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US20140357637A1 - Substituted annulated pyrimidines and triazines, and use thereof - Google Patents

Substituted annulated pyrimidines and triazines, and use thereof Download PDF

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Publication number
US20140357637A1
US20140357637A1 US14/371,046 US201314371046A US2014357637A1 US 20140357637 A1 US20140357637 A1 US 20140357637A1 US 201314371046 A US201314371046 A US 201314371046A US 2014357637 A1 US2014357637 A1 US 2014357637A1
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methyl
alkyl
group
compound
substituted
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Inventor
Markus Follmann
Johannes-Peter Stasch
Gorden Redlich
Nils Griebenow
Dieter Lang
Frank Wunder
Walter Hübsch
Alexandros Vakalopoulos
Adrian Tersteegen
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Bayer Pharma AG
Bayer Intellectual Property GmbH
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Bayer Pharma AG
Bayer Intellectual Property GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present application relates to novel substituted fused pyrimidines and triazines, to processes for their preparation, to their use alone or in combinations for the treatment and/or prophylaxis of diseases, and to their use for producing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular disorders.
  • cyclic guanosine monophosphate cGMP
  • NO nitrogen monoxide
  • GTP guanosine triphosphate
  • the soluble guanylate cyclases consist of two subunits and very probably contain one haem per heterodimer, which is part of the regulatory site. This is of central importance for the activation mechanism. NO can bind to the iron atom of haem and thus markedly increase the activity of the enzyme. Haem-free preparations cannot, by contrast, be stimulated by NO. Carbon monoxide (CO) is also able to bind to the central iron atom of haem, but the stimulation by CO is much less than that by NO.
  • CO Carbon monoxide
  • guanylate cyclase plays an important role in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, in platelet aggregation and platelet adhesion and in neuronal signal transmission, and also in disorders which are based on a disruption of the abovementioned processes.
  • the NO/cGMP system can be suppressed, which can lead, for example, to hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thromboses, stroke and sexual dysfunction.
  • inventive compounds exhibit an effect on recombinant guanylate cyclase reporter cell lines according to the study in B-2 as the minimal effective concentration (MEC) of ⁇ 3 ⁇ M and exhibit inhibition of human phosphodiesterase 5 (PDE5) according to the study in B-6 as IC 50 ⁇ 100 nM.
  • MEC minimal effective concentration
  • PDE5 human phosphodiesterase 5
  • Phosphodiesterase-5 is the name of one of the enzymes which cleave the phosphoric ester bond in cGMP, forming 5′-guanosine monophosphate (5′-GMP).
  • phosphodiesterase-5 occurs predominantly in the smooth musculature of the corpus cavernosum penis and the pulmonary arteries. Blockage of cGMP degradation by inhibition of PDE5 (with, for example, sildenafil, vardenafil or tadalafil) leads to increased signals of the relaxation signalling pathway and specifically to increased blood supply in the corpus cavernosum penis and lower pressure in the pulmonary blood vessels. They are used for treatment of erectile dysfunction and of pulmonary arterial hypertension. As well as PDE5, there are further, exclusively cGMP-cleaving phosphodiesterases (Stasch J.-P. et al. Circulation 2011).
  • WO 00/06568 and WO 00/06569 disclose fused pyrazole derivatives
  • WO 03/095451 discloses carbamate-substituted 3-pyrimidinylpyrazolopyridines.
  • 3-Pyrimidinylpyrazolopyridines with phenylamide substituents are described in E. M. Becker et al., BMC Pharmacology 1 (13), 2001.
  • WO 2004/009590 describes pyrazolopyridines with substituted 4-aminopyrimidines for treatment of CNS disorders.
  • WO 2010/065275 and WO 2011/149921 disclose substituted pyrrolo- and dihydropyridopyrimidines as sGC activators.
  • WO 2012/004259 describes fused aminopyrimidines
  • WO 2012/004258, WO 2012/143510 and WO 2012/152629 fused pyrimidines and triazines.
  • WO 2012/28647 discloses pyrazolopyridines with various azaheterocycles for treatment of cardiovascular disorders.
  • the present invention provides compounds of the general formula (I)
  • the present invention provides compounds of the general formula (I)
  • heterocycle may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine and (C 1 -C 4 )-alkyl,
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds, comprised by formula (I), of the formulae mentioned below and their salts, solvates and solvates of the salts and the compounds comprised by formula (I), mentioned below as working examples, and their salts, solvates and solvates of the salts, if the compounds, comprised by formula (I), mentioned below are not already salts, solvates and solvates of the salts.
  • Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also encompassed are salts which are not themselves suitable for pharmaceutical applications but can be used, for example, for isolation or purification of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, by way of example and with preference alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and with preference ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • alkali metal salts e.g. sodium and potassium salts
  • alkaline earth metal salts e.g. calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines
  • solvates refer to those forms of the compounds according to the invention which, in the solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a specific form of solvates in which the coordination is with water. Preferred solvates in the context of the present invention are hydrates.
  • the compounds according to the invention may, depending on their structure, exist in different stereoisomeric forms, i.e. in the form of configurational isomers or else optionally as conformational isomers (enantiomers and/or diastereomers, including those in the case of atropisomers).
  • the present invention therefore encompasses the enantiomers and diastereomers, and the respective mixtures thereof.
  • the stereoisomerically uniform constituents can be isolated from such mixtures of enantiomers and/or diastereomers in a known manner; chromatography processes are preferably used for this, in particular HPLC chromatography on an achiral or chiral phase.
  • the present invention also encompasses all suitable isotopic variants of the compounds according to the invention.
  • An isotopic variant of a compound according to the invention is understood here to mean a compound in which at least one atom within the compound according to the invention has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound according to the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • Particular isotopic variants of a compound according to the invention may be beneficial, for example, for the examination of the mechanism of action or of the active ingredient distribution in the body; due to comparatively easy preparability and detectability, especially compounds labelled with 3 H or 14 C isotopes are suitable for this purpose.
  • the incorporation of isotopes, for example of deuterium can lead to particular therapeutic advantages as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required; such modifications of the compounds according to the invention may therefore, in some cases, also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by the processes known to those skilled in the art, for example by the methods described below and the procedures described in the working examples, by using corresponding isotopic modifications of the respective reagents and/or starting compounds.
  • the present invention also encompasses prodrugs of the compounds according to the invention.
  • prodrugs refers to compounds which for their part can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their dwell time in the body.
  • Alkyl in the context of the invention is a straight-chain or branched alkyl radical having the number of carbon atoms specified in each case.
  • the following may be mentioned by way of example and by way of preference: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, isopentyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 3,3-dimethylbutyl, 1-ethylbutyl and 2-ethylbutyl.
  • Alkanediyl in the context of the invention is a straight-chain or branched divalent alkyl radical having 1 to 4 carbon atoms.
  • the following may be mentioned by way of example and by way of preference: methylene, ethane-1,2-diyl, ethane-1,-diyl, propane-1,3-diyl, propane-1,1-diyl, propane-1,2-diyl, propane-2,2-diyl, butane-1,4-diyl, butane-1,2-diyl, butane-1,3-diyl and butane-2,3-diyl.
  • Cycloalkyl or carbocycle in the context of the invention is a monocyclic saturated alkyl radical having the number of carbon atoms specified in each case.
  • the following may be mentioned by way of example and by way of preference: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Alkenyl in the context of the invention is a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms and a double bond.
  • the following may be mentioned by way of example and by way of preference: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.
  • Alkynyl in the context of the invention is an alkynyl radical having 2 to 4 carbon atoms and a triple bond. The following may be mentioned by way of example and by way of preference: ethynyl, propynyl and butynyl.
  • Alkoxy in the context of the invention is a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms.
  • the following may be mentioned by way of example: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, 1-ethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy and n-hexoxy.
  • Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms.
  • Alkoxycarbonyl in the context of the invention is a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms and a carbonyl group attached to the oxygen.
  • the following may be mentioned by way of example and by way of preference: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
  • Monoalkylamino in the context of the invention is an amino group having a straight-chain or branched alkyl substituent having 1 to 6 carbon atoms.
  • the following may be mentioned by way of example and by way of preference: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.
  • Dialkylamino in the context of the invention is an amino group having two identical or different, straight-chain or branched alkyl substituents each having 1 to 6 carbon atoms.
  • Preferred examples include: N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.
  • Heterocyclyl or heterocycle in the context of the invention is a saturated heterocycle which has a total of 4 to 7 ring atoms, contains one or two ring heteroatoms from the group consisting of N, O, S, SO and/or SO 2 and is attached via a ring carbon atom.
  • the following may be mentioned by way of example: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and dioxidothiomorpholinyl.
  • Preference is given to azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl and morpholinyl.
  • 5- or 6-membered heteroaryl which is attached via carbon in the context of the invention is a monocyclic aromatic heterocycle (heteroaromatic) which has a total of 5 or 6 ring atoms, contains up to three identical or different ring heteroatoms from the group consisting of N, O and/or S and is attached via a ring carbon atom.
  • heterocycle heterocycle
  • furyl pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
  • 5- or 6-membered heteroaryl in the context of the invention is a monocyclic aromatic heterocycle (heteroaromatic) which has a total of 5 or 6 ring atoms, contains up to three identical or different ring heteroatoms from the group consisting of N, O and/or S and is attached via a ring carbon atom or optionally via a ring nitrogen atom.
  • heterocycle monocyclic aromatic heterocycle (heteroaromatic) which has a total of 5 or 6 ring atoms, contains up to three identical or different ring heteroatoms from the group consisting of N, O and/or S and is attached via a ring carbon atom or optionally via a ring nitrogen atom.
  • furyl pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
  • furyl pyrrolyl, thienyl
  • pyrazolyl imidazolyl
  • thiazolyl oxazolyl
  • isoxazolyl isoxazolyl
  • isothiazolyl triazolyl
  • oxadiazolyl thiadiazolyl
  • pyridyl pyrimidinyl
  • pyridazinyl pyrazinyl and triazinyl.
  • Halogen in the context of the invention is fluorine, chlorine, bromine and iodine. Preference is given to bromine and iodine.
  • An oxo group in the context of the invention is an oxygen atom attached via a double bond to a carbon atom.
  • a thiooxo group in the context of the invention is a sulphur atom attached via a double bond to a carbon atom.
  • the end point of the line marked by the symbol # 1 , # 2 or * does not represent a carbon atom or a CH 2 group but is part of the bond to the respective atom to which L or R 2 is attached.
  • treatment includes inhibition, retardation, checking, alleviating, attenuating, restricting, reducing, suppressing, repelling or healing of a disease, a condition, a disorder, an injury or a health problem, or the development, the course or the progression of such states and/or the symptoms of such states.
  • therapy is understood here to be synonymous with the term “treatment”.
  • prevention refers to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disease, a condition, a disorder, an injury or a health problem, or a development or progression of such states and/or the symptoms of such states.
  • the treatment or prevention of a disease, a condition, a disorder, an injury or a health problem may be partial or complete.
  • radicals in the compounds according to the invention are substituted, the radicals may be mono- or polysubstituted, unless specified otherwise.
  • all radicals which occur more than once are defined independently of one another. Substitution by one, two or three identical or different substituents is preferred.
  • the invention furthermore provides a process for preparing the compounds of the formula (I) according to the invention, characterized in that a compound of the formula (II)
  • R 1 , R 2 , R 3 and R 4 each have the meanings given above
  • Inert solvents for the process step (II)+(III) ⁇ (IV) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile, sulpholane or else water. It is also possible to use mixtures of the solvents mentioned. Preference is given to
  • Suitable bases for the process step (II)+(III) ⁇ (IV) are alkali metal hydroxides such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate, alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DBN 1,5-diazabicyclo[
  • the reaction (II)+(III) ⁇ (IV) is generally carried out in a temperature range from +20° C. to +150° C., preferably at from +75° C. to +100° C., optionally in a microwave.
  • the conversion can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar).
  • the reaction is generally carried out at atmospheric pressure.
  • Suitable halogen sources in the conversion (IV) ⁇ (V) are, for example, diiodomethane, a mixture of caesium iodide, iodine and copper(I) iodide or copper(II) bromide.
  • Process step (IV) ⁇ (V) is carried out with or without solvent.
  • Suitable solvents are all organic solvents which are inert under the reaction conditions.
  • the preferred solvent is dimethoxyethane.
  • the reaction (IV) ⁇ (V) is generally carried out in a temperature range from +20° C. to +100° C., preferably within the range from +50° C. to +100° C., optionally in a microwave.
  • the conversion can be carried out at atmospheric, elevated or reduced pressure (for example in the range from 0.5 to 5 bar).
  • the reaction is generally carried out at atmospheric pressure.
  • Inert solvents for the process step (V) ⁇ (I-A) are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1,2-ethanediol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or else water. It is also possible to use mixtures of the solvents mentioned. Preference is given to DMF.
  • the reduction (V) ⁇ (I-A) is carried out with hydrogen in conjunction with transition metal catalysts, for example palladium (10% on activated carbon), Raney nickel or palladium hydroxide.
  • transition metal catalysts for example palladium (10% on activated carbon), Raney nickel or palladium hydroxide.
  • the reaction (V) ⁇ (I-A) is generally carried out in a temperature range from +20° C. to +50° C.
  • the conversion can be carried out at atmospheric or elevated pressure (for example in the range from 0.5 to 5 bar).
  • the reaction is generally carried out at atmospheric pressure.
  • Inert solvents for the process step (II)+(VI) ⁇ (VII) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. It is also possible to use mixtures of the solvents mentioned. Preference is given to methanol or ethanol.
  • Suitable bases for the process step (II)+(VI) ⁇ (VII) are alkali metal hydroxides such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate, alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DBN 1,5-diazabicyclo
  • the reaction (II)+(VI) ⁇ (VII) is generally carried out in a temperature range from +50° C. to +120° C., preferably from +50° C. to +100° C., optionally in a microwave.
  • the conversion can be performed at atmospheric or elevated pressure (for example in the range from 0.5 to 5 bar).
  • the reaction is generally carried out at atmospheric pressure.
  • the conversions (VII) ⁇ (VIII) and (XII) ⁇ (XIII) can be carried out in a solvent which is inert under the reaction conditions or without solvent.
  • the preferred solvent is sulpholane.
  • the reactions (VII) ⁇ (VIII) and (XII) ⁇ (XIII) are generally carried out in a temperature range from +70° C. to +150° C., preferably from +80° C. to +130° C., optionally in a microwave.
  • the conversion can be performed at atmospheric or elevated pressure (for example in the range from 0.5 to 5 bar).
  • the reaction is generally carried out at atmospheric pressure.
  • the conversion (XII) ⁇ (XIII) is carried out without solvent in a temperature range from 0° C. to +50° C. at atmospheric pressure.
  • Process step (VIII) ⁇ (IX) is carried out by reaction with sodium azide with intermediate formation of the azide derivatives which are directly reduced further to give the corresponding amines.
  • Inert solvents for the azide formation are, for example, ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or sulpholane. It is also possible to use mixtures of the solvents mentioned. Preference is given to DMF.
  • the azide formation is generally carried out in a temperature range from +50° C. to +100° C., preferably from +60° C. to +80° C., at atmospheric pressure.
  • the reduction is carried out in an inert solvent such as, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1,2-ethanediol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or else water. It is also possible to use mixtures of the solvents mentioned. Preference is given to DMF.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol or 1,2-ethaned
  • the reduction is carried out at from +10° C. to +30° C. using hydrogen in combination with transition metal catalysts such as, for example, palladium (10% on activated carbon), platinum dioxide or palladium hydroxide, or without hydrogen using tin(II) chloride and hydrochloric acid.
  • transition metal catalysts such as, for example, palladium (10% on activated carbon), platinum dioxide or palladium hydroxide, or without hydrogen using tin(II) chloride and hydrochloric acid.
  • conversion (VIII) ⁇ (IX) can also be carried out in one step analogously to process step (XIII) ⁇ (XIV).
  • Process step (XIII) ⁇ (XIV) is carried out in a solvent which is inert under the reaction conditions.
  • Suitable solvents are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or else water. It is also possible to use mixtures of the solvents mentioned. Preference is given to acetonitrile.
  • ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
  • other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonit
  • the reaction (XIII) ⁇ (XIV) is generally carried out in a temperature range from +20° C. to +100° C., preferably from +40° C. to +70° C., optionally in a microwave.
  • the conversion can be performed at atmospheric or elevated pressure (for example in the range from 0.5 to 5 bar).
  • the reaction is generally carried out at atmospheric pressure.
  • the cyclizations (IX) ⁇ (I-B) and (XIV) ⁇ (I-C) are carried out in a solvent which is inert under the reaction conditions, for example alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran (THF), glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or sulpholane.
  • Suitable bases for the process steps (IX) ⁇ (I-B) and (XIV) ⁇ (I-C) are alkali metal hydroxides such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate, alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DBN
  • the reactions (IX) ⁇ (I-B) and (XIV) ⁇ (I-C) are generally carried out in a temperature range from 0° C. to +50° C., preferably from +10° C. to +30° C., optionally in a microwave.
  • the reaction can be performed at atmospheric or elevated pressure (for example in the range from 0.5 to 5 bar).
  • the reaction is generally carried out at atmospheric pressure.
  • the cyclization to (I-B) or (I-C) occurs directly during the reduction of the azide to the corresponding amine (IX) or during the reaction (XIII) ⁇ (XIV) without addition of further reagents.
  • the conversions (XIII) ⁇ (XIV) ⁇ (XV) ⁇ (I-D) are preferably carried out without isolation of the intermediates.
  • Inert solvents for the process step (X)+(XI) ⁇ (XII) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. It is also possible to use mixtures of the solvents mentioned. Preference is given to methanol or ethanol.
  • the reaction (X)+(XI) ⁇ (XII) is generally carried out in a temperature range from +50° C. to +120° C., preferably from +50° C. to +100° C., optionally in a microwave.
  • the reaction can be performed at atmospheric or elevated pressure (for example in the range from 0.5 to 5 bar).
  • the reaction is generally carried out at atmospheric pressure.
  • Inert solvents for the process step (II) ⁇ (X) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. It is also possible to use mixtures of the solvents mentioned. Preference is given to ethanol.
  • Suitable bases for the process step (II) ⁇ (X) are alkali metal hydroxides such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or caesium carbonate, alkali metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Preference is given to triethylamine.
  • alkali metal hydroxides such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide
  • the reaction (II) ⁇ (X) is generally carried out in a temperature range of from 0° C. to +60° C., preferably from +10° C. to +30° C.
  • the reaction can be performed at atmospheric or elevated pressure (for example in the range from 0.5 to 5 bar).
  • the reaction is generally carried out at atmospheric pressure.
  • Process step (V)+(XV-A) or (XV-B) or (XV-C) or (XV-D) ⁇ (I-D) is carried out in a solvent which is inert under the reaction conditions.
  • Suitable solvents are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or else water. It is also possible to use mixtures of the solvents mentioned. Preference is given to acetonitrile, dioxane and tetrahydrofuran.
  • a suitable palladium catalyst is, for example, palladium on activated carbon, palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, bis(acetonitrile)palladium(II) chloride and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and the corresponding dichloromethane complex, optionally in conjunction with additional phosphane ligands, for example (2-biphenyl)di-tert-butylphosphine, dicyclohexyl[2′,4′,6′-tris(1
  • the conversion (V)+(XV-A) or (XV-B) or (XV-C) or (XV-D) ⁇ (I-D) is optionally carried out in the presence of a suitable base.
  • Suitable bases for this conversion are the customary inorganic or organic bases.
  • alkali metal hydroxides for example lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or caesium carbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or sodium or potassium tert-butoxide, alkali metal hydrides such as sodium hydride or potassium hydride, amides such as sodium amide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
  • DBN
  • the reaction (V)+(XV-A) or (XV-B) or (XV-C) or (XV-D) ⁇ (I-D) is generally carried out in a temperature range from 0° C. to +200° C., preferably from +10° C. to +150° C.
  • the reaction can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar).
  • the reaction is generally carried out at atmospheric pressure.
  • R 5A radical is unsaturated, it can subsequently be fully or partly saturated.
  • the reduction is effected with hydrogen in conjunction with transition metal catalysts, for example palladium (10% on activated carbon), Raney nickel or palladium hydroxide.
  • transition metal catalysts for example palladium (10% on activated carbon), Raney nickel or palladium hydroxide.
  • the reduction is generally carried out in a temperature range from +20° C. to +50° C.
  • the reaction can be performed at atmospheric or elevated pressure (for example in the range from 1 to 150 bar). In general, 1 to 3 bar are employed.
  • Process step (V)+(R 25 —Y) ⁇ (XVII) is carried out in a solvent which is inert under the reaction conditions.
  • Inert solvents for the process step (V)+(R 25 —Y) ⁇ (XVII) are, for example, halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethylene or chlorobenzene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, N,N-dimethylformamide, N,N-dimethylacet
  • Suitable bases for this conversion are the customary inorganic or organic bases.
  • These preferably include alkali metal hydroxides, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or caesium carbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or sodium carbonate or caesium carbonates, alkali metal hydrides such as sodium hydride or potassium hydride, amides such as sodium amide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-
  • the reaction (V)+(R 25 —Y) ⁇ (XVII) is generally carried out in a temperature range from ⁇ 20° C. to +200° C., preferably at from +10° C. to +100° C.
  • the conversion can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar).
  • the reaction is generally carried out at atmospheric pressure.
  • Process step (XVII)+(XV-A) or (XV-B) or (XV-C) or (XV-D) ⁇ (XVIII) is carried out in a solvent which is inert under the reaction conditions.
  • Suitable solvents are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), toluene, acetonitrile or else water. It is also possible to use mixtures of the solvents mentioned. Preference is given to dioxane and tetrahydrofuran.
  • a suitable palladium catalyst is, for example, palladium on activated carbon, palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, bis(acetonitrile)palladium(II) chloride and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and the corresponding dichloromethane complex, optionally in conjunction with additional phosphane ligands, for example (2-biphenyl)di-tert-butylphosphine, dicyclohexyl[2′,4′,6′-tris
  • the conversion (XVII)+(XV-A) or (XV-B) or (XV-C) or (XV-D) ⁇ (XVIII) is optionally carried out in the presence of a suitable base.
  • Suitable bases for this conversion are the customary inorganic or organic bases.
  • alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or caesium carbonate or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine, pyridine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,4-diazabicyclo[2.2.2]octane (DABCO®).
  • DBN 1,5-diazabicyclo[4.3.0]non-5-ene
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DBU 1,4-diazabicyclo[2.2.2]octane
  • the reaction (XVII)+(XV-A) or (XV-B) or (XV-C) or (XV-D) ⁇ (XVIII) is generally carried out in a temperature range from 0° C. to +200° C., preferably from +10° C. to +150° C.
  • the conversion can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar).
  • the reaction is generally carried out at atmospheric pressure.
  • Process step (XVIII) ⁇ (I-D) in the case of PMB is carried out by reaction with a mixture of trifluoromethanesulphonic anhydride and trifluoroacetic acid or trifluoroacetic acid and trifluoromethanesulphonic acid or cerium(IV) ammonium nitrate in suitable solvents such as acetonitrile, DMF or NMP and in the case of SEM as protective group by reaction initially with trifluoroacetic acid in suitable solvents such as dichloromethane and then with aqueous mineral acid in suitable solvents such as ethanol, THF or dioxane.
  • suitable solvents such as acetonitrile, DMF or NMP
  • SEM sulfur-sulfate
  • the reaction (XVIII) ⁇ (I-D) is generally carried out in a temperature range from 0° C. to +200° C., preferably at from +10° C. to +150° C., optionally in a microwave.
  • the conversion can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 20 bar).
  • the reaction is generally carried out at from 0.5 to 10 bar.
  • Process step (XVIII)+(XIX) ⁇ (XX) is carried out in a solvent which is inert under the reaction conditions.
  • Suitable solvents are, for example, ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or sulpholane. It is also possible to use mixtures of the solvents mentioned. Preference is given to DMF.
  • Suitable bases for this conversion are the customary inorganic or organic bases. These preferably include alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or caesium carbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or sodium or potassium tert-butoxide, alkali metal hydrides such as sodium hydride or potassium hydride, amides such as sodium amide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine, pyridine
  • the reaction (XVIII)+(XIX) ⁇ (XX) is generally carried out in a temperature range from 0° C. to +200° C., preferably from +20° C. to +100° C.
  • the conversion can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar).
  • the reaction is generally carried out at atmospheric pressure.
  • Process step (V)+copper cyanide ⁇ (XXI) is carried out in a solvent which is inert under the reaction conditions.
  • Suitable solvents are, for example, ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or sulpholane. It is also possible to use mixtures of the solvents mentioned. Preference is given to DMSO.
  • the reaction (V)+copper cyanide ⁇ (XXI) is generally carried out in a temperature range of from 0° C. to +200° C., preferably from +40° C. to +180° C.
  • the conversion can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar).
  • the reaction is generally carried out at atmospheric pressure.
  • the reduction (XXI) ⁇ (I-F) is carried out with hydrogen in conjunction with transition metal catalysts, for example palladium (10% on activated carbon), Raney nickel or palladium hydroxide.
  • transition metal catalysts for example palladium (10% on activated carbon), Raney nickel or palladium hydroxide.
  • the reaction (XXI) ⁇ (I-F) is generally carried out in a temperature range from +20° C. to +100° C.
  • the conversion can be carried out at atmospheric or elevated pressure (for example in the range from 0.5 to 100 bar). In general, 1 to 3 bar are employed.
  • Process step (I-F)+(XXII) ⁇ (I-G) is carried out in a solvent which is inert under the reaction conditions.
  • Suitable solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethylene or chlorobenzene, ethers such as diethyl ether, dioxane, dimethoxyethane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulphoxide (DMSO), N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or sulpholane
  • Suitable bases for this conversion are the customary inorganic or organic bases. These preferably include alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or caesium carbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or sodium or potassium tert-butoxide, alkali metal hydrides such as sodium hydride or potassium hydride, amides such as sodium amide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide or lithium diisopropylamide, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropylethylamine,
  • the reaction (I-F)+(XXII) ⁇ (I-G) is generally carried out in a temperature range from 0° C. to +200° C., preferably from +10° C. to +50° C.
  • the conversion can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar).
  • the reaction is generally carried out at atmospheric pressure.
  • the preparation of the compounds of the formula (I) according to the invention can take place by reversing the order of the reaction steps using protective group chemistry, as shown by way of example in the synthesis scheme below (Scheme 9):
  • Further compounds according to the invention can optionally also be prepared by conversions of functional groups of individual substituents, especially those listed for L and R 5 , proceeding from compounds of the formulae (I), (V), (VIII) and (XIII) obtained by the above processes.
  • These conversions are performed by customary methods known to those skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalysed coupling reactions, Grignard reactions, eliminations, alkylation, acylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of carbonamides, and introduction and removal of temporary protective groups.
  • Preferred conversions are illustrated in an exemplary manner by the synthesis schemes below (Schemes 10-13).
  • the compounds of the formula (II) are known from the literature (see, for example WO 2011/147809, WO 03/095451, Example 6A) or can be prepared analogously to processes known from the literature.
  • the compounds according to the invention act as potent stimulators of soluble guanylate cyclase and inhibitors of phosphodiesterase-5, have useful pharmacological properties and have an improved therapeutic profile, for example with respect to the in vivo properties thereof and/or the pharmacokinetic characteristics and/or metabolic profile thereof. They are therefore suitable for the treatment and/or prophylaxis of diseases in humans and animals.
  • the compounds according to the invention cause vasorelaxation and inhibition of platelet aggregation, and lead to a decrease in blood pressure and to a rise in coronary blood flow. These effects are mediated by a direct stimulation of soluble guanylate cyclase and an intracellular rise in cGMP.
  • the compounds according to the invention enhance the action of substances which increase the cGMP level, for example EDRF (endothelium-derived relaxing factor), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
  • the compounds according to the invention are suitable for the treatment and/or prophylaxis of cardiovascular, pulmonary, thromboembolic and fibrotic disorders.
  • the compounds according to the invention can be used in medicaments for the treatment and/or prophylaxis of cardiovascular disorders such as, for example, hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular disorders, arrhythmias, atrial and ventricular arrhythmias and impaired conduction such as, for example, atrioventricular blocks degrees I-III (AB block I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, Torsade de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles, sick sinus syndrome, syncopes, AV-nodal re-entry tachycardia, Wolff-Parkinson-White syndrome, of acute coronary syndrome (ACS), autoimmune cardiac disorders (pericarditis, end
  • heart failure encompasses both acute and chronic forms of heart failure, and also more specific or related types of disease, such as acute decompensated heart failure, right heart failure, left heart failure, global failure, ischaemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, heart failure associated with heart valve defects, mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid valve stenosis, tricuspid valve insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure and systolic heart failure, and
  • the compounds according to the invention can also be used for the treatment and/or prophylaxis of arteriosclerosis, impaired lipid metabolism, hypolipoproteinaemias, dyslipidaemias, hypertriglyceridaemias, hyperlipidaemias, hypercholesterolaemias, abetalipoproteinaemia, sitosterolaemia, xanthomatosis, Tangier disease, adiposity, obesity and of combined hyperlipidaemias and metabolic syndrome.
  • the compounds according to the invention can additionally be used for the treatment and/or prophylaxis of primary and secondary Raynaud's phenomenon, of microcirculation impairments, claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic retinopathy, diabetic ulcers on the extremities, gangrene, CREST syndrome, erythematosis, onychomycosis, rheumatic disorders and for promoting wound healing.
  • the compounds according to the invention are also suitable for treatment of muscular dystrophy, such as Becker-Kiener muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD).
  • the compounds according to the invention are furthermore suitable for treating urological disorders such as, for example, benign prostate syndrome (BPS), benign prostate hyperplasia (BPH), benign prostate enlargement (BPE), bladder outlet obstruction (BOO), lower urinary tract syndromes (LUTS, including Feline Urological Syndrome (FUS)), disorders of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as, for example, mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence or overflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, benign and malignant disorders of the organs of the male and female urogenital system.
  • BPS benign prostate syndrome
  • BPH benign prostate hyperplasia
  • BPE benign prostate enlargement
  • BOO bladder outlet obstruction
  • LUTS lower urinary tract syndromes
  • LUTS lower urinary tract syndromes
  • FUS Feline Urological Syndrome
  • UI incontinence
  • kidney disorders in particular of acute and chronic renal insufficiency and acute and chronic renal failure.
  • renal insufficiency comprises both acute and chronic manifestations thereof, as well as underlying or related kidney diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathic diseases such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as kidney graft rejection and immunocomplex-induced kidney diseases, nephropathy induced by toxic substances, nephropathy induced by contrast agents, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis
  • the present invention also encompasses the use of the compounds according to the invention for the treatment and/or prophylaxis of sequelae of renal insufficiency, for example pulmonary oedema, heart failure, uraemia, anaemia, electrolyte disturbances (for example hyperkalaemia, hyponatraemia) and disturbances in bone and carbohydrate metabolism.
  • sequelae of renal insufficiency for example pulmonary oedema, heart failure, uraemia, anaemia, electrolyte disturbances (for example hyperkalaemia, hyponatraemia) and disturbances in bone and carbohydrate metabolism.
  • the compounds according to the invention are also suitable for the treatment and/or prophylaxis of asthmatic disorders, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH) including left-heart disease, HIV, sickle cell anaemia, thromboembolisms (CTEPH), sarcoidosis, COPD or pulmonary fibrosis-associated pulmonary hypertension, chronic-obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (for example pulmonary emphysema induced by cigarette smoke) and cystic fibrosis (CF).
  • PAH pulmonary arterial hypertension
  • PH pulmonary hypertension
  • COPD chronic-obstructive pulmonary disease
  • ARDS acute respiratory distress syndrome
  • ALI acute lung injury
  • AATD alpha-1-antitrypsin deficiency
  • the compounds described in the present invention are also active compounds for control of central nervous system disorders characterized by disturbances of the NO/cGMP system. They are suitable in particular for improving perception, concentration, learning or memory after cognitive impairments like those occurring in particular in association with situations/diseases/syndromes such as mild cognitive impairment, age-associated learning and memory impairments, age-associated memory losses, vascular dementia, craniocerebral trauma, stroke, dementia occurring after strokes (post stroke dementia), post-traumatic craniocerebral trauma, general concentration impairments, concentration impairments in children with learning and memory problems, Alzheimer's disease, Lewy body dementia, dementia with degeneration of the frontal lobes including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelinisation, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis
  • the compounds according to the invention are also suitable for regulating cerebral blood flow and are thus effective agents for control of migraine. They are also suitable for prophylaxis and control of sequelae of cerebral infarction (cerebral apoplexy) such as stroke, cerebral ischaemia and craniocerebral trauma.
  • the compounds according to the invention can likewise be employed for controlling states of pain and tinnitus.
  • the compounds according to the invention have antiinflammatory action and can therefore be used as antiinflammatory agents for the treatment and/or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic intestinal inflammations (IBD, Crohn's disease, UC), pancreatitis, peritonitis, rheumatoid disorders, inflammatory skin diseases and inflammatory eye diseases.
  • SIRS sepsis
  • MODS multiple organ failure
  • IBD chronic intestinal inflammations
  • Crohn's disease UC
  • pancreatitis peritonitis
  • rheumatoid disorders inflammatory skin diseases and inflammatory eye diseases.
  • the compounds according to the invention can also be used for the treatment and/or prophylaxis of autoimmune diseases.
  • the compounds according to the invention are furthermore suitable for the treatment and/or prophylaxis of fibrotic disorders of the internal organs such as, for example, the lung, the heart, the kidney, the bone marrow and in particular the liver, and also dermatological fibroses and fibrotic eye disorders.
  • fibrotic disorders includes in particular the following terms: hepatic fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage resulting from diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma , morphea, keloids, hypertrophic scarring (also following surgical procedures), naevi, diabetic retinopathy, proliferative vitroretinopathy and disorders of the connective tissue (for example sarcoidosis).
  • the compounds according to the invention are furthermore suitable for controlling postoperative scarring, for example as a result of glaucoma operations.
  • the compounds according to the invention can also be used cosmetically for ageing and keratinized skin.
  • the compounds according to the invention are suitable for the treatment and/or prophylaxis of hepatitis, neoplasms, osteoporosis, glaucoma and gastroparesis.
  • the present invention further provides for the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above.
  • the present invention further provides for the use of the compounds according to the invention for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and arteriosclerosis.
  • the present invention further provides the compounds according to the invention for use in a method for treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and arteriosclerosis.
  • the present invention further provides for the use of the compounds according to the invention for production of a medicament for the treatment and/or prophylaxis of disorders, especially of the aforementioned disorders.
  • the present invention further provides for the use of the compounds according to the invention for producing a medicament for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and arteriosclerosis.
  • the present invention further provides a method for the treatment and/or prophylaxis of disorders, in particular the disorders mentioned above, using an effective amount of at least one of the compounds according to the invention.
  • the present invention further provides a method for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and arteriosclerosis using an effective amount of at least one of the compounds according to the invention.
  • the compounds according to the invention can be employed alone or, if required, in combination with other active compounds.
  • the present invention further provides medicaments comprising at least one of the compounds according to the invention and one or more further active compounds, especially for the treatment and/or prophylaxis of the aforementioned disorders.
  • suitable active compound combinations include:
  • Antithrombotic agents are preferably understood to mean compounds from the group of the platelet aggregation inhibitors, the anticoagulants or the profibrinolytic substances.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, by way of example and with preference aspirin, clopidogrel, ticlopidin or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, by way of example and with preference ximelagatran, dabigatran, melagatran, bivalirudin or clexane.
  • the compounds according to the invention are administered in combination with a GPIIb/IIIa antagonist such as, by way of example and with preference, tirofiban or abciximab.
  • the inventive compounds are administered in combination with a factor Xa inhibitor, preferred examples being rivaroxaban, DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor preferred examples being rivaroxaban, DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428
  • the compounds according to the invention are administered in combination with heparin or with 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, by way of example and with preference coumarin.
  • Hypotensive agents are preferably understood to mean compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, and the diuretics.
  • the compounds according to the invention are administered in combination with a calcium antagonist, by way of example and with preference nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist by way of example and with preference nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, by way of example and with preference prazosin.
  • the compounds according to the invention are administered in combination with a beta-receptor blocker, by way of example and with preference propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
  • a beta-receptor blocker by way of example and with preference propranolol, atenolol, timolol, pindo
  • the compounds according to the invention are administered in combination with an angiotensin AII antagonist, by way of example and with preference losartan, candesartan, valsartan, telmisartan or embusartan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor, by way of example and with preference enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor by way of example and with preference enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with an endothelin antagonist, by way of example and with preference bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds according to the invention are administered in combination with a renin inhibitor, by way of example and with preference aliskiren, SPP-600 or SPP-800.
  • a renin inhibitor by way of example and with preference aliskiren, SPP-600 or SPP-800.
  • the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, by way of example and with preference spironolactone or eplerenone.
  • the compounds according to the invention are administered in combination with a loop diuretic, for example furosemide, torasemide, bumetanide and piretanide, with potassium-sparing diuretics, for example amiloride and triamterene, with aldosterone antagonists, for example spironolactone, potassium canrenoate and eplerenone, and also thiazide diuretics, for example hydrochlorothiazide, chlorthalidone, xipamide and indapamide.
  • a loop diuretic for example furosemide, torasemide, bumetanide and piretanide
  • potassium-sparing diuretics for example amiloride and triamterene
  • aldosterone antagonists for example spironolactone
  • potassium canrenoate and eplerenone potassium canrenoate and eplerenone
  • thiazide diuretics for example hydrochlorothiazide, chlorthalidon
  • Lipid metabolism modifiers are preferably understood to mean compounds from the group of the CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists.
  • the CETP inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR-alpha PPAR-gamma and/or PPAR-delta agonists
  • cholesterol absorption inhibitors polymeric bile acid
  • the compounds according to the invention are administered in combination with a CETP inhibitor, by way of example and with preference dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • a CETP inhibitor by way of example and with preference dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • the compounds according to the invention are administered in combination with a thyroid receptor agonist, by way of example and with preference D-thyroxin, 3,5,3′-triiodothyronin (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist by way of example and with preference D-thyroxin, 3,5,3′-triiodothyronin (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 with preference lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • an HMG-CoA reductase inhibitor from the class of statins, by way of example and with preference lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, by way of example and with preference BMS-188494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, by way of example and with preference avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor by way of example and with preference avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds according to the invention are administered in combination with an MTP inhibitor, by way of example and with preference implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds according to the invention are administered in combination with a PPAR-gamma agonist, by way of example and with preference pioglitazone or rosiglitazone.
  • the compounds according to the invention are administered in combination with a PPAR-delta agonist, by way of example and with preference GW 501516 or BAY 68-5042.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, by way of example and with preference ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, a preferred example being orlistat.
  • the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent, by way of example and with preference cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.
  • a polymeric bile acid adsorbent by way of example and with preference cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.
  • ASBT IBAT
  • the compounds according to the invention are administered in combination with a lipoprotein(a) antagonist, by way of example and with preference gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein(a) antagonist by way of example and with preference gemcabene calcium (CI-1027) or nicotinic acid.
  • the present invention further provides medicaments which comprise at least one compound according to the invention, typically together with one or more inert, non-toxic, pharmaceutically suitable auxiliaries, and for the use thereof for the aforementioned purposes.
  • the compounds according to the invention may act systemically and/or locally.
  • they can be administered in a suitable manner, for example by the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route, or as an implant or stent.
  • the compounds according to the invention can be administered in administration forms suitable for these administration routes.
  • Administration forms which function according to the prior art, release the compounds according to the invention rapidly and/or in a modified manner and contain the compounds according to the invention in crystalline and/or amorphized and/or dissolved form are suitable for oral administration, such as e.g. tablets (non-coated or coated tablets, for example with enteric coatings or coatings that dissolve in a delayed manner or are insoluble and control the release of the compound according to the invention), tablets or films/oblates, films/lyophilisates or capsules which disintegrate rapidly in the oral cavity (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets non-coated or coated tablets, for example with enteric coatings or coatings that dissolve in a delayed manner or are insoluble and control the release of the compound according to the invention
  • tablets or films/oblates, films/lyophilisates or capsules which disintegrate rapidly in the oral cavity for example hard or soft
  • Parenteral administration can bypass an absorption step (e.g. intravenously, intraarterially, intracardially, intraspinally or intralumbally) or include an absorption (e.g. intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
  • Suitable administration forms for parenteral administration include injection and infusion formulations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • suitable examples are inhalable medicament forms (including powder inhalers, nebulizers), nasal drops, solutions or sprays, tablets, films/oblates or capsules for lingual, sublingual or buccal administration, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milk, pastes, foams, sprinkling powders, implants or stents.
  • the compounds according to the invention can be converted to the administration forms mentioned. This can be done in a manner known per se, by mixing with inert, nontoxic, pharmaceutically suitable excipients.
  • excipients include carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecylsulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants, for example ascorbic acid), dyes (e.g. inorganic pigments, for example iron oxides) and flavour and/or odour correctants.
  • carriers for example microcrystalline cellulose, lactose, mannitol
  • solvents e.g. liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents for example sodium do
  • parenteral administration amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight to achieve effective results.
  • the dose is about 0.001 to 2 mg/kg, preferably about 0.001 to 1 mg/kg, of body weight.
  • Instrument Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9 ⁇ 50 ⁇ 1 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 97% A ⁇ 0.5 min 97% A ⁇ 3.2 min 5% A ⁇ 4.0 min 5% A; oven: 50° C.; flow rate: 0.3 ml/min; UV detection: 210 nm.
  • MS instrument type Waters ZQ; HPLC instrument type: Agilent 1100 Series; UV DAD; column: Thermo Hypersil GOLD 3 ⁇ 20 mm ⁇ 4 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50% strength formic acid; gradient: 0.0 min 100% A ⁇ 3.0 min 10% A ⁇ 4.0 min 10% A oven: 55° C.; flow rate 2 ml/min; UV detection: 210 nm.
  • Instrument Micromass Quattro Premier with Waters UPLC Acquity; column: Thermo Hypersil GOLD 1.9 ⁇ 50 ⁇ 1 mm; mobile phase A: 1 l of water+0.5 ml of 50% strength formic acid, mobile phase 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; oven: 50° C.; flow rate: 0.33 ml/min; UV detection: 210 nm.
  • Instrument Thermo Fisher-Scientific DSQ; chemical ionization; reactant gas NH 3 ; source temperature: 200° C.; ionization energy 70 eV.
  • MS instrument Waters (Micromass) Quattro Micro
  • HPLC instrument Agilent 1100 series
  • column YMC-Triart C18 3 ⁇ 50 ⁇ 3 mm
  • mobile phase A 1 l of water+0.01 mol of ammonium carbonate
  • mobile phase B 1 l of acetonitrile
  • gradient 0.0 min 100% A ⁇ 2.75 min 5% A ⁇ 4.5 min 5% A
  • oven 40° C.
  • flow rate 1.25 ml/min
  • UV detection 210 nm.
  • Instrument Thermo DFS, Trace GC Ultra; column: Restek RTX-35, 15 m ⁇ 200 ⁇ m ⁇ 0.33 ⁇ m; constant flow rate with helium: 1.20 ml/min; oven: 60° C.; inlet: 220° C.; gradient: 60° C., 30° C./min ⁇ 300° C. (maintained for 3.33 min).
  • Example 3A 55.00 g (135 mmol) of Example 3A were initially charged in sulpholane (220 ml), and 41.40 g (270 mmol) of phosphoryl chloride were added. The mixture was then heated at 120° C. for 1 h. After cooling, the mixture was added to warm water (1500 ml) and then neutralized with solid sodium bicarbonate. The precipitate that formed was filtered off with suction and washed with water. The product was purified further by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 3:2). After drying under high vacuum, 43.0 g of the title compound were obtained (73% of theory).
  • Example 4A 10.00 g (23.482 mmol) of Example 4A were initially charged in DMF (200 ml), and 2.290 g (35.223 mmol) of sodium azide were added. The mixture was then heated at 60° C. for 1 h. After cooling, the reaction mixture was added to water and extracted three times with ethyl acetate. The organic phases were combined and washed once with saturated aqueous sodium chloride solution, then dried over sodium sulphate, filtered and concentrated. The residue was used for the next step without further purification.
  • Example 7A 2.00 g (5.550 mmol) of Example 7A were initially charged in dioxane (200 ml), 3.079 g (27.751 mmol) of selenium dioxide were added and the mixture was then heated at reflux for 2 h. After cooling, the mixture was filtered and the filtrate was concentrated and purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1:1). This gave 890 mg of the title compound (42% of theory).
  • Example 9A 232 mg (0.522 mmol) of Example 9A in dichloromethane (14 ml) were cooled to 0° C., and 436 l (3.133 mmol) of triethylamine were then added. 190 ⁇ l (2.611 mmol) of thionyl chloride were then added dropwise, and the mixture was stirred at 0° C. for 15 min. The reaction mixture was subsequently diluted with dichloromethane and extracted three times with water. The phases were separated and the organic phase was dried with sodium sulphate, filtered and concentrated to dryness. The residue obtained was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). This gave 120 mg of the title compound (50% of theory).
  • Example 12A 1.45 g (about 4.950 mmol) of Example 12A were initially charged in ethanol (20 ml), a suspension of 1.37 g (about 3.300 mmol) of Example 11A in 20 ml of ethanol was added dropwise and the mixture was then heated at reflux overnight. After cooling, a precipitate was filtered off and washed with ethanol. The filtrate was concentrated and diethyl ether was added to the residue. Once more, a precipitate was filtered off and the filtrate was concentrated and then purified by preparative HPLC (methanol:water gradient). This gave 297 mg of the title compound (18% of theory).
  • Example 3 337 mg (0.682 mmol) of Example 3 were reacted analogously to Example 10A. This gave 236 mg of the title compound (67% of theory).
  • reaction mixture was filtered with suction through kieselguhr and the filter product was washed three times with ethyl acetate (517 ml each time).
  • the organic phase was separated off and the aqueous phase was washed with ethyl acetate (258 ml).
  • the combined organic phases were washed once with saturated aqueous sodium bicarbonate solution (414 ml), dried and concentrated under reduced pressure.
  • Dichloromethane (388 ml) was added to the crystals thus obtained, and extraction was effected by stirring for 20 min. The mixture was once more filtered off with suction, washed with diethyl ether and sucked dry.
  • the diazonium salt thus prepared was added a little at a time to a solution at 0° C. of 12.81 g (85.45 mmol) of sodium iodide in acetone (329 ml), and the mixture was stirred at RT for 30 min.
  • the reaction mixture was poured into ice-water (1.8 l) and extracted twice with ethyl acetate (487 ml each time).
  • the collected organic phases were washed with saturated aqueous sodium chloride solution (244 ml), dried, filtered and concentrated. This gave 12.1 g (86% purity, 60% of theory) of the title compound as a solid.
  • the crude product was converted without further purification.
  • Example 21A 1.00 g (3.152 mmol) of Example 21A was stirred in 10 ml of a 7N solution of ammonia in methanol at RT for three days. This was followed by concentration under reduced pressure. This gave 908 mg (99% of theory) of the title compound.
  • the aqueous phase was removed and extracted two more times with ethyl acetate (200 ml each time).
  • the combined organic phases were washed twice with 10% aqueous sodium chloride solution (100 ml each time), dried and concentrated under reduced pressure.
  • the crude product was converted without further purification.
  • Example 24A 23.000 g (66.22 mmol) of Example 24A were dissolved in 322 ml of ethanol, and 26.804 g (264.88 mmol) of triethylamine and 6.027 g (66.22 mmol) of hydrazine hydrate (55% strength solution in water) were added at 0° C. The mixture was stirred at RT overnight and then added to 1.715 l of a 10% strength aqueous sodium chloride solution and extracted twice with ethyl acetate. The combined organic phases were washed with 10% strength aqueous sodium chloride solution, dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified on silica gel (mobile phase: dichloromethane/methanol 95:5). This gave 15.000 g (75% of theory) of the title compound.
  • Example 26A 1.272 g (about 4.962 mmol) of Example 26A were initially charged in 10 ml of ethanol and heated to reflux. A suspension of 1.00 g (3.308 mmol) of Example 25A in 40 ml of ethanol was then added dropwise. The mixture was heated overnight, a further 2.24 g of Example 26A were added and the mixture was heated at reflux for a further night. After cooling, a solid was filtered off with suction and washed with a little ethanol, and the filtrate was concentrated. The residue was purified by preparative HPLC (acetonitrile:water gradient). This gave 270 mg (16% of theory) of the title compound.
  • Example 30A 1.143 g (4.962 mmol) of Example 30A were converted in analogy to Example 27A. The residue was purified by preparative HPLC (acetonitrile:water (+1% trifluoroacetic acid) gradient). This gave 334 mg (21% of theory) of the title compound.
  • Example 19A 10.00 g (38.021 mmol) of Example 19A were reacted analogously to the procedure of Example 20A with 4-methoxybenzyl chloride. Chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate mixture) gave 8.94 g (61% of theory) of the title compound.
  • Example 32A 8.94 g (23.332 mmol) of Example 32A were reacted analogously to the procedure of Example 23A, variant A. The crude product obtained was reacted without further purification.
  • Example 33A 6.52 g (23.098 mmol) of Example 33A were reacted analogously to the procedure of Example 24A.
  • Example 34 A 6.16 g (17.141 mmol) of Example 34 A were reacted analogously to the procedure of Example 25A. Purification on silica gel was dispensed with. This gave 4.90 g (90% of theory) of the title compound which was reacted without further purification.
  • Example 25A 1.00 g (3.308 mmol) of the compound from Example 25A were reacted analogously to the procedure of Example 27A with 1.510 g (6.616 mmol) of Example 37A. This gave 0.458 g (29% of theory) of the title compound.
  • Example 40A 0.150 g (0.349 mmol) of the compound from Example 40A were reacted analogously to the procedure of Example 41A with 1-(bromomethyl)-2-fluoro-3-methylbenzene. After filtration, the mixture was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). This gave 83 mg of the title compound (44% of theory).
  • Example 44A 0.50 g (1.654 mmol) of the compound from Example 44A were reacted analogously to the procedure of Example 27A with 907 mg (3.308 mmol) of Example 25A. This gave 42 mg (5% of theory) of the title compound.
  • Example 2A 5.887 g (19.256 mmol) of Example 2A were initially charged in tert-butanol (50 ml), and 2.593 g (23.107 mmol) of potassium tert-butoxide were added. Subsequently, 3.2 g (19.256 mmol) of Example 1A in tert-butanol (25 ml) were added dropwise and the mixture was heated to reflux overnight. The next day, another 0.64 g (3.851 mmol) of Example 1A was added and the mixture was heated to reflux for a further day. After cooling, a precipitate was filtered off, which was washed with diethyl ether. Subsequently, the precipitate was slurried in water, filtered off once more and washed with diethyl ether. After drying under high vacuum, 6.65 g of the title compound were obtained (85% of theory).
  • Example 46A 5.00 g (12.394 mmol) of Example 46A were initially charged in isopentyl nitrite (35.87 ml) and diiodomethane (1.16 mol, 93.71 ml), and the mixture was heated at 85° C. for 12 h. After cooling, solids were filtered off, the mixture was concentrated and the residue was then purified by chromatography on silica gel (mobile phase: initially cyclohexane/dichloromethane gradient, then dichloromethane/methanol gradient). This gave 5.50 g of the title compound (67% of theory).
  • Example 48A 28 g (168.513 mmol) of Example 48A were reacted analogously to the procedure of Example 19A. Chromatography on silica gel (cyclohexane:ethyl acetate 9:1) gave 14.9 g (31% of theory) of the title compound.
  • Example 49A 13 g (46.925 mmol) of Example 49A were reacted analogously to the procedure of Example 20A. Chromatography on silica gel (cyclohexane:ethyl acetate gradient) gave 8.4 g (43% of theory) of the title compound.
  • Example 50A 9.3 g (24.146 mmol) of Example 50A were reacted analogously to the procedure of Example 23A, variant A. Chromatography on silica gel (cyclohexane:ethyl acetate gradient) gave 5.7 g (80% of theory, about 95% pure) of the title compound.
  • Example 51A 5.7 g (18.908 mmol, about 95% pure) of Example 51A were reacted analogously to the procedure of Example 24A. This gave 6.6 g (96% of theory) of the title compound.
  • Example 52A 500 mg (1.384 mmol) of Example 52A were reacted analogously to the procedure of Example 25A. This gave 365 mg (83% of theory) of the title compound.
  • Example 53A 365 mg (1.154 mmol) of Example 53A were reacted analogously to the procedure of Example 13A with 325 mg (1.731 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate. This gave 589 mg (92% of theory, purity 82%) of the title compound.
  • Example 52A 1 g (2.767 mmol) of Example 52A were reacted analogously to the procedure of Example 46A. This gave 971 mg (80% of theory) of the title compound.
  • Example 55A 960 mg (2.205 mmol) of Example 55A were reacted analogously to the procedure of Example 47A. This gave 749 mg (62% of theory, 84% pure) of the title compound.
  • Example 63A Under argon, 100 mg (0.27 mmol) of Example 63A were initially charged in 3 ml of THF. At 0° C., 56 l (0.32 mmol) of N,N-diisopropylethylamine were added, and 0.16 ml (0.32 mmol) of ammonia (2M in ethanol) was added dropwise. The mixture was then stirred at RT overnight. The mixture was then partitioned between dichloromethane and 1N aqueous hydrochloric acid, the aqueous phase was extracted with dichloromethane and the combined organic phases were dried over sodium sulphate and concentrated under reduced pressure.
  • Example 65A 84.37 g (348.23 mmol) of Example 65A were initially charged in 1.10 l of ethanol. Under reflux, 55 g (0.174 mol, purity 90%) of Example 11A were added a little at a time, and heating under reflux was continued overnight. The reaction was then combined with a test batch starting with 11.1 g (35.1 mmol) of Example 65A. The mixture was then cooled to 5° C. and the precipitated solid was filtered off and washed with tert-butyl methyl ether. The solid was discarded. The filtrate was concentrated under reduced pressure, 500 ml of tert-butyl methyl ether were added to the residue and the mixture was stirred at room temperature for 1 h.
  • Example 47A Under argon, 4.9 g (9.53 mmol) of Example 47A and 3.75 g (11.43 mmol) of caesium carbonate were initially charged in 15 ml of N,N-dimethylformamide. With ice cooling, 2 ml (11.4 mmol) of 2-(trimethylsilyl)ethoxymethyl chloride were then added dropwise, and the mixture was stirred at room temperature overnight. After addition of 375 mg (1.14 mmol) of caesium carbonate and 0.2 ml (1.14 mmol) of 2-(trimethylsilyl)ethoxymethyl chloride, the mixture was stirred at room temperature for a further night.
  • Example 69A Under argon, 100 mg (0.16 mmol) of Example 69A were initially charged in 3.3 ml of a mixture of DMF, water and triethylamine (25:4:4), 170 ⁇ l (1.55 mmol) of ethyl acrylate, 25 mg (0.03 mmol) of palladium(II) acetate and 115 mg (0.31 mmol) of tetra-n-butylammonium iodide were added and the mixture was stirred at 60° C. for 9 h.
  • Example 70A 37 mg (0.06 mmol) of Example 70A were dissolved in 0.5 ml of dichloromethane, 100 ⁇ l (1.30 mmol) of trifluoroacetic acid were added and the mixture was stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure and dried under high vacuum. The crude product was reacted further without purification.
  • Example 2A Under an atmosphere of argon, 4.69 g (15.32 mmol) of Example 2A were initially charged in 120 ml of tert-butanol, and 3.07 g (30.66 mmol) of potassium bicarbonate and 4.2 g (17.63 mmol) of Example 74A were added at room temperature. The mixture was stirred at a bath temperature of 85° C. for 5 h. After cooling, water was added and the reaction mixture was stirred at room temperature for 30 min. The precipitated solid was filtered off and washed with water and diethyl ether. Drying under high vacuum gave 6.2 g (88% of theory) of the title compound.
  • Example 33 Under an atmosphere of argon, 600 mg (0.77 mmol, purity 57%) of Example 33 were initially charged and 2.50 ml (64.12 mmol) of 80% pure hydrazine hydrate were added. The mixture was stirred at 80° C. for 30 min, cooled, concentrated on a rotary evaporator and dried under high vacuum. This gave 566 mg of the title compound as a crude product.
  • Example 78A Under an atmosphere of argon, 500 mg (1.36 mmol) of Example 78A were initially charged in 10 ml of t-butanol, and 272.6 mg (2.72 mmol) of potassium bicarbonate and 373 mg (1.57 mmol) of Example 74A were added. After 5 h of stirring at 85° C., the mixture was cooled and water was added. After 30 min of stirring at room temperature, the precipitated solid was filtered off and washed with water and a little ether. Drying under high vacuum gave 458 mg (63% of theory) of the title compound.
  • Example 25A 4.12 g (13.62 mmol) of Example 25A were converted in analogy to Example 66A. This gave 2.03 g (22% of theory, purity 70%) of the title compound.
  • Example 75A Under an atmosphere of argon, 3 g (6.50 mmol) of Example 75A were initially charged in 100 ml of dichloroethane. 1.31 ml (9.75 mmol) of isopentyl nitrite and 1.74 g (7.80 mmol) of copper(II) bromide were added and the mixture was stirred at a bath temperature of 65° C. overnight. After cooling, water and dichloromethane were added. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, concentrated and purified by flash chromatography on silica gel (mobile phase: dichloromethane/methanol 100:1). Drying under high vacuum gave 2.32 g of the title compound (68% of theory).
  • Ethyl 5-amino-1-(2-fluorobenzyl)-4-formyl-1H-pyrazole-3-carboxylate was prepared analogously to compounds known from the literature from 2-fluorobenzyl bromide and sodium 1,4-diethoxy-1,4-dioxobut-2-en-2-olate (cf. Kelley et al. J. Med. Chem. 1995, 38, 3884-3888, Toche et al. J. Het. Chem. 2010, 47, 287-291 and patent: U.S. Pat. No. 4,833,246, column 24.
  • Example 69A Under argon, 500 mg (0.78 mmol) of Example 69A, 14.8 mg (0.08 mmol) of copper(I) iodide, 127 mg (1.51 mmol) of sodium bicarbonate, 0.31 ml (304.4 mg, 3.1 mmol) of ethyl propiolate and 54.6 mg (0.08 mmol) of dichlorobistriphenylphosphinepalladium(II) in 7 ml of DMF were stirred at 60° C. overnight. Aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic phases were dried and concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using cyclohexane/ethyl acetate.
  • Example 90A 140 mg (0.23 mmol) of Example 90A were dissolved in 15 ml of ethyl acetate, 50 mg of 10% palladium on carbon were added and the mixture was hydrogenated at standard pressure for 3 h. Another 50 mg of 10% palladium on carbon were added and the mixture was hydrogenated overnight. The mixture was filtered through kieselguhr, the filter cake was washed with ethyl acetate and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (gradient DCM/MeOH (0.5-1%).
  • Example 60 1.0 g (2.37 mmol) of Example 60 were dissolved in 20 ml of anhydrous DMF and stirred with 847.6 mg (2.60 mmol) of caesium carbonate and 0.32 ml (2.37 mmol) of 4-methoxybenzyl chloride at RT for 2 h. 0.1 ml (0.71 mmol) of 4-methoxybenzyl chloride was added and the mixture was stirred overnight. Water was added, the reaction mixture was partially concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The water phase was extracted repeatedly with ethyl acetate, and the combined organic phases were dried over sodium sulphate and concentrated. The residue was purified first by flash chromatography on silica gel (gradient DCM/EE 0-20%) and then by preparative HPLC (gradient: 0.1% formic acid in water/5-95% acetonitrile).
  • Example 94A 330 mg (0.61 mmol) of Example 94A in 4.4 ml of DMF and 0.19 ml of ethyl cyanoacetate (1.82 mmol) and 136.4 mg (1.22 mmol) of potassium tert-butoxide were stirred at RT for 5 min and at 60° C. overnight. Water was added, the mixture was extracted repeatedly with ethyl acetate and the combined organic phases were concentrated under reduced pressure. The residue was purified by preparative HPLC (gradient: 0.1% formic acid in water/5-95% acetonitrile).
  • Example 10A 4 ml of a 2N solution of ammonia in ethanol were added to 119 mg (0.257 mmol) of Example 10A, and the mixture was then treated at 100° C. in a microwave for 30 min. This was followed by concentration to dryness. The residue obtained was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). This gave 16 mg of the title compound (14% of theory).
  • Example 8A 290 mg (0.775 mmol) of Example 8A were reacted analogously to the procedure of Example 9A with (pentafluoroethyl)trimethylsilane. This gave 218 mg of the title compound (57% of theory).
  • Example 14A 233 mg (0.454 mmol) of Example 14A were reacted analogously to the procedure of Example 1. This gave 22 mg of the title compound (9% of theory).
  • Example 56A 100 mg (0.183 mmol) of Example 56A in DMF (10 ml) were hydrogenated with palladium on carbon (10%) at standard pressure. After complete conversion, the mixture was filtered through Celite, the filter residue was washed with DMF, the filtrate was concentrated and the residue was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). This gave 61 mg of the target compound (80% of theory).

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140100229A1 (en) * 2011-04-21 2014-04-10 Bayer Intellectual Property Gmbh Fluoroalkyl-substituted pyrazolopyridines and use thereof
US9133191B2 (en) 2012-01-11 2015-09-15 Bayer Intellectual Property Gmbh Substituted triazine derivatives and use thereof as stimulators of soluble guanylate cyclase
US9216978B2 (en) 2010-07-09 2015-12-22 Bayer Intellectual Property Gmbh Ring-fused pyrimidines and triazines and use thereof for the treatment and/or prophylaxis of cardiovascular diseases
US20160002267A1 (en) * 2013-03-01 2016-01-07 Bayer Pharma Aktiengesellschaft Benzyl-substituted pyrazolopyridines and use thereof
US9266871B2 (en) 2013-03-01 2016-02-23 Bayer Pharma Aktiengesellschaft Trifluoromethyl-substituted fused pyrimidines and their use
US20160145271A1 (en) * 2013-07-10 2016-05-26 Bayer Pharma Aktiengesellschaft Benzyl-1h-pyrazolo[3,4-b]pyridines and use thereof
US9498480B2 (en) 2012-03-06 2016-11-22 Bayer Intellectual Property Gmbh Substituted azabicycles and use thereof
US9505786B2 (en) 2012-01-11 2016-11-29 Bayer Pharma Aktiengesellschaft Substituted annulated triazines and use thereof
US9611278B2 (en) 2013-12-11 2017-04-04 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
US9688699B2 (en) 2014-02-19 2017-06-27 Bayer Pharma Aktiengesellschaft 3-(pyrimidine-2-yl)imidazo[1,2-a]pyridines
US9776997B2 (en) 2013-06-04 2017-10-03 Bayer Pharma Aktiengesellschaft 3-aryl-substituted imidazo[1,2-A]pyridines and their use
US9783552B2 (en) 2013-12-11 2017-10-10 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
US9796733B2 (en) 2014-06-04 2017-10-24 Merck Sharp & Dohme Corp. Imidazo-pyrazine derivatives useful as soluble guanylate cyclase activators
US9822130B2 (en) 2014-11-21 2017-11-21 Merck Sharp & Dohme Corp. Triazolo-pyrazinyl derivatives useful as soluble guanylate cyclase activators
US10030027B2 (en) 2015-12-22 2018-07-24 Merck Sharp & Dohme Corp. Soluble guanylate cyclase stimulators
US10213429B2 (en) 2015-05-28 2019-02-26 Merck Sharp & Dohme Corp. Imidazo-pyrazinyl derivatives useful as soluble guanylate cyclase activators
US10245264B2 (en) 2015-05-27 2019-04-02 Merck Sharp & Dohme Corp. Substituted imidazo[1,2-a]pyrazines as soluble guanylate cyclase activators
US10292970B2 (en) 2014-12-02 2019-05-21 Bayer Pharma Aktiengesellschaft Heteroaryl-substituted imidazo[1,2-A]pyridines and their use
US10780092B2 (en) 2016-05-16 2020-09-22 Merck Sharp & Dohme Corp. Fused pyrazine derivatives useful as soluble guanylate cyclase stimulators
US10925876B2 (en) 2016-05-18 2021-02-23 Merck Sharp & Dohme Corp. Methods for using triazolo-pyrazinyl soluble guanylate cyclase activators in fibrotic disorders
CN113368240A (zh) * 2021-06-13 2021-09-10 重庆医科大学 一种二茂铁基金属有机框架纳米粒及其制备方法
US11166932B2 (en) 2015-07-23 2021-11-09 Bayer Pharma Aktiengesellschaft Stimulators and/or activators of soluble guanylate cyclase (sGC) in combination with an inhibitor of neutral endopeptidase (NEP inhibitor) and/or an angiotensin AII antagonist and the use thereof

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102012200352A1 (de) * 2012-01-11 2013-07-11 Bayer Intellectual Property Gmbh Substituierte, annellierte Imidazole und Pyrazole und ihre Verwendung
JP6056872B2 (ja) 2012-11-30 2017-01-11 アステラス製薬株式会社 イミダゾピリジン化合物
EP3092231B1 (en) 2013-12-11 2018-06-27 Ironwood Pharmaceuticals, Inc. Sgc stimulators
EP3094327A1 (en) 2014-01-13 2016-11-23 Ironwood Pharmaceuticals, Inc. USE OF sGC STIMULATORS FOR THE TREATMENT OF NEUROMUSCULAR DISORDERS
CN107074883A (zh) 2014-08-29 2017-08-18 拜耳医药股份有限公司 氨基取代的环状嘧啶及其用途
EP3186251A1 (de) 2014-08-29 2017-07-05 Bayer Pharma Aktiengesellschaft Substituierte annellierte pyrimidine und ihre verwendung
JP6748113B2 (ja) 2015-05-06 2020-08-26 バイエル・ファルマ・アクティエンゲゼルシャフト 全身性硬化症（ＳＳｃ）に付随する指潰瘍（ＤＵ）を治療するための単独のまたはＰＤＥ５阻害剤と組み合わせたｓＧＣ刺激剤、ｓＧＣ活性化剤の使用
KR101753652B1 (ko) * 2015-10-21 2017-07-05 한국화학연구원 N-아릴-1h-피라졸로피리딘-3-아민 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 melk 관련 질환의 예방 또는 치료용 약학적 조성물
MX2018007152A (es) 2015-12-14 2018-08-15 Ironwood Pharmaceuticals Inc Uso de estimuladores de guanilato ciclasa soluble (sgc) para el tratamiento de la disfuncion del esfinter gastrointestinal.
PL3507291T3 (pl) 2016-09-02 2021-11-22 Cyclerion Therapeutics, Inc. Połączone bicykliczne stymulatory sgc
CA3039734A1 (en) 2016-10-11 2018-04-19 Bayer Pharma Aktiengesellschaft Combination containing sgc stimulators and mineralocorticoid receptor antagonists
JP7237823B2 (ja) 2016-10-11 2023-03-13 バイエル ファーマ アクチエンゲゼルシャフト Ｓｇｃアクチベーターとミネラルコルチコイド受容体アンタゴニストとを含む組合せ
US20190381039A1 (en) 2016-12-13 2019-12-19 Cyclerion Therapeutics, Inc. USE OF sGC STIMULATORS FOR THE TREATMENT OF ESOPHAGEAL MOTILITY DISORDERS
ES2924359T3 (es) 2017-04-11 2022-10-06 Sunshine Lake Pharma Co Ltd Compuestos de indazol sustituidos con flúor y usos de los mismos
BR112020022340A2 (pt) 2018-05-15 2021-02-02 Bayer Aktiengesellschaft benzamidas substituídas por 1,3-tiazol-2-il para o tratamento de doenças associadas com sensibilização de fibras nervosas
CN108640923A (zh) * 2018-07-09 2018-10-12 湖南天地恒制药有限公司 一种托法替布关键中间体的制备方法
BR112021000358A2 (pt) 2018-07-11 2021-04-06 Cyclerion Therapeutics, Inc. Uso de estimulantes de sgc para o tratamento de distúrbios mitocondriais
WO2020164008A1 (en) 2019-02-13 2020-08-20 Bayer Aktiengesellschaft Process for the preparation of porous microparticles
WO2025016393A1 (zh) * 2023-07-17 2025-01-23 海思科医药集团股份有限公司 一种4-氨基-吡咯并[2,3-d]嘧啶-6-酮衍生物及其在医药上的应用

Family Cites Families (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES537947A0 (es) 1984-11-26 1985-11-01 Fordonal Sa Procedimiento de preparacion de un derivado de piracina.
JPS63139949A (ja) 1986-12-02 1988-06-11 Fuji Photo Film Co Ltd 新規ピラゾロン染料
SE8704248D0 (sv) 1987-10-30 1987-10-30 Haessle Ab Medical use
GB9314412D0 (en) 1993-07-13 1993-08-25 Rhone Poulenc Agriculture New compositions of matter
WO1996034866A1 (en) 1995-05-01 1996-11-07 Fujisawa Pharmaceutical Co., Ltd. Imidazo 1,2-a pyridine and imidazo 1,2-a pyridezine derivatives and their use as bone resorption inhibitors
EP0743066A3 (en) 1995-05-16 1998-09-30 Mitsui Pharmaceuticals, Inc. Wound-healing agent
DE19642255A1 (de) 1996-10-14 1998-04-16 Bayer Ag Verwendung von 1-Benzyl-3-(substituierten-hetaryl) -kondensierten Pyrazol-Derivaten
HUP0001115A3 (en) 1996-10-14 2001-06-28 Bayer Ag Heterocyclylmethyl-substituted pyrazol derivatives, process for their preparation and pharmaceuticals containing the same
US6451805B1 (en) 1997-11-14 2002-09-17 Bayer Aktiengesellschaft Substituted pyrazole derivatives for the treatment of cardiocirculatory diseases
DE19834044A1 (de) 1998-07-29 2000-02-03 Bayer Ag Neue substituierte Pyrazolderivate
DE19834047A1 (de) 1998-07-29 2000-02-03 Bayer Ag Substituierte Pyrazolderivate
DE10021069A1 (de) 2000-04-28 2001-10-31 Bayer Ag Substituiertes Pyrazolderivat
WO2002059083A2 (en) 2000-10-23 2002-08-01 Smithkline Beecham Corporation Novel compounds
WO2002042299A1 (de) 2000-11-22 2002-05-30 Bayer Aktiengesellschaft Neue lactam-substituierte pyrazolopyridinderivate
DE10132416A1 (de) 2001-07-04 2003-01-16 Bayer Ag Neue Morpholin-überbrückte Pyrazolopyridinderivate
DE10220570A1 (de) * 2002-05-08 2003-11-20 Bayer Ag Carbamat-substituierte Pyrazolopyridine
DE10232571A1 (de) 2002-07-18 2004-02-05 Bayer Ag 4-Aminosubstituierte Pyrimidinderivate
CA2521695C (en) 2003-05-09 2011-08-16 Asahi Glass Company, Limited Method for producing 3-substituted 2-chloro-5-fluoro-pyridine or its salt
CN100355732C (zh) 2003-11-03 2007-12-19 上海药明康德新药开发有限公司 2－氯－5－氟－烟酸酯及酸的制备方法
ATE433452T1 (de) 2004-01-31 2009-06-15 Actimis Pharmaceuticals Inc Imidazoä1,2-cüpyrimidinylessigsäurederivate
WO2006081230A2 (en) 2005-01-26 2006-08-03 Schering Corporation 3-(indazol-5-yl)-(1,2, 4) triazine derivatives and related compounds as protein kinase inhibitors for the treatment of cancer
WO2006130673A1 (en) 2005-05-31 2006-12-07 Janssen Pharmaceutica, N.V. 3-benzoimidazolyl-pyrazolopyridines useful in treating kinase disorders
WO2007041052A2 (en) 2005-09-29 2007-04-12 Merck & Co., Inc. Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
DE102006043443A1 (de) 2006-09-15 2008-03-27 Bayer Healthcare Ag Neue aza-bicyclische Verbindungen und ihre Verwendung
AR067762A1 (es) 2007-07-31 2009-10-21 Vertex Pharma Proceso para preparar 5-fluoro-1h-pirazolo (3,4-b) piridin-3-amina y derivados de la misma
JP2011513483A (ja) 2008-03-10 2011-04-28 バーテックス ファーマシューティカルズ インコーポレイテッド タンパク質キナーゼの阻害剤として有用なピリミジンおよびピリジン
WO2010065275A1 (en) 2008-11-25 2010-06-10 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
DE102009004245A1 (de) 2009-01-09 2010-07-15 Bayer Schering Pharma Aktiengesellschaft Neue anellierte, Heteroatom-verbrückte Pyrazol- und Imidazol-Derivate und ihre Verwendung
AR076601A1 (es) 2009-05-21 2011-06-22 Chlorion Pharma Inc Pirimidinas como agentes terapeuticos
JP5314192B2 (ja) 2009-08-07 2013-10-16 アルカテル−ルーセント ＶｏＩＰ会話のハンドオーバでのブレーク継続時間を低減するための方法及び装置
US20130178475A1 (en) 2010-03-17 2013-07-11 Ironwood Pharmaceuticals, Inc. sGC STIMULATORS
DE102010021637A1 (de) 2010-05-26 2011-12-01 Bayer Schering Pharma Aktiengesellschaft Substituierte 5-Fluor-1H-Pyrazolopyridine und ihre Verwendung
SG185777A1 (en) 2010-05-27 2012-12-28 Merck Sharp & Dohme Soluble guanylate cyclase activators
EP2585055A1 (de) 2010-06-25 2013-05-01 Bayer Intellectual Property GmbH Verwendung von stimulatoren und aktivatoren der löslichen guanylatzyklase zur behandlung von sichelzellanämie und konservierung von blutersatzstoffen
PH12013500055A1 (en) * 2010-07-09 2017-08-23 Bayer Ip Gmbh Ring-fused pyrimidines and triazines and use thereof for the treatment and/or prophylaxis of cardiovascular diseases
EP2590987B1 (de) 2010-07-09 2016-03-09 Bayer Intellectual Property GmbH Annellierte 4-aminopyrimidine und ihre verwendung als stimulatoren der löslichen guanylatcyclase
DE102010040234A1 (de) 2010-09-03 2012-03-08 Bayer Schering Pharma Aktiengesellschaft Verfahren zur Herstellung von 5-Flour-1H-pyrazolo[3,4-b]pyridin-3-carbonitril
DE102010040233A1 (de) 2010-09-03 2012-03-08 Bayer Schering Pharma Aktiengesellschaft Bicyclische Aza-Heterocyclen und ihre Verwendung
DE102010043380A1 (de) 2010-11-04 2012-05-10 Bayer Schering Pharma Aktiengesellschaft Benzyl-substituierte Carbamate und ihre Verwendung
US9090610B2 (en) 2011-04-21 2015-07-28 Bayer Intellectual Property Gmbh Fluoroalkyl-substituted pyrazolopyridines and use thereof
ES2592267T3 (es) 2011-05-06 2016-11-29 Bayer Intellectual Property Gmbh Imidazopiridinas e imidazopiridazinas sustituidas y su uso
EA201391769A1 (ru) 2011-05-30 2014-04-30 Астеллас Фарма Инк. Имидазопиридиновые соединения
EP2729476B1 (de) * 2011-07-06 2017-08-23 Bayer Intellectual Property GmbH Heteroaryl-substituierte pyrazolopyridine und ihre verwendung als stimulatoren der löslichen guanylatcyclase
WO2013030138A1 (en) 2011-09-01 2013-03-07 F. Hoffmann-La Roche Ag Pyrrolopyrazine kinase inhibitors
JP6054967B2 (ja) 2011-09-02 2016-12-27 バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＢａｙｅｒ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ ＧｍｂＨ 置換アネレート化ピリミジンおよびその使用
DE102012200349A1 (de) 2012-01-11 2013-07-11 Bayer Intellectual Property Gmbh Substituierte annellierte Pyrimidine und Triazine und ihre Verwendung
DE102012200352A1 (de) 2012-01-11 2013-07-11 Bayer Intellectual Property Gmbh Substituierte, annellierte Imidazole und Pyrazole und ihre Verwendung
DE102012200360A1 (de) 2012-01-11 2013-07-11 Bayer Intellectual Property Gmbh Substituierte Triazine und ihre Verwendung
EP2822951B1 (de) 2012-03-06 2017-07-26 Bayer Intellectual Property GmbH Substituierte azabicyclen und ihre verwendung
EA027689B1 (ru) 2013-03-01 2017-08-31 Байер Фарма Акциенгезельшафт Трифторметилзамещенные аннелированные пиримидины и их применение
EP2961754B1 (de) 2013-03-01 2016-11-16 Bayer Pharma Aktiengesellschaft Benzyl-substituierte pyrazolopyridine und ihre verwendung
MX2016000258A (es) 2013-07-10 2016-04-28 Bayer Pharma AG Bencil-1h-pirazolo[3,4-b]piridinas y su uso.

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Dermer et al., Bio/Technology, 1994, 12:320. *
Freshney et al.,Culture of Animal Cells, A Manual of Basic Technique, Alan R. Liss, Inc., 1983, New York, p4. *
Ghofrani et al. Eur Respir Rev 2009; 18:111,35-41. *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9216978B2 (en) 2010-07-09 2015-12-22 Bayer Intellectual Property Gmbh Ring-fused pyrimidines and triazines and use thereof for the treatment and/or prophylaxis of cardiovascular diseases
US9090610B2 (en) * 2011-04-21 2015-07-28 Bayer Intellectual Property Gmbh Fluoroalkyl-substituted pyrazolopyridines and use thereof
US20140100229A1 (en) * 2011-04-21 2014-04-10 Bayer Intellectual Property Gmbh Fluoroalkyl-substituted pyrazolopyridines and use thereof
US9133191B2 (en) 2012-01-11 2015-09-15 Bayer Intellectual Property Gmbh Substituted triazine derivatives and use thereof as stimulators of soluble guanylate cyclase
US9505786B2 (en) 2012-01-11 2016-11-29 Bayer Pharma Aktiengesellschaft Substituted annulated triazines and use thereof
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US9611278B2 (en) 2013-12-11 2017-04-04 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
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US9688699B2 (en) 2014-02-19 2017-06-27 Bayer Pharma Aktiengesellschaft 3-(pyrimidine-2-yl)imidazo[1,2-a]pyridines
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US9822130B2 (en) 2014-11-21 2017-11-21 Merck Sharp & Dohme Corp. Triazolo-pyrazinyl derivatives useful as soluble guanylate cyclase activators
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