WO2012010578A1 - Méthyle-pyrimidin-5-ylcarbamates substitués et leur utilisation - Google Patents

Méthyle-pyrimidin-5-ylcarbamates substitués et leur utilisation Download PDF

Info

Publication number
WO2012010578A1
WO2012010578A1 PCT/EP2011/062312 EP2011062312W WO2012010578A1 WO 2012010578 A1 WO2012010578 A1 WO 2012010578A1 EP 2011062312 W EP2011062312 W EP 2011062312W WO 2012010578 A1 WO2012010578 A1 WO 2012010578A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
salts
solvates
diseases
Prior art date
Application number
PCT/EP2011/062312
Other languages
German (de)
English (en)
Inventor
Markus Follmann
Johannes-Peter Stasch
Gorden Redlich
Jens Ackerstaff
Nils Griebenow
Andreas Knorr
Frank Wunder
Volkhart Min-Jian Li
Hartmut Schirok
Rolf Jautelat
Original Assignee
Bayer Pharma Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharma Aktiengesellschaft filed Critical Bayer Pharma Aktiengesellschaft
Publication of WO2012010578A1 publication Critical patent/WO2012010578A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present application relates to novel, substituted methyl-pyrimidin-5-ylcarbamate, processes for their preparation, their use alone or in combinations for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of Diseases, in particular for the treatment and / or prophylaxis of cardiovascular diseases.
  • cyclic guanosine monophosphate cGMP
  • NO nitric oxide
  • the guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP).
  • GTP guanosine triphosphate
  • the previously known members of this family can be divided into two groups according to both structural features and the nature of the ligands: the particulate guanylate cyclases stimulable by natriuretic peptides and the soluble guanylate cyclases stimulable by NO.
  • the soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer that is part of the regulatory center. This is central to the activation mechanism. NO can bind to the iron atom of the heme and thus significantly increase the activity of the enzyme. On the other hand, heme-free preparations can not be stimulated by NO. Also, carbon monoxide (CO) is able to bind to the central iron atom of the heme, with stimulation by CO being significantly less than by NO.
  • CO carbon monoxide
  • guanylate cyclase plays a crucial role in various physiological processes, in particular in the relaxation and proliferation of smooth muscle cells, platelet aggregation and adhesion, neuronal signaling and diseases based on a disturbance of the above operations.
  • the NO / cGMP system may be suppressed, which may, for example, lead to hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual dysfunction.
  • a NO-independent treatment option for such diseases which is aimed at influencing the cGMP pathway in organisms, is a promising approach on account of the expected high efficiency and low side effects.
  • WO 00/06569 discloses fused pyrazole derivatives and, in WO 03/095451, carbamate-substituted 3-pyrimidinyl-pyrazolopyridines as stimulators of soluble guanylate cyclase.
  • the object of the present invention was to provide new substances which act as potent stimulators of soluble guanylate cyclase.
  • the present invention relates to compounds of the general formula (I)
  • R 1 is hydrogen or fluorine
  • R 2 is trideuteromethyl, (C 1 -C 4 ) -alkyl, benzyl or amino, where (C 1 -C 4 ) -alkyl is substituted by 1 to 3 substituents of fluorine, and wherein benzyl may be substituted by 1 to 3 substituents fluorine, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic formic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the compounds according to the invention may exist in different stereoisomeric forms, ie in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in the case of atropisomers). The present invention therefore encompasses the enantiomers and diastereomers and their respective mixtures.
  • the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes that can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), H (tritium), 1 C , 14 C, 15 N, 17 0, 18 0, 2 P, P, S, 4 S, 5 S, 6 S, 18 F, 6 Cl, 82 Br, 12 I, 124 I, 129 I and 1 1 I.
  • isotopic variants of a compound of the invention such as those in which one or more radioactive isotopes are incorporated, may be useful, for example for the study of the mechanism of action or distribution of drug in the body; because of the comparatively easy production and detectability, compounds labeled with H or 14 C isotopes are particularly suitable for this purpose.
  • isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
  • modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically). Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
  • alkyl is a linear or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl.
  • Halogen is in the context of the invention for fluorine, chlorine, bromine and iodine.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Preferred in the context of the present invention are compounds of the formula (I) in which
  • R 1 is hydrogen or fluorine
  • R 2 is trideuteromethyl, methyl, ethyl, benzyl or amino, wherein methyl and ethyl is substituted with 1 to 3 fluorine substituents, and wherein benzyl is substituted with a fluorine substituent, and their salts, solvates and solvates of the salts.
  • R 1 is hydrogen, trideuteromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or amino, and their salts, solvates and solvates of the salts.
  • Particularly preferred in the context of the present invention are compounds of the formula (I) in which
  • R 1 is hydrogen
  • R 2 is 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl or amino, and their salts, solvates and solvates of the salts.
  • R 2 is 2,2-difluoroethyl or 2,2,2-trifluoroethyl, and their salts, solvates and solvates of the salts. Also preferred in the context of the present invention are compounds of the formula (I) in which R 2 is trideuteromethyl, and also their salts, solvates and solvates of the salts.
  • the invention further provides a process for the preparation of the compounds of the formula (I) according to the invention which comprises reacting a compound of the formula (II)
  • X 1 is a suitable leaving group, such as mesylate, tosylate or halogen, in particular bromine or iodine, is reacted, and optionally the resulting compounds of formula (I) with the corresponding (i) solvents and / or (ii) acids or bases converted into their solvates, salts and / or solvates of the salts.
  • Inert solvents for process step (II) + (III) -> (I) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran (THF ), Glycol dimethyl ether or diethylene glycol dimethyl ether, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ ) or
  • Suitable bases for process step (II) + (III) - »(I) are alkali metal hydrides such as potassium hydride or sodium hydride, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali hydrogen carbonates such as sodium or potassium bicarbonate, alkali metal such as sodium or potassium , Sodium or potassium ethoxide or potassium tert-butoxide, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, organometallic compounds such as butyl lithium or phenyllithium, or organic amines such as triethylamine, diisopropylethylamine , Pyridine, l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 5-diazabicyclo [4.3.0] non-5-ene (DBU) or l, 5-diazabicyclo [4.3.0] non
  • reaction (II) + (III) -> (I) is generally carried out in a temperature range of -10 ° C to + 30 ° C, preferably at 0 ° C to + 20 ° C.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • the compounds of the formula (II) are known from the literature (see, for example, WO 03/095451, Example 5) or can be prepared by reacting a compound of the formula (IV)
  • R 1 has the abovementioned meaning, reduced, and these are subsequently reacted with methyl chloroformate.
  • Inert solvents for process step (IV) - »(V) 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, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ ), pyridine, acetonitrile or also water.
  • alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol
  • reaction (IV) -> (V) is generally carried out in a temperature range of + 60 ° C to + 200 ° C, preferably at + 120 ° C to + 180 ° C.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Inert solvents for the reaction (V) - »(VI) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide ( DMSO), NN'-dimethyl propyleneurea (DMPU), N-methylpyrrolidone ( ⁇ ), pyridine or acetonitrile. Preference is given to DMF.
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene
  • ethers such as diethyl ether, dioxane, tetrahydro
  • the reaction (V) -> (VI) is carried out in The reaction can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • reaction (V) - »(VI) is carried out to form the corresponding diazonium salt by reaction in the presence of a suitable Lewis acid with isopentyl nitrite, and the subsequent reaction with sodium iodide in a temperature range from -78 ° C to + 40 ° C, preferably at 0 ° C to + 20 ° C.
  • suitable Lewis acids are boron trifluoride-diethyl ether complex, cerium (IV) ammonium nitrate (CAN), stannous chloride, lithium perchlorate, zinc (II) chloride, indium (III) chloride or indium (III) bromide. Boron trifluoride diethyl ether complex is preferred.
  • T 2 in formula (V) is hydrogen
  • the formation of formula (VI) is carried out by reaction with iodine in the presence of a suitable base in a temperature range from 0 ° C to + 80 ° C, preferably from + 40 ° C to + 60 ° C.
  • suitable bases are alkali metal hydroxides such as potassium, lithium or sodium hydroxide, alkali metal such as sodium or potassium, sodium or potassium or potassium tert-butoxide. Preference is given to sodium hydroxide in a mixture of water and dioxane.
  • Inert solvents for the reaction (VI) + (VII) -> (VIII) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide (DMF ), Dimethylsulfoxide (DMSO), N, N-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ ), pyridine, acetonitrile. Preferred is DMF.
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene
  • ethers such as diethyl ether, dioxane, tetra
  • Suitable bases for process step (VI) + (VII) - »(VIII) are alkali metal hydrides, such as potassium hydride or sodium hydride, alkali metal carbonates, such as lithium, sodium, potassium or cesium carbonate, alkali hydrogen carbonates, such as sodium or potassium bicarbonate, alkali metal alcoholates, such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-butoxide, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, organometallic compounds such as butyl lithium or phenyllithium, or organic amines such as triethylamine, diisopropylethylamine , Pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 5-diazabicyclo [4.3.0] non-5-ene (DBN). Cesium carbonate is preferred.
  • the reaction (VI) + (VII) -> (VIII) is generally carried out in a temperature range from 0 ° C to + 60 ° C, preferably at + 10 ° C to + 25 ° C.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar). Generally, one works at normal pressure.
  • Inert solvents for process step (VIII) + (IX) - »(X) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or Diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), dimethylacetamide, N-methylpyrrolidone ( ⁇ ), pyridine , Acetonitrile, sulfolane or even water. It is likewise possible to use mixtures of the solvents mentioned. Dioxane is
  • the palladium catalyst for process step (VIII) + (IX) - »(X) 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 [ ⁇ , - bis (diphenylphosphino) ferrocene] dichloalladium (II) -dichloromethane complex, optionally in combination with additional phosphine ligands such as (2-) biphenyl) di-fert.
  • additional phosphine ligands such as (2-) biphenyl) di-fert.
  • butylphosphine dicyclohexyl [2 ', 4', 6'-tris (1-methylethyl) biphenyl-2-yl] phosphine (XPHOS), bis (2-phenylphosphinophenyl) ether (DPEphos) or 4,5-bis (diphenylphosphino) 9,9-dimethylxanthene (xanthphos) [cf. e.g. Hassan J. et al, Chem. Rev. 102, 1359-1469 (2002)].
  • the reaction (VIII) + (IX) -> (X) is generally carried out in a temperature range from + 20 ° C to + 180 ° C, preferably at + 50 ° C to + 120 ° C, optionally in a microwave.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • the reduction (X) - »(XI) is carried out in the presence of a suitable catalyst in an inert solvent, in a temperature range from + 20 ° C to + 40 ° C under normal hydrogen pressure.
  • Inert solvents for the reduction (X) - »(XI) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or others Solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ ), pyridine, acetonitrile or even water. It is likewise possible to use mixtures of the solvents mentioned. Preferred are DMF and pyridine.
  • Suitable catalysts for the reaction (X) - »(XI) are, for example, palladium on activated carbon, platinum on carbon, palladium hydroxide or Raney nickel.
  • the reduction (X) - »(XI) may alternatively be treated with a metal or metal salt such as iron, zinc or stannous chloride in a suitable acid such as hydrochloric acid / hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid in a temperature range of +20 ° C to + 140 ° C.
  • a metal or metal salt such as iron, zinc or stannous chloride in a suitable acid such as hydrochloric acid / hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid in a temperature range of +20 ° C to + 140 ° C.
  • Inert solvents for process step (XI) - »(II) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, halogenated hydrocarbons such as Dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N-dimethylpropyleneurea (DMPU), N-methylpyrrolidone ( ⁇ ) or acetonitrile
  • Suitable bases for the process step are alkali metal hydrides such as sodium hydride, alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali metal bicarbonates such as sodium or potassium bicarbonate, alkali metal such as sodium or potassium, Sodium or potassium ethoxide or potassium tert-butoxide, or organic amines such as triethylamine, diisopropylethylamine, pyridine, l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or l, 5-diazabicyclo [4.3 .0] non-5-ene (DBN).
  • alkali metal hydrides such as sodium hydride
  • alkali metal hydroxides such as lithium, sodium or potassium hydroxide
  • alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate
  • alkali metal bicarbonates such as sodium or potassium bicarbon
  • reaction (XI) -> (II) is generally carried out in a temperature range of -10 ° C to + 30 ° C, preferably at 0 ° C to + 20 ° C.
  • the reaction can be carried out at normal, elevated or at reduced pressure (for example from 0.5 to 5 bar). Generally, one works at normal pressure.
  • the described preparation process can be exemplified by the following synthesis scheme (Scheme 2):
  • the compounds according to the invention act as potent stimulators of soluble guanylate cyclase, have valuable pharmacological properties, and are therefore suitable for the treatment and / or prophylaxis of diseases in humans and animals.
  • the compounds of the invention cause vasorelaxation and inhibition of platelet aggregation and lead to a reduction in blood pressure and to an increase in coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and an intracellular cGMP increase.
  • the compounds according to the invention enhance the action of substances which increase cGMP levels, such as, 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 therefore be used in medicaments for the treatment and / or prophylaxis of cardiovascular diseases such as hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, arrhythmia of the atria and the chambers and conduction disorders such for example atrio-ventricular blockades grade I-III (AB-B lock I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsades de pointes tachycardia, atrial and ventricular extrasystoles, AV-junctional extrasystoles , Sick sinus syndrome, syncope, AV node reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary artery disease Syndrome (ACS), autoimmune heart disease (pericarditis, endocardit
  • cardiac insufficiency also encompasses more specific or related forms of disease such as acutely decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, valvular heart failure, cardiac insufficiency in valvular heart failure, mitral stenosis, Mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular insufficiency, combined heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure, and systolic heart failure
  • myocarditis chronic my
  • the compounds according to the invention may also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, abetelipoproteinaemia, sitosterolemia, xanthomatosis, Tangier's disease, obesity (obesity) and combined hyperlipidemias and the metabolic syndrome.
  • the compounds of the invention may be used for the treatment and / or prophylaxis of primary and secondary Raynaud's phenomenon, microcirculatory disorders, claudication, peripheral and autonomic neuropathies, diabetic microangiopathies, diabetic Retinopathy, diabetic ulcers on the extremities, Gangren, CREST syndrome, erythematosis, onychomycosis, rheumatic diseases and to promote wound healing can be used.
  • the compounds according to the invention are suitable for the treatment of urological diseases such as benign prostatic syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS, including Feiine's urological syndrome ( FUS)), diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urge, stress, or overflow incontinence (MUI, UUI, SUI, OUI), Pelvic pain, benign and malignant diseases of the organs of the male and female urogenital system.
  • BPS benign prostatic syndrome
  • BPH benign prostatic hyperplasia
  • BPE benign prostate enlargement
  • BOO bladder emptying disorder
  • LUTS lower urinary tract syndromes
  • FUS lower urinary tract syndromes
  • UI incontinence
  • MUI mixed, urge, stress, or overflow incontinence
  • UUI UUI
  • SUI S
  • kidney diseases in particular of acute and chronic renal insufficiency, as well as of acute and chronic renal failure.
  • renal insufficiency includes both acute and chronic manifestations of renal insufficiency, as well as underlying or related renal diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulo-interstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as renal transplant rejection, immune complex-induced kidney disease, nephropathy induced by toxic substances, contrast agent-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hyperten
  • the present invention also encompasses the use of the compounds of the invention for the treatment and / or prophylaxis of sequelae of renal insufficiency, such as pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia), and disorders in bone and carbohydrate metabolism.
  • sequelae of renal insufficiency such as pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia), and disorders in bone and carbohydrate metabolism.
  • the compounds according to the invention are also suitable for the treatment and / or prophylaxis of asthmatic diseases, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including left heart disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoidosis, COPD or Pulmonary fibrosis-associated pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute respiratory tract syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (eg, cigarette smoke-induced Pulmonary emphysema) and cystic fibrosis (CF).
  • PAH pulmonary arterial hypertension
  • PH pulmonary hypertension
  • COPD chronic obstructive pulmonary disease
  • ARDS acute respiratory tract syndrome
  • ALI acute lung injury
  • AATD alpha-1-antitrypsin deficiency
  • CF
  • the compounds described in the present invention are also agents for controlling diseases in the central nervous system, which are characterized by disorders of the NO / cGMP system.
  • they are suitable for improving the perception, concentration performance, learning performance or memory performance after cognitive disorders such as occur in situations / diseases / syndromes such as mild cognitive impairment, age-associated learning and memory disorders, age-associated memory loss, vascular dementia, cranial brain -Trauma, stroke, post-stroke dementia, post-traumatic traumatic brain injury, generalized concentration disorder, difficulty concentrating in children with learning and memory problems, Alzheimer's disease, dementia with Lewy bodies , 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, demyelinization, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis. They are also
  • the compounds according to the invention are also suitable for regulating cerebral blood flow and are effective agents for combating migraine. They are also suitable for the prophylaxis and control of the consequences of cerebral infarct events (Apoplexia cerebri) such as stroke, cerebral ischaemias and craniocerebral trauma , Likewise, the compounds according to the invention can be used to combat pain and tinnitus.
  • cerebral infarct events Apoplexia cerebri
  • cerebral infarct events such as stroke, cerebral ischaemias and craniocerebral trauma
  • the compounds according to the invention can be used to combat pain and tinnitus.
  • the compounds of the invention have anti-inflammatory action and can therefore be used as anti-inflammatory agents for the treatment and / or prophylaxis of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory diseases of the kidney, chronic Enteritis (IBD, Crohn's Disease, UC), pancreatitis, peritonitis, rheumatoid diseases, inflammatory skin diseases and inflammatory ocular diseases.
  • SIRS sepsis
  • MODS multiple organ failure
  • IBD chronic Enteritis
  • Crohn's Disease UC
  • pancreatitis peritonitis
  • rheumatoid diseases inflammatory skin diseases and inflammatory ocular diseases.
  • the compounds of the invention can also be used for the treatment and / or prophylaxis of autoimmune diseases.
  • the compounds according to the invention are 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, as well as dermatological fibroses and fibrotic disorders of the eye.
  • fibrotic disorders includes in particular the following terms: liver fibrosis, cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage as a result of diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma, morphea, keloids, hypertrophic scarring (also after surgical interventions), nevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis).
  • the compounds of the invention are useful for controlling postoperative scarring, e.g. as a result of glaucoma surgery.
  • the compounds according to the invention can likewise be used cosmetically for aging and keratinizing skin.
  • the compounds according to the invention are suitable for the treatment and / or prophylaxis of hepatitis, neoplasm, osteoporosis, glaucoma and gastroparesis.
  • Another object of the present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • the present invention further provides for the use of the compounds according to the invention for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and arteriosclerosis.
  • the present invention furthermore relates to the compounds according to the invention for use in a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and atherosclerosis.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • the present invention further relates to the use of the compounds according to the invention for the production of a medicament for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and arteriosclerosis.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.
  • the present invention further provides a method for the treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular diseases, renal insufficiency, thromboembolic disorders, fibrotic diseases and atherosclerosis, using an effective amount of at least one of the compounds according to the invention ,
  • the compounds of the invention may be used alone or as needed in combination with other agents.
  • Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
  • suitable combination active ingredients may be mentioned by way of example and preferably:
  • organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • cGMP cyclic guanosine monophosphate
  • PDE phosphodiesterases
  • Inhibitors such as sildenafil, vardenafil and tadalafil;
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;
  • Hypotensive agents by way of example and preferably 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 diuretics; and or
  • Lipid metabolism-altering agents by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors and lipoprotein (a) antagonists.
  • cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid rea
  • Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.
  • the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • a platelet aggregation inhibitor such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamole.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, 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 by way of preference, tirofiban or abciximab.
  • a GPIIb / IIIa antagonist such as, by way of example and by way of preference, tirofiban or abciximab.
  • the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD 31 12, 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 such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-176b, apixaban, otamixaban, fidexaban, razaxaban, fondaparinux, idraparinux, PMD 31 12, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-10
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • a vitamin K antagonist such as by way of example and preferably coumarin.
  • the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor Antagonists and diuretics understood.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.
  • the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, Metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.
  • a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolol
  • the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • an angiotensin AII antagonist such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.
  • the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
  • the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
  • a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
  • the compounds of the invention are used in combination with a loop diuretic, such as furosemide, torasemide, bumetanide and piretanide, with potassium-sparing diuretics, such as amiloride and triamterene, with aldosterone antagonists, such as spironolactone, potassium canrenoate and eplerenone, and thiazide diuretics, such as Hydrochlorothiazide, chlorthalidone, xipamide, and indapamide.
  • lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR-alpha PPAR-alpha
  • PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers bil
  • 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 of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • statins such as by way of example and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.
  • the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as by way of example and preferably BMS-188494 or TAK-475.
  • a squalene synthesis inhibitor such as by way of example and preferably BMS-188494 or TAK-475.
  • the compounds according to the invention are administered in combination with an ACAT inhibitor, such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as by way of example and preferably avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • the compounds according to the invention are administered in combination with an MTP inhibitor, such as by way of example and preferably implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as by way of example and preferably implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds of the invention are administered in combination with a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • the compounds according to the invention are administered in combination with a PPAR delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a lipase inhibitor such as, for example and preferably, orlistat.
  • the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • a polymeric bile acid adsorbent such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.
  • the compounds of the invention are administered in combination with a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.
  • compositions containing at least one compound of the invention usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • suitable as application forms i.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or eye preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (eg plasters)
  • milk pastes, foams, powdered powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • excipients e.g., microcrystalline cellulose, lactose, mannitol
  • solvents e.g, liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents e.g., sodium dodecylsulfate, polyoxysorbitanoleate
  • binders e.g., polyvinylpyrrolidone
  • synthetic and natural polymers e.g.
  • Albumin e.g antioxidants such as ascorbic acid
  • dyes eg inorganic pigments such as iron oxides
  • Example 1A 100 mg (0.245 mmol) of Example 1A were initially charged in 4 ml of THF and cooled to 0 ° C. Thereafter, 269 ⁇ of an IM solution of bis (trimethylsilyl) sodium amide in THF was added, and it was stirred at 0 ° C for 30 minutes. Subsequently, 92 mg (0.49 mmol) 2-fluorobenzyl bromide were added and it was stirred overnight at RT. Thereafter, the reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (acetonitrile-water (+0.05% formic acid) gradient). 37 mg of the target compound were obtained (29% of the TL).
  • preparative HPLC acetonitrile-water (+0.05% formic acid
  • Example 1A 5,000 g (12,243 mmol) of Example 1A were suspended in 50 ml of THF, admixed at 0 ° C with 539 mg (13,467 mmol) of sodium hydride (60% suspension in mineral oil) and stirred at 0 ° C for 90 min had formed a solution. 3,791 g (13,467 mmol) of 2,2,2-trifluoroethyltrichloromethanesulfonate were added and the mixture was stirred at RT for 48 h. Water and IN hydrochloric acid were added and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator.
  • the force of contraction is detected with Statham UC2 cells, amplified and digitized via A / D converters (DAS-1802 HC, Keithley Instruments Munich) and registered in parallel on chart recorders.
  • DAS-1802 HC A / D converters
  • phenylephrine is added cumulatively to the bath in increasing concentration.
  • the substance to be examined is added in each subsequent course in increasing dosages and the height of the contraction is compared with the height of the contraction achieved in the last predistortion. This is used to calculate the concentration required to reduce the level of the control value by 50% (IC 50 value).
  • the standard application volume is 5 ⁇ , the DMSO content in the bath solution corresponds to 0.1%.
  • the system consists of 3 main components:
  • Implantable transmitters Physiotel® telemetry transmitters
  • Receivers Physiotel® receivers
  • a multiplexer DSI Data Exchange Matrix
  • Data acquisition computer are connected.
  • the telemetry system allows a continuous recording of blood pressure heart rate and body movement on awake animals in their habitual habitat.
  • the experimental animals are kept individually in macroion cages type 3 after transmitter implantation. You have free access to standard food and water.
  • the day - night rhythm in the experimental laboratory is changed by room lighting at 6:00 in the morning and at 19:00 in the evening.
  • the TAI 1 PA - C40 telemetry transmitters are surgically implanted into the experimental animals under aseptic conditions at least 14 days before the first trial.
  • the animals so instrumented are repeatedly used after healing of the wound and ingrowth of the implant.
  • the fasting animals are anesthetized with pentobabital (Nembutal, Sanofi: 50 mg / kg i.p.) and shaved and disinfected on the ventral side.
  • pentobabital Nembutal, Sanofi: 50 mg / kg i.p.
  • tissue adhesive VetBonD TM, 3M.
  • the transmitter housing is fixed intraperitoneally to the abdominal wall musculature and the wound is closed in layers.
  • an antibiotic is administered for infection prevention (Tardomyocel COMP Bayer 1ml / kg s.c.)
  • the existing telemetry measuring device is configured for 24 animals. Each trial is registered under a trial number (VYear month day).
  • the instrumented rats living in the plant each have their own receiving antenna (1010 receivers, DSI).
  • the implanted transmitters can be activated externally via a built-in magnetic switch. They will be put on the air during the trial run.
  • the emitted signals can be recorded online by a data acquisition system (Dataquest TM A.R.T. for Windows, DSI) and processed accordingly. The storage of the data takes place in each case in a folder opened for this purpose which carries the test number.
  • DBP Diastolic blood pressure
  • MAP Arterial mean pressure
  • the measured value acquisition is repeated computer-controlled in 5-minute intervals.
  • the absolute value of the source data is corrected in the diagram with the currently measured barometric pressure (Ambient Pressure Reference Monitor, APR-1) and stored in individual data. Further technical details can be found in the extensive documentation of the manufacturer (DSI).
  • test substances will take place at 9 o'clock on the day of the experiment. Following the application, the parameters described above are measured for 24 hours.
  • the collected individual data are sorted with the analysis software (DATAQUEST TM ART TM ANALYSIS).
  • the blank value is assumed here 2 hours before application, so that the selected data record covers the period from 7:00 am on the day of the experiment to 9:00 am on the following day.
  • the data is smoothed over a presettable time by averaging (15 minutes average) and transferred as a text file to a disk.
  • the presorted and compressed measured values are transferred to Excel templates and displayed in tabular form.
  • the filing of the collected data takes place per experiment day in a separate folder that bears the test number. Results and test reports are sorted into folders sorted by number in Pandafbrm.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • composition
  • the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
  • i.v. solution The compound of the present invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5%, and / or PEG 400 solution 30%). The solution is sterile filtered and filled into sterile and pyrogen-free injection containers.
  • a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5%, and / or PEG 400 solution 30%.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux méthyle-pyrimidin-5-ylcarbamates substitués, un procédé pour leur fabrication, leur utilisation seuls ou en combinaisons pour le traitement et/ou la prophylaxie de maladies ainsi que leur utilisation pour la fabrication de médicaments pour le traitement et/ou la prophylaxie de maladies, en particulier pour le traitement et/ou la prophylaxie de maladies cardiovasculaires.
PCT/EP2011/062312 2010-07-22 2011-07-19 Méthyle-pyrimidin-5-ylcarbamates substitués et leur utilisation WO2012010578A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102010031667.9 2010-07-22
DE102010031667A DE102010031667A1 (de) 2010-07-22 2010-07-22 Substituierte Methyl-pyrimidin-5-ylcarbamate und ihre Verwendung

Publications (1)

Publication Number Publication Date
WO2012010578A1 true WO2012010578A1 (fr) 2012-01-26

Family

ID=44503785

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2011/062312 WO2012010578A1 (fr) 2010-07-22 2011-07-19 Méthyle-pyrimidin-5-ylcarbamates substitués et leur utilisation

Country Status (2)

Country Link
DE (1) DE102010031667A1 (fr)
WO (1) WO2012010578A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014084312A1 (fr) 2012-11-30 2014-06-05 アステラス製薬株式会社 Composé imidazopyridine
CN106370754A (zh) * 2016-11-07 2017-02-01 西安科技大学 基于手性高效液相色谱‑质谱/质谱技术定量检测布新洛尔光学异构体含量的方法
WO2017106175A2 (fr) 2015-12-14 2017-06-22 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de la sgc pour le traitement d'un dysfonctionnement du sphincter gastro-intestinal
WO2017121692A1 (fr) * 2016-01-15 2017-07-20 Bayer Pharma Aktiengesellschaft Sulfamides substitués et leur utilisation
WO2018111795A2 (fr) 2016-12-13 2018-06-21 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de sgc pour le traitement de la motilité œsophagienne
WO2020014504A1 (fr) 2018-07-11 2020-01-16 Cyclerion Therapeutics, Inc. Utilisation de stimulateurs gcs pour le traitement de maladies mitochondriales
US11242335B2 (en) 2017-04-11 2022-02-08 Sunshine Lake Pharma Co., Ltd. Fluorine-substituted indazole compounds and uses thereof

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0634413A1 (fr) 1993-07-13 1995-01-18 Rhone Poulenc Agriculture Ltd. Herbicides
WO1998016223A1 (fr) 1996-10-14 1998-04-23 Bayer Aktiengesellschaft Utilisation de 1-benzal-3-derives condenses (hetaryl-substitues) de pyrazol pour le traitement de certaines affections du systeme cardiovasculaire et du systeme nerveux central
WO2000006569A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues, condenses avec des noyaux heterocycliques a six chaines
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
CN1613849A (zh) 2003-11-03 2005-05-11 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
EP1626045A1 (fr) 2003-05-09 2006-02-15 Asahi Glass Company, Limited Methodes de production de 2-chloro-5-fluoropyridine 3-substitue ou de son sel
WO2009018415A1 (fr) 2007-07-31 2009-02-05 Vertex Pharmaceuticals Incorporated Procédé de préparation de la 5-fluoro-1h-pyrazolo[3,4-b]pyridin-3-amine et des dérivés de celle-ci
WO2010078900A2 (fr) * 2008-12-19 2010-07-15 Bayer Schering Pharma Aktiengesellschaft Nouvelles pyrazolopyridines à substitution aliphatique et leur utilisation
WO2011056511A2 (fr) * 2009-10-26 2011-05-12 Auspex Pharmaceuticals, Inc. Stimulateurs de la guanylate cyclase soluble à base de 4,6-diaminopyrimidine

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0634413A1 (fr) 1993-07-13 1995-01-18 Rhone Poulenc Agriculture Ltd. Herbicides
WO1998016223A1 (fr) 1996-10-14 1998-04-23 Bayer Aktiengesellschaft Utilisation de 1-benzal-3-derives condenses (hetaryl-substitues) de pyrazol pour le traitement de certaines affections du systeme cardiovasculaire et du systeme nerveux central
WO2000006569A1 (fr) 1998-07-29 2000-02-10 Bayer Aktiengesellschaft Derives de pyrazole substitues, condenses avec des noyaux heterocycliques a six chaines
WO2003095451A1 (fr) 2002-05-08 2003-11-20 Bayer Healthcare Ag Pyrazolopyridines a substitution carbamate
EP1626045A1 (fr) 2003-05-09 2006-02-15 Asahi Glass Company, Limited Methodes de production de 2-chloro-5-fluoropyridine 3-substitue ou de son sel
CN1613849A (zh) 2003-11-03 2005-05-11 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
WO2009018415A1 (fr) 2007-07-31 2009-02-05 Vertex Pharmaceuticals Incorporated Procédé de préparation de la 5-fluoro-1h-pyrazolo[3,4-b]pyridin-3-amine et des dérivés de celle-ci
WO2010078900A2 (fr) * 2008-12-19 2010-07-15 Bayer Schering Pharma Aktiengesellschaft Nouvelles pyrazolopyridines à substitution aliphatique et leur utilisation
WO2011056511A2 (fr) * 2009-10-26 2011-05-12 Auspex Pharmaceuticals, Inc. Stimulateurs de la guanylate cyclase soluble à base de 4,6-diaminopyrimidine

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
F. WUNDER ET AL., ANAL. BIOCHEM., vol. 339, 2005, pages 104 - 112
FOSTER A B: "Deuterium isotope effects in the metabolism of drugs and xenobiotics: implications for drug design", ADVANCES IN DRUG RESEARCH, ACADEMIC PRESS, LONDON, GB, vol. 14, 1985, pages 1 - 40, XP009086953, ISSN: 0065-2490 *
GOLDBERG ET AL., J BIOL. CHEM., vol. 252, 1977, pages 1279
HASSAN J. ET AL., CHEM. REV., vol. 102, 2002, pages 1359 - 1469
KIRK ET AL: "Fluorine in medicinal chemistry: Recent therapeutic applications of fluorinated small molecules", JOURNAL OF FLUORINE CHEMISTRY, ELSEVIER, NL, vol. 127, no. 8, 1 August 2006 (2006-08-01), pages 1013 - 1029, XP025184855, ISSN: 0022-1139, [retrieved on 20060801], DOI: 10.1016/J.JFLUCHEM.2006.06.007 *
KLAUS WITTE, KAI HU, JOHANNA SWIATEK, CLAUDIA MÜSSIG, GEORG ERTL, BJÖRN LEMMER: "Experimental heart failure in rats: effects on cardiovascular circadian rhythms and on myocardial ßadrenergic signaling", CARDIOVASC RES, vol. 47, no. 2, 2000, pages 203 - 405
KOZO OKAMOTO: "Spontaneous hypertension in rats", INT REV EXP PATHOL, vol. 7, 1969, pages 227 - 270
MAARTEN VAN DEN BUUSE: "Circadian Rhythms of Blood Pressure, Heart Rate, and Locomotor Activity in Spontaneously Hypertensive Rats as Measured With Radio-Telemetry", PHYSIOLOGY & BEHAVIOR, vol. 55, no. 4, 1994, pages 783 - 787
MÜLSCH ET AL., BRIT. J PHARMACOL., vol. 120, 1997, pages 681
OKAMOTO KYOTO, SCHOOL OF MEDICINE, 1963
PETTIBONE ET AL., EUR. J PHARMACOL., vol. 116, 1985, pages 307
WINN M., J MED. CHEM., vol. 36, 1993, pages 2676 - 7688
WU ET AL., BLOOD, vol. 84, 1994, pages 4226
YU ET AL., BRIT. J PHARMACOL., vol. 114, 1995, pages 1587

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014084312A1 (fr) 2012-11-30 2014-06-05 アステラス製薬株式会社 Composé imidazopyridine
WO2017106175A2 (fr) 2015-12-14 2017-06-22 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de la sgc pour le traitement d'un dysfonctionnement du sphincter gastro-intestinal
WO2017121692A1 (fr) * 2016-01-15 2017-07-20 Bayer Pharma Aktiengesellschaft Sulfamides substitués et leur utilisation
CN106370754A (zh) * 2016-11-07 2017-02-01 西安科技大学 基于手性高效液相色谱‑质谱/质谱技术定量检测布新洛尔光学异构体含量的方法
CN106370754B (zh) * 2016-11-07 2019-03-08 西安科技大学 基于手性高效液相色谱-质谱/质谱技术定量检测布新洛尔光学异构体含量的方法
WO2018111795A2 (fr) 2016-12-13 2018-06-21 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de sgc pour le traitement de la motilité œsophagienne
US11242335B2 (en) 2017-04-11 2022-02-08 Sunshine Lake Pharma Co., Ltd. Fluorine-substituted indazole compounds and uses thereof
WO2020014504A1 (fr) 2018-07-11 2020-01-16 Cyclerion Therapeutics, Inc. Utilisation de stimulateurs gcs pour le traitement de maladies mitochondriales

Also Published As

Publication number Publication date
DE102010031667A1 (de) 2012-01-26

Similar Documents

Publication Publication Date Title
EP2576547B1 (fr) 5-fluoro-1h-pyrazolopyridines substituées et leur utilisation
EP2590987B1 (fr) Dérivés de 4-aminopyrimidine condensées et leur utilisation en tant que stimulateurs de la guanylate cyclase soluble
EP2635577B1 (fr) 6-fluoro-1h-pyrazolo[4,3-b]pyridines substituées et leur utilisation
EP2705037B1 (fr) Imidazopyridazines substituées et imidazopyridazines, et leur utilisation
EP2699578B1 (fr) Pyrazolopyridines substituées par un fluoro-alkyle et leur utilisation
EP2961755B1 (fr) Pyrimidines annelées à subsitution trifluorométhyle et utilisation correspondante
EP2822951B1 (fr) Azabicyles substitués et leur utilisation
EP2802580B1 (fr) Dérivés de la triazine substituée et leur utilisation en tant que stimulateurs de la guanylate cyclase soluble
EP2635576B1 (fr) Carbamates substitués par des benzyles et leur utilisation
EP2961754B1 (fr) Pyrazolopyridines à substitution benzyle et leur utilisation
DE102011075398A1 (de) Substituierte Imidazopyridazine und ihre Verwendung
WO2012010578A1 (fr) Méthyle-pyrimidin-5-ylcarbamates substitués et leur utilisation
WO2012010577A1 (fr) Oxazolidinones et oxazinanones substituées et leur utilisation
WO2012010576A1 (fr) Diaminopyrimidines substituées par du carbamate et leur utilisation
DE102011075399A1 (de) Substituierte Imidazopyridine und Imidazopyridazine und ihre Verwendung
WO2017121692A1 (fr) Sulfamides substitués et leur utilisation
DE102011007891A1 (de) Annellierte 4-Aminopyrimidine und ihre Verwendung
DE102011007890A1 (de) Fluoralkyl-substituierte Pyrazolopyridine und ihre Verwendung
DE102012200356A1 (de) Substituierte Imidazopyridine und Imidazopyridazine und ihre Verwendung
DE102010031148A1 (de) Annellierte 4-Aminopyrimidine und ihre Verwendung
DE102011078715A1 (de) Heteroaryl-substituierte Pyrazolopyridine und ihre Verwendung
DE102011082041A1 (de) Substituierte annellierte Pyrimidine und ihre Verwendung
DE102012200351A1 (de) Substituierte annellierte Pyrimidine und ihre Verwendung
DE102010031149A1 (de) Annellierte Pyrimidine und Triazine und ihre Verwendung
DE102012200357A1 (de) Fluoralkyl-substituierte Pyrazolopyridine und ihre Verwendung

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11743476

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11743476

Country of ref document: EP

Kind code of ref document: A1