EP3119777A1 - Imidazo[1,2-a]pyridine-carboxamides cyano-substitués et leur utilisation - Google Patents

Imidazo[1,2-a]pyridine-carboxamides cyano-substitués et leur utilisation

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Publication number
EP3119777A1
EP3119777A1 EP15710202.1A EP15710202A EP3119777A1 EP 3119777 A1 EP3119777 A1 EP 3119777A1 EP 15710202 A EP15710202 A EP 15710202A EP 3119777 A1 EP3119777 A1 EP 3119777A1
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European Patent Office
Prior art keywords
substituted
hydrogen
alkyl
group
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.)
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Application number
EP15710202.1A
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German (de)
English (en)
Inventor
Alexandros Vakalopoulos
Philipp BUCHGRABER
Niels Lindner
Markus Follmann
Frank Wunder
Johannes-Peter Stasch
Tobias Marquardt
Gorden Redlich
Lisa Dietz
Volkhart Min-Jian Li
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Bayer Pharma AG
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Bayer Pharma AG
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Publication of EP3119777A1 publication Critical patent/EP3119777A1/fr
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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
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present application relates to novel substituted imidazo [1,2-a] pyridine-3-carboxamides, 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 is (C 4 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, pyridyl or phenyl, where (C 4 -C 6 ) -alkyl can be substituted up to six times by fluorine, where (C 3 -C 4) -cycloalkyl having 1 to 4 substituents independently of one another can be substituted by the group fluorine, trifluoromethyl and (C 1 -C 4 -alkyl), and where phenyl having 1 to 4 substituents independently of one another selected from the group halogen, cyano , Monofluoromethyl, difluoromethyl, trifluoromethyl, (C 1 -C 4 alkyl, (C 3 -C 5) cycloalkyl, (C 1 -C 4 alkoxy, difluoromethoxy and trifluoromethoxy) or may be substituted on two adjacent carbon atoms of the phenyl with a difluo
  • attachment site to the carbonyl group is a bond or (C 1 -C 4 -alkanediyl in which (C 1 -C 3 -alkanediyl having 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 -alkyl) Alkyl, (C 3 -C 7 ) - cycloalkyl, hydroxy and (Ci-C alkoxy may be substituted, is a bond or (Ci-C alkanediyl, wherein (Ci-C alkanediyl having 1 to 3 substituents independently selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 -alkyl, (C 3 -C 7 ) -cycloalkyl, hydroxy and (C 1 -C 4 -alkoxy may be substituted, R 7 is hydrogen, (C 1 -C 6 ) -alkyl, (
  • R 10 is hydrogen or (Ci-C 6 ) -alkyl, and wherein phenyl and 5- or 6-membered heteroaryl having 1 to 3 substituents independently selected from the group halogen, cyano, trifluoromethyl, (Ci-C) alkyl , (C 1 -C 4 ) -alkoxy and (C 1 -C 4 ) -alkylsulfonyl may be substituted,
  • R 8 is hydrogen or (GC 4 ) -alkyl, wherein (GC 4 ) -alkyl may be substituted with hydroxy, or
  • R 7 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 in turn with 1 or 2 substituents independently selected from the group fluorine and (Ci-C alkyl may be substituted,
  • L 3 is a bond or (C 1 -C 4 -alkanediyl in which (C 1 -C 3 -alkanediyl having 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 -alkyl, (C 3 -C 7) - Cycloalkyl, hydroxy and (C 1 -C 4 -alkoxy may be substituted, n is 0, 1 or 2, the ring Q is 3- to 7-membered carbocyclyl, 4- to 7-membered heterocyclyl, phenyl or 5-6 is a heteroaryl-containing ring, where the ring Q may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, (C 1 -C 4 -alkyl, trifluoromethyl, amino, hydroxyl and (C 1 -C 4 -alkoxy),
  • R is hydrogen, halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, (C 1 -C 4 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, (C 2 -C 4 ) -alkenyl, (C 2 -C 4 ) Alkynyl, difluoromethoxy,
  • Trifluoromethoxy (C 1 -C 4) -alkoxy, amino, 4- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
  • R 6 represents hydrogen, cyano or halogen, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • the present invention relates to compounds of general formula (I) in which
  • A is CH 2 , CD 2 or CH (CH 3 ),
  • R 1 is (C 4 -C 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, pyridyl or phenyl, where (C 4 -C 6 ) -alkyl can be substituted up to six times by fluorine, where (C 3 -C 4 ) ) -Cycloalkyl having 1 to 4 substituents independently selected from the group fluorine, trifluoromethyl and (Ci-C alkyl may be substituted, and wherein phenyl having 1 to 4 substituents independently selected from the group halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, (Ci-C alkyl, (C3-C5) cycloalkyl, (Ci-C alkoxy, difluoromethoxy and trifluoromethoxy substituted may or may be substituted on two adjacent carbon atoms of the phenyl with a Difluormethylendioxy- bridge, where
  • attachment site to the carbonyl group is a bond or (C 1 -C 4 -alkanediyl in which (C 1 -C 3 -alkanediyl having 1 to 3 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 -alkyl) Alkyl, (C 3 -C 7 ) - cycloalkyl, hydroxy and (Ci-C alkoxy may be substituted, is a bond or (Ci-C alkanediyl, wherein (Ci-C alkanediyl having 1 to 3 substituents independently selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 -alkyl, (C 3 -C 7 ) -cycloalkyl, hydroxy and (C 1 -C 4 -alkoxy may be substituted, is a bond or (Ci-C alkanediyl, wherein (
  • R 9 is hydrogen, (C 1 -C 6 ) -alkyl or (C 3 -C 7 ) -cycloalkyl,
  • R 10 is hydrogen or (C 1 -C 6 ) -alkyl, and in which phenyl and 5- or 6-membered heteroaryl having 1 to 3 substituents independently of one another are selected from the group halogen, cyano, trifluoromethyl, (GC 4 ) -alkyl, (C 1 -C 4 ) -alkoxy and (C 1 -C 4 ) -alkylsulfonyl may be substituted,
  • R 8 is hydrogen or (GC 4 ) -alkyl, wherein (C 1 -C 4 ) -alkyl may be substituted by hydroxy, or
  • R 7 and R 8 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 by 1 or 2 substituents independently of one another selected from the group Huor and (GC 4 ) -alkyl,
  • L 3 is a bond or (GC 4 ) alkanediyl, wherein (C 1 -C 4) -alkanediyl having 1 to 3 substituents independently of one another can be substituted from the group fluorine, trifluoromethyl, (C 1 -C 4 -alkyl, (C 3 -C 7) -cycloalkyl, hydroxy and (C 1 -C 4) -alkoxy , n is 0, 1 or 2, the ring Q is 3- to 7-membered carbocyclyl, 4- to 7-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl, said ring Q having 1 to 3 substituents independently of one another can be substituted from the group halogen, (C 1 -C 4 -alkyl, trifluoromethyl and (C 1 -C 4 -alkoxy)
  • R 4 is hydrogen
  • R 5 is hydrogen, halogen, cyano, monofluoromethyl, difluoromethyl, trifluoromethyl, (C 1 -C 4 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, (C 2 -C 4 ) -alkenyl, (C 2 -C 4 ) -alkynyl, difluoromethoxy, trifluoromethoxy, (C 1 -C 4 ) -alkoxy, amino, 4- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
  • R 6 represents hydrogen, cyano or halogen, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, lactic, tartaric, Malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • mineral acids for example hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, formic, acetic, trifluoroacetic, propionic, lactic, tartaric, Malic acid, citric acid, fumaric acid, maleic
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts
  • solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or, if appropriate, also as conformational isomers (enantiomers and / or diastereomers, including those of atropisomers).
  • the present invention therefore includes the enantiomers and diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform 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, in particular with 3 H- or 14 C- Isotope labeled compounds suitable.
  • isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
  • isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically). Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
  • alkyl is a linear or branched alkyl radical having 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.
  • Carbocycle or cycloalkyl in the context of the invention is a monocyclic or bicyclic, saturated or partially unsaturated carbocycle having in each case the indicated number of ring carbon atoms and up to 3 double bonds.
  • Examples which may be mentioned by preference include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, indanyl, tetralinyl.
  • Alkenyl in the context of the invention represents a linear or branched alkenyl radical having 2 to 6 carbon atoms and one or two double bonds. Preferred is a linear or branched alkenyl radical having 2 to 4 carbon atoms and a double bond.
  • vinyl, allyl, isopropenyl and n-but-2-en-1-yl By way of example and by way of preference: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.
  • Alkynyl in the context of the invention is a linear or branched alkynyl radical having 2 to 6 carbon atoms and a triple bond.
  • Alkanediyl in the context of the invention is a linear or branched divalent alkyl radical having 1 to 4 carbon atoms.
  • 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 an oxygen-bonded carbonyl group.
  • alkoxycarbonyl in the context of the invention are a linear or branched alkoxy radical having 1 to 4 carbon atoms and an oxygen-bonded carbonyl group.
  • Alkylthio in the context of the invention is a thio group having a linear or branched alkyl substituent which has 1 to 4 carbon atoms.
  • a thio group having a linear or branched alkyl substituent which has 1 to 4 carbon atoms.
  • 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.
  • Mono-alkylamino in the context of the invention represents an amino group having a linear or branched alkyl substituent which has 1 to 4 carbon atoms. Examples which may be mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.
  • Di-alkylamino in the context of the invention represents an amino group having two identical or different linear or branched alkyl substituents, each having 1 to 4 carbon atoms.
  • -dimethylamino A ⁇ -diethylamino, -ethyl-methylamino, -methyl-n-propylamino, -isopropyl-n-propylamino and-tert-butyl / V-methylamino.
  • a 4- to 7-membered heterocycle is in the context of the invention for a monocyclic, saturated heterocycle having a total of 4 to 7 ring atoms containing 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, tetrahydrofinyl pyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, hexahydroazepinyl and hexahydro-1,4-diazepinyl.
  • Heteroaryl is in the context of the invention for a monocyclic aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms containing up to three identical or different ring heteroatoms from the series N, O and / or S and via a ring carbon atom or optionally linked via a ring nitrogen atom.
  • heterocycle monocyclic aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms containing up to three identical or different ring heteroatoms from the series N, O and / or S and via a ring carbon atom or optionally linked via a ring nitrogen atom.
  • Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
  • An oxo substituent in the context of the invention is an oxygen atom which is bonded via a double bond to a carbon or sulfur atom.
  • the end point of the line on which the symbol * and # stands does not represent a carbon atom or a CH 2 group but is part of the bond 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 CH (CH 3 )
  • R 1 is (C 4 -C 6 ) alkyl, (C 4 -C 6 ) cycloalkyl, pyridyl or phenyl wherein (C 4 -C 6 ) alkyl up to may be substituted six times with fluorine, wherein (C4-C6) -cycloalkyl may be substituted by 1 to 4 substituents fluorine, and wherein phenyl having 1 to 3 substituents independently selected from the group fluorine, chlorine, cyano, trifluoromethyl, methyl, cyclopropyl , Methoxy and ethoxy may be substituted, wherein pyridyl may be substituted by 1 or 2 substituents, R 2 is hydrogen, (Ci-C alkyl, cyclopropyl or trifluoromethyl, R 3 is a group of the formula
  • R 9 is hydrogen, (C 1 -C 4 -alkyl, cyclopropyl or cyclobutyl,
  • R 10 is hydrogen or (C 1 -C 4 ) -alkyl, and in which phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group of fluorine, chlorine, cyano, trifluoromethyl, methyl, ethyl, methoxy and ethoxy,
  • R 8 is hydrogen or (GC 4 ) -alkyl, or
  • R 7 and R 8 together with the carbon atom to which they are attached form a 3- to 6-membered carbocycle wherein the 3- to 6-membered carbocycle may be substituted with 1 or 2 substituents fluoro,
  • L 3 is a bond, methylene or ethylene, wherein methylene and ethylene may be substituted with 1 or 2 substituents independently of one another selected from the group fluorine, methyl, ethyl and trifluoromethyl, n is 0 or 1, the ring Q is cyclopentyl, Cyclohexyl, piperidinyl, piperazinyl, phenyl, pyrazolyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl or triazolyl, wherein the ring Q may be substituted with 1 or 2 substituents independently selected from the group fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy and ethoxy,
  • R 4 is hydrogen
  • R 5 is hydrogen, fluorine, bromine, chlorine, cyano, methyl, ethyl, cyclopropyl, ethynyl, methoxy or ethoxy,
  • R 6 is hydrogen or fluorine, and their TV oxides, salts, solvates, salts of the TV oxides and solvates of the TV oxides and salts.
  • A is CH 2 ,
  • R 1 is 3-methylbutyl, wherein 3-methylbutyl may be substituted up to six times by fluorine, or is cyclohexyl, wherein cyclohexyl may be substituted by 2 substituents fluorine, or a phenyl group of the formula
  • R 11 is hydrogen or fluorine
  • R 1Z and R lj are fluorine, or a pyridyl group of the formula
  • L 1 is a bond, methylene or ethylene
  • L 2 is a bond, methylene, ethylene or propylene
  • R 9 is hydrogen, R is hydrogen, and wherein phenyl may be substituted with chlorine, is hydrogen or methyl, or
  • L 3 is a bond or methylene, n is 0 or 1, the ring Q is cyclohexyl, piperidinyl, phenyl or pyrazolyl, in which the ring Q may be substituted by methoxy or ethoxy, R 4 is hydrogen,
  • R 5 is hydrogen, chlorine, methyl, cyclopropyl or methoxy
  • R 6 is hydrogen, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • A is CH 2 ,
  • R 1 is a phenyl group of the formula
  • R u is hydrogen, R 12 and R 13 are fluorine, R 2 is methyl, R 3 is a group of the formula
  • L 1 is a bond, methylene or ethylene
  • L 2 is a bond, methylene or ethylene
  • R 9 is hydrogen
  • R 10 is hydrogen, and wherein phenyl may be substituted with chlorine, R 8 is hydrogen or methyl, or
  • Form cyclopropyl ring or a cyclobutyl ring is a bond or methylene, n is 0 or 1, the ring Q is cyclohexyl, piperidin-3-yl, phenyl or 1H-pyrazol-5-yl, wherein phenyl may be substituted with methoxy or ethoxy, R 4 is Hydrogen stands,
  • R 5 is hydrogen, chlorine, methyl or methoxy
  • R 6 is hydrogen, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • A is CH 2 , and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 1 is 3-methylbutyl, where 3-methylbutyl may be substituted by fluorine up to six times, or is cyclohexyl, where cyclohexyl is substituted by 2 fluorine substituents can, or for a phenyl group of the formula
  • R 11 is hydrogen or fluorine
  • R 12 and R 13 are fluorine, or a pyridyl group of the formula
  • # represents the attachment point to A, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 1 is 3-methylbutyl, wherein 3-methylbutyl may be substituted up to six times by fluorine, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 1 is cyclohexyl, wherein cyclohexyl may be substituted by 2 substituents fluorine, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • compounds of the formula (I) which are preferred are also preferred.
  • R 1 is a phenyl group of the formula
  • R 11 is hydrogen or fluorine
  • R 12 and R 13 are fluorine, and their / V oxides, salts, solvates, salts of N-oxides and solvates of the / V oxides and salts.
  • R 1 is a phenyl group of the formula
  • R 11 is hydrogen
  • R 12 and R 13 are fluorine
  • their / V oxides, salts, solvates, salts of N-oxides and solvates of the / V oxides and salts are hydrogen
  • R 1 is a phenyl group of the formula
  • R 11 is fluorine
  • R 12 and R 13 are fluorine, and their / V oxides, salts, solvates, salts of N-oxides and solvates of the / V oxides and salts.
  • R 1 is a pyridyl group of the formula
  • # is the point of attachment to A, and their / V-oxides, salts, solvates, salts of N-oxides and solvates of / V-oxides and salts.
  • R 3 is a group of the formula
  • L 1 is a bond, methylene or ethylene
  • L 2 is a bond, methylene, ethylene or propylene
  • Phenyl, wherein (C 1 -C 4) alkyl may be substituted with hydroxy, methoxy, ethoxy or amino, wherein cyclopropyl may be substituted with 1 or 2 substituents fluorine, wherein
  • R 9 is hydrogen, R 10 is hydrogen, and wherein phenyl may be substituted with chlorine, R 8 is hydrogen or methyl, or
  • Form cyclopropyl ring or a cyclobutyl ring is a bond or methylene, n is 0 or 1, the ring Q is cyclohexyl, piperidinyl, phenyl or pyrazolyl, wherein the ring Q may be substituted with methoxy or ethoxy, and their N-oxides, salts, solvates, salts N-oxides and solvates of N-oxides and salts.
  • R 3 is a group of the formula stands, where
  • L 1 is a bond, methylene or ethylene
  • L 2 is a bond, methylene, ethylene or propylene
  • R 10 is hydrogen and in which phenyl may be substituted by chlorine, R 8 is hydrogen or methyl, or
  • Cyclopropyl ring or a cyclobutyl ring and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 3 is a group of the formula
  • L 3 is a bond or methylene
  • n is 0 or 1
  • the ring Q is cyclohexyl, piperidinyl, phenyl or pyrazolyl, in which the ring Q may be substituted by methoxy or ethoxy, and their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 3 is a group of the formula
  • L 3 is a bond or methylene, n is 0 or 1, the ring Q is cyclohexyl, piperidin-3-yl, phenyl or lH-pyrazol-5-yl, wherein phenyl may be substituted by methoxy or ethoxy, as well as their N-oxides, salts, solvates, salts of N-oxides and solvates of N-oxides and salts.
  • R 5 is hydrogen, chlorine, methyl or methoxy, and also their N-oxides, salts, solvates, salts of N-oxides and solvates of the 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.
  • the invention further provides a process for the preparation of the compounds of the formula (I) according to the invention, which comprises [A] 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
  • x 1 (VI) in which A and R 1 have the abovementioned meaning and X 1 is a suitable leaving group, in particular chlorine, bromine, iodine, mesylate, triflate or tosylate, is reacted, then optionally cleaves off any protecting groups present, and the resulting compounds of formula (I) optionally with the corresponding (i) solvents and / or (ii) acids or bases in their solvates, salts and / or solvates of the salts.
  • a and R 1 have the abovementioned meaning and X 1 is a suitable leaving group, in particular chlorine, bromine, iodine, mesylate, triflate or tosylate, is reacted, then optionally cleaves off any protecting groups present, and the resulting compounds of formula (I) optionally with the corresponding (i) solvents and / or (ii) acids or bases in their solvates, salts and / or solvates of the salts.
  • the compounds of the formulas (I-A) and (I-B) form a subset of the compounds of the formula (I) according to the invention.
  • the free bases of (IV-A) or (IV-B) may be released from the optionally amino-protecting compounds (IV-A) or (IV-B), e.g. by using acids such as hydrogen chloride and trifluoroacetic acid in suitable solvents such as diethyl ether, dichloromethane, 1,4-dioxane, water, methanol, ethanol and mixtures thereof.
  • acids such as hydrogen chloride and trifluoroacetic acid
  • suitable solvents such as diethyl ether, dichloromethane, 1,4-dioxane, water, methanol, ethanol and mixtures thereof.
  • 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, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, ⁇ , ⁇ '-dimethylpropy
  • condensing agent for amide formation in process steps (III) + (IV) - (I) and (III-B) + (IV-A) -> (IA) or (III-B) + (IV-B) - > (IB) are, for example, carbodiimides such as N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl, ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminopropyl) - / V'-ethylcarbodiimide hydrochloride (EDC), phosgene derivatives such as ⁇ , ⁇ '-carbonyldiimidazole (CDI), 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-yl-butyl-5-methylisoxazolium perchlorate
  • Triethylamine, methylmorpholine, / V-methylpiperidine or / V, / V-diisopropylethylamine Preferably, TBTU is used in conjunction with N-methylmorpholine, HATU in conjunction with diisopropylethylamine or 1-chloro / V, / V, 2-trimethylprop-1-ene-lamin.
  • the condensations (III) + (IV) -> (I) and (III-B) + (IV-A) -> (IA) and (III-B) + (IV-B) -> (I-B ) is generally carried out in a temperature range from -20 ° C to + 100 ° C, preferably at 0 ° C to + 60 ° 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.
  • carboxylic acid of the formula (III) can also first be converted into the corresponding carboxylic acid chloride and then reacted directly or in a separate reaction with an amine of the formula (IV-A) or (IV-B) to give the compounds according to the invention.
  • the formation of carboxylic acid chlorides from carboxylic acids is carried out by the methods known in the art, for example by treatment with thionyl chloride, sulfuryl chloride or oxalyl chloride in the presence of a suitable base, for example in the presence of pyridine, and optionally with the addition of dimethylformamide, optionally in a suitable inert solvent.
  • 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.
  • the reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, one works at normal pressure.
  • Inert solvents for process step (VA) + (VI) -> (I) or (VB) + (VI) -> (I) are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, 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, / V, / V-dimethylformamide, N, N-methylacetamide , Dimethylsulfoxide, / V, / V'-dimethylpropyleneurea (DMPU),
  • Suitable bases for process step (V) + (VI) -> (I) or (VB) + (VI) -> (I) 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, 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, methylmorpholine, / V -Methylpiperidine, diisopropylethylamine, pyridine, 4- (N
  • DBU undec-7-ene
  • DABCO 4-diazabicyclo [2.2.2] octane
  • potassium carbonate, cesium carbonate or sodium methoxide is used.
  • 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 can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar).
  • the amino-protecting group used is preferably ferric. Butoxycarbonyl (Boc) or benzyloxycarbonyl (Z).
  • a protective group for a hydroxy or carboxyl function tert-butyl or benzyl is preferably used.
  • the cleavage of these protecting groups is carried out by conventional methods, preferably by reaction with a strong acid such as hydrogen chloride, hydrogen bromide or trifluoroacetic acid in an inert solvent such as dioxane, diethyl ether, dichloromethane or acetic acid; optionally, the cleavage can also be carried out without an additional inert solvent.
  • benzyl and benzyloxycarbonyl as a protective group, these can also be removed by hydrogenolysis in the presence of a palladium catalyst.
  • the cleavage of the protective groups mentioned can optionally be carried out simultaneously in a one-pot reaction or in separate reaction steps.
  • the cleavage of the benzyl group in reaction step (IA) - (VA) or (IB) - (VB) is carried out here by conventional methods known from protective group chemistry, preferably by hydrogenolysis in the presence of a palladium catalyst, such as palladium on activated carbon, in one inert solvents such as, for example, ethanol or ethyl acetate [see also eg TW Greene and PGM Wuts, Protective Croups in Organic Synthesis, Wiley, New York, 1999].
  • a palladium catalyst such as palladium on activated carbon
  • inert solvents such as, for example, ethanol or ethyl acetate
  • the compounds of the formula (II) are known from the literature or can be prepared by reacting a compound of the formula (VII)
  • 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 (VIII) + (IX) -> (II) or (VII) + (IX) -> (X) 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.
  • the reaction (VIII) + (IX) -> (II) or (VII) + (IX) -> (X) is carried out using an excess of the reagent of the formula (IX), for example with 1 to 20 equivalents of the reagent ( IX), 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.
  • an activating reagent eg diethylazodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD)
  • a phosphine reagent eg triphenylphosphine or tributylphosphine
  • an inert solvent eg THF, Dichloromethane, toluene or DMF
  • 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, eliminations, alkylation, amino acidification, esterification, ester cleavage, etherification, ether cleavage, formation of carbonamides , as well as 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, rhythm disorders Atria 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 tachycardia,
  • 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, for example, benign prostate syndrome (BPS), benign prostatic hyperplasia (BPH), benign prostate enlargement (BPE), bladder emptying disorder (BOO), lower urinary tract syndromes (LUTS, including Feiine's urological syndrome ( FUS)), diseases of the urogenital system including neurogenic overactive bladder (OAB) and (IC), incontinence (UI) such as mixed, urge, stress, or overflow incontinence (MUI, UUI, SUI, OUI), Pelvic pain, benign and malignant diseases of the organs of the male and female urogenital system.
  • BPS benign prostate syndrome
  • BPH benign prostatic hyperplasia
  • BPE benign prostate enlargement
  • BOO bladder emptying disorder
  • LUTS lower urinary tract syndromes
  • FUS lower urinary tract syndromes
  • UI incontinence
  • MUI UUI, SUI, OUI
  • Pelvic pain benign and malignant diseases of the organs
  • 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;
  • Antihypertensive agents by way of example and preferably from the group of calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, 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) antagonists understood.
  • CETP inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • ACAT inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors
  • MTP inhibitors MTP inhibitors
  • PPAR alpha- , PPAR gamma and / or PPAR delta agonists cholesterol absorption inhibitors
  • polymeric bile acid adsorbers bile acid rea
  • the compounds according to the invention are administered in combination with a CETP inhibitor, such as 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.
  • Device Type MS Waters Micromass Quattro Micro
  • Device type HPLC Agilent 1100 series
  • 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
  • Oven 50 ° C
  • Flow 2 ml / min
  • UV detection 210 nm.
  • Method 5 Instrument MS: Waters ZQ 2000; Instrument HPLC: Agilent 1100, 2-column circuit, Autosampler: HTC PAL; Column: YMC-ODS-AQ, 50 mm ⁇ 4.6 mm, 3.0 ⁇ m; Eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A - 0.2 min 95% A - 1.8 min 25% A - 1.9 min 10% A - 2.0 min 5% A - 3.2 min 5% A - 3.21 min 100% A - 3.35 min 100% A; Oven: 40 ° C; Flow: 3.0 ml / min; UV detection: 210 nm.
  • Method 11 (Preparative HPLC): Instrument MS: Waters, Instrument HPLC: column Waters X-Bridge C18, 18 mm ⁇ 50 mm, 5 ⁇ , eluent A: water + 0.05% triethylamine, eluent B: acetonitrile (ULC) + 0.05% Triethylamine, gradient: 0.0 min 95% A - 0.15 min 95% A - 8.0 min 5% A - 9.0 min 5% A; Flow: 40 ml / min; UV detection: DAD; 210 - 400 nm or: Instrument MS: Waters, Instrument HPLC: Waters (column Phenomenex Luna 5 ⁇ C18 (2) 100A, AXIA Tech 50 x 21.2 mm, eluent A: water + 0.05% formic acid, eluent B: acetonitrile (ULC) + 0.05% formic acid, gradient : 0.0 min 95% A - 0.15 min 95% A -
  • Device DSQ II; Thermo Fisher-Scientific; DCI with NH 3 , flow: 1.1 ml / min; Source temperature: 200 ° C; Ionization energy 70 eV; Heat DCI filament up to 800 ° C; Mass Range 80-900.
  • Method 14 Instrument: Micromass GCT, GC6890; Column: Restek RTX-35, 15 m ⁇ 200 ⁇ x 0.33 ⁇ ; constant flow with helium: 0.88 ml / min; Oven: 70 ° C; Inlet: 250 ° C; Gradient: 70 ° C, 30 ° C / min -> 310 ° C (hold for 3 min).
  • Instrument MS Waters (Micromass) QM; Instrument HPLC: Agilent 1100 series; Column: Agilent ZORBAX Extend-C18 3.0x50mm 3.5-micron; Eluent A: 1 l of water + 0.01 mol of ammonium carbonate, eluent B: 1 l of acetonitrile; Gradient: 0.0 min 98% A-> 0.2 min 98% A 3.0 min 5% ⁇ -> 4.5 min 5% A; Oven: 40 ° C; Flow: 1.75 ml / min; UV detection: 210 nm.
  • Device Type MS Waters Synapt G2S
  • Device type UPLC Waters Acquity I-CLASS
  • Eluent A 1 liter of water + 0.01% of formic acid
  • Eluent B 1 liter acetonitrile + 0.01% formic acid
  • Oven 50 ° C
  • Flow 1.20 ml / min
  • UV detection 210 nm.
  • Device type MS Thermo Scientific FT-MS; Device type UHPLC +: Thermo Scientific UltiMate 3000;
  • multiplicities of proton signals in ⁇ - ⁇ spectra represent the respective observed signal shape and do not take into account higher-order signal phenomena. All data in ⁇ -NMR spectra indicate the chemical shifts ⁇ in ppm.
  • the starting compounds, intermediates and embodiments may be present as hydrates. A quantitative determination of the water content was not. Under certain circumstances, 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 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.
  • salts are not stoichiometrically understood, but have only descriptive character with respect to the salt-forming components contained.
  • Example 5A 50 g of ethyl 8- (cyclohexylmethoxy) -2-methylimidazo [1,2-a] pyridine-3-carboxylate (Example 5A, 158 mmol, 1 equivalent) was dissolved in 600 ml of 1,4-dioxane, with 790 ml of 2 N sodium hydroxide solution (1.58 mol, 10 equivalents) and stirred for 16 h at RT. It was mixed with 316 ml of 6 N hydrochloric acid and concentrated to about 1/5 of the total volume. The resulting solid was filtered off, washed with water and tert-butyl methyl ether and dried in vacuo. There were obtained 35 g (74% of theory) of the title compound.
  • the reaction mixture was concentrated in vacuo, the residue taken up in dichloromethane and chromatographed on silica gel (dichloromethane / methanol 20: 1 as eluent).
  • the product-containing fractions were concentrated, the residue was stirred with 100 ml of diethyl ether for 30 min. It was then filtered off, washed with a little diethyl ether and dried. 15 g (45% of theory) of the title compound were obtained.
  • Example 21A was dissolved in 275 ml of THF / methanol (5/1), treated with 64.4 ml of 1 N aqueous lithium hydroxide solution and stirred at 40 ° C for 3.5 h. It was acidified at 0 ° C with 6 N aqueous hydrochloric acid to about pH 4 and concentrated. The resulting solid was filtered off, washed with water and dried in vacuo. 4.77 g (98% of theory, purity about 93%) of the title compound were obtained.
  • Example 20A in 122.3 ml of DMF was treated with 1.23 ml (9.4 mmol) of 1-iodo-3-methyl butane and 6.12 g (18.8 mmol) of cesium carbonate and it was stirred for 40 min at 60 ° C.
  • the reaction mixture which had cooled to RT was admixed with 900 ml of water, stirred at RT for 1 h, the resulting solid was filtered off, washed with water and dried under high vacuum. This gave 2.25 g (84% of theory, purity 97%) of the title compound.
  • Example 33A was initially charged in 157 ml of THF / methanol (5: 1), with 37 ml (37 mmol) of 1 N lithium hydroxide solution and the reaction mixture was stirred at RT over the weekend. It was then cooled to 0 ° C, acidified to pH 4 with 6 N hydrochloric acid and freed from the organic solvent in vacuo. The resulting solid was filtered off, washed with water and dried under high vacuum. This gave 1.64 g (80% of theory, purity 100%) of the title compound.
  • Example 35A 6.8 g of Example 35A were separated into the enantiomers by preparative separation on a chiral phase [column: Daicel Chiralpak AD-H, 5 ⁇ m, 250 ⁇ 30 mm, eluent: 70% isohexane, 30% ethanol, flow: 50 ml / min ; 40 ° C, detection: 210 nm].
  • the aqueous phase was made alkaline with concentrated aqueous sodium hydroxide solution and admixed with 1200 ml of dichloromethane and stirred vigorously for 1 h.
  • the mixture was filtered off with suction through kieselguhr and washed several times well with a total of about 2,800 ml of dichloromethane.
  • the mother liquor was separated, the organic phase was dried and concentrated. 77.8 g of the target compound (96% of theory) were obtained.
  • the aqueous phase was stirred again with ethyl acetate for 1.5 h and the phases were separated. The organic phase was dried over sodium sulfate, filtered and concentrated. This gave 70 mg of the title compound.
  • the aqueous phase was stirred again with dichloromethane for 2 h and the phases were separated. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. This gave 60 mg of the title compound.
  • the aqueous phase was concentrated under reduced pressure and the residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA). This gave 300 mg of the title compound as the trifluoroacetate salt. A total of 920 mg of the title compound (52% of theory) were obtained (proportionately as the trifluoroacetate salt).
  • Variant B 144 mg of ethyl 8-hydroxy-2-methylimidazo [1,2-a] pyridine-3-carboxylate (Example 3A, 0.65 mmol) was dissolved in 3.9 ml of THF containing 100 mg of (3-fluoropyridin-2-yl ) methanol (0.79 mmol), 189 mg of triphenylphosphine (0.72 mmol) and then with 0.15 ml of diisopropyl azodicarboxylate (0.72 mmol). The reaction mixture was stirred overnight at RT and then purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient with the addition of 0.1% TFA). 198 mg (68% of theory, purity 99%) of the target compound were obtained.
  • Example 63A were dissolved in 151 mL THF / methanol (5: 1). 1), mixed with 35.3 mL (35.3 mmol) of 1 N aqueous lithium hydroxide solution and stirred for 2 d at RT. The reaction mixture was acidified to pH 4 with 1 N aqueous hydrochloric acid solution and concentrated. The solid was filtered off, washed with water and dried under high vacuum. This gave 1.63 g (71% of theory, purity 95%) of the title compound.
  • reaction mixture was stirred for 20 min at RT, then 253 mg (0.55 mmol) of 9H-Huoren-9-ylmethyl-3-amino-5-cyanpiperidin-l-carboxylate (mixture of stereoisomers) and stirred for 1 hour at RT.
  • the reaction solution was mixed with water and the resulting solid was stirred for about 30 minutes at room temperature.
  • the solid was then filtered off, washed well with water and dried under high vacuum.
  • the solid was mixed with water / TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA). 175 mg of the target compound (53% of theory) were obtained.
  • rac-Benzyl- (1-chloro-3-cyanopropan-2-yl) carbamate (crude product from Example 70A) was dissolved in 9.2 ml of 1,4-DMF and treated with 262 mg (4.04 mmol) of sodium azide. The mixture was stirred at RT for 1 h, at 50 ° C. for 2 h and then at 80 ° C. for 6 h. The reaction mixture was diluted with dichloromethane and washed twice with water. The aqueous phase was extracted once with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered off, evaporated and dried under high vacuum.
  • reaction mixture was stirred at RT for 20 min, then admixed with 105 mg (0.39 mmol) of rac-benzyl- (1-amino-3-cyanopropan-2-yl) carbamate hydrochloride from Example 72A and stirred at RT overnight.
  • the reaction solution was admixed with acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA). 144 mg of the target compound (69% of theory, purity about 95%) were obtained.
  • the target compound can be prepared by reacting rac-methyl-N - [(benzyloxy) carbonyl] -5-nitrilonorvalinate [preparable analogously to Stapon, A. et al. Journal of the American Chemical Society 2003, 125, 8486-8493; Boger, D.L. et al. 1999, 121, 6197-6205; US5747499 (Example 10); US5789417 (Example 12) from racemic starting material] with sodium borohydride (NaBEL) in THF (or with other reducing agents such as lithium borohydride or lithium aluminum hydride) are prepared at room temperature by literature methods.
  • NaBEL sodium borohydride
  • THF or with other reducing agents such as lithium borohydride or lithium aluminum hydride
  • the target compound can be prepared analogously to Scott, A.I. et al. Synthetic Communications 1980, 10, 127-132 and Huang, S.-B. et al. Synthetic Communications 1989, 19, 3485-3496 from racemic starting material.
  • Example 77A 1.40 g (2.58 mmol, purity 72%) of rac-benzyl- [5-cyano-l, 3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -pentan-2-yl] carbamate
  • Example 77A was dissolved in 11.1 ml (129 mmol) of methanamine (40% in water) and stirred for two hours at 60 ° C. The reaction solution was concentrated and distilled three times with methanol. The residue was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA). 502 mg (52% of theory) of the target compound were obtained.
  • reaction solution was admixed with acetonitrile, water and TFA and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA). There were obtained 353 mg of the target compound (81% of theory, purity 95%).
  • Example 1 In analogy to Example 1, the example compounds shown in Table 1 were prepared by reacting the carboxylic acid from Example 16A with the corresponding commercially available or known amines (1.1-8 equivalents), HATU (1.1-2.5 equivalents) and N, N-diisopropylethylamine ( 2.5-8 equivalents) in DMF was reacted under the reaction conditions described (reaction time: 0.5-24 h, temperature: RT or 60 ° C.).
  • reaction solution was mixed with water and the resulting solid was stirred for about 30 minutes at room temperature. The solid was then filtered off, washed well with water and dried under high vacuum.
  • the reaction mixture was diluted with water / TFA and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient with the addition of 0.1% TFA or 0.05% formic acid).
  • the crude product was additionally or alternatively purified by silica gel chromatography (eluent: dichloromethane / methanol or cyclohexane / ethyl acetate) and / or thick-layer chromatography (eluent: dichloromethane / methanol).
  • the product-containing fractions of the preparative HPLC were concentrated, the residue taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane, the combined organic phases dried over sodium sulfate, filtered, concentrated and lyophilized.
  • Table 1 Table 1 :
  • Example 1 155 mg from Example 1 were separated on a chiral phase into the enantiomers [column: Daicel Chiralpak AD-H, 5 ⁇ m, 250 ⁇ 20 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 20 ml / min; 20 ° C, detection: 220 nm].
  • the product was purified again by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA).
  • the product-containing fractions were concentrated, the residue taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution.
  • the aqueous phase was extracted twice with dichloromethane, the combined organic phases dried over sodium sulfate, filtered, concentrated and lyophilized.
  • Example 1 155 mg from Example 1 were separated on a chiral phase into the enantiomers [column: Daicel Chiralpak AD-H, 5 ⁇ m, 250 ⁇ 20 mm, eluent: 50% iso-hexane, 50% ethanol; Flow: 20 ml / min; 20 ° C, detection: 220 nm].
  • the product was purified again by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% TFA).
  • the product-containing fractions were concentrated, the residue taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution.
  • the aqueous phase was extracted twice with dichloromethane, the combined organic phases dried over sodium sulfate, filtered, concentrated and lyophilized.
  • Example 17 In analogy to Example 17, the example compounds shown in Table 2 were prepared by reacting the corresponding carboxylic acids with rac-amino (4-chlorophenyl) acetonitrile [CAS RN No .: 49704-71-4] under the conditions described:
  • Example 3 In analogy to Example 32, the example compounds shown in Table 3 were prepared by reacting the corresponding carboxylic acids with the corresponding, commercially available or previously described amines under the conditions described: Table 3:
  • the reaction solution was admixed with acetonitrile / water and TFA and purified by preparative HPLC (RP18 column, eluent: acetonitrile / water gradient with the addition of 0.1% TFA).
  • the product fractions were concentrated, taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution.
  • the aqueous phase was extracted twice with dichloromethane, the combined organic phases dried over sodium sulfate, filtered, the filtrate was concentrated and lyophilized. 67 mg of the target compound (67% of theory) were obtained.

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  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne de nouveaux imidazo[1,2-a]pyridine-3-carboxamides substitués de formule (I), leurs procédés de production, leur utilisation seuls ou en association pour le traitement et/ou la prophylaxie de maladies ainsi que leur utilisation pour la production de médicaments servant au traitement et/ou à la prophylaxie de maladies, notamment au traitement et/ou à la prophylaxie de maladies cardiovasculaires.
EP15710202.1A 2014-03-21 2015-03-18 Imidazo[1,2-a]pyridine-carboxamides cyano-substitués et leur utilisation Withdrawn EP3119777A1 (fr)

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PCT/EP2015/055642 WO2015140199A1 (fr) 2014-03-21 2015-03-18 Imidazo[1,2-a]pyridine-carboxamides cyano-substitués et leur utilisation

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US9771360B2 (en) 2017-09-26
WO2015140199A1 (fr) 2015-09-24
CN106715426A (zh) 2017-05-24
JP2017508810A (ja) 2017-03-30
US20170217954A1 (en) 2017-08-03

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