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WO2010020366A1 - 5-aminopyrazoles à substitution azabicyclique et leur utilisation - Google Patents

5-aminopyrazoles à substitution azabicyclique et leur utilisation Download PDF

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Publication number
WO2010020366A1
WO2010020366A1 PCT/EP2009/005839 EP2009005839W WO2010020366A1 WO 2010020366 A1 WO2010020366 A1 WO 2010020366A1 EP 2009005839 W EP2009005839 W EP 2009005839W WO 2010020366 A1 WO2010020366 A1 WO 2010020366A1
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formula
methyl
hydrogen
compound
fluorine
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PCT/EP2009/005839
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German (de)
English (en)
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Lars BÄRFACKER
Raimund Kast
Nils Griebenow
Heinrich Meier
Peter Kolkhof
Barbara ALBRECHT-KÜPPER
Adam Nitsche
Johannes-Peter Stasch
Dirk Schneider
Nicole Teusch
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Bayer Schering Pharma Aktiengesellschaft
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Publication of WO2010020366A1 publication Critical patent/WO2010020366A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present application relates to novel 4-azabicyclic-substituted 5-aminopyrazoles, processes for their preparation, their use alone or in combinations for the treatment and / or prevention of diseases and their use for the preparation of medicaments for the treatment and / or prevention of diseases ,
  • Adenosine a purine nucleoside
  • Adenosine is present in all cells and is released from a variety of physiological and pathophysiological stimuli.
  • Adenosine is produced by the degradation of adenosine 5'-monophosphate (AMP) and S-adenosyl homocysteine and can be released from the cell via transporters or after cell damage.
  • Extracellular adenosine may also be produced by nuclothidase-catalyzed degradation of adenine nucleotides. Released adenosine then exerts functions as a hormone-like substance or neurotransmitter through binding to specific receptors.
  • the concentration of extracellular adenosine varies considerably and is dependent on the organ and extent of stress on the particular tissue. Thus, the extracellular concentration of adenosine increases dramatically under ischemic or hypoxic conditions. Then, adenosine generally has cytoprotective functions, e.g. Increase of the supply of oxygen or
  • adenosine is mediated by specific receptors, which are subdivided into the four previously known subtypes, Al, A2a, A2b and A3. These receptors belong to the family of G-protein coupled receptors characterized by seven transmembrane domains. While the Al and A3 receptors are coupled to Gi proteins that inhibit adenylate cyclase, resulting in a decrease in intracellular cAMP content, the A2a and A2b receptors activate adenylate cyclase via Gs proteins, resulting in an increase in intracellular cAMP. Adenosine receptors may also be coupled to other signal transmission systems, e.g. Phospholipase C. Thus, the activation of Al receptors may also lead to the stimulation of potassium channels or the inhibition of calcium channels.
  • adenosine receptor-selective ligands are those substances which bind selectively to one or more subtypes of adenosine receptors and either mimic the action of adenosine (adenosine agonists) or block its action (adenosine antagonists).
  • the aforementioned receptor selectivity can be determined by the effect of the substances on cell lines which after stable transfection with the corresponding cDNA, the respective - -
  • adenosine receptor subtypes offers a broad spectrum of therapeutic potential, such as e.g. Regulation of heart rate, contraction force and blood pressure in the cardiovascular system, regulation of renal function and respiratory system, immune system and influence on some functions of the central nervous system and cell growth (Jacobson KA and Gao Z., Adenosine receptors as therapeutic targets., Nature Reviews Drug Discovery 2006 , 5, 247-264).
  • Adenosine A1 receptors are strongly expressed in the brain (e.g., cortex, hippocampus), but also in peripheral organs and tissues such as the heart, kidney, lung or adipocyte.
  • adenosine A1 receptors play a key role in controlling the fluid and electrolyte balance.
  • Al receptors are used in the preglomerular microcirculation, in the
  • Glomerulus expressed in juxtaglomerular apparatus, as well as in the collecting tube and the Henle loop. Activation of Al receptors in the kidney causes a decrease in glomerular
  • TGF tubuloglomerular feedback mechanism
  • Plasma flux has also been demonstrated in various animal models of acute and chronic renal failure (Welch JW, Current Opinion in Pharmacology 2002, 2, 165-170; Nagashima K., Kusaka H. and Karasawa A., Protective effects of KW-3902, on adenosine Al-receptor antagonist, against cisplatin-induced acute renal failure in rats, Jpn. J.
  • Selective Al antagonists are thus suitable, inter alia, for the treatment of acutely decompensated heart failure and chronic heart failure. Furthermore, they may be used for kidney protection in nephropathy and other kidney diseases such as e.g. acute and chronic renal failure and chronic renal insufficiency.
  • WO 2004/050651, WO 2005/086656, WO 2005/112923 and WO 2007/027842 disclose variously substituted 5-aminopyrazoles for the treatment of diabetes.
  • WO 93/19054 describes arylaminopyrazoles as fungicides.
  • JP 07-285962 claims pyridyloxypyrazoles as herbicides.
  • WO 2008/008286 discloses substituted pyrazoles as Grehlin receptor antagonists for the treatment of obesity.
  • the object of the present invention is to provide novel compounds which act as potent and selective antagonists of the adenosine A1 receptor and are suitable as such for the treatment and / or prophylaxis of diseases.
  • the present invention relates to compounds of the general formula (I)
  • Q is phenyl or pyridyl
  • R 1 is hydrogen, cyano, (C r C 3 ) -alkyl, trifluoromethyl, (C 1 -C 3 ) -alkoxy or trifluoromethoxy,
  • R 2 is phenyl, naphthyl or 5- or 6-membered heteroaryl
  • phenyl, naphthyl and 5- or 6-membered heteroaryl having 1 or 2 substituents independently selected from the group halogen, cyano, (Ci-C4) -alkyl, monofluoromethyl, difluoromethyl, trifluoromethyl, (C] -C4) - Alkoxy, monofluoromethoxy, difluoromethoxy and trifluoromethoxy can be substituted,
  • R 3 is hydroxycarbonyl, aminocarbonyl, cyanoaminocarbonyl, (C 1 -C 4 ) -alkylsulfonylaminocarbonyl, oxadiazolonyl or tetrazol-5-yl,
  • R 4 is hydrogen, halogen, (C 1 -C 4 ) -alkyl, monofluoromethyl, difluoromethyl, trifluoromethyl, (C 1 -C 4 ) -alkoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy,
  • R 5 represents hydrogen, halogen, (C 1 -C 4 ) -alkyl, monofluoromethyl, difluoromethyl, trifluoromethyl, (C 1 -C 4 ) -alkoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy,
  • R 6 is a group of the formula
  • the ring U is phenyl, pyridyl, pyrimidinyl or pyrazinyl,
  • ring V 2 is a 5- to 7-membered heterocycle fused to ring U and containing at least one nitrogen atom
  • heterocycle may be substituted by 1 to 5 substituents selected from the group consisting of halogen, oxo, thiooxo, (C 1 -C 4 ) -alkyl, (C 1 -C 4 ) -alkoxy and (C 1 -C 4 ) -alkylthio,
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by 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 of the formula (I) according to the invention can be used both in pure form and as mixtures of various possible isomeric forms, in particular of stereoisomers, such as E and Z, threo and erythro, as well as optical isomers, such as R and S isomers or atropisomers, but optionally also of tautomers.
  • stereoisomers such as E and Z, threo and erythro
  • optical isomers such as R and S isomers or atropisomers
  • tautomers such as R and S isomers or atropisomers
  • the present invention encompasses all tautomeric forms.
  • 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 of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid acetic acid, trifluoroacetic acid, propi
  • 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, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, trisethanolamine, dicyclohexylamine, dimethylaminoethanol, 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 salt
  • 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.
  • the present invention also comprises prodrugs of the compounds according to the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically).
  • alkyl is a linear or branched alkyl radical having 1 to 4 or 1 to 3 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 4 or 1 to 3 carbon atoms. Examples which may be mentioned by way of example include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
  • Alkylthio in the context of the invention is a thio group having a linear or branched alkyl substituent which has 1 to 4 carbon atoms. Exemplary and preferred The following may be mentioned: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio and tert-butylthio.
  • Heterocycle is in the context of the invention for a fused to the ring U monocyclic, saturated or partially unsaturated heterocycle having a total of 5 to 7 ring atoms containing 1 to 3 ring nitrogen atoms and may contain another heteroatom from the series O or S.
  • Examples include: pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,
  • Tetrahydrotriazinyl triazinanyl, oxazinanyl, monochlorinyl, thiomorpholinyl, thiadiazinanyl, diazepanyl, dihydrodiazepinyl and tetrahydrodiazepinyl.
  • Tetrahydropyridazinyl Tetrahydropyridazinyl, tetrahydropyrimidinyl, hexahydropyrimidinyl and tetrahydrotriazinyl.
  • Heteroaryl is in the context of the invention for a monocyclic aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms containing up to three identical or different ring heteroatoms from the series N, O and / or S and via a ring carbon atom or optionally linked via a ring nitrogen atom.
  • heterocycle monocyclic aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms containing up to three identical or different ring heteroatoms from the series N, O and / or S and via a ring carbon atom or optionally linked via a ring nitrogen atom.
  • Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to fluorine or chlorine.
  • An oxo group in the context of the invention is an oxygen atom which is bonded via a double bond to a carbon atom.
  • a thiooxo group in the context of the invention represents a sulfur atom which is bonded via a double bond to a carbon atom.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly - - is. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
  • R 1 is hydrogen, cyano, methyl, ethyl or trifluoromethyl
  • R 2 is phenyl
  • phenyl having 1 or 2 substituents independently of one another may be substituted from the group fluorine, chlorine, (C 1 -C 4 ) -alkyl, trifluoromethyl, (C 1 -C 4 ) -alkoxy and trifluoromethoxy,
  • R 3 is hydroxycarbonyl or methylsulfonylaminocarbonyl
  • R 4 is hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy,
  • R 5 represents hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy,
  • R 6 is a group of the formula
  • K 1 is CR 33 or N, wherein R 33 is hydrogen, fluorine, chlorine or methyl,
  • K 2 is CR 34 or N, in which
  • R 34 is hydrogen, fluorine, chlorine or methyl
  • K 3 is CR 35A R 35B , NR 36 or O, wherein
  • R 35A is hydrogen, fluorine or methyl
  • R 35B is hydrogen, fluorine or methyl, or
  • R 35A and R 35B together form an oxo or thiooxo group
  • R 36 is hydrogen or methyl
  • K 4 is CR 37A R 37B or NR 38 wherein
  • R 37A is hydrogen, fluorine or methyl
  • R 37B is hydrogen, fluorine or methyl, or
  • R 37A and R 37B together form an oxo or thiooxo group
  • R 38 is hydrogen or methyl
  • K 5 is CR 39 or N, - - in which
  • R 39 is hydrogen, fluorine, chlorine or methyl
  • R 30 is hydrogen, fluorine, chlorine or methyl
  • R 3 ' is hydrogen or methyl
  • R 32A is hydrogen, fluorine or methyl
  • R 32B is hydrogen, fluorine or methyl
  • R 32A and R 32B together form an oxo or thiooxo group
  • R 3 is hydroxycarbonyl
  • R 4 is hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy,
  • R 5 is hydrogen or fluorine
  • R 1 is methyl
  • R 2 is phenyl, wherein phenyl may be substituted with 1 or 2 substituents independently of one another selected from the group fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy,
  • K 1 is CR 33 or N
  • R 33 is hydrogen, fluorine, chlorine or methyl
  • K 2 is CR 34 or N
  • R 34 is hydrogen, fluorine, chlorine or methyl
  • K 5 is CR 39A or N
  • R 39A represents hydrogen, (C r C4) alkyl or (C, -C 4) alkoxy;
  • R 30 is hydrogen, fluorine, chlorine or methyl
  • R 31 is hydrogen or (C r C 4) alkyl
  • R 36 is hydrogen or (C r C 4) alkyl
  • R 38 is hydrogen or (C r C 4) alkyl
  • R 39 is hydrogen, (C r C4) alkyl or (C r C 4) alkoxy,
  • R 3 is hydroxycarbonyl
  • R 4 is hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl,
  • R 5 is hydrogen or fluorine
  • R 1 is hydrogen or methyl
  • R 2 is phenyl
  • Group fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy may be substituted, - -
  • R is a group of the formula
  • K 1 is CR 33 or N
  • R 33 is hydrogen
  • K 5 is CR 39 or N
  • R 39 is hydrogen
  • R 3 is hydroxycarbonyl, - -
  • R 4 is hydrogen, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy,
  • R 5 is hydrogen or fluorine
  • R 1 is methyl
  • R 2 is a group of the formula
  • R 40 represents hydrogen, fluorine, chlorine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy,
  • R 6 is a group of the formula
  • R 33 is hydrogen, fluorine, chlorine or methyl
  • K 5 is CR 39A or N
  • R 39A is hydrogen or methyl
  • R 38 is hydrogen or methyl
  • R 2 is a group of the formula
  • R 40 is hydrogen, fluorine, chlorine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy.
  • R 2 is phenyl, wherein phenyl may be substituted with 1 or 2 substituents independently selected from the group fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy.
  • R 6 is a group of the formula
  • R 33 is hydrogen, fluorine, chlorine or methyl
  • K 5 is CR 39A or N
  • R> 3 j 9 y A A is hydrogen or methyl
  • R 38 is hydrogen or methyl.
  • Another object of the invention is a process for the preparation of compounds of the formula (I-1) according to the invention, in which R 3 is hydroxycarbonyl, characterized in that
  • X 1 is halogen, in particular bromine or iodine
  • T 1 is hydrogen or both radicals T 1 together form a -C (CH 3 ) 2 -C (CH 3 ) 2 - or -CH 2 C (CH 3 ) 2 CH 2 bridge,
  • T 2 is (C 1 -C 4 ) -alkyl
  • X 2 is halogen, preferably bromine or iodine
  • X 3 is halogen, preferably bromine or iodine, in an inert solvent in the presence of a suitable palladium catalyst with trimethylsilylacetonitrile to give a compound of the formula (DC)
  • T 3 is (C 1 -C 4 ) -alkyl
  • R 1 and R 6 each have the meanings given above, and
  • Ak + represents an alkali ion, preferably sodium
  • Suitable halogenating agents in process steps (II) ⁇ (HI-A) or (HI-B) ⁇ (VB) are elemental bromine with acetic acid, 1,3-dibromo-5,5-dimethylhydantoin and in particular N-bromosuccinimide ( ⁇ BS ), N-iodosuccinimide ( ⁇ IS), optionally with the addition of ⁇ , ⁇ '-azobis (isobutyronitrile) (AIB ⁇ ) as an initiator.
  • ⁇ BS N-bromosuccinimide
  • ⁇ IS N-iodosuccinimide
  • AIB ⁇ isobutyronitrile
  • halogenation in process steps (II) -> (III-A) or (DI-B) -> (VB) is in the use of ⁇ BS or ⁇ IS preferably in acetonitrile in a temperature range of 0 0 C to +100 0 C Practitionerm and in the use of l, 3-dibromo-5,5-dimethylhydantoin preferably in dichloromethane in a temperature range of -20 0 C to +30 0 C.
  • Inert solvents for process steps (DI-A) + (IV) ⁇ (VA) and (VB) + (IV) ⁇ (VD) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert.
  • Suitable bases for the process steps (DI-A) + (IV) ⁇ (VA) and (VB) + (IV) ⁇ (VD) are customary inorganic bases.
  • These include in particular alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali hydrogen carbonates such as sodium or potassium bicarbonate, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, or alkali hydrogen phosphates such as disodium or dipotassium hydrogencarbonate. phosphate.
  • sodium or potassium carbonate is used.
  • AIs palladium catalyst for the process steps (mA) + (IV) ⁇ (VA) and (VB) + (IV) ⁇ (VE) ["Suzuki coupling”] are, for example, palladium on activated carbon, palladium (II) acetate, Tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium ( ⁇ ) chloride and [1,1 'bis (diphenylphosphino) ferrocene] dichlo ⁇ alladium (II) - Dichloromethane complex suitable [cf. e.g. Hassan J. et al., Chem. Rev. 102, 1359-1469 (2002)].
  • the reactions (UI-A) + (IV) ⁇ (VA) and (VB) + (IV) ⁇ (VII) are generally in a temperature range from +20 0 C to +150 0 C, preferably at +50 0 C. carried out to +100 0 C.
  • Inert solvents for process steps (VA) + (VI-A) ⁇ (VII) and (II) + (VI-A) ⁇ (EI-B) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as Benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide, N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ MP), pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Preferably, toluene is used.
  • DMPU N, N'-dimethylpropyleneurea
  • ⁇ MP N-methylpyrrolidone
  • transition metal catalysts for the coupling reactions are copper catalysts such as copper (I) iodide, and palladium catalysts such as palladium on activated charcoal, bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (O), tetrakis (triphenylphosphine) palladium (0), palladium (II) acetate, bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) -palladium (II) chloride or [1, l'-bis (diphenylphosphino) -ferrocene] -palladium (II) chloride, optionally in combination with additional phosphine ligands such as (2-biphenyl) di-ter /
  • XPHOS (1-methylethyl) biphenyl-2-yl] phosphine
  • DPEphos bis (2-phenylphosphinophenyl) ether
  • xanthphos 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene
  • the process steps (VA) + (VI-A) ⁇ (VII) and (EQ + (VI-A) ⁇ (UI-B) are generally in a temperature range of +20 0 C to +200 0 C, preferably + 80 0 C to +180 0 C, optionally carried out in a microwave.
  • the reaction can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar). in general, one operates at atmospheric pressure.
  • inert solvents are for example ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using tetrahydrofuran.
  • Suitable bases for this reaction are the customary inorganic or organic bases. These include preferably alkali metal hydrides such as sodium hydride, alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal such as sodium or potassium, sodium or potassium or potassium tert-butoxide, amides such as sodium amide, lithium, sodium or potassium bis - (Trimethylsilyl) amide or lithium diisopropylamide or organometallic compounds such as butyl lithium or phenyllithium. Natrimhydrid is preferably used.
  • the process step (DX) + (X) - »(XI) is generally carried out in a temperature range from -78 ° C to + 100 0 C, preferably from -20 0 C to + 80 0 C, optionally in a microwave performed.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • reaction (XI) + (Xu) -> (V-A) is carried out, for example, under the conditions described in Sorokin V.I. et al., Chem. Heterocycl. Comp. 2003, 39, 937-942.
  • the hydrolysis of the esters of the compounds (VIT) to compounds of formula (I-1) is carried out by conventional methods by treating the esters in inert solvents with acids or bases, the salts formed in the latter by treatment with acid in the free Carboxylic acids are transferred.
  • the tert-butyl ester ester cleavage is preferably carried out with acids.
  • Suitable inert solvents for these reactions are water or the organic solvents customary for ester cleavage. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, dichloromethane, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned.
  • the usual inorganic bases are suitable. These include preferably alkali or alkaline earth hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Particularly preferred are sodium or lithium hydroxide.
  • Suitable acids for the ester cleavage are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water.
  • Hydrogen chloride or trifluoroacetic acid are preferred in the case of the tert-butyl esters and hydrochloric acid in the case of the methyl esters.
  • the Esterspaltung is generally carried out in a temperature range of 0 0 C to +100 0 C, preferably at +0 0 C to +50 0 C.
  • the reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, one works at normal pressure.
  • the compounds of the formula (II) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature [cf. e.g. WO 2004/050651 p. 18-19; Sorokin V.I. et al., Chem. Heterocycl. Comp. 2003, 39, 937-942].
  • the compounds of the formula (I) according to the invention in which R 3 is 1, 3,4-oxadiazol-2 (3H) on-5-yl can be prepared by first reacting a compound of the formula (VII) in an inert Solvent with hydrazine in a compound of formula (XIH)
  • phosgene or a phosgene equivalent such as N, N'-carbonyldiimidazole.
  • Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether are suitable as inert solvents for the first step of this reaction sequence. It is also possible to use mixtures of these solvents. Preferably, a mixture of methanol and tetrahydrofuran is used.
  • the second reaction step is preferably carried out in an ether, in particular in tetrahydrofuran.
  • the reactions are generally carried out in a temperature range of 0 0 C to +70 0 C under atmospheric pressure.
  • PG 1 stands for a protective group
  • reaction (VI-B) ⁇ (XTV) is carried out according to the methods known to the person skilled in the art [cf. e.g. Iwao M., Kurashi T., J. Heterocycl. Chem. 1979, 16, 689-698].
  • Suitable protective groups PG 1 in the reaction (XIV) -> (XV) are, for example, allyl, trityl, 2-nitrobenzyl, 2-trimethylsilylethoxymethyl (SEM), 2-cyanoethyl, methoxybenzyl, dimethoxybenzyl and trimethoxybenzyl [cf. eg Weller HN et al., Heterocycles 1993, 36, 1027-1038].
  • SEM 2-trimethylsilylethoxymethyl
  • 2-cyanoethyl methoxybenzyl, dimethoxybenzyl and trimethoxybenzyl
  • the cleavage of the protective groups in the reaction (XV) ⁇ (1-2) takes place according to the methods known to the skilled person [cf. Green TW, Wuts PGM, Protective Groups in Organic Synthesis, 3rd ed., John Wiley and Sons, 1999].
  • the compounds of the formula (I) according to the invention in which R 3 is tetrazol-5-yl can be prepared by converting a compound of the formula (VI-B) into a compound of the formula (XVI) by methods known from the literature.
  • PG 2 stands for a protective group
  • Suitable protective groups PG 2 in the reaction (XVI) ⁇ (XVII-A) or (XVII-B) are, for example, allyl, trityl, 2-nitrobenzyl, 2-trimethylsilylethoxymethyl (SEM), 2-cyanoethyl, methoxybenzyl, dimethoxybenzyl and trimethoxybenzyl [see. eg Kerdesky FAJ, Synth. Commun. 1996, 26, 1007-1013].
  • SEM 2-trimethylsilylethoxymethyl
  • the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and / or treatment of various diseases and disease-related conditions in humans and animals.
  • the compounds according to the invention are potent, selective adenosine A1 receptor antagonists which inhibit adenosine activity in vitro and in vivo.
  • adenosine A1 receptor selective ligands refers to those adenosine receptor ligands in which, on the one hand, a marked effect on the Al adenosine receptor and, on the other hand, no or a significantly weaker effect (factor 10 or higher) on A2a , A2b and A3 adenosine receptor subtypes, with respect to the test methods for the selectivity of activity referred to in the section BI. described tests.
  • the compounds according to the invention are particularly suitable for the prophylaxis and / or treatment of cardiovascular diseases.
  • the target indications are exemplified and preferably named: acute and chronic heart failure, acutely decompensated heart failure, arterial hypertension, coronary heart disease, stable and unstable angina pectoris, myocardial ischemia, myocardial infarction, shock, arteriosclerosis, atrial and ventricular arrhythmias, transient and ischemic attacks , Stroke, inflammatory cardiovascular diseases, peripheral and cardiovascular diseases, peripheral circulatory disorders, arterial pulmonary hypertension, spasms of the coronary arteries and peripheral arteries, thrombosis, thromboembolic disorders, edema formation such as pulmonary edema, cerebral edema, renal edema or congestive heart failure edema, and restenosis such as after thrombolytic therapies, percutaneous transluminal angioplasties (PTA), transluminal coronary angioplasties (PTCA), heart transplants and bypass operations
  • cardiac failure also encompasses more specific or related forms of disease such as right heart failure, left heart failure, global insufficiency.
  • - - Ciency ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, valvular heart failure, valvular heart failure, mitral stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined valvular heart failure, myocarditis, chronic Myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure and systolic heart failure.
  • the compounds of the invention are suitable for use as a diuretic for the treatment of edema and in electrolyte disorders, especially in the hypervolemic and euvolämischen hyponatremia.
  • the compounds according to the invention are also suitable for the prophylaxis and / or treatment of polycystic kidney disease (PCKD) and of the syndrome of inadequate ADH secretion (SIADH).
  • PCKD polycystic kidney disease
  • SIADH syndrome of inadequate ADH secretion
  • kidney diseases in particular renal insufficiency, as well as acute and chronic kidney failure.
  • renal insufficiency encompasses both acute and chronic manifestations of renal insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, obstructive uropathy, glomerulonephritis, acute glomerulonephritis, tubulo-interstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis toxic substances induced nephropathy, diabetic nephropathy, pyelonephritis, renal cysts and nephrosclerosis, which are diagnostically characterized by, for example, abnormally decreased creatinine and / or water excretion, abnormally increased blood concentrations of urea, nitrogen, potassium and / or creatinine, altered activity of renal enzymes such as glutamyls
  • the present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
  • sequelae of renal insufficiency such as pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
  • the compounds of the invention may be useful for the prophylaxis and / or treatment of cirrhosis of the liver, ascites, diabetes mellitus, and diabetic sequelae, e.g. Neuropathy can be used.
  • the compounds according to the invention are suitable for the prophylaxis and / or treatment of central nervous disorders such as anxiety and depression, glaucoma and cancer, in particular lung tumors.
  • COPD chronic obstructive pulmonary diseases
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • the present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of acutely decompensated and chronic heart failure, hypervolemic and euphermal hyponatremia, liver cirrhosis, ascites, edema, nephropathy, acute and chronic renal failure, renal insufficiency and the syndrome of inadequate ADH secretion (SIADH).
  • SIADH inadequate ADH secretion
  • 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 prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • the compounds of the invention may be used alone or as needed in combination with other agents.
  • Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more further active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • Suitable combination active ingredients for this purpose are by way of example and preferably mentioned: - -
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-I, and inhaled NO;
  • Diuretics especially loop diuretics and thiazides and thiazide-like diuretics
  • Positive inotropic compounds such as cardiac glycosides (digoxin), beta adrenergic and dopaminergic agonists such as isoproterenol, epinephrine, norepinephrine, dopamine and dobutamine;
  • cGMP cyclic guanosine monophosphate
  • cAMP cyclic adenosine monophosphate
  • PDE phosphodiesterases
  • sildenafil sildenafil
  • Vardenafil tadalafil
  • PDE 3 inhibitors such as amrinone and milrinone
  • Natriuretic peptides e.g. atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP, Nesiritide), C-type natriuretic peptide (CNP) and urodilatin;
  • ABP atrial natriuretic peptide
  • BNP B-type natriuretic peptide
  • CNP C-type natriuretic peptide
  • urodilatin urodilatin
  • Calcium sensitizers such as by way of example and preferably levosimendan
  • Guanylate cyclase NO- and heme-independent activators in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;
  • NO-independent, but heme-dependent guanylate cyclase stimulators such as, in particular, the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;
  • Antagonists of vasopressin receptors such as Conivaptan, Tolvaptan, RWJ-676070 or RWJ-351647;
  • HNE human neutrophil elastase
  • the signal transduction cascade inhibiting compounds such as tyrosine kinase inhibitors, in particular sorafenib, imatinib, Gef ⁇ tinib and erlotinib;
  • Compounds affecting the energy metabolism such as, for example and preferably, etomoxir, perhexiline, dichloroacetate, ranolazine or trimetazidine;
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;
  • Anti-hypertensive agents by way of example and with preference from the group of calcium antagonists, angiotensin AH antagonists, ACE inhibitors, vasopeptidase inhibitors, inhibitors of neutral endopeptidase, endothelin antagonists, renin inhibitors, alpha-
  • Receptor blockers beta-receptor blockers, mineralocorticoid receptor antagonists and rho-kinase inhibitors; and or
  • Lipid metabolism-altering agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, CETP
  • Inhibitors MTP inhibitors, PPAR-alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein (a) antagonists.
  • the compounds according to the invention are administered in combination with a diuretic, such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, chlorthalidone, indapamide, metolazone, quineth- azon, acetazolamide, dichlo ⁇ henamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.
  • a diuretic such as by way of example and preferably furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, t
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor such as, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.
  • the compounds according to the invention are administered in combination with a GPUb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab. - -
  • the compounds according to the invention are used in combination with a factor Xa inhibitor such as, by way of example and preferably, roxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD No. 3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • roxaban BAY 59-7939
  • DU-176b apixaban
  • otamixaban otamixaban
  • fidexaban fidexaban
  • razaxaban fondaparinux
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AH antagonists, ACE inhibitors, vasopeptidase inhibitors, inhibitors of neutral endopeptidase, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta Receptor blockers, mineralocorticoid receptor antagonists, Rho kinase inhibitors, prostanoid IP receptor agonists and diuretics understood.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an angiotensin Aü antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.
  • angiotensin Aü antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embusartan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with a vasopeptidase inhibitor or inhibitor of neutral endopeptidase (NEP), such as by way of example and preferably omapatrilate or AVE-7688.
  • NEP neutral endopeptidase
  • the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • a renin inhibitor such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
  • the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, Carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucine dolol administered.
  • a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolol
  • the compounds of the invention are administered in combination with a mineralocorticoid receptor antagonist such as, by way of example and by way of preference, spironolactone, eplerenone, canrenone or potassium canrenoate.
  • a mineralocorticoid receptor antagonist such as, by way of example and by way of preference, spironolactone, eplerenone, canrenone or potassium canrenoate.
  • the compounds according to the invention are used in combination with a rho-kinase inhibitor, such as, for example and preferably, Faslyil, Y-27632, SAR407899, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.
  • a rho-kinase inhibitor such as, for example and preferably, Faslyil, Y-27632, SAR407899, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.
  • the compounds according to the invention are administered in combination with an agonist of the prostanoid IP receptor, such as, for example and preferably, iloprost, treprostinil, beraprost or NS-304.
  • an agonist of the prostanoid IP receptor such as, for example and preferably, iloprost, treprostinil, beraprost or NS-304.
  • lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha- , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR alpha- , PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers bile acid rea
  • the compounds according to the invention are administered in combination with a CETP inhibitor, such as, for example and preferably, torcetrapib (CP-529 414), JJT-705, BAY 60-5521, BAY 78-7499 or CETP vaccine ( Avant).
  • a CETP inhibitor such as, for example and preferably, torcetrapib (CP-529 414), JJT-705, BAY 60-5521, BAY 78-7499 or CETP vaccine ( Avant).
  • the compounds according to the invention are administered in combination with a thyroid receptor agonist, such as by way of example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist such as by way of example and preferably D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin ,
  • an HMG-CoA reductase inhibitor from the class of statins, by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin ,
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds of the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • the compounds according to the invention are administered in combination with a PPAR-delta agonist, such as by way of example and preferably GW-501516 or BAY 68-5042.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • a lipase inhibitor such as, for example and preferably, orlistat.
  • the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • ASBT IBAT
  • AZD-7806 S-8921
  • AK-105 AK-105
  • BARI-1741 AK-105
  • SC-435 SC-635.
  • the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • 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.
  • 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
  • parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments 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 patches), 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 for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecy
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • UV ultraviolet spectrometry v / v volume-to-volume ratio (of a mixture) - -
  • 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 5O 0 C
  • UV detection 210 nm.
  • Method 3 Device Type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2.5 ⁇ MAX-RP 100A Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 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.
  • Instrument Micromass GCT, GC6890; Column: Restek RTX-35, 15 m ⁇ 200 ⁇ m ⁇ 0.33 ⁇ m; constant flow with helium: 0.88 ml / min; Oven: 70 ° C; Inlet: 250 ° C; Gradient: 70 0 C, 30 ° C / min -> 310 0 C (hold for 3 min).
  • 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% formic acid
  • eluent B 1 l of acetonitrile + 0.5 ml of 50% formic acid
  • UV detection 210 nm.
  • Example 5A Under an argon atmosphere 850 mg (2.97 mmol) of Example 5A in 15 ml of abs. Dioxane solved. There were 525 mg (5.35 mmol) of potassium acetate, 194 mg (0.238 mmol) of l, r-bis (diphenylphosphino) ferrocenepalladium ( ⁇ ) chloride-dichloromethane complex and 830 mg (3.7 mmol) of 4,4,4 ', 4' , 5,5,5 ', 5'-octamethyl-2,2'-bi-l, 3 > 2-dioxaborolane added. Then it was over - -
  • Tetrakis (triphenylphosphine) palladium (0) The mixture was reacted at 110 ° C. overnight. After cooling, it was poured onto water and extracted with ethyl acetate (3x). The combined organic phases were dried with magnesium sulfate. It was then concentrated on a rotary evaporator under reduced pressure. The residue was purified by preparative HPLC (eluent: acetonitrile / water, gradient 10:90 ⁇ 90:10). There were obtained 110 mg (92% of theory) of the target compound.
  • the reaction was diluted with dichloromethane and filtered through a bed of diatomaceous earth and silica gel. It was then washed with ethyl acetate. The volatile components were dried under high vacuum. There was obtained 600 mg of raw material. The material thus obtained was used without further work-up steps. The following reactions were based on a 70% content of target compound.
  • Example 25A Under an argon atmosphere, 110 mg (0.46 mmol) Example 25A was dissolved in 8 ml dioxane. Then, 135 mg (1.38 mmol) of potassium acetate, 30 mg (0.037 mmol) of 1,1-bis (diphenylphosphino) ferrocenepalladium ( ⁇ ) chloride-dichloromethane complex and 129 mg
  • Cells of the permanent line CHOKl (Chinese hamster ovary) are stably transfected with a reporter construct (CRE-luciferase) and the cDNA for the adenosine receptor subtypes A2a or A2b.
  • A2a and A2b receptors are coupled to the adenylate cyclase via G ⁇ s proteins. Receptor activation activates adenylate cyclase, thereby increasing the cAMP level in the cell.
  • a cAMP-dependent promoter the change of the cAMP level is coupled to the luciferase expression.
  • CHO Kl cells are also stably transfected, this time with a Ca 2+ -sensitive reporter construct (NFAT-TA-Luc, Clontech) and an Al-G ⁇ l6 fusion construct.
  • This receptor chimera is coupled to the phospholipase C in contrast to the native Al receptor (G ⁇ i coupling).
  • the luciferase is expressed here as a function of the cytosolic Ca 2+ concentration.
  • the permanent cell lines are cultured in DMEM / F12 (Cat. No BE04-687Q, BioWhittaker) with 10% FCS (Fetal Calf Serum) and various additives (20 ml / liter IM HEPES (Cat. No 15630, Gibco), 20 ml / Liter of GlutaMAX (Cat. No. 35050-038, Gibco), 14 ml / liter MEM sodium pyruvate (Cat. No 11360-039; Gibco), 10 ml / liter PenStrep (Cat. No 15070-063, Gibco) Cultured at 37 ° C under 5% carbon dioxide and split twice a week.
  • FCS Fetal Calf Serum
  • the cells are seeded at 2000 and 5000 cells / well in 25 and 50 .mu.l / well sowing medium and until substance testing at 37 ° C. - 1 - cultured under 5% carbon dioxide.
  • the A2a and A2b cells are seeded 24 h prior to substance testing in medium supplemented with 5% FCS, using the A2a cells as the basic medium DMEM / F12 and for the A2b cells OptiMEM (Cat. No 31985-047; Gibco) is used.
  • the Al-G ⁇ l6 cells are seeded 48 hours before substance testing in OptiMEM with 2.5% dialysed or activated carbon-treated FCS and additives.
  • the substances are added to a final concentration of 1 x 10 "5 M to 1 x 10 ⁇ u M to the test cultures, the DMSO content not exceeding on the cells 0.5%.
  • the agonist is for the A2a and A2b cells NECA (5-N-Ethylcarboxamido-adenosine) in a final concentration of 30 nM, which corresponds approximately to the EC 50.
  • NECA 5-N-Ethylcarboxamido-adenosine
  • NECA N-Ethylcarboxamido-adenosine
  • Al-G ⁇ l6 cells 25 nM CPA (N6-cyclopentyl-adenosine) is used as an agonist
  • the cell plates are incubated for 3-4 h at 37 ° C.
  • a solution consisting of 50% lysis reagent directly before the measurement 30 mM disodium hydrogen phosphate, 10% glycerol, 3% Triton X-100, 25 mM TrisHCl, 2 mM dithiothreitol (DTT), pH 7.8) and 50% luciferase substrate solution (2.5 mM ATP, 0.5 mM luciferin, 0.1 mM Coenzyme A, 10 mM Tricine, 1.35 mM magnesium sulfate, 15 mM DTT, pH 7.8) t is detected by a luminescence reader.
  • IC 5 o values ie the concentration at which the luciferase response caused by the respective agonist is inhibited to 50%.
  • the reference antagonist used is ZM241385 for the A2a and A2b cells and DPCPX (1,3-dipropyl-8-cyclopentylxanthine) for the Al-G ⁇ l6 cells.
  • the permanent cell lines are transfected into DMEM / F12 Glutamax (Cat. No 31331-028; Gibco) with 10% FCS (Fetal Calf Serum) and various additives (10 ml / liter IM HEPES (Cat. No 15630, Gibco), 14 ml / liter of MEM sodium pyruvate (Cat. No. 11360-039; Gibco) at 37 ° C under 5% carbon dioxide and split twice a week.
  • FCS Fetal Calf Serum
  • the cells are seeded at 2000 and 5000 cells / well in 25 and 50 .mu.l / well test medium (OptiMEM Glutamax with 2.5% charcoal-treated FCS, Hyclone) and up to substance testing at 37 ° C below 5% - -
  • the A2a and A2b cells are seeded 24 hours prior to substance testing in OptiMEM with 2.5% charcoal-treated FCS (Hyclone).
  • the Al-G ⁇ l6 cells are seeded 48 hours before substance testing in OptiMEM glutamax with 2.5% charcoal-treated FCS and additives.
  • the substances are added to a final concentration of 1 x 10 -5 M to 1 x 10 '11 M to the test cultures, the DMSO content not exceeding 0.5% of the cells.
  • the agonist used for the A2a and A2b cells is NECA (5-N-ethylcarboxamidoadenosine) in a final concentration of 30 nM, which corresponds approximately to the ECso concentration.
  • CPA N6-cyclopentyl-adenosine
  • agonist N6-cyclopentyl-adenosine
  • the cell plates are incubated for 3-4 h at 37 ° C. under 5% carbon dioxide.
  • the cells are then immediately before the measurement with 50 .mu.l of a solution consisting of 50% lysis reagent (Triton buffer, PAA Cat.No T21-160) and 50% luciferase substrate solution (2.5 mM ATP, 0.5 mM Luciferin, 0.1mM coenzyme A, 10mM tricine, 1.35mM magnesium sulfate, 15mM DTT, pH 7.8).
  • 50% lysis reagent Triton buffer, PAA Cat.No T21-160
  • luciferase substrate solution 2.5 mM ATP, 0.5 mM Luciferin, 0.1mM coenzyme A, 10mM tricine, 1.35mM magnesium sulfate, 15mM DTT,
  • the luciferase activity is detected with a luminescence reader.
  • the IC 50 values are determined, ie the concentration at which the luciferase response caused by the respective agonist is inhibited to 50%.
  • the IC 50 values are calculated using the computer program GraphPad PRISM (version 3.02).
  • the reference antagonist used is ZM241385 for the A2a and A2b cells and DPCPX (1,3-dipropyl-8-cyclopentylxanthine) for the Al-G ⁇ l6 cells.
  • the plates are washed with binding buffer mixed with 0.1% bovine serum albumin and then dried at 40 0 C overnight. Thereafter, liquid scintillator (Ultima Gold, Perkin Elmer) is added and the radioactivity remaining in the plates is measured in liquid scintillation counter (Microbeta, Wallac).
  • Non-specific binding is defined as radioactivity in the presence of 1 ⁇ M DPCPX (Sigma) and is typically ⁇ 25% of the total bound radioactivity.
  • the binding data (IC50 and dissociation constant Ki) are determined by means of the program GraphPad Prism Version 1 4.0.
  • a commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA is used for the blood pressure measurement on awake rats described below.
  • the system consists of 3 main components:
  • Implantable Transmitter Physiotel® Telemetry Transmitter
  • Receiver Physiotel® Receiver
  • multiplexer DSI Data Exchange Matrix
  • the telemetry system allows a continuous recording of blood pressure heart rate and body movement on awake animals in their habitual habitat.
  • the experimental animals are kept individually in Makrolon cages type 3 after transmitter implantation. You have free access to standard food and water.
  • the day - night rhythm in the experimental laboratory is changed by room lighting at 6:00 in the morning and at 19:00 in the evening.
  • the TAH PA - C40 telemetry transmitters are surgically implanted into the experimental animals under aseptic conditions at least 14 days before the first trial.
  • the animals so instrumented are repeatedly used after healing of the wound and ingrowth of the implant.
  • the fasting animals are anesthetized with pentobabital (Nembutal, Sanofi: 50 mg / kg i.p.) and shaved and disinfected on the ventral side.
  • pentobabital Nembutal, Sanofi: 50 mg / kg i.p.
  • the system's liquid-filled measuring catheter above the bifurcation is inserted cranially into the descending aorta and secured with tissue adhesive (VetBonD TM, 3M).
  • the transmitter housing is fixed intraperitoneally to the abdominal wall musculature and the wound is closed in layers.
  • an antibiotic is administered for infection prevention (Tardomyocel COMP Bayer 1ml / kg s.c.)
  • a solvent-treated group of animals is used as a control.
  • the existing telemetry measuring device is configured for 24 animals. Each trial is registered under a trial number (VYear month day).
  • the instrumented rats living in the plant each have their own receiving antenna (1010 receivers, DSI).
  • the implanted transmitters can be activated externally via a built-in magnetic switch. They will be put on the air during the trial run.
  • the emitted signals can be recorded online by a data acquisition system (Dataquest TM A.R.T. for Windows, DSI) and processed accordingly. The storage of the data takes place in each case in a folder opened for this purpose which carries the test number.
  • the measured value acquisition is repeated computer-controlled in 5-minute intervals.
  • the absolute value of the source data is corrected in the diagram with the currently measured barometric pressure (Ambient Pressure Reference Monitor, APR-I) and stored in individual data. Further technical details can be found in the extensive documentation of the manufacturer (DSI).
  • test substances will take place at 9 o'clock on the day of the experiment. Following the application, the parameters described above are measured for 24 hours.
  • the collected individual data are sorted with the analysis software (DATAQUEST TM A.RT. TM ANALYSIS).
  • the blank value is assumed to be 2 hours before the application, so that the selected data record covers the period from 7:00 am on the test day to 9:00 am on the following day.
  • the data is smoothed over a presettable time by averaging (15 minutes average) and transferred as a text file to a disk.
  • the presorted and compressed measured values are transferred to Excel templates and displayed in tabular form.
  • the filing of the collected data takes place per experiment day in a separate folder that bears the test number. Results and test reports are sorted in folders and sorted by paper.
  • Wistar rats (200-400 g body weight) are kept with free access to food (Altromin) and drinking water. During the experiment, the animals are kept individually for 4 hours in metabolic cages suitable for rats of this weight class (Tecniplast GmbH, D-82383 Hohenpeissenberg) with free access to drinking water.
  • the substance to be tested is administered in a volume of 1 to 2 ml / kg body weight of a suitable solvent orally by gavage into the stomach, or administered intravenously. Animals serving as control receive only solvents via the corresponding route of administration. Controls and substance testing are done in parallel on the same day. Control groups and substance dose groups each consist of 4 to 8 animals.
  • the urine excreted by the animals is continuously collected in a container on the floor of the cage.
  • the urine volume per unit of time is determined separately for each animal, and the concentration of the sodium or potassium ions excreted in the urine is measured by means of standard flame photometric methods.
  • a defined amount of water is supplied to the animals at the beginning of the experiment by gavage (typically 10 ml per kg of body weight).
  • gavage typically 10 ml per kg of body weight.
  • Wistar rats (200-320 g body weight) are kept with free access to feed (Altromin) and drinking water.
  • feed Altromin
  • drinking water In each experiment in age-matched rats in mild ether anesthesia by intramuscular injection of a glycerol-water mixture (volume mixing ratio - -
  • a control collective of rats of the same age is examined simultaneously, which at the same time receive ether anesthesia and solvents but no intramuscular glycerol injection.
  • the rats are kept individually in metabolic cages after substance administration or solvent administration (Tecniplast GmbH, D-82383 Hohenpeissenberg).
  • the urine is collected on the 1st and 2nd day after glycerol injection over a period of 24 hours.
  • sodium, potassium, uric acid and creatinine are determined.
  • the blood for the determination of urea, creatinine, uric acid and sodium takes place at the end of the urinary period by retroorbital puncture under mild ether anesthesia, or by cardiac puncture (48 hours after glycerol injection).
  • Sodium or potassium ions The determination of the sodium and potassium ions is measured by standard flame photometric methods. Creatinine, urea and uric acid are determined by standard enzymatic and biochemical methods.
  • the detection of the kidney-protective effect of the test substances is carried out in rats with 5/6 nephrectomy (chronic renal failure). These rats are characterized by glomerular hyperfiltration and the development of progressive renal failure leading to end-stage renal disease and hypertension-induced left ventricular hypertrophy and cardiac fibrosis.
  • different groups are compared: a sham-operated control group, a group with 5/6 nephrectomy and groups treated with test substances with 5/6 nephrectomy.
  • the test substances are administered orally. Renal failure due to 5/6 nephrectomy is induced by complete removal of the right kidney and after two more weeks by ligation of the upper and lower third of the remaining kidney.
  • rats develop progressive renal failure (decrease in GFR) with proteinuria and hypertension.
  • the heart is characterized by uremic hypertensive heart disease. Without treatment, rats will die of end-stage or end-stage renal disease between week 19 and 26 - -
  • the serum concentrations of glucose, CrP C-reactive peptide
  • ALAT alanine aminotransferase
  • ASAT aspartate aminotransferase
  • potassium, sodium, calcium, phosphate, urea and creatinine are determined with assay kits in an automatic analyzer.
  • Protein concentrations in urine and serum are determined using a pyrogallol red molybdate complex reagent in an automatic analyzer.
  • the glomerular filtration rate is calculated using creatinine clearance.
  • Systolic blood pressure and heart rate are measured by plethysmography with a tail cuff on awake rats. Body weight is measured weekly. Plasma renin activity and aldosterone in urine are determined by commercially available radioimmunoassays.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • a single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h. - 1 -
  • the compound according to the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
  • the compound of the invention is dissolved in a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%).
  • a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

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  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention porte sur de nouveaux 5-aminopyrazoles à substitution 4-azabicyclique, sur des procédés pour les préparer, sur leur utilisation à titre individuel ou en combinaison pour le traitement et/ou la prévention de maladies, ainsi que sur leur utilisation pour fabriquer des médicaments destinés au traitement et/ou à la prévention de maladies.
PCT/EP2009/005839 2008-08-21 2009-08-12 5-aminopyrazoles à substitution azabicyclique et leur utilisation WO2010020366A1 (fr)

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DE102008039082A DE102008039082A1 (de) 2008-08-21 2008-08-21 Azabicyclisch-substituierte 5-Aminopyrazole und ihre Verwendung

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US8754085B2 (en) 2010-07-14 2014-06-17 Novartis Ag Pyrido[2,3-b]pyrazine compounds useful as IP receptor agonist
US8937069B2 (en) 2012-01-13 2015-01-20 Novartis Ag Substituted pyrrolo[2,3-B]pyrazine compounds and their use
US9061030B2 (en) 2010-11-09 2015-06-23 Ironwood Pharmaceuticals, Inc. sGC stimulators
US9139564B2 (en) 2011-12-27 2015-09-22 Ironwood Pharmaceuticals, Inc. 2-benzyl, 3-(pyrimidin-2-yl) substituted pyrazoles useful as sGC stimulators
CN105418525A (zh) * 2015-12-16 2016-03-23 郑州轻工业学院 一种n-取代1,2,3-苯并三嗪-4-酮的制备方法
US9604981B2 (en) 2013-02-13 2017-03-28 Novartis Ag IP receptor agonist heterocyclic compounds
WO2018161876A1 (fr) * 2017-03-08 2018-09-13 中国科学院上海药物研究所 Inhibiteur de protéine de reconnaissance de bromodomaine dihydroquinoxaline, son procédé de préparation et son utilisation
WO2024125464A1 (fr) * 2022-12-11 2024-06-20 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Dérivés de tétrahydroisoquinoléinone, leurs procédés de préparation et leurs utilisations médicinales

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KR101813931B1 (ko) 2010-06-30 2018-01-02 아이언우드 파마슈티컬스, 인코포레이티드 Sgc 자극제
US10189809B2 (en) 2010-06-30 2019-01-29 Ironwood Pharmaceuticals, Inc. SGC stimulators
WO2012003405A1 (fr) * 2010-06-30 2012-01-05 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
EA026692B1 (ru) * 2010-06-30 2017-05-31 Айронвуд Фармасьютикелз, Инк. Стимуляторы sgc
EP3173407A1 (fr) * 2010-06-30 2017-05-31 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
US8754085B2 (en) 2010-07-14 2014-06-17 Novartis Ag Pyrido[2,3-b]pyrazine compounds useful as IP receptor agonist
US9132127B2 (en) 2010-07-14 2015-09-15 Novartis Ag Substituted pyrido[2,3-B]pyrazines as IP receptor agonists
US9061030B2 (en) 2010-11-09 2015-06-23 Ironwood Pharmaceuticals, Inc. sGC stimulators
US9139564B2 (en) 2011-12-27 2015-09-22 Ironwood Pharmaceuticals, Inc. 2-benzyl, 3-(pyrimidin-2-yl) substituted pyrazoles useful as sGC stimulators
US8937069B2 (en) 2012-01-13 2015-01-20 Novartis Ag Substituted pyrrolo[2,3-B]pyrazine compounds and their use
US9073932B2 (en) 2012-01-13 2015-07-07 Novartis Ag Substituted pyrrolo[2,3-B]pyrazines for the treatment of disorders and diseases
US9604981B2 (en) 2013-02-13 2017-03-28 Novartis Ag IP receptor agonist heterocyclic compounds
CN105418525A (zh) * 2015-12-16 2016-03-23 郑州轻工业学院 一种n-取代1,2,3-苯并三嗪-4-酮的制备方法
WO2018161876A1 (fr) * 2017-03-08 2018-09-13 中国科学院上海药物研究所 Inhibiteur de protéine de reconnaissance de bromodomaine dihydroquinoxaline, son procédé de préparation et son utilisation
CN108570038A (zh) * 2017-03-08 2018-09-25 中国科学院上海药物研究所 二氢喹喔啉类溴结构域识别蛋白抑制剂及制备方法和用途
US11078188B2 (en) 2017-03-08 2021-08-03 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Dihydroquinoxaline bromodomain recognition protein inhibitor, preparation method and use thereof
CN108570038B (zh) * 2017-03-08 2021-09-28 中国科学院上海药物研究所 二氢喹喔啉类溴结构域识别蛋白抑制剂及制备方法和用途
WO2024125464A1 (fr) * 2022-12-11 2024-06-20 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Dérivés de tétrahydroisoquinoléinone, leurs procédés de préparation et leurs utilisations médicinales

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