Hydroxy-2-methylpropyl) benzylmethanesulfonate
  • Step 4 3 - (1 - ⁇ [(Triisopropylsilyl) oxy] methyl ⁇ cyclopropyl) benzaldehyde
  • Step 5 [3 - (1 - ⁇ [(Triisopropylsilyl) oxy] methyl ⁇ cyclopropyl) phenyl] methanol
  • the aqueous phase was extracted twice with 150 ml of tert-butyl methyl ether and then acidified with 20 ml of 1 M hydrochloric acid.
  • the resulting precipitate was filtered off, washed with water and dried under high vacuum. There were thus obtained 2.66 g of a crude product (purity 86%) of which 300 mg were used directly for the preparation of the compound in Example 1 (see there).
  • the remaining 2.30 g of the crude product were purified by preparative HPLC (Method 10). From this purification, 1.54 g (22% of theory) of the title compound were obtained.
  • 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 3 1 Bromo-4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzene
  • Step 4 4- (1,1,1-trifluoro-2-methylpropan-2-yl) benzenecarbonitrile
  • Step 5 N'-hydroxy-4- (1,1-trifluoro-2-methylpropan-2-yl) benzenecarboximidamide
  • Activated zinc bromide on montmorillonite was initially prepared as follows: 7.0 g (31.1 mmol) of zinc bromide were initially charged in 225 ml of methanol in a 1 liter flask and 28.2 g of montmorillonite Kl 0 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.
  • Step 2 4- [1- (trifluoromethyl) cyclopropyl] benzonitrile
  • the crude product obtained 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 1 tert. Butyl-3 - ⁇ [tert. -butyl (diphenyl) silyl] oxy ⁇ azetidine-1-carboxylate
  • Step 2 3 - ⁇ [tert. Butyl (diphenyl) silyl] oxy ⁇ azetidine
  • Example 22A Analogously to the process described under Example 22A, from 367 mg (0.760 mmol) of the compound from Example 23A, the title compound was prepared as crude product which was used directly for further reactions.
  • the aqueous phase was extracted twice with 30 ml of ethyl acetate, and the combined organic phases were washed with 50 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (Biotage, silica gel, mobile phase cyclohexane / ethyl acetate 9: 1). After drying under high vacuum, 366 mg (62% of theory) of the title compound were obtained.
  • Example 20A Analogously to the process described under Example 20A, from 1.0 g (2.95 mmol) of the compound from Example 11A and 849 mg of the compound from Example 4A a total of 874 mg (64% of theory) of the title compound were obtained.
  • the crude product initially obtained was stirred here with pure ethyl acetate, resulting in a first fraction of the title compound of 647 mg.
  • a second fraction of 227 mg was obtained by chromatography of the evaporated mother liquor as described in Example 20A.
  • Example 30A [(2-chloropyridin-4-yl) methyl] -5- (3 - ⁇ 4- [1- (trifluoromethyl) cyclopropyl] phenyl ⁇ -1,2,4-oxadiazol-5-yl) pyridine 2 (lH) -one
  • the aqueous phase was extracted once with 100 ml of ethyl acetate, and the combined organic phases were washed once with 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was taken up in dichloromethane and purified by column chromatography (Interchim, silica gel, eluent cyclohexane / ethyl acetate 4: 1). After drying under high vacuum, 1.18 g (74% of theory) of the title compound were obtained.
  • Example 38A 3 - ⁇ [6-Oxy-3 - ⁇ 3 - [4- (1,1-trifluoro-2-methylpropan-2-yl) -phenyl] -1,2,4-oxadiazol-5-yl ⁇ pyridazine-1 (6H) -yl] methyl ⁇ benzoic acid
  • Example 29A Analogously to the method described under Example 29A, from 324 mg (1.00 mmol) of the compound from Example 14A and 288 mg (1.30 mmol) of the compound from Example 4A 292 mg (65% of theory) of the title compound were obtained.
  • the reaction time in the alkylation step here was 2 h (instead of 30 min), and the chromatographic purification of the crude product was carried out with cyclohexane / ethyl acetate 7: 3 as the eluent.
  • the aqueous phase was extracted twice with 80 ml of ethyl acetate each time, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in a mixture of trifluoroacetic acid, DMSO and methanol, filtered again and then purified by preparative HPLC (Method 13). The combined product fractions were concentrated on a rotary evaporator to a residual volume of aqueous phase and adjusted to pH 8 with saturated aqueous sodium carbonate solution. The precipitate formed was filtered off, washed with a little water and dried under high vacuum. 1 12 mg (49% of theory) of the title compound were obtained.
  • Example 8 1- (4-Aminobenzyl) -5- ⁇ 3- [4- (1,1,2-trifluoro-2-methylpropan-2-yl) phenyl] -1,4,4-oxadiazol-5-yl ⁇ - pyridine-2 (1H) -one
  • the mixture was mixed with 50 ml of water and ethyl acetate, transferred to a separatory funnel and shaken out. After phase separation, the aqueous phase was extracted twice with 50 ml of ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Method 15). The combined product fractions were concentrated to a residual volume of aqueous phase and adjusted to pH 8 with saturated aqueous sodium bicarbonate solution. After extracting twice with 50 ml of ethyl acetate each time, the combined organic phases were dried over sodium sulfate, filtered and concentrated.
  • Example 10 1 - (3 - ⁇ [2-Oxo-5- (3 - ⁇ 4- [(trifluoromethyl) sulfanyl] phenyl ⁇ -1,2,4-oxadiazol-5-yl) pyridin-1 (2H) -yl ] - methyl ⁇ phenyl) piperidine-4-carbonitrile
  • the mixture was mixed with 100 ml of water and ethyl acetate, transferred to a separatory funnel and shaken out. After phase separation, the aqueous phase was extracted twice with 70 ml of ethyl acetate, and the combined organic phases were washed once with 100 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 24 ml of THF and admixed with 2.4 ml of a 1 M solution of tetra-n-butylammonium fluoride in THF.
  • the mixture was diluted with about 50 ml of ethyl acetate and washed successively with about 50 ml of water and saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, it was filtered and the solvent removed on a rotary evaporator. The remaining residue was dissolved in 5 ml of THF and combined with 393 .mu.l (0.393 mmol) of a 1 M solution of tetra-n-butylammonium fluoride in THF. After stirring for 2 h at RT, the reaction mixture was diluted with about 5 ml of methanol and completely separated into its components by preparative HPLC (Method 16).
  • Example 28 1 - [3 - (Pyrrolidin-1-ylcarbonyl) benzyl] -5- ⁇ 3 - [4- (trifluoromethoxy) phenyl] -1,2,4-oxadiazol-5-yl ⁇ -pyridine-2 (lH) -one
  • Example 39 1 - ⁇ 3 - [(4-Cyclopropylpiperazin-1-yl) carbonyl] benzyl ⁇ -5- ⁇ 3- [4- (1,1,2-trifluoro-2-methylpropan-2-yl) -phenyl] -l, 2,4-oxadiazol-5-yl ⁇ pyridine-2 (1H) -one
  • the aqueous phase was extracted once with 40 ml of ethyl acetate, and the combined organic phases were washed once with 50 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was stirred in cyclohexane / ethyl acetate 7: 3. The solid was filtered off and washed with 4 ml of cyclohexane / ethyl acetate mixture. After drying under high vacuum, 222 mg (47% of theory) of the title compound were obtained.
  • the aqueous phase was extracted once with 30 ml of ethyl acetate, and the combined organic phases were washed once with 50 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated.
  • the residue was purified by column chromatography (Biotage, silica gel, eluent cyclohexane / ethyl acetate 1: 1). After drying under high vacuum, 396 mg (79% of theory) of the title compound were obtained.
  • Example 43 1 - ⁇ 3- [1- (Hydroxymethyl) cyclopropyl] benzyl ⁇ -5- ⁇ 3 - [4- (trifluoromethoxy) phenyl] -1,4,4-oxadiazol-5-yl ⁇ pyridine-2 (1H) -one
  • the crude product was purified by MPLC (silica gel, eluent dichloromethane / methanol 10: 1). The combined product fractions were again concentrated to dryness and the residue was then stirred with a mixture of 4 ml of pentane and 1 ml of diisopropyl ether. After filtration and drying of the solid in a high vacuum, 33 mg (23% of theory) of the title compound were obtained.
  • the aqueous phase was extracted twice with 30 ml of dichloromethane each time, and the combined organic phases were dried over sodium sulfate, filtered and concentrated.
  • the residue was purified by column chromatography (Biotage, silica gel, mobile phase cyclohexane / ethyl acetate 7: 3). After drying under high vacuum, 53 mg (24% of theory) of the title compound were obtained.
  • a mixture of 100 mg (0.223 mmol) of the compound from Example 57 and 1.8 ml (22.3 mmol) of a 70% solution of ethylamine in water was stirred for 45 min in a microwave oven at 150 ° C (Biotage initiator, with dynamic control of the irradiation power ). Then, another 1 ml of the 70% ethylamine solution in water was added, and the mixture was again stirred for 2 hours at 150 ° C in a microwave oven. Thereafter, another 1.5 ml of the 70% ethylamine solution in water was added and the mixture was stirred for a further 3 hours at 150 ° C in a microwave oven. After cooling to RT, the volatiles were removed on a rotary evaporator.

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140073634A1 (en) * 2012-08-24 2014-03-13 Institute For Applied Cancer Science/The University of Texas MD Anderson Cancer Center Heterocyclic modulators of hif activity for treatment of disease
MX2016002974A (es) 2013-09-09 2016-06-02 Peloton Therapeutics Inc Eteres de arilo y sus usos.
WO2015095048A1 (en) 2013-12-16 2015-06-25 Peloton Therapeutics, Inc. Cyclic sulfone and sulfoximine analogs and uses thereof
US9522907B2 (en) * 2014-07-07 2016-12-20 Council Of Scientific & Industrial Research Anticancer agent and process for the preparation thereof
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US10512626B2 (en) 2015-03-11 2019-12-24 Peloton Therapeautics, Inc. Compositions for use in treating glioblastoma
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WO2016144826A1 (en) 2015-03-11 2016-09-15 Peloton Therapeutics, Inc. Substituted pyridines and uses thereof
US10335388B2 (en) 2015-04-17 2019-07-02 Peloton Therapeutics, Inc. Combination therapy of a HIF-2-alpha inhibitor and an immunotherapeutic agent and uses thereof
US9796697B2 (en) 2015-06-12 2017-10-24 Peloton Therapeutics, Inc. Tricyclic inhibitors of HIF-2-alpha and uses thereof
EA038108B1 (ru) 2016-10-27 2021-07-07 Фуцзян Косантер Фармасьютикал Ко., Лтд. Пиридоновое соединение в качестве ингибитора c-met
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
CA3098336C (en) * 2018-04-26 2024-03-19 Fujian Cosunter Pharmaceutical Co., Ltd. Crystal form of c-met inhibitor and salt form thereof and preparation method therefor
LT3877376T (lt) 2018-11-06 2023-09-11 Edgewise Therapeutics, Inc. Piridazinono junginiai ir jų panaudojimas
CN113272280A (zh) 2018-11-06 2021-08-17 艾知怀斯治疗学公司 哒嗪酮化合物及其用途
WO2020097265A1 (en) 2018-11-06 2020-05-14 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
US20230101768A1 (en) * 2021-08-13 2023-03-30 The Board Of Regents Of The University Of Texas System Method to treat manganese toxicity and manganese-induced parkinsonism in humans
CN116444454B (zh) * 2023-06-16 2023-09-12 中国医学科学院医药生物技术研究所 N-羟基脒衍生物及制备方法和应用、肿瘤免疫治疗药物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008141731A2 (en) * 2007-05-18 2008-11-27 Bayer Healthcare Ag Inhibitors of hypoxia inducible factor (hif) useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
WO2009129945A1 (de) * 2008-04-23 2009-10-29 Bayer Schering Pharma Aktiengesellschaft Substituierte dihydropyrazolone als hemmer der hif-prolyl-4-hydroxylase

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1379525E (pt) * 2001-02-21 2007-12-04 Astrazeneca Ab Compostos heteropolicíclicos e sua utilização como antagonistas dos receptores metabotrópicos de glutamato
OA12771A (en) * 2002-02-14 2006-07-04 Pharmacia Corp Substituted pyridinones as modulators of P38 map kinase.
CA2530679A1 (en) 2003-06-30 2005-04-07 Hif Bio, Inc. Compounds for treating angiogenesis
NL1026826C2 (nl) 2003-08-13 2007-01-04 Pharmacia Corp Gesubstitueerde pyridinonen.
US20060189661A1 (en) * 2003-11-03 2006-08-24 Wagenen Bradford V Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
WO2007065010A2 (en) 2005-12-02 2007-06-07 Hif Bio, Inc. Anti-angiogenesis compounds
MX2010013399A (es) * 2008-06-06 2010-12-21 Abbott Lab Nuevos compuestos de 1,2,4-oxadiazol y sus metodos de uso.
DE102008057344A1 (de) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft Aminoalkyl-substituierte Aryl-Verbindungen und ihre Verwendung
EP2356113B1 (de) 2008-11-14 2015-01-07 Bayer Intellectual Property GmbH Heterocyclisch substituierte aryl-verbindungen als hif-inhibitoren
RU2011123672A (ru) 2008-11-14 2012-12-20 Байер Шеринг Фарма Акциенгезельшафт Гетероароматические соединения для применения в качестве hif ингибиторов
US20140073634A1 (en) * 2012-08-24 2014-03-13 Institute For Applied Cancer Science/The University of Texas MD Anderson Cancer Center Heterocyclic modulators of hif activity for treatment of disease

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008141731A2 (en) * 2007-05-18 2008-11-27 Bayer Healthcare Ag Inhibitors of hypoxia inducible factor (hif) useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
WO2009129945A1 (de) * 2008-04-23 2009-10-29 Bayer Schering Pharma Aktiengesellschaft Substituierte dihydropyrazolone als hemmer der hif-prolyl-4-hydroxylase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2013057101A1 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US10208059B2 (en) 2012-08-24 2019-02-19 Board Of Regents, The University Of Texas System Heterocyclic modulators of HIF activity for treatment of disease
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

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