EP2705038A1 - Imidazopyridazines substituées et leur utilisation - Google Patents

Imidazopyridazines substituées et leur utilisation

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Publication number
EP2705038A1
EP2705038A1 EP12724584.3A EP12724584A EP2705038A1 EP 2705038 A1 EP2705038 A1 EP 2705038A1 EP 12724584 A EP12724584 A EP 12724584A EP 2705038 A1 EP2705038 A1 EP 2705038A1
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EP
European Patent Office
Prior art keywords
compound
formula
substituted
salts
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12724584.3A
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German (de)
English (en)
Inventor
Markus Follmann
Johannes-Peter Stasch
Gorden Redlich
Alexander Straub
Jens Ackerstaff
Nils Griebenow
Andreas Knorr
Frank Wunder
Volkhart Min-Jian Li
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Bayer Intellectual Property GmbH
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Bayer Pharma AG
Bayer Intellectual Property GmbH
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Publication of EP2705038A1 publication Critical patent/EP2705038A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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

Definitions

  • the present application relates to novel substituted Imidazopyridazine, 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.
  • cGMP cyclic guanosine monophosphate
  • NO nitric oxide
  • GTP guanosine triphosphate
  • the soluble guanylate cyclases consist of two subunits and most likely contain one heme per heterodimer, which 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. In contrast, heme-free preparations can not be stimulated by NO. Also, carbon monoxide (CO) is able to bind to the iron central atom of the heme, with stimulation by CO being significantly less than that 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 signaling pathway in organisms, is a promising approach on account of the expected high efficiency and low side effects.
  • the stimulators of soluble guanylate cyclase disclosed in WO 00/06569 are fused pyrazole derivatives and 3-pyrimidinyl-pyrazolopyridines which are disclosed in WO 03/095451 C amide-sub stituted.
  • WO 2008/031513 describes inter alia substituted imidazopyridne and imidazopyrimidines as stimulators of soluble guanylate cyclase.
  • 4-Amino-5,5-dimethyl-5,7-dihydro-6H-pyrrolo [2,3-d] pyrimidones having imidazopyridine and pyrimidine substituents as sGC activators are disclosed in WO 2010/065275.
  • 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)
  • (C 1 -C 6) -alkyl or benzyl where (C 1 -C 6) -alkyl is substituted by a substituent trifluoromethyl, where (C 1 -C 6) -alkyl may be substituted by 1 to 3 substituents of fluorine, and wherein benzyl is substituted with 1 to 3 fluorine substituents,
  • R " is hydrogen, (C 1 -C 4) -alkyl or benzyl, in which (C 1 -C 4) -alkyl and benzyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine and trifluoromethyl,
  • R 3 is (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl, (C 1 -C 6 ) alkoxy or (C 3 -C 7 ) cycloalkoxy, wherein (C 1 -C 6 ) alkyl and (C 1 -C 6) -alkoxy having 1 or 2 substituents independently selected from the group consisting of fluorine and trifluoromethyl, or
  • a 4- to 7-membered heterocycle wherein the 4- to 7-membered heterocycle is 1 or 2
  • Substituents (Ci-C4) alkyl may be substituted, as well as their TV oxides, salts, solvates, salts of N-oxides and solvates of the TV 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 according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, lactic, tartaric, 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 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 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 of the invention may exist in different stereoisomeric forms, i. in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those in atropisomers).
  • the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform constituents 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 according to 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 used in a compound of the invention can be incorporated, are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), ⁇ (tritium) ,! 3 C, 14 C ,! N ,!
  • Certain isotopic variants of a compound of the invention may be useful, for example for the study of the mechanism of action or distribution of the drug in the body; Because of the comparatively easy production and detectability, compounds labeled with 3 H or 4 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;
  • 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 reproduced 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).
  • alkyl is a linear or branched alkyl radical having 1 to 6 carbon atoms. Preference is given to a linear or branched alkyl radical having 1 to 4 carbon atoms.
  • a linear or branched alkyl radical having 1 to 4 carbon atoms By way of example and preferably mention may be made of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-ethylpropyl and n-1-hexyl.
  • Cycloalkyl is in the context of the invention for a monocyclic, saturated carbocycle with
  • Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 6 carbon atoms. Preference is given to a linear or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, n-butoxy, isobutoxy and tert-butoxy.
  • Cycloalkoxy in the context of the invention is a monocyclic, saturated carbocycle having 3 to 7 carbon atoms, which is bonded via an oxygen atom.
  • Heterocycle in the context of the invention is a saturated heterocycle having a total of 4 to 7 ring atoms, which contains one or two ring heteroatoms from the series N, O and / or S and is substituted by an oxo group.
  • Examples which may be mentioned are: pyrrolidinonyl, oxazolidinonyl, piperidinonyl, piperazinonyi, morpholinonyl and thiomorpholinonyl. Preference is given to pyrrolidinonyl and oxazolidinonyl.
  • Halogen is in the context of the invention for fluorine, chlorine, bromine and iodine.
  • An oxo group in the context of the invention is an oxygen atom which is bonded via a double bond to a carbon atom.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred.
  • treatment includes inhibiting, delaying. Stopping, alleviating, mitigating, restraining, reducing, suppressing, restraining or curing a disease, condition, illness, injury or disorder, the unfolding, course or progression of such conditions and / or the symptoms of such conditions.
  • therapy is understood to be synonymous with the term "treatment”.
  • prevention means the avoidance or reduction of the risk, a disease, a disease, a disease, an injury or a health disorder, a development or a Progression of such conditions and / or to get, experience, suffer or have the symptoms of such conditions.
  • R 1 is 3,3,4,4,4-pentafluorobut-1-yl or 2-fluorobenzyl
  • R 2 is hydrogen, methyl, ethyl, iso-propyl or benzyl, wherein methyl, ethyl and benzo! with I or 2 substituents independently of one another can be substituted from the group fluorine and trifluoromethyl,
  • R 3 is (C 1 -C 4 ) -alkyl, (C 3 -C 5 ) -cycloalkyl, (C 1 -C 4 ) -alkoxy or (C 3 -C 5 ) -cycloalkoxy, wherein (C 1 -C 4 ) -alkyl and (C 1 -C 4) -alkoxy having 1 or 2 substituents independently selected from the group consisting of fluorine and trifluoromethyl, or
  • Substituents methyl may be substituted, and their salts, solvates and solvates of the salts.
  • R 2 is hydrogen, methyl, ethyl or 2,2,2-trifluoroethyl
  • R 3 is (Ci-C4) alkoxy, cyclobutoxy or cyclopentoxy, wherein (Ci-C4) alkoxy having 1 or 2 substituents independently selected from the group fluorine and trifluoromethyl may be substituted, or R 2 and R 3 together with the atoms to which they are attached form a pyrrolidinonyl or oxazolidinonyl ring, and their salts, solvates and solvates of the salts.
  • R ! represents 2-fluorobenzyl, and their salts, solvates and solvates of the salts.
  • Another object of the invention is a process for the preparation of compounds of the formula (I) according to the invention characterized in that
  • X 1 is a suitable leaving group, such as, for example, mesylate, tosylate or halogen, in particular bromine or iodine, into a compound of the formula (IC)
  • R ! , R 2 and R 3 each have the meanings given above, optionally converted the resulting compounds of formula (IA), (IB) and (IC) with the corresponding (i) solvents and / or (ii) acids or bases in their solvates, salts and / or solvates of the salts.
  • Inert solvents for process step (II) - (IA) 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), NN'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), acetonitrile or Water. It is likewise possible to use mixtures of the solvents mentioned. Preferred is DMSO.
  • Suitable bases for process step (II)> (IA) are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, 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. Preference is given to sodium hydroxide.
  • the reaction (II) - »(I-A) is generally carried out in a temperature range from + 20 ° C to + 180 ° C, preferably at + 100 ° C to + 160 ° C.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., from 0.5 to 5 bar).
  • Inert solvents for process step (III) + (IV) - (IB) 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, carbon tetrachloride, trichlorethylene or chlorobenzene, Kohlenwas s horro ffe such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), NN'- Dimethylpropyleneurea (DMPU), N-methylpyrrolidon
  • Suitable bases for process step (III) + (IV) (I-B) are alkali metal hydrides such as
  • 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 methoxide, sodium or potassium ethoxide or potassium tert-butoxide
  • organic amines such as triethylamine, diisopropylethylamine, pyridine, l, 8-diazabicyclo [5.4.0] undec-7 -en (DBU) or 1,5-diazabicyclo [4.3.0] non-5-ene (DBN).
  • DBU 8-diazabicyclo [5.4.0] undec-7 -en
  • DBN 1,5-diazabicyclo [4.3.0] non-5-ene
  • the reaction (III) + (IV)> (IB) 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.
  • Inert solvents for process step (IB) + (V) - (IC) 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), dimethylsulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU) , N-methylpyrrolidone (NMP), acet
  • Suitable bases for process step (IB) + (V) (IC) 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 methoxide, sodium or potassium ethoxide or potassium tert.
  • amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide
  • organometallic compounds such as butyl lithium or phenyllithium
  • organic amines such as triethylamine, diisopropylethylamine, pyridine, l, 8-diazabicyclo [5.4.0 ] undec-7-ene (DBU) or 1,5-diazabicyclo [4.3.0] non-5-ene (DBN).
  • DBU 8-diazabicyclo [5.4.0 ] undec-7-ene
  • DBN 1,5-diazabicyclo [4.3.0] non-5-ene
  • Preference is given to lithium bis (trimethylsilyl) amide or sodium hydride.
  • the reaction (I-B) + (V) - »(I-C) is generally carried out in a temperature range of -10 ° C to + 30 ° C, preferably at 0 ° C to + 20 ° 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.
  • the compounds of the formula (II) can be prepared by reacting a compound of the formula (VI) in which R ! has the abovementioned meaning, in an inert solvent with a suitable brominating agent in a compound of formula (VII)
  • the compound of the formula (III) can be prepared by reacting a compound of the formula (II) in an inert solvent in a compound of the formula (VIII)
  • R ! has the abovementioned meaning, and then reduced in an inert solvent in the presence of a suitable reducing agent.
  • Suitable inert solvents for the bromination (VI) -> (VII) are ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, halohydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, trichlorethylene or chlorobenzene, or other solvents, such as dimethylformamide (DMF ), Dimethylsulfoxide (DMSO), NN'-dimethylpropyldiurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to dichloromethane.
  • As brominating agent in process step (VI) - »(VII) is elemental bromine with acetic acid, 1, 3-dibromo-5,5-dimethylhydantoin and in particular iV bromosuccinimide (NBS).
  • the bromination (VI) -> (VII) is generally carried out in a temperature range of -10 ° C to + 50 ° C, preferably between 0 ° C and + 30 ° 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 process step (VII)> (II) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents, such as dimethylformamide (DMF). , Dimethylsulfoxide (DMSO), TV, N'-dimethyl propyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preferred is DMSO.
  • the reaction (VII) - »(II) is generally carried out in a temperature range from + 20 ° C to + 180 ° C, preferably at + 100 ° C to + 160 ° C, optionally in a microwave.
  • 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.
  • reaction (II) (VIII) is carried out by the methods known in the art in a two-step process initially to form the iminoester with sodium methoxide in methanol at 0 ° C to + 40 ° C and subsequent nucleophilic addition of an ammonia equivalent such as ammonia or ammonium chloride in acetic acid to give the amidine (VII) at +50 to + 150 ° C.
  • Inert solvents for process step (VIII) + (IX)> (X) are alcohols, such as methanol,
  • Suitable bases for process step (VIII) + (IX) - »(X) are 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 methoxide, sodium or potassium ethoxide or potassium tert.
  • reaction (VIII) + (IX) -> (X) is generally carried out in a temperature range from + 20 ° C to + 150 ° C, preferably at + 80 ° 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 compound of formula (IX) can be prepared analogously to LFCavalieri, JFTanker, A. Bendich, J. Am. Chem. Soc., 1949, 71, 533.
  • Solvent in a temperature range of + 20 ° C to + 40 ° C under normal hydrogen pressure.
  • Inert solvents for the reduction (X)> (III) 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 Diethylenglykoldimethylether, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N'-dimethylpropylene-urea (DMPU), NM ethyl pyrrolidone ( ⁇ ), pyridine, acetone or even water. It is likewise possible to use mixtures of the solvents mentioned. Preferred are DMF and pyridine.
  • Suitable catalysts for the reduction (X) »(III) are, for example, palladium on activated carbon, platinum on carbon, palladium hydroxide or Raney nickel.
  • the reduction (X) (III) 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.
  • T 5 is (Ci-G alkyl, in an inert solvent in the presence of a suitable base with hydrazine hydrate compound of formula (XII)
  • Inert solvents for process step (XI)> (XII) are 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), dimethylsulfoxide (DMSO), N, N'-dimethylpropylene urea (DMPU), ⁇ ⁇ - ⁇ ethyl lpyrrolidon (NMP), pyridine, acetonitrile or also Water. It is likewise possible to use mixtures of the solvents mentioned. Preferred is ethanol.
  • Suitable bases for the process step (XI) -> (XII) are alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate, alkali hydrogen carbonates such as sodium or potassium bicarbonate, alkali alcoholates such as sodium or potassium methoxide, sodium 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 l, 5 -Diazabicyclo [4.3.0] non-5-ene (DBN). Preferred is triethylamine.
  • alkali metal hydroxides such as lithium, sodium or potassium hydroxide
  • alkali metal carbonates such as lithium, sodium, potassium or cesium carbonate
  • alkali hydrogen carbonates such as sodium or potassium bicarbonate
  • alkali alcoholates
  • reaction (XI) -> (XII) is generally carried out in a temperature range from + 20 ° C to + 150 ° C, preferably at + 80 ° C to + I20 ° 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.
  • Inert solvents for process step (XII) + (XIII) -> (XIV) are ethers, such as diethyl ether,
  • Suitable bases for process step (XII) + (XIII)> (XIV) are alkali metal carbonates such as
  • Lithium, sodium, potassium or cesium carbonate, or organic amines such as triethylamine, diisopropylethylamine, pyridine, l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 5-diazabicyclo- [4.3.0 ] non-5-en (DBN).
  • DBU 8-diazabicyclo [5.4.0] undec-7-ene
  • DBN 1, 5-diazabicyclo- [4.3.0 ] non-5-en
  • Preferred is triethylamine.
  • the reaction (XII) + (XIII) -> (XIV) is generally carried out in a temperature range from -20 ° C to + 40 ° C, preferably at 0 ° C to + 20 ° 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.
  • the Oxdiation (XIV)> (XV) is preferably carried out in an organic acid such as
  • cyclization (XV) ⁇ (XVI) takes place without solvent or in a solvent which is inert under the reaction conditions.
  • suitable solvents are, for example, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethyl propyleneurea (DMPU), N-methylpyrrolidone (NMP). , Pyridine, sulfolane or acetonitrile. Preferably, sulfolane is used.
  • the cyclization (XV) (XVI) is generally carried out in a temperature range of + 50 ° C to + 140 ° C, preferably at + 80 ° C to + 120 ° 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.
  • Process step (XVI) -> (VI) takes place 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, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, carbon monoxide, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N - Methylpyrrolidone (MP), pyridine, sulfolane or acetonitrile.
  • a solvent which is inert under the
  • Suitable bases for process step (XVI) - »(VI) are 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 (DB). Preferred is triethylamine.
  • the cyclization (XVI) - »(VI) is generally carried out in a temperature range from 0 ° C to + 60 ° C, preferably at + 10 ° C to + 30 ° C.
  • the compounds of the invention act as potent stimulators of soluble guanylate cyclase and possess valuable pharmacological, 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 a 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, endothelium-derived relaxing factor (EDRF), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.
  • EDRF endothelium-derived relaxing factor
  • NO donors 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, rhythm disorders of the atria and the chambers and conduction disorders such as atrio-ventricular blockade grade I-III ( ⁇ ⁇ block I-III), supraventricular tachyarrhythmia, atrial fibrillation, Vorhoff flutter, ventricular fibrillation, ventricular tachyarrhythmia, Tors ade de pointes tachycardia, extrasystoles of Vorhoffs and ventricles , AV-junctional extrasystoles, sick sinus syndrome, syncope, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disease (pericarditis, endocarditis, valvolitis,
  • cardiac failure includes both acute and chronic manifestations of cardiac insufficiency, as well as more specific or related forms of disease such as acute decompensated heart failure, right heart failure, left heart failure, global insufficiency, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects.
  • 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 valve insufficiency, combined valvular heart failure, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure as well as systolic heart failure and acute phases of Worsening of an existing chronic heart failure.
  • the compounds according to the invention can also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dysipidemias, hypertriglyceridemias, lyperlipidemias. Hypercholesterolemia, abetelipoproteinemia, sitosterolemia, xanthomatosis, Tangier disease, obesity (obesity), obesity, and combined Iperlipidemia 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 of the invention are suitable for the treatment of urological diseases such as benign Prostata syndrome (BPS), benign prostate! lyperplasia (BPH), benign prostatic hypertrophy (BPE), bladder dysfunction (BOO), lower urinary tract syndromes (LUTS, including Feiine urological syndrome (FUS)), diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urgency, 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 Prostata syndrome
  • BPH benign prostate! lyperplasia
  • BPE benign prostatic hypertrophy
  • BOO bladder dysfunction
  • LUTS lower urinary tract syndromes
  • LUTS including Feiine urological syndrome (FUS)
  • diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (
  • kidney insufficiency includes both acute and chronic forms of kidney insufficiency, as well as underlying or related kidney diseases such as renal hypoperfusion, intradialytic hypotension, obstructive uropathy, glomerulopathies, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial diseases, nephropathic disorders such as primary and congenital kidney disease, nephritis, immunological kidney diseases such as renal transplant rejection, immune complex-induced renal disease, toxicant-induced nephropathy, contrast-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive n
  • 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, cardiac insufficiency, uremia, anemia, electrolyte disorders (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metabolism.
  • sequelae of renal insufficiency such as pulmonary edema, cardiac insufficiency, uremia, anemia, electrolyte disorders (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 syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (eg, cigarette smoke induced lung emphysema) and cystic fibrosis (CF).
  • PAH pulmonary arterial hypertension
  • PH pulmonary hypertension
  • COPD chronic obstructive pulmonary disease
  • ARDS acute respiratory syndrome
  • ALI acute lung injury
  • AATD alpha-1-antitrypsin deficiency
  • CF cystic fibro
  • 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, as occur especially in situations / diseases / syndromes such as mild cognitive impairment, age-associated learning and memory disorders, age-related memory loss, vascular trauma.
  • dementia traumatic brain injury, stroke, post-stroke dementia, post-traumatic craniocerebral trauma, generalized attention deficit disorder, impaired concentration in children with learning and memory problems 'Alzheimer' illness, 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.
  • ALS amyolateral sclerosis
  • the compounds according to the invention are also suitable for regulating cerebral blood flow and are effective agents for controlling 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 traumas , Likewise, the compounds according to the invention can be used to combat pain states and tinnitus.
  • cerebral infarct events Apoplexia cerebri
  • cerebral infarct events such as stroke, cerebral ischaemias and craniocerebral traumas
  • the compounds according to the invention can be used to combat pain states 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 inflammatory bowel disease (IBD, Crohn's Disease, UC), pancreatitis , Peritonitis, rheumatoid diseases, inflammatory skin diseases as well as inflammatory eye diseases.
  • SIRS sepsis
  • MODS multiple organ failure
  • IBD chronic inflammatory bowel disease
  • UC chronic inflammatory bowel disease
  • pancreatitis inflammatory skin diseases as well as inflammatory eye diseases.
  • the compounds according to the invention can likewise 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 especially the liver, as well as dermatological fibroses and fibrotic disorders of the eye.
  • fibrotic disorders includes in particular the following terms: liver fibrosis, cirrhosis of the liver, 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), aevi, diabetic retinopathy, proliferative vitroretinopathy and connective tissue disorders (eg sarcoidosis).
  • the compounds of the invention are suitable for controlling postoperative
  • 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 compounds according to the invention 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 treatment and / or prophylaxis of cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and atherosclerosis.
  • 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 preparation 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 inventive compounds.
  • 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 disorders.
  • Suitable combinations of active compounds are by way of example and preferably mentioned:
  • organic nitrates and NO donors such as sodium nitrate, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;
  • cGMP cyclic guanosine monophosphate
  • PDE phosphodiesterases
  • Antithrombotic agents by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;
  • Antihypertensive agents by way of example and by way of preference from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocortics co-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 used in combination with a platelet aggregation inhibitor, such as by way of example and preferably aspirin, clopidogrel, ticlopidine or dipyridamole. administered.
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, such as by way of example and preferably ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as by way of example and preferably ximelagatran, dabigatran, melagatran, bivalirudin or Clexane.
  • the compounds according to the invention are used in combination with a GPIIb / IIIa antagonist, such as, for example and preferably, Tyrol! or abciximab.
  • a GPIIb / IIIa antagonist such as, for example and preferably, Tyrol! 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-1 76b.
  • a factor Xa inhibitor such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-1 76b.
  • Apixaban, otamixaban, fidexaban, razaxaban, fondaparinux such as by way of example and preferably rivaroxaban (BAY 59-7939), DU-1 76b.
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • LMW low molecular weight
  • the compounds according to the invention are administered in combination with a vitamin K antagonist, such as by way of example and preferably coumarin.
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin ⁇ antagonists, ACE inhibitors, endothelin antagonists,
  • Renin inhibitors alpha-receptor blockers, beta-receptor blockers, Min eralocorticoid 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 B, such as by way of example and preferably prazosin.
  • the compounds of the invention are used in combination with a beta-receptor blocker, as exemplified and preferably Propranolol, Atenolol, Timolol, Pindolol, Alprenolol, Oxprenolol, Penbutolol, Bupranolol, Metiprolanol, Nadolol, Mepindolol, Carazalol, Sotalol, Metoprolol, Betaxolol, Celiprolol, Bisoprolol, Carteolol, Esmolol, Labetalol, Carvedilol, Adaprolol, Landiolol, Nebivolol, Epanolol or Bucindolol administered.
  • a beta-receptor blocker as exemplified and preferably Propranolol, Atenolol, Timolol, Pindolol, Alprenol
  • the compounds of the invention are administered in combination with an angiotensin AII antagonist such as, by way of example and by way of example, losartan, candesartan, valsartan, telmisartan or embursatan.
  • angiotensin AII antagonist such as, by way of example and by way of example, losartan, candesartan, valsartan, telmisartan or embursatan.
  • the compounds according to the invention in combination with an ACE inhibitor, such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, Delaprii.
  • an ACE inhibitor such as by way of example and preferably enalapril, captopril, lisinopril, ramipril, Delaprii.
  • the compounds of 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 according to 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 Min eralocorticoid receptor antagonists, such as by way of example and preferably spironolactone or eplerenone.
  • a Min eralocorticoid receptor antagonists such as by way of example and preferably spironolactone or eplerenone.
  • the compounds of the present invention will be used in combination with a grinding endiuretic 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 for example, hydrochlorothiazide, chlorthalidone, xipamide. and indapamide.
  • a grinding endiuretic such as furosemide, torasemide, bumetanide and piretanide
  • potassium sparing diuretics such as amiloride and triamterene with aldosterone antagonists such as spironolactone, potassium canrenoate and eplerenone and thiazide diuretics
  • hydrochlorothiazide chlorthalidone
  • xipamide. and indapamide indapamide
  • the fat metabolism changing agents are preferably compounds from the
  • CETP inhibitors 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-inhibitors delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein a) antagonists understood.
  • 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 vaccines (CETi-1).
  • the compounds of the invention will be administered in combination with a thyroid receptor agonist, such as by way of example and preferably D-thyroxine. 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist such as by way of example and preferably D-thyroxine. 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, 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, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.
  • an ACAT inhibitor such as, for 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 5015 16 or BAY 68-5042.
  • the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • a cholesterol absorption inhibitor such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.
  • the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, orlistat.
  • a lipase inhibitor such as, for example and preferably, orlistat.
  • the compounds according to the invention are administered in combination with a polymeric bile acid adsorbent such as, for example and preferably, 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 according to the invention are pharmaceutical compositions containing at least one compound according to 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. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as
  • Implant or stent
  • the compounds according to the invention can be administered in suitable administration forms.
  • inventive compounds 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-dissolving or insoluble coatings which control the release of the compound of the invention, rapidly disintegrating in the oral cavity
  • the parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • involvement of resorption eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • par- enteral administration are suitable as application forms, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicaments including powder inhalers, ebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (eg plasters)
  • milk pastes, foams, powdered powders, implants or stents.
  • compositions 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.
  • adjuvants include, among others.
  • Excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders for example polyvinyl pyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg antioxidants such as ascorbic acid
  • dyes eg inorganic pigments such as iron oxides
  • flavor and / or odoriferous agents for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitol oleate
  • binders for example polyvinyl pyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers e
  • the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
  • Step a) [phenyldiazenyl jmalononitrile To 10.00 g (107.377 mmol) of aniline and ice (32 g) were concentrated in an ice bath. Hydrochloric acid (17.84 ml) and then a solution of 7.409 g (107.377 mmol) of sodium nitrite in water (18 ml) was added dropwise between 0 ° C and 5 ° C and stirred at 0 ° C for 30 min.
  • Step h) 2- [7- (2-Fluorobenzyl) imidazo [1,5-b] pyridazin-5-yl] -5- [(E) -phenyldiazenyl] pyrimidine-4,6-diamine 2.85 g (16,745 mmol) [Phenyldiazenyl] malononitrile (step a)) were dissolved in DMF (0.5 ml) and added dropwise to a solution of 4.266 g (13.954 mmol) Example 7A in DMF (0.5 ml) and triethylamine (2.139 ml) at exactly 85 ° C. The mixture was then stirred at 100 ° C.
  • the precipitated crystals of the target product were washed with ethyl acetate (50 ml) and diethyl ether (50 ml).
  • the crystals of the first precipitate were washed with ethyl acetate (2000 ml) and dichloromethane (1000 ml), combined with the other crystals and dried under high vacuum. 5.03 g of the target compound were obtained in 90% purity (48% of theory).
  • Example 9A 150 mg (0.378 mmol) of Example 9A were reacted with 46.38 mg (0.378 mmol) of propyl chloroformate. The residue was purified by preparative HPLC (acetonitrile: water (+0.05% formic acid) gradient). 24 mg of the target compound were obtained (1 1% of the TL).
  • Example 9A 150 mg (0.378 mmol) of Example 9A with 41.07 mg (0.378 mmol)
  • Example 2 400 mg (0.979 mmol) of Example 2 were initially charged in THF (5 ml) at 0 ° C. and admixed with 1,077 ml (1,077 mmol) of bis (trimethylsilyl) sodium amide (IM in THF). After 30 min at 0 ° C 0.157 ml (1959 mmol) of ethyl iodide was added and stirred at 20 ° C for 16 hours. It was then added to water and extracted with ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative I IPLC (acetonitrile: water (+0.05% formic acid) gradient). 209 mg of the target compound were obtained (44% of theory).
  • reaction mixture was stirred for 10 minutes in an ice bath and then treated with 2 ml of saturated aqueous atriumhydrogencarbonat solution.
  • the evaporated mixture was purified by preparative HPLC (acetonitrile: water (+0.1% formic acid) gradient). 25 mg (20% of theory) of the target compound were obtained.
  • Example 2 80 mg (0.196 mmol) of Example 2 were reacted in analogy to Example 8 with 74 mg (0.392 mmol) of 2-fluorobenzyl bromide. 77 mg of the target compound were obtained (70% of theory).
  • Example 2 80 mg (0.196 mmol) of Example 2 were reacted in analogy to Example 8 with 74 mg (0.392 mmol) of 3-fluorobenzyl bromide. 49 mg of the target compound were obtained (44% of theory).
  • Example 2 80 mg (0.196 mmol) of Example 2 were reacted in analogy to Example 8 with 74 mg (0.392 mmol) of 4-fluorobenzyl bromide. 40 mg of the target compound were obtained (36% of theory).
  • Example 10A 314 mg (about 0.687 mmol) of Example 10A were initially charged in TI IF (10 ml) at 0 ° C. and admixed with 0.687 ml (0.687 mmol) of an IM solution of bis (trimethylsilyl) sodium amide in THF. After 30 minutes at 0 ° C., the reaction mixture was stirred at 20 ° C. for 30 minutes. It was then added to water and extracted with ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated.
  • the force of contraction is detected with Statham UC ' 2 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% (IC50 value).
  • the standard application volume is 5 ⁇ , the DMSO content in the bath solution corresponds to 0.1%.
  • Radiotelemetric blood pressure measurement on conscious, spontaneously hypertensive rats A commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA, is used for the blood pressure measurement on awake rats described below.
  • the system consists of 3 main components:
  • Implantable transmitters Physiotel® telemetry transmitters
  • Receivers Physiotel® receivers
  • a multiplexer DSI Data Exchange Matrix
  • Data acquisition computer are connected.
  • the telemetry system allows 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 TAH PA - C40 telemetry transmitters are surgically implanted into the experimental animals under aseptic conditions at least 14 days before the first trial.
  • the animals so instrumented are repeatedly used after healing of the wound and ingrowth of the implant.
  • the fasting animals are anesthetized with pentobabital (Nembutal, Sanofi: 50 mg / kg i.p.) and shaved and disinfected on the ventral side.
  • pentobabital Nembutal, Sanofi: 50 mg / kg i.p.
  • tissue adhesive VetBonD TM, 3M.
  • the transmitter housing is fixed intraperitoneally to the B wall muscles 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 radiated signals can by a
  • Data acquisition system (Dataquest TM A.R.T. for WINDOWS, DSI) are recorded online 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.
  • SBP Systolic blood pressure
  • DBP Diastolic blood pressure
  • MAP Mean arterial 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). As Leewert be here 2 hours before application assuming that the selected record comprises the period from 7:00 on the trial day to 9:00 on the following day.
  • the data is smoothed over a pre-settable time by averaging (15 minutes average) and transferred as a text file to a disk.
  • the presorted and compressed measured values are transferred to Excel templates and displayed in tabular form.
  • the filing of the collected data takes place per experiment day in a separate folder that bears the test number. Results and test reports are sorted in folders and sorted by paper.
  • 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 according to the invention is dissolved in a concentration below the saturation solubility in a physiologically tolerated solvent (for example isotonic saline solution, glucose solution 5% and / or PEG 400 solution 30%). The solution is sterile filtered and bottled in sterile and pyrogen-free injection containers.

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

Abstract

Nouvelles imidazopyridazines substituées, procédé de production desdites imidazopyridazines et leur utilisation seules ou en combinaison, 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 cardio-vasculaires.
EP12724584.3A 2011-05-06 2012-05-02 Imidazopyridazines substituées et leur utilisation Withdrawn EP2705038A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102011075398A DE102011075398A1 (de) 2011-05-06 2011-05-06 Substituierte Imidazopyridazine und ihre Verwendung
PCT/EP2012/058048 WO2012152630A1 (fr) 2011-05-06 2012-05-02 Imidazopyridazines substituées et leur utilisation

Publications (1)

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EP2705038A1 true EP2705038A1 (fr) 2014-03-12

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EP12724584.3A Withdrawn EP2705038A1 (fr) 2011-05-06 2012-05-02 Imidazopyridazines substituées et leur utilisation

Country Status (8)

Country Link
US (1) US9150580B2 (fr)
EP (1) EP2705038A1 (fr)
JP (1) JP6100756B2 (fr)
CN (1) CN103842363B (fr)
CA (1) CA2834903A1 (fr)
DE (1) DE102011075398A1 (fr)
HK (1) HK1198646A1 (fr)
WO (1) WO2012152630A1 (fr)

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Publication number Priority date Publication date Assignee Title
AU2013353117A1 (en) 2012-11-30 2015-06-04 Astellas Pharma Inc. Imidazopyridine compound
WO2015106268A1 (fr) 2014-01-13 2015-07-16 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de la sgc pour le traitement de troubles neuromusculaires
BR112017023855A2 (pt) 2015-05-06 2018-07-17 Bayer Pharma Aktiengesellschaft o uso de estimulantes de sgc, ativadores de scg, em separado e combinações com inibidores de pde5 para o tratamento de úlceras digitais (du) concomitantes à esclerose múltipla (ssc)
ES2839248T5 (es) 2015-07-23 2024-02-22 Bayer Pharma AG Estimuladores y/o activadores de la guanilatociclasa soluble (sGC) en combinación con un inhibidor de la endopeptidasa neutra (inhibidor de NEP) y/o un antagonista de angiotensina AII y su uso
EA201891416A1 (ru) 2015-12-14 2018-12-28 Айронвуд Фармасьютикалз, Инк. ПРИМЕНЕНИЕ СТИМУЛЯТОРОВ sGC ДЛЯ ЛЕЧЕНИЯ ДИСФУНКЦИИ ЖЕЛУДОЧНО-КИШЕЧНОГО СФИНКТЕРА
CN109890379A (zh) 2016-10-11 2019-06-14 拜耳制药股份公司 包含sGC活化剂和盐皮质激素受体拮抗剂的组合产品
CA3039734A1 (fr) 2016-10-11 2018-04-19 Bayer Pharma Aktiengesellschaft Combinaison contenant des stimulateurs gcs et des antagonistes du recepteur des mineralocorticoides
EP3554488A2 (fr) 2016-12-13 2019-10-23 Cyclerion Therapeutics, Inc. Utilisation de stimulateurs de sgc pour le traitement de la motilité sophagienne
KR102615821B1 (ko) 2017-04-11 2023-12-21 선샤인 레이크 파르마 컴퍼니 리미티드 불소-치환된 인다졸 화합물 및 이의 용도
CN112384213A (zh) 2018-05-15 2021-02-19 拜耳公司 用于治疗与神经纤维敏化有关的疾病的1,3-噻唑-2-基取代的苯甲酰胺
JP2021530491A (ja) 2018-07-11 2021-11-11 サイクレリオン・セラピューティクス，インコーポレーテッド ミトコンドリア（ｍｉｔｏｃｈｏｎｒｉａｌ）障害の処置のためのｓＧＣ刺激剤の使用
WO2020164008A1 (fr) 2019-02-13 2020-08-20 Bayer Aktiengesellschaft Procédé de préparation de microparticules poreuses

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DE19642255A1 (de) 1996-10-14 1998-04-16 Bayer Ag Verwendung von 1-Benzyl-3-(substituierten-hetaryl) -kondensierten Pyrazol-Derivaten
DE19834044A1 (de) 1998-07-29 2000-02-03 Bayer Ag Neue substituierte Pyrazolderivate
DE10220570A1 (de) 2002-05-08 2003-11-20 Bayer Ag Carbamat-substituierte Pyrazolopyridine
DK1869049T3 (da) * 2005-03-21 2009-05-18 Lilly Co Eli Imidazopyridazinforbindelser
DE102006043443A1 (de) * 2006-09-15 2008-03-27 Bayer Healthcare Ag Neue aza-bicyclische Verbindungen und ihre Verwendung
EP2240488B1 (fr) * 2008-02-06 2016-11-02 Bristol-Myers Squibb Company Imidazopyridazines substituées utiles en tant qu'inhibiteurs de kinase
CA2743864A1 (fr) 2008-11-25 2010-06-10 Merck Sharp & Dohme Corp. Activateurs de guanylate cyclase soluble
DE102009004245A1 (de) * 2009-01-09 2010-07-15 Bayer Schering Pharma Aktiengesellschaft Neue anellierte, Heteroatom-verbrückte Pyrazol- und Imidazol-Derivate und ihre Verwendung
US9284301B2 (en) * 2010-03-25 2016-03-15 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators

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Publication number Publication date
DE102011075398A1 (de) 2012-11-08
JP2014513113A (ja) 2014-05-29
CN103842363A (zh) 2014-06-04
US20140113900A1 (en) 2014-04-24
HK1198646A1 (en) 2015-05-22
WO2012152630A1 (fr) 2012-11-15
US9150580B2 (en) 2015-10-06
JP6100756B2 (ja) 2017-03-22
CN103842363B (zh) 2017-09-26
CA2834903A1 (fr) 2012-11-15

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