EP3137464A1 - Imidazo[1,2-a]pyridines utilisées en tant que stimulateurs de la guanylate cyclase pour traiter des maladies cardiovasculaires - Google Patents

Imidazo[1,2-a]pyridines utilisées en tant que stimulateurs de la guanylate cyclase pour traiter des maladies cardiovasculaires

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Publication number
EP3137464A1
EP3137464A1 EP15721624.3A EP15721624A EP3137464A1 EP 3137464 A1 EP3137464 A1 EP 3137464A1 EP 15721624 A EP15721624 A EP 15721624A EP 3137464 A1 EP3137464 A1 EP 3137464A1
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EP
European Patent Office
Prior art keywords
substituted
hydrogen
alkyl
fluorine
formula
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Withdrawn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
EP15721624.3A
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German (de)
English (en)
Inventor
Alexandros Vakalopoulos
Markus Follmann
Frank Wunder
Johannes-Peter Stasch
Tobias Marquardt
Lisa Dietz
Volkhart Min-Jian Li
Nicholas Charles Ray
Ines VUJASINOVIC
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
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Bayer Pharma AG
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Publication date
Application filed by Bayer Pharma AG filed Critical Bayer Pharma AG
Publication of EP3137464A1 publication Critical patent/EP3137464A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • 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 heterocyclyl and heteroaryl-substituted imidazo [l, 2 a] pyridines, 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. On the other hand, heme-free preparations can not be stimulated by NO. Carbon monoxide (CO) is also able to bind to the central iron atom of the heme, with stimulation by CO being markedly lower 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, leading, for example, to hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, 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.
  • the object of the present invention was to provide new substances which act as stimulators of soluble guanylate cyclase, and as such are suitable for the treatment and / or prophylaxis of diseases.
  • the present invention relates to compounds of the general formula (I)
  • A is CH 2 , CD 2 or CH (CH 3 ),
  • R 1 is (C 3 -C 7 ) -cycloalkyl, phenyl or pyridyl, where (C 3 -C 4) -cycloalkyl having 1 to 4 substituents independently of one another selected from the group of fluorine, trifluoromethyl and (C 1 -C 4 -alkyl may be substituted .
  • E is carbon or nitrogen
  • n is 0, 1 or 2
  • X is oxygen or nitrogen, in which nitrogen is substituted with hydrogen or hydroxy
  • R 7 is hydrogen or (GC 6 ) -alkyl, in which (GG alkyl may be substituted by amino or hydroxy and in which (C 1 -C 6 ) -alkyl may be substituted up to five times by fluorine,
  • R 8 is hydrogen or (GC 4 ) -alkyl, in which (GC / O-alkyl may be substituted up to five times by fluorine, R 9 is hydrogen or (GC 4 ) -alkyl, wherein (GC-alkyl may be substituted up to five times by fluorine, or
  • R and R together with the carbon atom to which they are attached form a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle, wherein the 3- to 7-membered carbocycle and the 4- to 7-membered Heterocycle may in turn be substituted with 1 or 2 substituents independently of one another selected from the group fluorine and (GC-alkyl,
  • R 10 is hydrogen or (GC 8 ) alkyl, wherein (Ci-Cs) alkyl may be substituted with amino or hydroxy, and wherein (Ci-Cs) alkyl may be substituted up to five times with fluorine
  • R 11 is Is hydrogen or (GC 8 ) -alkyl, in which (C 1 -C 5) -alkyl can be substituted by amino or hydroxyl, and in which (C 1 -C 5) -alkyl may be substituted up to five times by fluorine, or from 5 to 10 -Helige heteroaryl, wherein 5- to 10-membered heteroaryl is substituted by (Ci-Cs) alkoxy, wherein (Ci-Cs) alkoxy is substituted with amino, and wherein (Ci-Cs) alkoxy up to five times with Fluorine may be substituted, and said 5- to 10-membered heteroaryl having 1 or 2 substituents independently selected from the group halogen, cyano, trifluor
  • R 4 is hydrogen
  • R 5 is hydrogen, halogen, cyano, (GC 4 ) -alkyl, (C 2 -C 4 ) -alkynyl, (C 1 -C 4 ) -alkoxy, (C 3 -C 5) -cycloalkyl, Difluoromethoxy, difluoromethyl, trifluoromethyl, 4- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
  • R 6 is hydrogen or halogen, and their oxides, salts, solvates, salts of the oxides and solvates of the 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.
  • 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 of the invention may exist in different stereoisomeric forms depending on their structure, 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 encompasses the enantiomers and diastereoisomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isotopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 L
  • Certain 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 drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 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;
  • 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 by the methods described below. Examples reproduced by appropriate isotopic modifications of the respective reagents and / or starting compounds are used.
  • 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 in each case the number of carbon atoms specified.
  • alkyl is a linear or branched alkyl radical having in each case the number of carbon atoms specified.
  • Cycloalkyl or carbocycle in the context of the invention is a monocyclic, saturated alkyl radical having in each case the number of ring carbon atoms specified. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Alkoxy in the context of the invention is 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.
  • Alkoxycarbonyl in the context of the invention are a linear or branched alkoxy radical having 1 to 4 carbon atoms and a carbonyl group attached to the oxygen atom. Examples which may be mentioned by way of example are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
  • Alkylsulfonyl in the context of the invention is a linear or branched alkyl radical having 1 to 4 carbon atoms, which is bonded via a sulfonyl group.
  • a sulfonyl group By way of example and preferably its name: methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl and tert-butylsulfonyl.
  • a 4- to 7-membered heterocycle or 4- to 7-membered heterocyclyl in the context of the invention is a monocyclic, saturated heterocycle having a total of 4 to 7 ring atoms, one or two ring heteroatoms from the series N, O, S , SO and / or SO 2 and is linked via a ring carbon atom or optionally a ring nitrogen atom.
  • Examples which may be mentioned are: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, Piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl and hexahydro-1,4-diazepinyl.
  • Heteroaryl is in the context of the invention for a monocyclic aromatic heterocycle (heteroaromatic) having a total of 5 to 10 ring atoms, which contains up to three identical or different ring heteroatoms from the series N, O and / or S and via a ring carbon atom or optionally linked via a ring nitrogen atom.
  • furyl By way of example and by way of preference: furyl, pyrrolyl, thienyl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, imidazolyl, 1, 3-thiazol-5-yl, 1,3-thiazol-2-yl, l, 3-oxazol-5-yl, l, 3-oxazol-2-yl, isoxazolyl, isothiazolyl, triazolyl, 1,3,4-oxadiazol-2-yl, l, 2,4-oxadiazol-3-yl, l, 2,4-oxadiazol-5-yl, l, 3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, l, 2,4-thiadiazol-5-yl, pyridyl, Pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
  • the end point of the line on which the symbols *, # or ## stand does not represent a carbon atom or a CH 2 group but is part of the group Binding to the respectively designated atom to which R 3 or R 1 is bonded.
  • 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, arresting, alleviating, attenuating, restraining, reducing, suppressing, restraining or curing a disease, a disease, a disease, an injury or a medical condition , the unfolding, the 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.
  • the treatment or the prevention of a disease, a disease, a disease, an injury or a health disorder can be partial or complete.
  • A is CH 2 or CD 2 ,
  • R 1 is cyclohexyl, phenyl or pyridyl, wherein phenyl is substituted with 1 to 4 substituents independently selected from the group of fluorine, bromine, chlorine, cyano and methyl, and wherein pyridyl having 1 or 2 substituents independently selected from the group fluorine , Cyano and methyl,
  • R 2 is (C 1 -C 4 -alkyl, cyclopropyl or trifluoromethyl,
  • R 3 is a group of the formula
  • E is carbon or nitrogen, n is 0 or 1,
  • X is oxygen or nitrogen, in which nitrogen may be substituted by hydrogen or hydroxy, is hydrogen or (Ci-Ce) alkyl, wherein (Ci-Ce) alkyl may be substituted with amino or hydroxy, and in which (C 1 -C 6) -alkyl can be substituted up to five times by fluorine,
  • R 8 is hydrogen or (GC 4 ) -alkyl, in which (GC-alkyl may be substituted up to five times by fluorine,
  • R 9 is hydrogen or ( Ci-C 4 ) -alkyl, wherein (GC-alkyl may be substituted up to five times with fluorine, or
  • R 8 and R 9 together with the carbon atom to which they are attached form a 3- to 7-membered carbocycle wherein the 3- to 7-membered carbocycle having 1 or 2 substituents independently selected from the group consisting of fluorine and methyl substituted can be,
  • R 10 is hydrogen or (GC 8 ) -alkyl, in which (C 1 -C 5) -alkyl can be substituted by amino or hydroxyl, and in which (C 1 -C 5) -alkyl can be substituted up to five times by fluorine,
  • R 11 is hydrogen or (GC 8 ) alkyl, wherein (Ci-Cs) alkyl may be substituted with amino or hydroxy, and wherein (Ci-Cs) alkyl may be substituted up to five times with fluorine, or for a Group of formula stands, where
  • R is (C 1 -C 8 ) -alkoxy, in which (C 1 -C 5 ) -alkoxy is substituted by amino, and in which (C 1 -C 5) -alkoxy may be substituted up to five times by fluorine, and for hydrogen, cyano, trifluoromethyl , Difluoromethyl or methyl, represents hydrogen, fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl or methyl, represents hydrogen, fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl or methyl, represents hydrogen, cyano, trifluoromethyl, difluoromethyl or methyl, represents hydrogen, fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl or methyl, represents hydrogen, fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl or methyl,
  • R 4 is hydrogen
  • R 5 is hydrogen, chlorine, cyano, methyl, methoxy or cyclopropyl
  • R 6 is hydrogen or fluorine, and their oxides, salts, solvates, salts of the oxides and solvates of the oxides and salts.
  • R 6 is hydrogen or fluorine, and their oxides, salts, solvates, salts of the oxides and solvates of the oxides and salts.
  • A is CH 2 , a phenyl group of the formula
  • attachment site is A
  • R 1S, R iy and R are each independently hydrogen or fluorine, with the proviso that at least two of R 18, R 19, R 20 are different from hydrogen, is methyl, a group of the formula
  • X is oxygen or nitrogen, wherein nitrogen with hydrogen or hydroxy which may be substituted
  • R 7 is hydrogen
  • R 8 is hydrogen, methyl or ethyl, where methyl may be substituted up to three times by fluorine, and wherein ethyl may be substituted up to five times by fluorine
  • R 9 represents hydrogen, methyl or ethyl, in which methyl may be substituted up to three times by fluorine, and in which ethyl may be substituted up to five times by fluorine, or
  • R 8 and R 9 together with the carbon atom to which they are attached form a 3- to 6-membered carbocycle
  • R 10 is hydrogen or (C 1 -C 8 ) -alkyl, in which (C 1 -C 5 ) -alkyl is substituted by amino, and in which (C 1 -C 5) -alkyl may be substituted up to five times by fluorine
  • R 11 is hydrogen or (GC 8 ) -alkyl, wherein (Ci-Cs) -alkyl is substituted with amino, and wherein (Ci-Cs) -alkyl can be substituted up to five times with fluorine, or for a group of the formula
  • R 13 is hydrogen or methyl
  • R 14 is hydrogen, fluorine, chlorine or methyl
  • R 15 is hydrogen, fluorine, chlorine or methyl
  • R 16 is hydrogen or methyl
  • R 17 is hydrogen, fluorine, chlorine or methyl
  • R 4 is hydrogen
  • R 5 is hydrogen, chlorine or methyl
  • R 6 represents hydrogen
  • attachment site is A
  • R 18 , R 19 and R 2 are independently hydrogen or fluoro, provided that at least two of R 18 , R 19 , R : o are other than hydrogen, is methyl, is a group of the formula
  • X is oxygen or nitrogen, in which nitrogen may be substituted by hydrogen or hydroxy, is hydrogen
  • R 8 is hydrogen, methyl or ethyl wherein methyl may be substituted up to three times by fluorine, and wherein ethyl may be substituted up to five times by fluorine
  • R 9 is hydrogen, methyl or ethyl wherein methyl is up to three times fluorine and wherein ethyl may be substituted up to five times with fluorine, or R 8 and R 9 together with the carbon atom to which they are attached, one
  • R 10 is hydrogen or (GC 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl is substituted by amino, and in which (C 1 -C 6 ) -alkyl may be substituted up to five times by fluorine,
  • R 11 is hydrogen or (GC 6 ) -alkyl, wherein (C 1 -C 6 ) -alkyl is substituted by amino, and wherein (C 1 -C 6 ) -alkyl can be substituted up to five times by fluorine, or a group of the formula
  • R 12 is (C 1 -C 6 ) -alkoxy, in which (C 1 -C 6 ) -alkoxy is substituted by amino, and in which (C 1 -C 6 ) -alkoxy may be substituted up to five times by fluorine,
  • R 13 is hydrogen
  • R 14 is hydrogen or fluorine
  • R 15 is hydrogen or fluorine
  • R 4 is hydrogen
  • R 5 is hydrogen, chlorine or methyl
  • R 6 is hydrogen, and their TV oxides, salts, solvates, salts of the TV oxides and solvates of the TV oxides and salts.
  • A is CH 2 , and their TV oxides, salts, solvates, salts of the TV oxides and solvates of the TV oxides and salts.
  • R 18 , R 19 and R 20 independently of one another are hydrogen or fluorine, with the proviso that at least two of the radicals R 18 , R 19 , R 20 are different from hydrogen, and Oxides, salts, solvates, salts of oxides and solvates of oxides and salts.
  • R 1 is a phenyl group of the formula
  • R 18 is hydrogen
  • R 19 and R 20 are fluorine, and their oxides, salts, solvates, salts of oxides and solvates of the oxides and salts.
  • R 2 is methyl
  • R 3 is a group of the formula
  • E is carbon or nitrogen
  • n 1,
  • X is oxygen or nitrogen
  • R 7 is hydrogen
  • R 8 is hydrogen, methyl or ethyl
  • methyl may be substituted up to three times by fluorine
  • R 9 is hydrogen, methyl or ethyl
  • methyl may be substituted up to three times with fluorine, and wherein ethyl may be substituted up to five times with fluorine or
  • R 10 is hydrogen or (GC 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl is substituted by amino, and in which (C 1 -C 6 ) -alkyl can be substituted up to five times by fluorine
  • R 11 is hydrogen or ( C 1 -C 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl is substituted by amino, and in which (C 1 -C 6 ) -alkyl may be substituted up to five times by fluorine, or a group of the formula
  • R 12 is (C 1 -C 6 ) -alkoxy, in which (C 1 -C 6 ) -alkoxy is substituted by amino, and in which (C 1 -C 6 ) -alkoxy may be substituted up to five times by fluorine, R 13 is hydrogen,
  • R 14 is hydrogen or fluorine
  • R 15 is hydrogen or fluorine
  • R 3 is a group of the formula
  • E is carbon or nitrogen
  • n 1,
  • X is oxygen or nitrogen
  • R 7 is hydrogen
  • R 8 is hydrogen, methyl or ethyl
  • methyl may be substituted up to three times by fluorine
  • R 9 is hydrogen, methyl or ethyl, wherein methyl may be substituted up to three times by fluorine, and wherein ethyl may be substituted up to five times by fluorine, or R 8 and R 9 taken together with the carbon atom to which they are bonded, one
  • R 10 is hydrogen or (GC 6 ) -alkyl, in which (C 1 -C 6 ) -alkyl is substituted by amino, and in which (C 1 -C 6 ) -alkyl may be substituted up to five times by fluorine,
  • R 11 is hydrogen or (GC 6 ) -alkyl, wherein (Ci-Ce) -alkyl is substituted with amino, and wherein (Ci-Ce) -alkyl can be substituted up to five times with fluorine, and their -oxides, salts , Solvates, salts of oxides and solvates of oxides and salts.
  • R 3 is a group of the formula
  • X is oxygen or nitrogen, in which nitrogen may be substituted by hydrogen or hydroxy
  • R 7 is hydrogen
  • R 8 is hydrogen, methyl or ethyl wherein methyl may be substituted up to three times by fluorine, and wherein ethyl may be substituted up to five times by fluorine
  • R 9 is hydrogen, methyl or ethyl wherein methyl is up to three times fluorine and wherein ethyl may be substituted up to five times with fluorine, or R 8 and R 9 together with the carbon atom to which they are attached, one
  • E is carbon or nitrogen
  • n 1,
  • R 7 is hydrogen
  • R 8 is methyl or ethyl
  • methyl may be substituted up to three times by fluorine
  • R 9 is hydrogen, methyl or ethyl
  • methyl may be substituted up to three times by fluorine
  • R 3 is a group of the formula
  • R 12 is (C 1 -C 6 ) -alkoxy
  • R 13 is hydrogen
  • R 14 is hydrogen or fluorine
  • R 15 is hydrogen or fluorine
  • R 3 is a group of the formula
  • R 12 is (C 1 -C 6 ) -alkoxy
  • R 14 is hydrogen
  • R 15 is hydrogen
  • their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts preference is also given to compounds of the formula (I) in which R 5 is hydrogen, chlorine or methyl, and also their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts .
  • R 5 is hydrogen, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 5 is chlorine, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 5 is methyl, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • Another object of the invention is a process for the preparation of the compounds of the formula (I) according to the invention, characterized in that a compound of the formula (II)
  • R 1 , R 2 , R 4 , R 5 and R 6 are each as defined above and T 1 is (Ci-C 4 ) alkyl or benzyl, in an inert solvent in the presence of a suitable base or acid
  • R 3A has the meanings given above for R 3 , and is hydrogen or (Ci-C alkyl, or both radicals T 2 together form a -C (CH 3 ) 2 C (CH 3 ) 2 bridge, to form a compound of Formula (IA)
  • R 10A - X 2 (VIII) in which represents a suitable leaving group, in particular chlorine, bromine, iodine, mesylate, triflate or tosylate, and is (Ci-C 8 ) -alkyl, wherein (Ci-Cs) alkyl substituted with nitro, and wherein (Ci-Cs) alkyl may be substituted up to five times with fluorine, to compounds of formula (VII-A) or (VII-B)
  • R 10A is (C 1 -C 8 ) -alkyl, wherein (C 1 -C 5 ) -alkyl is substituted by nitro, and in which (C 1 -C 5) -alkyl can be substituted up to five times by fluorine, and the nitro compounds in an inert one Solvent in the presence of Raney nickel or palladium / carbon in a hydrogen atmosphere in compounds of formula (IB and IC)
  • Scheme 2 [a): cesium carbobate, dioxane, RT; b): Raney nickel, EtOH, H2, 1 bar, RT].
  • the hydrolysis of the ester group T 1 of the compounds of formula (II) is carried out by conventional methods by treating the esters in inert solvents with acids or bases, wherein in the latter the initially formed salts are converted by treatment with acid into the free carboxylic acids ,
  • the ester cleavage is preferably carried out with acids.
  • the ester cleavage is preferably carried out by hydrogenolysis with palladium on activated carbon or Raney nickel.
  • Suitable inert solvents for this reaction are water or the organic solvents customary for ester cleavage.
  • These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, dichloromethane, dimethylformamide or dimethyl sulfoxide , It is likewise possible to use mixtures of the solvents mentioned. In the case of basic ester hydrolysis, preference is given to using mixtures of water with dioxane, tetrahydrofuran, methanol and / or ethanol.
  • the usual inorganic bases are suitable. These include preferably alkali or alkaline earth hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Particularly preferred are sodium or lithium hydroxide.
  • Suitable acids for the ester cleavage are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water.
  • Hydrogen chloride or trifluoroacetic acid are preferred in the case of the tert-butyl esters and hydrochloric acid in the case of the methyl esters.
  • the ester cleavage is generally carried out in a temperature range from 0 ° C to + 100 ° C, preferably at + 0 ° C to + 50 ° C.
  • Suitable solvents for process step (III) - (IV) are water and dioxane. It is likewise possible to use mixtures of the solvents mentioned.
  • Suitable acids for process step (III) - (IV) are hydrogen chloride / hydrochloric acid, hydrogen bromide / hydrobromic acid, sulfuric acid, acetic acid or mixtures thereof, optionally with the addition of water. Hydrochloric acid is preferably used.
  • the decarboxylation (III) - (IV) is generally carried out in a temperature range from + 20 ° C to + 100 ° C, preferably at 75 ° C to + 100 ° 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.
  • Suitable solvents for process step (IV) - (V) are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or Glycoldimethyl ether, or other solvents such as acetone, dichloromethane, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using methanol and / or ethanol.
  • Suitable halogen sources in the reaction (IV) - (V) are, for example, / V-bromosuccinimide, / V-chlorosuccinimide, / V-iodo-succinimide, chlorine, bromine or iodine. Preference is given to using / V-bromosuccinimide.
  • the reaction (IV) - (V) is generally carried out in a temperature range of + 20 ° C to + 100 ° C, preferably in the range of + 20 ° C to + 80 ° C.
  • the reaction may be carried out at normal, elevated or reduced pressure (e.g., in the range of 0.5 to 5 bar). Generally, one works at normal pressure.
  • Process step (V) + (VI) - (I-A) is carried out in a solvent which is inert under the reaction conditions.
  • suitable solvents 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 other solvents such as 1,2-dimethoxyethane (DME ), Dimethylformamide (DMF), dimethylsulfoxide (DMSO), JV, JV'-dimethylpropyleneurea (DMPU), / V-methylpyrrolidone (NMP), pyridine, acetonitrile, toluene or even water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to methanol, ethanol, toluene and water
  • the reaction (V) + (VI) - (IA) can be carried out in the presence of a suitable palladium and / or copper catalyst.
  • a suitable palladium catalyst for example, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), bis (tri-tert-butyl-phosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, bis (acetonitrile) palladium (II) chloride, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and corresponding dichloromethane.
  • phosphine ligands such as (2-biphenyl) di-iron.
  • Suitable bases for this reaction are the usual inorganic or organic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium or potassium, sodium or potassium or sodium or Potassium tert-butoxide, alkali hydrides such as sodium or potassium hydride, amides such as sodium amide, lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as triethylamine, methylmorpholine, N-methylpiperidine, A ⁇ Diisopropylethylamine, pyridine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec
  • the reaction (V) + (VI) - (I-A) is generally carried out in a temperature range of 0 ° C to + 200 ° C, preferably at + 100 ° C to + 150 ° 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 (IA) + (VIII) -> (VII-A) or (IA) + (VIII) -> (VII-B) 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, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, dimethylformamide, N, N-methylacetamide, Dimethylsulfoxide, / V'-dimethylpropyleneurea (DMPU), methylpyrrol
  • Suitable bases for process step (IA) + (VIII) -> (VII-A) or (IA) + (VIII) -> (VII-B) are the customary inorganic or organic bases.
  • alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium optionally with the addition of an alkali iodide such as sodium iodide or potassium iodide, alkali metal alcoholates such as sodium or Potassium methoxide, sodium or potassium ethanolate or sodium or potassium tert.-butylate, alkali metal hydrides such as sodium or potassium hydride, amides such as sodium amide, lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organic amines such as triethylamine, / V-methylmorpholine, -methylpiperidine, -diisopropylethylamine, pyridine, 4- ( N, N-dimethylamino) -pyridine (DMAP), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8
  • the reaction is generally carried out in a temperature range from 0 ° C to + 120 ° C, preferably at + 20 ° C to + 80 ° 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).
  • Inert solvents for process step (VII-A) -> (IB) or (VII-B) -> (IC) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol and Dichloromethane, ethyl acetate, THF, dioxane, DMF, water, acetic acid, dilute hydrochloric acid or water. It is likewise possible to use mixtures of the solvents mentioned.
  • ethanol is used.
  • the reactions (VII-A) - (I-B) or (VII-B) - (I-C) take place in the presence of a suitable catalyst.
  • suitable catalysts are palladium / carbon, palladium (II) hydroxide / carbon, platinum (IV) oxide, platinum and Raney nickel. Preference is given to using Raney nickel or palladium / carbon.
  • the reaction is generally carried out in a temperature range from 0 ° C to + 120 ° C, preferably at + 20 ° C to + 80 ° C.
  • the reaction is carried out in a hydrogen atmosphere at normal or elevated pressure (for example from 1.0 to 50 bar). Preferably, the reaction is carried out at normal hydrogen pressure.
  • X 3 is a suitable leaving group, in particular chlorine, bromine, iodine, mesylate, triflate or tosylate, to give a compound of the formula (XI)
  • Inert solvents for process step (IX) + (X) - (XI) 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, hydrocarbons, such as benzene, toluene, Xylene, hexane, cyclohexane or petroleum fractions, alcohols such as methanol, ethanol, feri-butanol, or other solvents such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, A ⁇ -Dimethylformamid, dimethyl sulfoxide, N, N'-Dimefhylpropylenharnstoff (DM
  • Suitable bases for process step (IX) + (X) - (XI) are the customary inorganic or organic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate optionally with the addition of an alkali iodide such as sodium iodide or potassium iodide, alkali alcoholates such as sodium or Potassium methoxide, sodium or potassium ethoxide or sodium or potassium tert-butoxide, alkali metal hydrides such as sodium or potassium hydride, amides such as sodium amide, lithium or potassium bis (trimethylsilyl) - amide or lithium diisopropylamide, or organic amines such as triethylamine, / V Methylmorpholine, / V-methylpiperidine, diisopropylethylamine, pyridine, l, 5-diazabic
  • the reaction is generally carried out in a temperature range from 0 ° C to + 120 ° C, preferably at + 20 ° C to + 80 ° 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).
  • Inert solvents for ring closure to the imidazo [1,2-a] pyridine backbone (XI) + (XII) -> (II) or (IX) + (XII) -> (XIII) are the usual organic solvents.
  • These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, dichloromethane , 1,2-dichloroethane, acetonitrile, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned.
  • ethanol is used.
  • the ring closure is generally carried out in a temperature range from + 50 ° C to + 150 ° C, preferably at + 50 ° C to + 100 ° C, optionally in a microwave.
  • the ring closure (XI) + (XII) -> (II) or (IX) + (XII) -> (XIII) is optionally carried out in the presence of water-withdrawing reaction additives, for example in the presence of molecular sieve (4 ⁇ pore size) or by means of water.
  • reaction (XI) + (XII) -> (II) or (IX) + (XII) -> (XIII) is carried out using an excess of the reagent of the formula (XII), for example with 1 to 20 equivalents of the reagent ( XII), optionally with the addition of bases (such as sodium bicarbonate) wherein the addition of this reagent can be carried out once or in several portions.
  • bases such as sodium bicarbonate
  • Other compounds of the invention may optionally also be prepared by conversions of functional groups of individual substituents, in particular the compounds listed under R 3 , starting from the compounds of formula (I) obtained by the above method.
  • transformations are carried out by conventional methods known to those skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, elimination, alkylation, amino acidification, esterification, ester cleavage, etherification, ether cleavage, formation of carbonamines and introduction and removal of temporary protection groups.
  • the compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals.
  • the compounds according to the invention open up a further treatment alternative and thus represent an enrichment of pharmacy.
  • 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 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, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, atrial arrhythmias and the chambers as well as conduction disorders such as for example atrio-ventricular blockades grade ⁇ - ⁇ (AB block I-III), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular tachyarrhythmia, torsades de pointes tachycardia, atrial and ventricular extrasystoles, atrioventricular extrasystoles, Sick sinus syndrome, syncope, AV nodal reentry tachycardi
  • 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.
  • Heart failure in heart valve defects mitral valve stenosis, mitral valve insufficiency, aortic valve stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valvular 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 de w worsening of heart failure.
  • the compounds according to the invention may also be used for the treatment and / or prophylaxis of arteriosclerosis, lipid metabolism disorders, hypolipoproteinemias, dyslipidaemias, hypertriglyceridemias, hyperlipidemias, hypercholesterolemias, abetelipoproteinemia, Sitosterolemia, xanthomatosis, Tangier disease, obesity (obesity), obesity and combined hyperlipidaemias and 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, gangrenous, CREST syndrome, erythematosis, onychomycosis , rheumatic diseases and to promote wound healing.
  • 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 dysfunction (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 dysfunction
  • LUTS lower urinary tract syndromes
  • FUS lower urinary tract syndromes
  • UI incontinence
  • MUI UUI, SUI, OUI
  • Pelvic pain benign and malignant diseases of the organs of the male and female
  • 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, tubulointerstitial disorders, nephropathic disorders such as primary and congenital kidney disease, nephritis, renal immunological diseases such as renal transplant rejection, immune complex-induced renal disease, toxicant-induced nephropathy, contrast agent-induced nephropathy, diabetic and nondiabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive
  • the present invention also encompasses the use of the compounds according to the invention for the treatment and / or prophylaxis of secondary effects of renal insufficiency, such as, for example, pulmonary edema, cardiac insufficiency, uremia, anemia, Electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metaboli smu s.
  • renal insufficiency such as, for example, pulmonary edema, cardiac insufficiency, uremia, anemia, Electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders in bone and carbohydrate metaboli smu s.
  • 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, general attention deficit disorder, impaired concentration in children with learning and memory problems, Alzheimer's disease, dementia with Lewy Corpuscles, 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 disease 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 of 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 inflammatory bowel disease (IBD, Crohn's Disease, UC), pancreatitis , Peritonitis, rheumatoid diseases, inflammatory skin diseases and inflammatory ocular diseases.
  • SIRS sepsis
  • MODS multiple organ failure
  • IBD chronic inflammatory bowel disease
  • UC chronic inflammatory bowel disease
  • pancreatitis atitis
  • 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 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 procedures), 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 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 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;
  • Hypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endofhelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticides 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 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.
  • 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 No.
  • the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
  • 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 AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor - understood antagonists and diuretics.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as by way of example and preferably 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 by way of preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, Caroteneol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucinolol.
  • a beta-receptor blocker such as, by way of example and by way of preference, propranolol, atenolol,
  • 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 of the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
  • the compounds of the present 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.
  • a loop diuretic 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 xipamide
  • indapamide 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, the ACAT inhibitors, MTP inhibitors, PPAR alpha , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) - understood antagonists.
  • 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
  • the compounds according to the invention are administered in combination with a CETP inhibitor, such as by way of example and preferably dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • a CETP inhibitor such as by way of example and preferably dalcetrapib, BAY 60-5521, anacetrapib or CETP vaccine (CETi-1).
  • the compounds according to the invention are administered in combination with a thyroid receptor agonist 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 MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds according to the invention are administered in combination with a PPAR-gamma agonist, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
  • the compounds according to the invention are administered in combination with a PPAR delta agonist, such as by way of example and preferably GW 501516 or BAY 68-5042.
  • 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.
  • 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 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 are pharmaceutical 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. For this purpose, they can be administered in a suitable manner, such as, for example, orally, parenterally, pulmonary, 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
  • tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates, capsules (for example Hart - or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicines including powder inhalers, nebulizers
  • nasal drops solutions or sprays
  • lingual, sublingual or buccal tablets films / wafers or capsules
  • suppositories ear or eye preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures ), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, foams, powdered powders, implants or stents.
  • Preference is given to oral or parenteral administration, in particular oral administration.
  • 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 include excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (For example, albumin), stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.
  • excipients for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecy
  • the dosage is about 0.001 to 2 mg / kg, preferably about 0.001 to 1 mg kg of body weight.
  • the starting compounds, intermediates and embodiments may be present as hydrates.
  • a quantitative determination of the water content was not.
  • the hydrates may have an influence on the NMR spectrum and possibly shift the water signal in H-NMR and / or greatly broaden it.
  • the percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume.
  • the compounds of the invention may be in salt form, for example as trifluoroacetate, formate or ammonium salt, if the Compounds according to the invention contain a sufficiently basic or acidic functionality.
  • a salt can be converted into the corresponding free base or acid by various methods known to those skilled in the art.
  • a compound in the form of a salt of the corresponding base or acid is listed in the synthesis intermediates and embodiments of the invention described below, the exact stoichiometric composition of such a salt, as according to the respective preparation and / or purification process was received, usually unknown.
  • salt-forming components such as “hydrochloride”, “trifluoroacetate”, “sodium salt” or “x HCl”, “x CF 3 COOH”, “x Na +” are not included in such salts stoichiometrically, but are solely descriptive of the salt-forming components contained.
  • Instrument Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 ⁇ 50 mm x 1 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A-> 0.1 min 90% A-> 1.5 min 10% A -> 2.2 min 10% A; Flow: 0.33 ml / min; Oven: 50 ° C; UV detection: 210 nm.
  • Instrument Acquity UPLC coupled with Quattro Micro mass spectrometer; Column: Acquity UPLC BEH C18 (50 mm x 2.1 mm ID, 1.7 ⁇ m packing diameter); mobile phase A: 10 mM aqueous ammonium bicarbonate solution (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile; Gradient: 0.0 min 97% A, 3% B, flow rate 1 ml / min; 1.5 min 100% B, flow rate 1 ml / min; 1.9 min.
  • Method 6 Instrument: Acquity UPLC coupled with Quattro Micro mass spectrometer; Column: Acquity UPLC BEH C18 (50 mm x 2.1 mm ID, 1.7 ⁇ m packing diameter); mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile; Gradient: 0.0 min 97% A, 3% B, flow rate 1 ml / min; 1.5 min 100% B, flow rate 1 ml / min; 1.9 min.
  • Method 7 Instrument: Waters 2690, Waters 2996 PDA detector coupled with Quattro Micro mass MS detector; Column: Waters Sunfire C18 3.5 ⁇ , 2.1x50 mm; mobile phase A: 10 mM aqueous ammonium bicarbonate solution (adjusted to pH 10 with ammonia), mobile phase B: acetonitrile; Gradient: 0.0 min 95% A, 5% B, flow rate 0.5 ml / min; 3.0 min 95% A, 5% B, flow rate 0.5 ml / min; 17.50 min 5% A, 95% B, flow rate 0.5 ml / min; 19.00 min 5% A, 95% B, flow rate 0.5 ml / min; 19.50 min 95% A, 5% B, flow rate 0.5 ml / min; 20.00 min 95% A, 5% B, flow rate 0.5 ml / min; Column temperature: 30 ° C; UV detection: from 210 nm to 400 nm
  • the target compound is known from the literature and described:
  • Example 12A were initially charged in 77 ml of THF and treated with 3.56 ml (44.0 ml mmol) of pyridine. 6.22 ml (44.0 mmol) of trifluoroacetic anhydride were then added dropwise at RT, and the reaction mixture was stirred at RT for 3 h. After completion of the reaction time was added to water and extracted three times with ethyl acetate.
  • Example 21A 1 H-Benzotriazol-1-yl ⁇ 8- [(2,6-difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl-1-methanone
  • reaction mixture was stirred at room temperature for 16 h, then 0.1 M aqueous hydrochloric acid (5 ml) and stirred for a further 5 min.
  • the organic phase was washed with water (20 ml), separated, dried by means of a phase separation cartridge and evaporated in vacuo to give 1.5 g (86% of theory) of the target compound.
  • 0.1M aqueous hydrochloric acid (10ml) was added and stirring was continued for a further 5 minutes.
  • the aqueous phase was extracted with dichloromethane (2 x 30 ml).
  • the combined organic extracts were dried with a phase separation cartridge and concentrated in vacuo.
  • the residue was purified by flash chromatography using a silica gel cartridge (eluent: dichloromethane / methanol 100: 1 to 10: 1) to give 1.05 g (41% yield, purity 67%) of the title compound, which was purified without further purification next step was used.
  • Example 22A in 15 ml of absolute ethanol was treated with 2.3 g (29.0 mmol) of ammonium bicarbonate. The mixture was heated to 80 ° C and stirred for 15 min. The contents were cooled to room temperature and stirred for a further 15 h. The reaction mixture was filtered and the mother liquor was concentrated in vacuo to give 1 g (33% yield, 28% purity) of Example 23A. The crude product was used in the next step without further purification.
  • Example 4 1 - [(4- ⁇ 8 - [(2,6-Difluorobenzyl) oxy] -2,6-dimethylimidazo [1,2-a] pyridin-3-yl ⁇ pyridin-2-yl) oxy] -2 methyl methane-2-amine
  • reaction mixture was cooled to room temperature and then concentrated in vacuo.
  • residue was purified by flash chromatography using a silica gel cartridge (eluent: dichloromethane-methanol 100: 1 to 10: 1) to give 50 mg (26% yield, purity 81%) of the title compound.
  • Soluble guanylyl cyclase converts GTP to cGMP and pyrophosphate (PPi) upon stimulation.
  • PPi is detected by the method described in WO 2008/061626.
  • the signal generated in the test increases as the reaction progresses and serves as a measure of the sGC enzyme activity.
  • the enzyme can be characterized in a known manner, e.g. in terms of turnover rate, stimulability or Michaelis constant.
  • 29 ⁇ M enzyme solution (0-10 nM soluble guanylyl cyclase (prepared according to Hönicka et al., Journal of Molecular Medicine 77 (1999) 14-23) was dissolved in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (fraction V ), 0.005% Brij 35, pH 7.5) in the microplate and 1 ⁇ of the stimulator solution (0- 10 ⁇ 3-Morpholinosydnonimine, SIN-1, Merck in DMSO) added. It was incubated at RT for 10 min.
  • the enzyme reaction was started by the addition of 20 .mu. ⁇ substrate solution (1.25 mM guanosine 5 'triphosphate (Sigma) in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (fraction V), 0.005% Brij 35, pH 7.5) and continuously luminometric measured.
  • 20 .mu. ⁇ substrate solution (1.25 mM guanosine 5 'triphosphate (Sigma) in 50 mM TEA, 2 mM magnesium chloride, 0.1% BSA (fraction V), 0.005% Brij 35, pH 7.5) and continuously luminometric measured.
  • B-2 Effect on recombinant guanylate cyclase reporter cell line
  • MEC minimum effective concentration
  • aorta Rabbits are stunned and bled by a stroke of the neck.
  • the aorta is harvested, detached from adherent tissue, divided into 1.5 mm wide rings and placed individually under bias in 5 ml organ baths with 37 ° C warm, carbogen-gassed Krebs-Henseleit solution of the following composition (in each case mM): Sodium chloride: 119; Potassium chloride: 4.8; Calcium chloride dihydrate: 1; Magnesium sulfate heptahydrate: 1.4; Potassium dihydrogen phosphate: 1.2; Sodium hydrogencarbonate: 25; Glucose: 10.
  • 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. From this, the concentration is calculated, the is 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%.
  • 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. animal material
  • the experimental animals are kept individually in macroion cages type 3 after transmitter implantation. You have free access to standard food and water.
  • the TAH PA - C40 telemetry transmitters are surgically implanted into the experimental animals under aseptic conditions at least 14 days before the first trial.
  • the animals so instrumented are repeatedly used after healing of the wound and ingrowth of the implant.
  • the fasting animals are anesthetized with pentobabital (Nembutal, Sanofi: 50 mg / kg i.p.) and shaved and disinfected on the ventral side.
  • pentobabital Nembutal, Sanofi: 50 mg / kg i.p.
  • the system's liquid-filled measuring catheter above the bifurcation is inserted cranially into the descending aorta and secured with tissue adhesive (VetBonD TM, 3M).
  • the transmitter housing is fixed intraperitoneally to the abdominal wall musculature and the wound is closed in layers.
  • an antibiotic is administered for infection prevention (Tardomyocel COMP Bayer 1ml / kg s.c.)
  • 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 ART 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. In the standard procedure, duration is measured for every 10 seconds Systolic blood pressure (SBP)
  • SBP Systolic blood pressure
  • DBP Diastolic Blood Pressure
  • MAP Mean Arterial Pressure
  • HR Heart Rate
  • ACT Activity
  • 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 pharmacokinetic parameters of the compounds of the invention are determined in male CD-1 mice, male Wistar rats and female beagle dogs.
  • Intravenous administration is in mice and rats using a species-specific plasma / DMSO formulation and in dogs using a water / PEG400 / ethanol formulation.
  • Oral administration of the solute by gavage is performed in all species based on a water / PEG400 / ethanol formulation. Rats are placed in the right external jugular vein for ease of blood sampling prior to drug administration. The operation is carried out at least one day before the experiment under isoflurane anesthesia and with the administration of an analgesic (atropine / rimadyl (3/1) 0.1 mL s.c.).
  • an analgesic atropine / rimadyl (3/1) 0.1 mL s.c.
  • the blood collection (usually more than 10 times) takes place in a time window, which includes terminal times of at least 24 to a maximum of 72 hours after substance administration.
  • the blood is transferred to heparinized tubes at collection. So then the blood plasma is recovered by centrifugation and optionally stored at -20 ° C until further processing.
  • the pharmacokinetic parameters such as AUC, C ma x (terminal half-life), F (bioavailability), MRT (Mean Residence Time) and CL hn (clearance) by means of a validated pharmacokinetic computer program calculated.
  • the blood / plasma distribution of the substance must be determined in order to adjust the pharmacokinetic parameters accordingly.
  • a defined amount of substance is incubated in heparinized whole blood of the corresponding species for 20 min in a tumble roll mixer. After centrifugation at 1000 g, the concentration in the plasma is measured (by means of LC-MS / MS, see above) and the quotient formation of the C ⁇ iut / Cpiasma value is determined.
  • CYP cytochrome P450
  • the compounds of the invention were incubated at a concentration of about 0.1-10 ⁇ .
  • stock solutions of the compounds according to the invention with a concentration of 0.01-1 mM in acetonitrile were prepared, and then pipetted with a 1: 100 dilution into the incubation mixture.
  • the liver microsomes and recombinant enzymes were incubated in 50 mM potassium phosphate buffer pH 7.4 with and without NADPH-generating system consisting of 1 mM NADP + , 10 mM glucose-6-phosphate and 1 unit glucose-6-phosphate dehydrogenase at 37 ° C.
  • Primary hepatocytes were also incubated in suspension in Williams E medium also at 37 ° C.
  • the incubation mixtures were stopped with acetonitrile (final concentration about 30%) and the protein was centrifuged off at about 15,000 ⁇ g. The samples thus stopped were either analyzed directly or stored at -20 ° C until analysis.
  • the analysis is carried out by high performance liquid chromatography with ultraviolet and mass spectrometric detection (HPLC-UV-MS / MS).
  • HPLC-UV-MS / MS ultraviolet and mass spectrometric detection
  • the supernatants of the incubation samples are chromatographed with suitable C18-reversed-phase columns and variable eluent mixtures of acetonitrile and 10 mM aqueous ammonium formate solution or 0.05% formic acid.
  • the UV chromatograms in combination with mass spectrometry data serve to identify, structure elucidate and quantitatively estimate the metabolites, and quantitative metabolic decrease of the compound of the invention in the incubation approaches.
  • the permeability of a test substance was determined using the Caco-2 cell line, an established in vitro model for permeability predictions at the gastrointestinal barrier (Artursson, P. and Karlsson, J. (1991) Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells, Biochem., Biophys. 175 (3), 880-885).
  • the Caco-2 cells (ACC No. 169, DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany) were seeded in 24-well plates with use and cultured for 14 to 16 days.
  • test substance was dissolved in DMSO and diluted to the final test concentration with transport buffer (Hanks Buffered Salt Solution, Gibco / Invitrogen, with 19.9 mM glucose and 9.8 mM HEPES).
  • transport buffer Hanks Buffered Salt Solution, Gibco / Invitrogen, with 19.9 mM glucose and 9.8 mM HEPES.
  • P app AB the solution containing the test substance was added to the apical side of the Caco-2 cell monolayer and transport buffer to the basolateral side.
  • P app BA the solution containing the test substance was added to the basolateral side of the Caco-2 cell monolayer and transport buffer to the apical side.
  • hERG human ether-a-go-go related gene
  • the functional hERG assay used here is based on a recombinant HEK293 cell line stably expressing the KCNH2 (HERG) gene (Zhou et al., 1998). These cells are assayed by the whole-cell voltage-clamp technique (Hamill et al., 1981) in an automated system (Patchliner TM, Nanion, Kunststoff, D) which controls membrane voltage and hERG potassium current at room temperature measures.
  • the PatchControlHT TM software (Nanion) controls patchliner system, data acquisition and data analysis. The voltage is controlled by 2 EPC-10 quadro amplifiers under the control of the PatchMasterPro TM software (both: HEKA Elektronik, Lambrecht, D).
  • NPC-16 medium resistance chips ( ⁇ 2 ⁇ , Nanion) serve as a planar substrate for the voltage-clamp experiments.
  • NPC-16 chips are filled with intra- and extracellular solution (see Himmel, 2007) as well as with cell suspension.
  • the cell membrane After formation of a giga-ohm seal and production of the whole cell mode (including several automated quality control steps), the cell membrane is clamped to the hold potential -80 mV.
  • the following voltage logic protocol changes the command voltage to +20 mV (duration 1000 ms), -120 mV (duration 500 ms), and back to the holding potential -80 mV; this is repeated every 12 seconds.
  • an initial stabilization phase about 5-6 minutes
  • test substance solution in ascending concentrations (eg, 0.1, 1, and 10 ⁇ / L) (exposure about 5-6 minutes per concentration), followed by several washout steps.
  • the amplitude of the inward TaiF current generated by a potential change from +20 mV to -120 mV serves to quantify the hERG potassium current and is plotted as a function of time (IgorPro TM software)
  • Periods of time eg, stabilization phase before test substance, first / second / third concentration of test substance serve to produce a concentration-effect curve from which the half-maximal inhibitory concentration IC50 of the test substance is calculated.
  • the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • a single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • 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. iv solution:
  • the compound of the invention is dissolved at a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%).
  • a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%.
  • the resulting solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

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Abstract

L'invention concerne de nouvelles imidazo[1,2-a]pyridines substituées par hétérocyclyle et par hétéroaryle, des procédés pour les produire, leur utilisation individuellement ou en combinaisons pour assurer le traitement et/ou la prophylaxie de maladies, ainsi que leur utilisation pour la production de médicaments en vue du traitement et/ou de la prophylaxie de maladies, notamment du traitement et/ou de la prophylaxie de maladies cardiovasculaires.
EP15721624.3A 2014-05-02 2015-04-29 Imidazo[1,2-a]pyridines utilisées en tant que stimulateurs de la guanylate cyclase pour traiter des maladies cardiovasculaires Withdrawn EP3137464A1 (fr)

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EP14166910 2014-05-02
PCT/EP2015/059275 WO2015165931A1 (fr) 2014-05-02 2015-04-29 Imidazo[1,2-a]pyridines utilisées en tant que stimulateurs de la guanylate cyclase pour traiter des maladies cardiovasculaires

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US (1) US20170050962A1 (fr)
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CN (1) CN106459047A (fr)
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WO (1) WO2015165931A1 (fr)

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US9624214B2 (en) 2012-11-05 2017-04-18 Bayer Pharma Aktiengesellschaft Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use
CN106414440A (zh) * 2013-12-05 2017-02-15 拜耳制药股份公司 芳基和杂芳基取代的咪唑并[1,2-a]吡啶-3-羧酰胺及其用途
CN106715426A (zh) 2014-03-21 2017-05-24 拜耳医药股份有限公司 氰基取代的咪唑并[1,2‑a]吡啶甲酰胺及其用途
CN107001361A (zh) 2014-12-02 2017-08-01 拜耳医药股份有限公司 杂芳基取代的咪唑并[1，2‑a]吡啶及其用途
WO2018184976A1 (fr) 2017-04-05 2018-10-11 Bayer Pharma Aktiengesellschaft Imidazo[1,2-a]pyridine-carboxamides substitués et leur utilisation
WO2019179494A1 (fr) * 2018-03-23 2019-09-26 深圳市塔吉瑞生物医药有限公司 Composé d'acide pentadécanedioïque substitué, composition pharmaceutique et utilisation associée
AR117291A1 (es) 2018-12-14 2021-07-28 Syngenta Crop Protection Ag Compuestos heterocíclicos de cianamida con actividad pesticida

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JP2017514899A (ja) 2017-06-08

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